Displaying 44 drugs.
Name | Class types | Target | Status for MS | Administration | Commercial | |
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[+] | Alemtuzumab |
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[+] | Amiloride |
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[+] | ATX-MS-1467 |
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[+] | BGC20-0134 |
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[+] | BIIB033 |
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[+] | Cladribine |
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[+] | Cyclophosphamide |
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[+] | Daclizumab |
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[+] | Dalfampridine |
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[+] | Dimethyl fumarate |
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[+] | Dronabinol |
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[+] | Estriol |
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[+] | Fingolimod |
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[+] | Firategrast |
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[+] | Flupirtine |
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[+] | Glatiramer acetate |
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[+] | GNbAC1 |
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[+] | Idebenone |
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[+] | Imilecleucel-T |
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[+] | Interferon beta-1a |
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[+] | Interferon beta-1b |
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[+] | Laquinimod |
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[+] | Masitinib |
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[+] | MEDI-551 |
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[+] | Minocycline |
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[+] | MIS416 |
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[+] | Mitoxantrone |
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[+] | Mycophenolate mofetil |
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[+] | Naltrexone |
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[+] | Natalizumab |
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[+] | Ocrelizumab |
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[+] | Ofatumumab |
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[+] | ONO-4641 |
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[+] | Ozanimod |
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[+] | Phenytoin |
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[+] | Raltegravir |
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[+] | Riluzole |
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[+] | Rituximab |
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[+] | RTL1000 |
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[+] | Secukinumab |
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[+] | Simvastatin |
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[+] | Siponimod |
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[+] | Teriflunomide |
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[+] | Ustekinumab |
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Name | Trade name | Synonyms | Systematic name | |
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[+] | Alemtuzumab |
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[+] | Amiloride |
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[+] | ATX-MS-1467 |
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[+] | BGC20-0134 |
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[+] | BIIB033 |
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[+] | Cladribine |
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[+] | Cyclophosphamide |
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[+] | Daclizumab |
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[+] | Dalfampridine |
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[+] | Dimethyl fumarate |
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[+] | Dronabinol |
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[+] | Estriol |
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[+] | Fingolimod |
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[+] | Firategrast |
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[+] | Flupirtine |
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[+] | Glatiramer acetate |
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[+] | GNbAC1 | |||
[+] | Idebenone |
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[+] | Imilecleucel-T |
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[+] | Interferon beta-1a |
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[+] | Interferon beta-1b |
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[+] | Laquinimod |
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[+] | Masitinib |
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[+] | MEDI-551 |
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[+] | Minocycline |
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[+] | MIS416 | |||
[+] | Mitoxantrone |
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[+] | Mycophenolate mofetil |
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[+] | Naltrexone |
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[+] | Natalizumab |
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[+] | Ocrelizumab |
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[+] | Ofatumumab |
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[+] | ONO-4641 |
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[+] | Ozanimod |
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[+] | Phenytoin |
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[+] | Raltegravir |
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[+] | Riluzole |
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[+] | Rituximab |
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[+] | RTL1000 | |||
[+] | Secukinumab |
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[+] | Simvastatin |
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[+] | Siponimod |
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[+] | Teriflunomide |
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[+] | Ustekinumab |
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Name | Class types | Target | Properties | Mechanism/Effects (Human) | Mechanism/Effects (Animal) | |
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[+] | Alemtuzumab |
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[+] | Amiloride |
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[+] | ATX-MS-1467 |
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[+] | BGC20-0134 |
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[+] | BIIB033 |
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[+] | Cladribine |
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[+] | Cyclophosphamide |
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[+] | Daclizumab |
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[+] | Dalfampridine |
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[+] | Dimethyl fumarate |
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[+] | Dronabinol |
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[+] | Estriol |
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[+] | Fingolimod |
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[+] | Firategrast |
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[+] | Flupirtine |
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[+] | Glatiramer acetate |
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[+] | GNbAC1 |
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[+] | Idebenone |
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[+] | Imilecleucel-T |
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[+] | Interferon beta-1a |
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[+] | Interferon beta-1b |
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[+] | Laquinimod |
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[+] | Masitinib |
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[+] | MEDI-551 |
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[+] | Minocycline |
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[+] | MIS416 |
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[+] | Mitoxantrone |
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[+] | Mycophenolate mofetil |
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[+] | Naltrexone |
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[+] | Natalizumab |
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[+] | Ocrelizumab |
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[+] | Ofatumumab |
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[+] | ONO-4641 |
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[+] | Ozanimod |
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[+] | Phenytoin |
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[+] | Raltegravir |
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[+] | Riluzole |
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[+] | Rituximab |
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[+] | RTL1000 |
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[+] | Secukinumab |
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[+] | Simvastatin |
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[+] | Siponimod |
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[+] | Teriflunomide |
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[+] | Ustekinumab |
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Name | Status for MS | Highest status achieved (for any condition) | Other uses | Administration | Negative effects | Commercial | |
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[+] | Alemtuzumab |
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[+] | Amiloride |
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[+] | ATX-MS-1467 |
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[+] | BGC20-0134 |
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[+] | BIIB033 |
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[+] | Cladribine |
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[+] | Cyclophosphamide |
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[+] | Daclizumab |
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[+] | Dalfampridine |
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[+] | Dimethyl fumarate |
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[+] | Dronabinol |
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[+] | Estriol |
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[+] | Fingolimod |
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[+] | Firategrast |
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[+] | Flupirtine |
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[+] | Glatiramer acetate |
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[+] | GNbAC1 |
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[+] | Idebenone |
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[+] | Imilecleucel-T |
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[+] | Interferon beta-1a |
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[+] | Interferon beta-1b |
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[+] | Laquinimod |
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[+] | Masitinib |
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[+] | MEDI-551 |
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[+] | Minocycline |
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[+] | MIS416 |
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[+] | Mitoxantrone |
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[+] | Mycophenolate mofetil |
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[+] | Naltrexone |
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[+] | Natalizumab |
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[+] | Ocrelizumab |
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[+] | Ofatumumab |
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[+] | ONO-4641 |
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[+] | Ozanimod |
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[+] | Phenytoin |
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[+] | Raltegravir |
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[+] | Riluzole |
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[+] | Rituximab |
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[+] | RTL1000 |
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[+] | Secukinumab |
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[+] | Simvastatin |
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[+] | Siponimod |
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[+] | Teriflunomide |
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[+] | Ustekinumab |
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Name | Placebo-controlled Trials | Head-to-Head Trials | Other Trials |
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Alemtuzumab |
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Amiloride |
Trial name: Multiple Sclerosis-Secondary Progressive Multi-Arm Randomisation Trial (MS-SMART) (Study start date, October 2013) [[12584]] Phase: Phase IIB trial [[12584]] Study Design: University-, institute-, and society-sponsored, multicenter, multi-arm, randomized, double-blind, placebo-controlled trial to compare the effects of three repurposed, candidate neuroprotective drugs [amiloride (5 mg once per day for 4 weeks, then 5 mg twice per day), riluzole (50 mg once per day for 4 weeks, then 50 mg twice per day), and ibudilast (50 mg once per day for 4 weeks, then 50 mg twice per day), each versus matched placebo] on the rate of brain volume loss as assessed by MRI (primary outcome measure) and other measures [[12584]] Disease Stage: SPMS [[12584]] Enrollment/Number of Patients: 440 (estimated) [[12584]] Duration: 96 weeks [[12584]] Status/Outcome: Not yet recruiting as of July 2013; estimated study completion date, September 2016 [[12584]] Trial name: Amiloride Clinical Trial In Optic Neuritis (ACTION) trial (recruiting as of March 2013) [[12599]] [[23629]] Phase: Phase II trial [[12599]] Study Design: University- and society-sponsored, randomized, double-blind, placebo-controlled trial to examine the neuroprotective effects of amiloride (10 mg once per day for 5 months) by comparing the retinal nerve fiber layer thickness in the affected eye (at 6 months) and in the unaffected eye (at baseline) (primary outcome measure), as well as with other measures [[12599]] [[23629]] Disease Stage: Unilateral optic neuritis (within 28 days of onset of first symptoms; can be with an existing RRMS diagnosis) [[12599]] [[23629]] Enrollment/Number of Patients: 46 (estimated) [[12599]] [[23629]] Duration: 12 months [[12599]] Status/Outcome: Estimated study completion date, February 2015 [[12599]] Trial name: Amiloride Hydrochlorothiazide as Treatment of Acute Inflammation of the Optic Nerve (recruiting as of May 2014) [[12600]] Phase: Phase IIa trial [[12600]] Study Design: University-sponsored, randomized, double-blind, placebo-controlled trial to study the effect of amiloride hydrochlorothiazide (5.68 mg amiloridhydrochloride 2H20 and 50 mg hydrochlorothiazid) on the change in the thickness of the retinal nerve fiber layer between baseline and followup (primary outcome measure) [[12600]] Disease Stage: First episode of optic neuritis [[12600]] Enrollment/Number of Patients: 78 (estimated) [[12600]] Duration: 24 weeks [[12600]] Status/Outcome: Estimated study completion date, April 2016 [[12600]] |
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ATX-MS-1467 |
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BGC20-0134 |
Trial name: A Study of Orally Administered BGC20-0134 (Structured Lipid) in Patients With Relapsing Remitting Multiple Sclerosis (RRMS) [[791]] Phase: IIa [[791]] Study Design: Company-sponsored, randomized, double-blind, placebo-controlled, multi-center, multinational study evaluating the cumulative number of new T1 gadolinium-enhancing lesions (primary endpoint) and safety during treatment Disease Stage: RRMS [[791]] Enrollment/Number of Patients: Estimated enrollment 166 patients [[791]] Duration: 24 weeks double-blind and placebo controlled, followed by 24 weeks open-label extension [[473]] Status/Outcome: Did not meet primary or secondary endpoints [[792]] |
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BIIB033 |
Trial name: BIIB033 In Acute Optic Neuritis (RENEW) (press releases, January, April 2015) [[16280]] [[16281]] [[18493]] Phase: Phase II trial [[16280]] Study Design: Industry-sponsored, multinational, randomized, double-blind, parallel-group, placebo-controlled trial to examine the efficacy of BIIB033 (6 doses of 100 mg per kg intravenous infusion, given once every 4 weeks for 20 weeks) in individuals experiencing their first episode of unilateral acute optic neuritis, with the primary outcome measure the change in optic nerve latency (time for a nerve signal to move from the retina to the visual cortex) at week 24 in the affected eye as compared with the baseline measure in the unaffected eye; secondary outcome measures included changes in the thickness of retinal layers and in low-contrast letter acuity at week 24 as compared with baseline [[16280]] [[16281]] Disease Stage: Acute optic neuritis (first episode) [[16280]] Enrollment/Number of Patients: 82 [[16280]] Duration: 24 weeks [[16280]] Status/Outcome: Study completion date, October 2014 [[16280]]; BIIB033 was associated with a recovery of optic nerve latency (a 34% improvement as compared with placebo) at week 24, but not with a change in the thickness of retinal layers or with improved visual function [[16281]]; at week 32, 12 weeks after the last dose, additional latency recovery was measured (a 41% improvement) [[18493]] Trial name: Study to Assess the Efficacy, Safety, Tolerability, and Pharmacokinetics of BIIB033 in Subjects With Relapsing Forms of Multiple Sclerosis When Used Concurrently With Avonex (SYNERGY) (recruiting as of May 2014) [[13427]] Phase: Phase II trial [[13427]] Study Design: Company-sponsored, randomized, double-blind, placebo-controlled, parallel-group, dose-ranging trial to examine the efficacy and safety of BIIB033 (intravenous infusion of 0, 3, 10, 30, or 100 mg per kg every 4 weeks) when used together with interferon beta-1a (Avonex, given by weekly intramuscular injections); the primary outcome measure is the percentage of participants who display improved neurophysical or cognitive function [[13427]] Disease Stage: Relapsing forms of MS [[13427]] Enrollment/Number of Patients: 396 (estimated) [[13427]] Duration: 84 weeks [[13427]] Status/Outcome: Estimated study completion date, June 2016 [[13427]] Trial name: BIIB033 single ascending dose study in healthy volunteer subjects; Tran et al., Neurol. Neuroimmunol. Neuroinflammation, August 2014 trial [[485]] [[13242]] Phase: Phase I trial [[485]] [[13242]] Study Design: Company-sponsored, randomized, blinded, placebo-controlled, single-ascending dose trial to evaluate the safety and tolerability (primary outcome measures) and pharmacokinetics, serum antibody levels, and exploratory biomarkers (secondary outcome measures); single ascending doses (0.1 to 100 mg per kg) were administered by intravenous infusion or subcutaneous injection [[485]] [[13242]] Disease Stage: Healthy individuals [[485]] [[13242]] Enrollment/Number of Patients: 72 [[485]] [[13242]] Duration: Up to 4 months [[485]] Status/Outcome: The drug was well tolerated; adverse events occurred at similar frequencies in the drug and placebo groups and no serious adverse events occurred; furthermore, anti-drug antibodies were detected in only one participant [[13242]] Trial name: Safety study of BIIB033 in subjects with multiple sclerosis; Tran et al., Neurol. Neuroimmunol. Neuroinflammation, August 2014 trial [[486]] [[13242]] Phase: Phase I trial [[486]] [[13242]] Study Design: Company-sponsored, randomized, blinded, placebo-controlled, serial-cohort, multiple ascending dose trial to determine the safety and tolerability (primary outcomes) and pharmacokinetics and potential biomarkers of activity (secondary outcomes) of two doses of drug (intravenous infusion of 0.3, 1, 3, 10, 30, 60, or 100 mg per kg) administered 14 days apart [[486]] [[13242]] Disease Stage: RRMS or SPMS [[486]] [[13242]] Enrollment/Number of Patients: 47 [[13242]] Duration: 6 months [[486]] Status/Outcome: The drug was well tolerated; adverse events occurred at similar frequencies in the drug and placebo groups and no serious adverse events occurred [[13242]] |
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Cladribine |
Trial name: Oral Cladribine in Early Multiple Sclerosis (ORACLE MS) (publ February 2014) [[795]] [[9678]] Phase: Phase III trial [[795]] [[9678]] Study Design: Company-sponsored, multicenter, randomized, double-blind, placebo-controlled trial to evaluate the safety and efficacy of cladribine (cumulative doses of either 5.25 mg or 3.5 mg per kilogram) on reducing the time to conversion to MS after a first clinical demyelinating event (primary outcome) [[795]] [[9678]] Disease Stage: Patients who had sustained their first clinical demyelinating event ≤75 days before screening, who were at at high risk of converting to MS [[795]] [[9678]] Enrollment/Number of Patients: 616 [[9678]] Duration: 96 weeks [[9678]] Status/Outcome: Both doses were associated with a delay in the diagnosis of MS; the safety profile was comparable to that seen in individuals with RRMS [[9678]] Trial name: Phase II Cladribine Add-on to Interferon-beta (IFN-b) Therapy in MS Subjecs With Active Disease (ONWARD) (ongoing as of January 19, 2012) [[800]] Phase: Phase II trial [[800]] Study Design: Company-sponsored, multicenter, randomized, double-blind, placebo-controlled study to evaluate the safety, tolerability, and effectiveness of oral claribine (up to 4 cycles, of 0.875 mg per kilogram per cycle) when taken in combination with interferon-beta therapy (Rebif, Avonex, or Betaseron), in treating MS [[800]] Disease Stage: RRMS or SPMS [[800]] Enrollment/Number of Patients: 214 [[800]] Duration: 96 weeks [[800]] Status/Outcome: Final data collection for primary outcome measure is September 2011; estimated study completion date is June 2012 [[800]] Trial name: Cladribine Tablets Treating Multiple Sclerosis Orally (CLARITY) (publ 2010; additional analyses publ 2011, 2012) [[559]] [[4317]] [[4465]] [[4464]] [[4463]] Phase: Phase III trial [[559]] Study Design: Company-supported, randomized, double-blind, placebo-controlled trial to test the effects of oral cladribine (a cumulative dose of either 3.5 mg or 5.25 mg per kilogram of body weight, given in several short courses) on on the rate of relapse at 96 weeks (primary outcome) and several other outcome measures [[559]] Disease Stage: RRMS [[559]] Enrollment/Number of Patients: 1326, with 1184 completing the study [[559]] Duration: 96 weeks [[559]] Status/Outcome: Drug was associated with a reduction in the annualized rate of relapse in both treatment groups [0.14 in the 3.5 mg group (a relative reduction of 57.6%) and 0.15 in the 5.25 mg group (a relative reduction of 54.5%) as compared with 0.33 in the placebo group] and a lower mean number of brain lesions per patient as compared to the placebo; lymphocytopenia and herpes zoster occurred more frequently in patients receiving cladribine than in those receiving placebo [[559]] [[4465]]; posthoc analysis of data indicated that cladribine increased the proportion of patients with sustained freedom from disease activity (no relapse, no 3-month sustained change in expanded disability status scale score, and no new MRI lesions), such that over 96 weeks, 44% of patients in the 3.5 mg group, 46% in the 5.25 mg group, and 16% in the placebo group were free from disease activity [[4463]]; additional assessment of MRI outcomes showed that, when data were stratified by baseline disease characteristics, active lesion counts were significantly reduced, and the proportions of patients without active lesions were significantly increased, by cladribine [[4317]]; analysis of economic data from this study indicated that cladribine efficacy was associated with reduced need for medical and societal support and less consumption of healthcare resources [[4464]] Trial name: CLARITY Extension Study (meeting report, April 2016) [[794]] [[29281]] Phase: Phase IIIb trial [[794]] Study Design: Company-sponsored, re-randomized, placebo-controlled, double blind, parallel assignment, multicenter extension trial involving patients from the CLARITY trial, such that participants from the placebo group were re-randomized to receive 3.5 mg/kg cladribine and participants originally receiving cladribine were re-randomized 2:1 to receive either 3.5 mg/kg cladribine or placebo [[794]] [[29281]] Disease Stage: RRMS (in original CLARITY trial) [[794]] [[559]] Enrollment/Number of Patients: 883 [[794]] Duration: 2 years [[29281]] Status/Outcome: A low annual relapse rate (ARR) was generally maintained in all arms of the study over 2.5 years; participants treated with cladribine for 4 years exhibited an ARR of 0.10 and those who switched from cladribine in the trial to placebo in the extension exhibited an ARR of 0.15, indicating the beneficial effects of the drug persist (meeting report, April 2016) [[29281]] |
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Cyclophosphamide |
Trial name: Likosky et al., J. Neurol. Neurosurg. Psychiatry, December 1991 trial [[932]] Phase: Phase II trial [[932]] Study Design: Hospital-supported, randomized, single-blinded, placebo-controlled trial to study the ability of intensive immunosuppression induced by intravenous cyclophosphamide (400 to 500 mg given 5 days a week until a target leucocyte count was reached) to stabilize progressive MS [[932]] Disease Stage: Chronic progressive MS [[932]] Enrollment/Number of Patients: 42 [[932]] Duration: 2 years [[932]] Status/Outcome: Cyclophosophamide and control were associated with similar disease progression [[932]] Trial name: Canadian Cooperative Multiple Sclerosis Study Group, Lancet, February 1991 trial [[943]] Phase: Phase II trial [[943]] Study Design: Research council supported, randomized, multicenter, placebo-controlled, single-masked trial to test the safety and efficacy of (i) intravenous cyclophosphamide (1 g on alternate days until a target white blood cell count was reached or until 9 g had been given) with oral prednisone, (ii) oral cyclophosphamide (1.5 to 2.0 mg per kg daily) with alternate day prednisone for 22 weeks and weekly plasma exchange for 20 weeks, or (iii) sham plasma exchange and placebo medications; the primary analysis was a comparison of the rates of treatment failure on two consecutive 6 month assessments [[943]] Disease Stage: Progressive MS [[943]] Enrollment/Number of Patients: 168 [[943]] Duration: 3 years [[943]] Status/Outcome: Neither drug regime was associated with a reduction in the rate of treatment failure, which was statistically similar among all groups [[943]] |
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Daclizumab |
Trial name: Safety and Efficacy Study of Daclizumab HYP to Treat Relapsing-Remitting Multiple Sclerosis (SELECT) (results reported 2011, publ 2013) [[803]] [[5545]] [[7538]] [[9125]] [[29032]] Phase: Phase IIb trial [[803]] Study Design: Company-sponsored, randomized, double-blind, placebo-controlled, multinational, multicenter trial to evaluate the efficacy of two doses (150 mg or 300 mg) of daclizumab high-yield process (HYP), given subcutaneously every 4 weeks for 52 weeks, on the annualized relapse rate (primary endpoint) [[803]] [[5545]] Disease Stage: RRMS [[803]] [[5545]] Enrollment/Number of Patients: 621, with over 90% completing the study [[5545]] Duration: 1 year [[803]] [[5545]] Status/Outcome: Compared to placebo, daclizumab HYP was associated with a lower annualized relapse rate (0.21 for the 150 mg dose and 0.23 for the 300 mg dose versus 0.46 for placebo, representing 54% and 50% reductions for the two doses, respectively), and a reduction in cumulative number of gadolinium-enhancing lesions between weeks 8 and 24, a reduction in number of newly enlarging T2 hyperintense lesions at one year, and reduction in proportion of individuals who relapsed [[803]] [[5545]]; three cases of autoimmune attacks (hepatic and renal) occurred [[3771]]; further analysis showed that at 1 year, daclizumab HYP was associated with an increase in the percentage of individuals who were free of disease activity (39% versus 11% of those receiving placebo), as defined by both clinical and radiological criteria [[7538]]; posthoc analysis showed that daclizumab HYP had similar effects in individuals with highly active versus less active RRMS (disease activity was assessed before treatment began) [[9125]]; a prospectively defined analysis showed that daclizumab HYP is associated with an increase in CD56(bright) natural killer cells, and that the numbers of such cells at weeks 4 and 8 correlate with the number of new or newly enlarging T2-hyperintense lesions in weeks 24 to 52, although treated individuals who displayed less expansion of these NK cells still exhibited fewer lesions than those on placebo [[16658]]; posthoc analysis (of pooled results representing both doses) showed that daclizumab HYP decreased the development of new gadolinium-enhancing lesions to T1 hypointense lesions (black holes) [[26040]]; daclizumab HYP (150 mg dose) had positive effects on health-related quality of life [[29032]] Trial name: Daclizumab in active, relapsing multiple sclerosis (CHOICE) trial (publ 2010; additional analysis publ 2013) [[433]] [[6748]] Phase: Phase IIa trial [[433]] [[6748]] Study Design: Company-sponsored randomized, placebo controlled, multinational, multicenter study to evaluate the efficacy of daclizumab [at either high (2 mg per kg every 2 weeks) or low (1 mg per kg every 4 weeks) dose] combined with interferon beta therapy on the number of new or enlarged gadolinium-enhancing lesions (primary endpoint) [[433]] Disease Stage: RRMS patients taking interferon beta [[433]] Enrollment/Number of Patients: 230 patients enrolled; all completed the study [[433]] Duration: 24 weeks [[433]] Status/Outcome: Both high and low doses of daclizumab, given with interferon beta, were associated with fewer gadolinium-enhancing lesions as compared to placebo and interferon beta [[433]]; longitudinal analysis showed a 30% reduction in the fraction of CD4+ T cells that were CD25+ two weeks after one dose of daclizumab (at either dose), which was not seen in the interferon beta therapy alone group [[6748]] |
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Dalfampridine |
Trial name: Zörner et al., Mult. Scler., January 2016 trial (FAMPKIN trial) [[25634]] Phase: Phase II trial [[25634]] Study Design: Prospective, randomized, double-blind, placebo-controlled, crossover trial to examine the effects of dalfampridine (10 mg, twice per day) on parameters measured with 3D motion analysis of treadmill walking, as well as on results of the timed 25-foot walk test and the 6-minute walk test; an accelerometer device was used to measure physical activity in daily life [[25634]] Disease Stage: MS [[25634]] Enrollment/Number of Patients: 55 [[25634]] Duration: 6 weeks of placebo or drug followed by 6 weeks of the other treatment [[25634]] Status/Outcome: Dalfampridine was associated with increased walking speed and distance in a subset of participants, as well as changes in the gait pattern at the individual level that correlated with better results in the walking speed and distance tests; participants who showed increased walking speed also exhibited increased physical activity in daily life [[25634]] Trial name: Ampyra for Optic Neuritis in MS (meeting report, September 2015) [[22305]] [[22306]] Phase: Phase II trial [[22305]] [[22306]] Study Design: Industry-sponsored, investigator-initiated, randomized, blinded crossover, placebo-controlled trial to examine whether dalfampridine improves vision (contrast sensitivity, primary outcome measure); participants received either active treatment or placebo for 3 weeks, underwent a 2-week washout, and then received the other treatment for 3 weeks [[22305]] Disease Stage: Long-term visual impairment from optic neuritis from MS [[22305]] Enrollment/Number of Patients: 40 participants, 59 eyes studied [[22306]] Duration: 8 weeks [[22305]] Status/Outcome: Dalfampridine did not improve the ability of participants to read standardized contrast eye charts [[22306]] Trial name: Yapundich et al., Int. J. MS Care, May-June 2015 trial (press release, 13 August 2012) [[3018]] [[19432]] Phase: Postmarketing trial (required by the US Food and Drug Administration) [[3019]] [[19432]] Study Design: Industry-sponsored, randomized, double-blind, placebo-controlled trial to compare the effects of 5 mg versus 10 mg (the currently marketed dose) of dalfampridine extended release, twice daily, using a timed 25-foot walk (at 2 and 4 weeks) and a 6-minute walk (at 2 weeks) [[3018]] [[19432]] Disease Stage: MS [[3018]] [[19432]] Enrollment/Number of Patients: 429 [[19432]] Duration: 4 weeks [[3018]] [[19432]] Status/Outcome: Neither the 10 mg nor the 5 mg dose met the primary endpoint, which was the change in walking speed from that at baseline to that 3 to 4 hours after administration of the dose at 4 weeks [[3018]] [[3019]] [[19432]]; however, the 10 mg dose, but not the 5 mg dose, resulted in increased mean walking speed (0.443 versus 0.303 feet per second for placebo), when walking speed was averaged over all visit measurements in posthoc analysis [[19432]]; the different analyses were similar to those used in the pivotal studies that led to the approval of Ampyra [[3018]] [[3019]]; results from the subgroup (153 individuals) who were assessed in the 6-minute walk test indicated that the 10 mg dose, but not the 5 mg dose, was associated with significantly increased distance walked at 2 weeks versus baseline as compared with placebo (10 mg, +39.2 m; 5 mg, +23.4 m; placebo, +12.7 m) [[19432]]; posthoc analysis of the 6-minute walk test results indicated that 45.1% of individuals in the 10 mg group achieved ≥20% improvement in the 6-minute walk distance versus 14.3% in the placebo group and 28.3% in the 5 mg group (not significant relative to placebo) [[23756]] Trial name: Hupperts et al., Mult. Scler., April 2015 trial (MOBILE trial) [[18542]] Phase: Phase II trial [[18648]] Study Design: Industry-sponsored, multicenter, randomized, double-blind, exploratory, placebo-controlled trial to examine the effects of extended-release dalfampridine (10 mg, twice daily) on walking, balance, and safety [[18542]] [[18648]] Disease Stage: Progressve MS or RRMS [[18542]] Enrollment/Number of Patients: 132 [[18542]] Duration: 24 weeks [[18542]] Status/Outcome: Dalfampridine was associated with improvements in the 12-item MS Walking Scale score, the Timed Up and Go test, and the Berg Balance Scale score as compared with placebo [[18542]] Trial name: Horton et al., Neurology, April 2013 study [[5770]] Phase: Phase II trial [[5770]] Study Design: Randomized, placebo-controlled, double-blind, crossover trial to study the effect of 4-aminopyridine on vision in MS patients with demyelinating optic neuropathy; patients received either placebo or drug for 5 weeks and then crossed to the other treatment for 5 weeks [[5770]] Disease Stage: MS patients with optic neuropathy [[5770]] Enrollment/Number of Patients: Not stated in abstract [[5770]] Duration: 10 weeks [[5770]] Status/Outcome: 4-Aminopyridine improved visual acuity in a subset of patients; the highest response rates occurred in eyes with a retinal nerve fiber layer that measured between 60 and 80 microns [[5770]] Trial name: Goodman et al., Ann. Neurol., Oct 2010 trial (MS-F204) [[347]]; additional analyses publ 2014 [[14685]] Phase: Phase III trial [[347]] Study Design: Randomized, 39-center, double-blind, placebo-controlled trial to test the effects of oral dalfampridine-extended release (10 mg twice daily) on walking ability, as measured by a timed 25-foot walk (primary outcome, percentage of timed walk responders) [[347]] Disease Stage: Any stage of MS [[347]] Enrollment/Number of Patients: 239, with 237 in final analysis [[347]] Duration: 9 weeks [[347]] Status/Outcome: Dalfampridine improved walking ability in some MS patients (42.9% timed-walk responders with drug versus 9.3% with placebo), such that the effect is continued between doses and the average improvement in speed among responders was 24.7% [[347]]; pooled analysis from 2 Phase III trials showed that dalfampridine increased the percentage of timed-walk responders (37.6% versus 8.9% for placebo); the response was not dependent on any clinical or demographic trait [[14685]] Trial name: Goodman et al., Lancet, Feb 2009 trial (MS-F203) [[367]]; additional analyses publ 2013, 2014 [[6565]] [[14685]] Phase: Phase III trial [[367]] Study Design: Randomized, multicenter, double-blind, placebo-controlled trial to test the effects of dalfampridine-extended release [prolonged-release fampridine (EU)] (10 mg twice daily) on walking ability, as measured by a timed 25-foot walk (primary outcome, percentage of timed walk responders) [[367]] Disease Stage: Any stage of MS [[367]] Enrollment/Number of Patients: 301, with efficacy analyses based on 296 [[367]] Duration: 14 weeks [[367]] Status/Outcome: Dalfampridine improved walking ability (25.2% increase in speed versus 4.7% with placebo) in some MS patients (35% versus 8% for placebo) [[367]]; to examine the effect of the drug on health utility, scores from the 12-Item Multiple Sclerosis Walking Scale were mapped to the Euroqol 5-Dimension health utility index and two mapping equations showed that a response to the drug was linked to an improvement in health utility [[6565]]; pooled analysis from 2 Phase III trials showed that dalfampridine increased the percentage of timed-walk responders (37.6% versus 8.9% for placebo); the response was not dependent on any clinical or demographic trait [[14685]] Trial name: Goodman et al., Neurology, Oct 2008 trial [[374]] Phase: Phase II trial [[374]] Study Design: Multicenter, randomized, double-blind, placebo-controlled, parallel-group trial to test the effects of fampridine (10, 15, or 20 mg twice daily) on walking speed (primary efficacy variable, percent change in speed in a timed 25-foot walk) [[374]]
Disease Stage: People with MS [[374]] Enrollment/Number of Patients: 206 [[374]] Duration: 2 weeks of placebo for all participants, followed by 15 weeks of drug or placebo [[374]] Status/Outcome: Drug was associated with a non-significant trend toward increased walking speed in prospective analysis, but in post hoc analysis, subsets of patients in each dose group consistently showed increased walking speeds during the treatment versus the nontreatment period (36.7% were consistent responders in treatment groups versus 8.5% in placebo group) [[374]] |
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Dimethyl fumarate |
Trial name: BG00012 and Disability Progression in Secondary Progressive Multiple Sclerosis (SPMS) (INSPIRE) (Phase III program in SPMS discontinued, October 2015) [[23071]] [[23072]] Phase: Phase III trial [[23071]] Study Design: Company-sponsored, multicenter, randomized, double-blind, placebo-controlled trial to examine the safety and effects of dimethyl fumarate (120 mg twice a day for 1 week, then 240 mg twice a day) on delaying the time to onset of confirmed disability progression (primary outcome measure) [[23071]] Disease Stage: SPMS [[23071]] Enrollment/Number of Patients: 1170 (estimated) [[23071]] Duration: Up to 108 weeks [[23071]] Status/Outcome: Biogen discontinued its Phase III program for dimethyl fumarate in SPMS in October 2015 [[23072]] Trial name: COmparator and aN oral Fumarate In RRMS (CONFIRM) (publ 2012, 2013, 2014, 2015) [[1793]] [[3222]] [[3590]] [[5513]] [[6366]] [[7848]] [[8180]] [[10843]] [[12362]] [[14494]] [[17461]] Phase: Phase III trial [[1793]] [[3222]] Study Design: Company-sponsored, global, randomized, double-blind, placebo-controlled, dose-comparison study to determine the safety and efficacy of oral BG-12 (dimethyl fumarate) (240 mg given either twice a day or three times a day) or glatiramer acetate (20 mg subcutaneous injection each day) in reducing the annualized relapse rate (ARR) (primary endpoint) and the proportion of patients who relapse at two years and the number of T2-hyperintense lesions (secondary endpoints); study was not designed to test whether dimethyl fumarate is superior or noninferior to glatiramer acetate [[1793]] [[3222]] Disease Stage: RRMS [[1793]] [[3222]] Enrollment/Number of Patients: 1430 [[1793]] [[3222]] Duration: 2 years [[1793]] [[3222]] Status/Outcome: Dimethyl fumarate reduced the ARR by 44% (twice a day dose; ARR=0.22) or 51% (three times a day dose; ARR=0.20) and glatiramer acetate reduced this rate by 29% (ARR=0.29) as compared to placebo (ARR=0.40); dimethyl fumarate reduced the proportion of patients who relapsed at two years by 34% (twice a day dose) or 45% (three times a day dose) and glatiramer acetate reduced this rate by 29% as compared to placebo; dimethyl fumarate also had a significant effect on brain lesions [[1793]] [[3222]]; pooled analysis from 2301 participants in the CONFIRM and DEFINE studies indicated that at 2 years, both doses of dimethyl fumarate decreased the ARR by 49%; dimethyl fumarate decreased the proportion of patients who relapsed by 43% (twice a day dose) and 47% (three times a day dose) and reduced the risk of 12-week confirmed disability progression by 32% (twice a day dose) and 30% (three times a day dose), and, in a subset of participants, decreased the mean number of new or enlarging T2-hyperintense lesions by 78% (twice a day dose) and 73% (three times a day dose) [[3590]] [[17461]]; secondary analysis showed that the twice a day dose of dimethyl fumarate led to a reduction in relapse rate within 10 weeks [[5513]]; additional analyses of patient subgroups (based on demographics and disease characteristics) showed that the ARR was reduced across subgroups by dimethyl fumarate, with reductions ranging from 34% to 53% (twice a day dose) and from 13% to 67% (three times a day dose) [[6366]]; glatiramer acetate also reduced the ARR in most subgroups [[6366]]; posthoc analysis of CONFIRM and DEFINE showed that the drug delays disease progression over time and reduces relapses in treatment-naïve participants [[7848]]; in CONFIRM, additional analysis showed that dimethyl fumarate was associated with an improvement in health-related quality of life, whereas placebo was associated with a decrease [[8180]]; posthoc analysis of pooled CONFIRM and DEFINE data indicates that at 2 years, the twice a day dose of dimethyl fumarate reduced the ARR by 60% among individuals with highly active disease [[10843]]; posthoc analysis of integrated CONFIRM and DEFINE data indicates that at 2 years in individuals who were newly diagnosed with RRMS, the twice a day and three times a day doses reduced the ARR by 56% and 60%, the risk of relapse by 54% and 57%, the risk of 12-week confirmed progression of disability by 71% and 47%, and the mean number of new or enlarging T2-hyperintense lesions by 80% and 81%, respectively [[12362]]; integrated analysis of DEFINE and CONFIRM data showed an increase in scores indicating a better health-related quality of life as compared with baseline after 2 years of treatment with either dose, and a decrease in such scores with placebo [[14494]]; posthoc analysis of integrated DEFINE and CONFIRM data indicated that both doses reduced the ARR starting in weeks 0-12; the twice a day dose reduced the proportion of patients relapsing beginning at week 10 and the three times a day dose reduced that proportion beginning at week 12 [[16146]]; in a subset of 681 CONFIRM participants, both doses consistently reduced a variety of MRI measures including the number of new or enlarging T2-hyperintense lesions and new T1-hypointense lesions (after 1 and 2 years) and the number of gadolinium-enhancing lesions (at week 24, year 1, and year 2) but did not reduce brain atrophy or magnetization transfer ratio changes [[16991]]; posthoc analysis of integrated CONFIRM and DEFINE data indicates that at 2 years in newly-diagnosed individuals with highly active MS, the drug reduced the ARR by 56%, the proportion of participants who relapsed by 56%, and the time to sustained 12-week progression of disability by 78% [[18345]]; analysis of DEFINE and CONFIRM results indicated that dimethyl fumarate reduced the ARR by 63% and the 12-week confirmed disability progression by 40% relative to placebo in individuals who began treatment early in the course of MS, with little or no disability at baseline [[22564]]; posthoc analysis of the MRI group indicated that dimethyl fumarate reduced inflammatory disease activity (measured by the presence of relapses and MRI lesions) relative to glatiramer acetate, such that 36% of individuals on dimethyl fumarate were free of such activity during weeks 0-24 versus 29% of those on glatiramer acetate [[22564]]; analysis of pooled data from DEFINE and CONFIRM indicates that dimethyl fumarate reduced MS-associated hospitalizations and relapses treated with intravenous steroids [[23329]] Trial name: Determination of the Efficacy and safety of oral Fumarate IN rElapsing-remitting MS (DEFINE) (publ 2012, 2013, 2014, 2015) [[583]] [[3221]] [[3590]] [[5513]] [[6541]] [[7848]] [[8179]] [[10843]] [[12362]] [[14494]] [[17461]] Phase: Phase III trial [[583]] [[3221]] Study Design: Global, randomized, double-blind, placebo-controlled, dose-comparison trial to determine the safety and efficacy of BG-12 (dimethyl fumarate) (240 mg, twice a day or three times a day) at reducing the proportion of relapsing patients at two years (primary endpoint) and at reducing the annualized relapse rate (ARR), the risk of disability progression, and the number of lesions as measured by brain MRI (secondary endpoints) [[583]] [[3221]] Disease Stage: RRMS [[583]] [[3221]] Enrollment/Number of Patients: 1237, with 952 completing the study [[583]] [[3221]] Duration: 2 years [[583]] [[3221]] Status/Outcome: Drug reduced the risk of relapse by 49% (twice a day dose; 27% of these patients, versus 46% in the placebo group, had at least one relapse by 2 years) or 50% (three times a day dose; 26% had at least one relapse by 2 years), the ARR by 53% (twice a day; ARR=0.17 versus 0.36 for the placebo group) or 48% (three times a day; ARR=0.19), and the risk of disability progression by 38% (twice a day) or 34% (three times a day), as well as reducing the mean number of several types of brain lesions [[583]] [[3221]]; pooled analysis from 2301 participants in the CONFIRM and DEFINE studies indicated that at 2 years, both doses of dimethyl fumarate decreased the ARR by 49%; dimethyl fumarate decreased the proportion of patients who relapsed by 43% (twice a day dose) and 47% (three times a day dose) and reduced the risk of 12-week confirmed disability progression by 32% (twice a day dose) and 30% (three times a day dose), and, in a subset of participants, decreased the mean number of new or enlarging T2-hyperintense lesions by 78% (twice a day dose) and 73% (three times a day dose) [[3590]] [[17461]]; additional analyses of patient subgroups (based on demographics and disease characteristics) showed that both doses reduced the risk of relapse and the ARR at 2 years in all subgroups; depending on the group, reductions in the relapse risk were 68%-26% (twice a day dose) and 66%-25% (three times a day dose) as compared to placebo; the twice a day dose reduced the risk of disability progression at 2 years in most subgroups and the three times a day dose reduced that risk in all subgroups [[6541]]; posthoc analysis of CONFIRM and DEFINE showed that the drug delays disease progression over time and reduces relapses in treatment-naïve participants [[7848]]; in DEFINE, additional analysis showed that dimethyl fumarate was associated with benefits for health-related quality of life as compared with placebo [[8179]]; posthoc analysis of pooled CONFIRM and DEFINE data indicates that at 2 years, the twice a day dose of dimethyl fumarate reduced the ARR by 60% among individuals with highly active disease [[10843]]; posthoc analysis of integrated CONFIRM and DEFINE data indicates that at 2 years in individuals who were newly diagnosed with RRMS, the twice a day and three times a day doses reduced the ARR by 56% and 60%, the risk of relapse by 54% and 57%, the risk of 12-week confirmed progression of disability by 71% and 47%, and the mean number of new or enlarging T2-hyperintense lesions by 80% and 81%, respectively [[12362]]; evaluation of changes in brain magnetization transfer ratio (MTR), a possible indicator of myelin density, in 392 participants, showed that both doses were associated with increases in MTR in brain tissue over 2 years, whereas placebo was associated with decreases, suggesting that the drug may increase myelin density [[14126]]; integrated analysis of DEFINE and CONFIRM data showed an increase in scores indicating a better health-related quality of life as compared with baseline after 2 years of treatment with either dose, and a decrease in such scores with placebo [[14494]]; posthoc analysis of integrated DEFINE and CONFIRM data indicated that both doses reduced the ARR starting in weeks 0-12; the twice a day dose reduced the proportion of patients relapsing beginning at week 10 and the three times a day dose reduced that proportion beginning at week 12 [[16146]]; posthoc analysis of integrated CONFIRM and DEFINE data indicates that at 2 years in newly-diagnosed individuals with highly active MS, the drug reduced the ARR by 56%, the proportion of participants who relapsed by 56%, and the time to sustained 12-week progression of disability by 78% [[18345]]; analysis of DEFINE and CONFIRM results indicated that dimethyl fumarate reduced the ARR by 63% and the 12-week confirmed disability progression by 40% relative to placebo in individuals who began treatment early in the course of MS, with little or no disability at baseline [[22564]]; analysis of pooled data from DEFINE and CONFIRM indicates that dimethyl fumarate reduced MS-associated hospitalizations and relapses treated with intravenous steroids [[23329]]; analyses of data from a subset of 540 DEFINE participants showed that both doses reduced T2-hyperintense, gadolinium-enhancing, and T1-hypointense lesion counts, such that reductions were evident at 6 months and maintained at 1 and 2 years; lesion volume reductions also occurred [[23745]] Trial name: Kappos et al., Lancet, Oct 2008 trial [[370]] Phase: Phase IIb trial [[370]] Study Design: Multicenter, randomized, double-blind, placebo-controlled trial to evaluate the safety and efficacy of dimethyl fumarate (120 mg, 1 time per day; 120 mg, 3 times per day; or 240 mg, 3 times per day) at reducing the number of new gadolinium enhancing lesions (primary endpoint) and at reducing other types of brain lesions and the annualized relapse rate (secondary endpoints) [[370]] Disease Stage: RRMS [[370]] Enrollment/Number of Patients: 257 [[370]] Duration: 24 weeks, with a 24 week extension period [[370]] Status/Outcome: 240 mg drug (3 times a day) reduced the mean total number of new gadolinium enhancing lesions by 69% from week 12 to 24 as compared to placebo and reduced the annualized relapse rate by 32% [[370]]; additional analysis showed that the 240 mg, 3 times a day dose reduced the number of new gadolinium-enhanced lesions in a range of patient subgroups (which were based on demographics and baseline disease characteristics), and the reduction varied depending on the subgroup [[2193]] Trial name: Schimrigk et al., Eur. J. Neurol., Jun 2006 trial [[385]] Phase: Pilot study [[385]] Study Design: Exploratory, prospective, baseline-controlled, open-label study to examine the effects of Fumaderm (which contains dimethyl fumarate and and salts of monoethylfumarate) [6 weeks baseline, 18 weeks treatment (target dose of 720 mg per day), 4 weeks washout, 48 weeks treatment (target dose of 360 mg per day)] on number and volume of gadolinium enhancing lesions (primary outcome) [[385]] Disease Stage: RRMS [[385]] Enrollment/Number of Patients: 10, with 3 withdrawing [[385]] Duration: 76 weeks [[385]] Status/Outcome: Drug was associated with reductions from baseline in the number and volume of gadolinium enhancing lesions [[385]] |
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Dronabinol |
Trial name: Cannabinoid Use in Progressive Inflammatory brain Disease (CUPID) (publ 2013, 2015) [[6803]] [[9468]] [[17132]] Phase: Phase III trial [[9467]] Study Design: Government institute- and foundation-funded, multicenter, parallel, randomized, double-blind, placebo-controlled trial to examine whether oral dronabinol (with a maximum dose of 28 mg per day, depending on body weight and adverse effects) can slow disease progression, as assessed by progression in the Expanded Disability Status Scale score and change in the physical impact subscale of the MS impact scale (primary outcomes) and a variety of secondary outcomes [[6803]] Disease Stage: PPMS or SPMS [[6803]] Enrollment/Number of Patients: 498 [[6803]] Duration: 36 months [[6803]] Status/Outcome: Dronabinol was not associated with any significant effects on primary or secondary outcomes [[17132]] Trial name: CAnnabinoids for treatment of spasticity and other symptoms related to Multiple Sclerosis (CAMS) (publ November 2003, December 2005) [[9470]] [[9472]] Phase: Phase III trial [[9471]] Study Design: Government institute- and foundation-funded, multicenter, randomized, placebo-controlled trial to test the effects of oral dronabinol (with a maximum daily dose of 25 mg, depending on body weight) or cannabis extract versus placebo on spasticity, as measured by a change in the Ashworth score (primary outcome measure), and other measures such as walking speed, as measured by a timed 10 m walk [[9470]]; individuals could continue treatment in a double-blinded, placebo-controlled followup study [[9472]] Disease Stage: Stable MS with muscle spasticity [[9470]] Enrollment/Number of Patients: 667 enrolled, with 611 followed to the primary endpoint [[9470]]; 502 continued in the followup study [[9472]] Duration: 15 weeks [[9470]], with 12 months of followup [[9472]] Status/Outcome: In the initial 15 week trial, neither active treatment had a positive effect on spasticity as measured by the Ashworth scale, but treatments did have some benefit on walking speed, patients' perceptions of spasticity, and pain [[9470]]; over 12 months, each active treatment was associated with a small reduction in spasticity [[9472]] Trial name: Svendsen et al., BMJ, July 2004 trial [[9502]] Phase: Phase II trial [[9502]] Study Design: Foundation-supported (with industry-supplied medication), randomized, double-blind, placebo-controlled crossover trial to examine the effects of oral dronabinol (with a maximum daily dose of 10 mg) on pain caused by lesions in the central nervous system [[9502]] Disease Stage: MS with central pain [[9502]] Enrollment/Number of Patients: 24 [[9502]] Duration: Two 3-week treatment periods separated by a 3-week washout period [[9502]] Status/Outcome: Dronabinol was associated with a reduction in the median spontaneous pain intensity and an increase in the median pain relief score [[9502]] Trial name: Killestein et al., Neurology, May 2002 trial [[9476]] Phase: Phase II trial [[9476]] Study Design: Randomized, double-blind, placebo-controlled, twofold crossover trial to determine the effects of dronabinol (2.5 to 5 mg) or Cannabis sativa plant extract versus placebo on spasticity; each treatment was given for 4 weeks, with the lower dose used for the first 2 weeks and doubled, if it was tolerated well, for the second 2 weeks [[9476]] [[9477]] Disease Stage: PPMS or SPMS with severe spasticity [[9476]] [[9477]] Enrollment/Number of Patients: 16 [[9476]] Duration: Three 4-week treatment periods separated by 4-week washout periods [[9476]] Status/Outcome: Neither active treatment was associated with a reduction of spasticity [[9476]] Trial name: Ungerleider et al., Adv. Alcohol Subst. Abuse, 1987 trial [[9475]] Phase: Phase II trial [[9475]] Study Design: Double-blind, placebo-controlled, crossover trial to examine the effects of dronabinol on spasticity, as assessed by subjective ratings; in random order, participants received 5 days of drug and 5 days of placebo, separated by a 2-day washout period; escalating doses of drug (2.5 to 15 mg) were tested [[9475]] Disease Stage: MS with spasticity [[9475]] Enrollment/Number of Patients: 13 [[9475]] Duration: For each dose, two 5-day treatment periods separated by a 2-day washout [[9475]] Status/Outcome: At doses >7.5 mg, dronabinol was associated with reduced spasticity as assessed by scoring by participants but not physicians [[9475]] [[9477]] Trial name: Clifford, Ann. Neurol., June 1983 trial [[9479]] Phase: Pilot trial [[9479]] Study Design: Single-blind, placebo-controlled trial to examine the effects of oral dronabinol (5 to 15 mg) on tremor and ataxia [[9479]] [[9481]] Disease Stage: MS with tremor and ataxia [[9479]] Enrollment/Number of Patients: 8 [[9479]] Status/Outcome: Dronabinol was associated with objective improvement in tremor in 2 participants and with mild subjective improvement in 5 participants [[9479]] [[9481]] Trial name: Petro et al., J. Clin. Pharmacol., August-September 1981 trial [[9473]] Phase: Pilot trial [[9473]] Study Design: Double-blind, placebo-controlled trial to examine the effects of oral dronabinol (5 or 10 mg) on reflexes, muscle tone, and muscle power [[9473]] Disease Stage: MS [[9473]] Enrollment/Number of Patients: 9 [[9473]] Duration: 1 day (?) [[9473]] Status/Outcome: Both doses reduced spasticity; a blinded examiner identified which indiivduals received dronabinol in 7 of the 9 cases [[9473]] [[9474]] |
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Estriol |
Trial name: A Combination Trial of Copaxone plus Estriol in Relapsing Remitting Multiple Sclerosis (meeting report, April 2014; publ December 2015) [[864]] [[868]] [[10842]] [[24356]] Phase: Phase II trial [[868]] [[24356]] Study Design: Investigator-initiated, institute-funded, randomized, double-blind, placebo-controlled, multicenter, US-based trial to compare the efficacy of oral estriol (8 mg per day) and injectable glatiramer acetate (20 mg per day) versus placebo and glatiramer acetate, with the annualised relapse rate (ARR) after 24 months as the primary endpoint [[868]] [[10842]] [[24356]] Disease Stage: RRMS [[868]] [[24356]] Enrollment/Number of Patients: 164 women [[24356]] Duration: 2 years [[868]] [[24356]] Status/Outcome: Estriol plus glatiramer acetate was associated with a 47% decrease (statistically significant) in the ARR at 12 months as compared with placebo plus glatiramer acetate, and a 32% decrease at 24 months [[10842]]; estriol plus glatiramer acetate was associated with an ARR of 0.25 relapses per year versus 0.37 for the glatiramer acetate alone group; similar proportions in the two groups exhibited serious adverse events; irregular menses occurred more frequently, but vaginal infections less frequently, in the estriol and glatiramer acetate group versus the glatiramer acetate alone group [[24356]]; independent analyses of trial results by two different organizations did not show differences that were statistically significant between estriol and glatiramer acetate versus glatiramer acetate alone for either clinical or MRI results at either 12 or 24 months; the ARR at 12 months was 0.13 versus 0.19 for the estriol plus glatiramer acetate group versus the glatiramer acetate alone group, and at 24 months was 0.17 versus 0.25 (February 2016) [[26483]] Trial name: Estriol Treatment in Multiple Sclerosis: Effect on Cognition [[865]] [[867]] Phase: Phase II trial [[867]] Study Design: Company-sponsored, randomized, double-blind, placebo-controlled, single-site, parallel-assignment trial to examine the efficacy of estriol on cognitive function as assessed by the Paced Serial Addition Test (primary endpoint) [[867]] Disease Stage: RRMS and SPMS [[867]] Enrollment/Number of Patients: Expected enrollment, 64 female patients [[867]] Duration: 1 year [[867]] Status/Outcome: Expected completion date, April 2013 [[867]] |
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Fingolimod |
Trial name: TOFINGO (meeting report, October 2013; publ May 2015) [[7941]] [[19230]] Phase: Phase IV trial [[19230]] Study Design: Company-sponsored, multicenter, randomized, double-blind, placebo-controlled trial to determine the optimum timing for beginning fingolimod treatment after discontinuation of natalizumab; individuals who had been treated with natalizumab for at least 6 months (and had reason to discontinue such as positive JC virus antibody status, a risk for progressive multifocal leukoencephalopathy) were randomized to the following regimens: a washout period of 8 weeks followed by 24 weeks of fingolimod, a washout period of 12 weeks (no therapy for 8 weeks followed by 4 weeks of placebo) followed by 20 weeks of fingolimod, or a washout period of 16 weeks (no therapy for 8 weeks followed by 8 weeks of placebo) followed by 16 weeks of fingolimod; the primary outcome was the number of active T2 lesions during the washout and first 8 weeks of fingolimod; brain MRIs were obtained at baseline and weeks 8, 12, 16, 20, and 24 [[7941]] [[19230]] Disease Stage: RRMS [[19230]] Enrollment/Number of Patients: 142, with 112 completing the trial [[7941]] [[19230]] Duration: 32 weeks from the last natalizumab infusion [[19230]] Status/Outcome: 8- and 12-week washout periods were associated with fewer active T2 lesions during washout and the first 8 weeks of fingolimod (2.1 and 1.7 versus 8.2 for the 16-week washout) and a higher percentage of relapse-free individuals (88% and 91% versus 84% for the 16-week washout) during the 24 weeks since the last natalizumab treatment [[7941]] [[19230]] Trial name: Efficacy and Safety of Fingolimod (FTY720) in Patients With Relapsing-remitting Multiple Sclerosis (FREEDOMS II) (press releases, 2012-2015; publ 2014, 2015) [[3592]] [[3591]] [[5361]] [[7847]] [[10486]] [[11095]] [[13751]] [[13931]] [[18346]] [[19899]] Phase: Phase III trial [[3592]] [[3591]] [[10486]] Study Design: Industry-sponsored, double-blind, randomized, multicenter, placebo-controlled, parallel-group study to compare the efficacy and safety of fingolimod at two doses (0.5 mg or 1.25 mg oral dose, once per day), with the primary outcome measure the aggregate annualized relapse rate (ARR) up to month 24 and the secondary endpoints the percentage brain volume change and time to disability progression [[3592]] [[3591]] [[10486]]; in 2009, individuals assigned to the 1.25 mg dose were switched in a blinded fashion to the 0.5 mg dose after review of other data [[10486]] Disease Stage: RRMS [[3592]] [[3591]] [[10486]] Enrollment/Number of Patients: 1083 [[3592]] [[10486]] Duration: 24 months [[3591]] [[10486]] Status/Outcome: FIngolimod was associated with an aggregate ARR estimate up to month 24 of 0.203 (1.25 mg dose) or 0.208 (0.5 mg dose) versus 0.403 for placebo [[3591]]; posthoc analysis indicated that the 0.5 dose resulted in significant relapse-related benefits within the first three months and brain volume-related benefits by six months [mean percent volume change of -0.23 (fingolimod) versus -0.38 (placebo) at six months] [[3592]]; over 2 years, fingolimod decreased the rate of brain volume loss by 33% as compared to placebo [[5361]]; fingolimod was associated with a mean percentage brain volume change from baseline of -0.86 versus -1.28 for placebo [[10486]]; fingolimod was not associated with a change in confirmed disability progression [[10486]]; fingolimod-associated reductions in ARR occurred across baseline disease activity, previous treatment, age, and gender [[5361]]; analysis of results from FREEDOMS, FREEDOMS II, and TRANSFORMS showed that progression of disability correlates with brain volume loss [[7847]]; analyses of pooled data from FREEDOMS and FREEDOMS II showed that more individuals treated with fingolimod versus placebo displayed rates of brain volume loss that were similar to rates in individuals without MS [[11095]]; analysis of FREEDOMS and FREEDOMS II data showed that individuals treated with fingolimod (0.5 mg) are more likely than those in the placebo group to show no evidence of disease activity on the basis of 4 measures (no relapses, MRI lesions, progression of disabilty, or MS-related brain volume loss) (at 2 years, 19.7% of the treated group versus 5.3% for the placebo group at a particular mean rate threshold for brain volume loss) [[13751]] [[24002]]; posthoc analysis of data from the FREEDOMS, FREEDOMS II, and TRANSFORMS trials indicated that fingolimod (0.5 mg) reduced the ARR by 52% (relative to placebo) and 35% (relative to interferon beta-1a) [with ARRs of 0.22 (fingolimod), 0.46 (placebo) or 0.34 (interferon beta-1a)] in Hispanic individuals; furthermore, the safety profile in this group was similar to that of the whole study population [[13931]]; posthoc analysis of data from FREEDOMS, FREEDOMS II, TRANSFORMS, and their extensions indicated that disease severity at baseline, and new disease activity during the studies, correlated with the rate of brain volume loss during these trials [[16634]]; analysis of FREEDOMS and FREEDOMS II data showed that, over 2 years, individuals with highly-active relapsing disease (who had been previously treated with an injectable drug) in the fingolimod group were 6 times more likely than those in the placebo group to show no evidence of disease activity on the basis of 4 measures (no relapses, MRI lesions, progression of disabilty, or MS-related brain volume loss) [[18346]]; posthoc analysis of data from FREEDOMS and FREEDOMS II indicated that fingolimod was effective in individuals with highly active RRMS despite previous disease-modifying therapy, such that fingolimod was associated with a reduction in (i) the ARR by 48%, (ii) the risk of 3-month and 6-month confirmed disability progression by 34% and 45%, and (iii) brain volume loss by 46%, in this group [[19899]]; analysis of pooled data from FREEDOMS, FREEDOMS II, and their extensions indicated that during year 1, 27.1% of participants receiving fingolimod exhibited no evidence of disease activity over 4 measures versus 9.1% on placebo; switching to fingolimod from placebo after year 2 increased the frequency of such participants from 12.7% to 27.4% [[22568]]; posthoc analysis of pooled data from FREEDOMS and FREEDOMS II from individuals receiving 0.5 mg fingolimod or placebo showed that fingolimod's effects on relapses, MRI, cognition, brain volume loss, and disability were apparent within 6 months after initiation; at 3 months, effects on ARR were apparent (0.32 versus 0.52) and from day 48 onwards, a delay in time to first relapse was apparent [[24595]] Trial name: FTY720 in Patients With Primary Progressive Multiple Sclerosis (INFORMS) (press release, December 2014; meeting report, October 2015; publ January 2016) [[471]] [[15550]] [[22566]] [[26245]] Phase: Phase III trial [[471]] [[26245]] Study Design: Industry-sponsored, multinational, double-blind, randomized, placebo-controlled, parallel-group trial to evaluate the effect of fingolimod (initially 1.25 mg per day, switched to 0.5 mg per day in 2009 following a protocol amendment) on a composite primary endpoint that measured disability progression [[471]] [[26245]] Disease Stage: PPMS [[471]] [[26245]] Enrollment/Number of Patients: 970 [[15550]] [[26245]] Duration: ≥36 months [[471]] [[26245]] Status/Outcome: Fingolimod did not slow progression of disease as measured by a combination of disability measures as compared with placebo [[15550]] [[26245]]; fingolimod did not affect atrophy of the brain or spinal cord (meeting report, October 2015) [[22566]] Trial name: Saida et al., Mult. Scler., September 2012 trial [[9649]] Phase: Phase II trial [[9649]] Study Design: Randomized, double-blind, parallel-group, placebo-controlled trial to examine the effects of fingolimod (0.5 mg or 1.25 mg per day) on gadolinium-enhanced lesions at months 3 and 6 (with the percentage of participants free from such lesions the primary endpoint) and the proportion of participants with relapses over 6 months (secondary endpoint) in Japanese individuals [[9649]] Disease Stage: Relapsing MS [[9649]] Enrollment/Number of Patients: 171 began the trial; 147 completed it [[9649]] Duration: 6 months [[9649]] Status/Outcome: Results were consistent with those from trials involving primarily Caucasian populations; fingolimod was associated with a greater proportion of participants with no gadolinium-enhanced lesions [70% (0.5 mg dose group) and 86% (1.25 mg dose group) versus 40% (placebo group)] but not with a significant change in the proportion of relapse-free participants [[9649]] Trial name: FTY720 Research Evaluating Effects of Daily Oral therapy in Multiple Sclerosis (FREEDOMS) (publ 2010, 2012-2015; press releases, 2013-2015) [[303]] [[2331]] [[3592]] [[5361]] [[7847]] [[10487]] [[11095]] [[13751]] [[13931]] [[19899]] Phase: Phase III trial [[303]] Study Design: Industry-supported, double-blind, placebo-controlled, multicenter, multinational trial to test the effects of daily oral fingolimod (0.5 mg or 1.25 mg dose) on the annualized relapse rate (ARR) (primary endpoint) and the time to disability progression and the number of gadolinium-enhancing lesions (secondary endpoints) [[303]]; MRI scans were obtained at 0, 6, 12, and 24 months [[2331]] Disease Stage: RRMS [[303]] Enrollment/Number of Patients: 1272 (with 1033 completing study) [[303]] Duration: 24 months [[303]] Status/Outcome: Fingolimod caused a relative reduction in the ARR of 54% (daily oral 0.5 mg dose) or 60% (1.25 mg dose), an increase in the time to disability, and a reduction in the number of gadolinium-enhancing lesions; drug was also associated with less reduction in brain volume [[303]]; both doses reduced inflammatory lesions (gadolinium-enhancing and new/newly enlarged T2 lesions) in a rapid and sustained manner and slowed the rate of brain volume loss [[2331]]; posthoc analysis indicated that the 0.5 dose resulted in significant relapse-related benefits within the first three months and brain volume-related benefits by six months [mean percent volume change of -0.22 (fingolimod) versus -0.34 (placebo) at six months] [[3592]]; over 2 years, fingolimod decreased the rate of brain volume loss by 35% as compared to placebo [[5361]]; continuous treatment over 4 years (as shown by collective data from the FREEDOMS trial and its extension study) was associated with as much as one third less brain volume loss than treatment with placebo for 2 years followed by fingolimod for 2 years, and a lower rate of brain volume loss was associated with being disease free [[7847]]; furthermore, analysis of results from FREEDOMS, FREEDOMS II, and TRANSFORMS showed that progression of disability correlates with brain volume loss [[7847]]; posthoc subgroup analyses showed that in individuals with early MS (who exhibited their first symptom <3 years before randomization), fingolimod reduced the ARR by 67.4% as compared with placebo; in individuals who exhibited their first symptom ≥3 years before randomization, the reduction was 51.4% [[10487]]; analyses of pooled data from FREEDOMS and FREEDOMS II showed that more individuals treated with fingolimod versus placebo displayed rates of brain volume loss that were similar to rates in individuals without MS [[11095]]; analysis of FREEDOMS and FREEDOMS II data showed that individuals treated with fingolimod (0.5 mg) are more likely than those in the placebo group to show no evidence of disease activity on the basis of 4 measures (no relapses, MRI lesions, progression of disabilty, or MS-related brain volume loss) (at 2 years, 19.7% of the treated group versus 5.3% for the placebo group at a particular mean rate threshold for brain volume loss) [[13751]] [[24002]]; posthoc analysis of data from the FREEDOMS, FREEDOMS II, and TRANSFORMS trials indicated that fingolimod (0.5 mg) reduced the ARR by 52% (relative to placebo) and 35% (relative to interferon beta-1a) [with ARRs of 0.22 (fingolimod), 0.46 (placebo) or 0.34 (interferon beta-1a)] in Hispanic individuals; furthermore, the safety profile in this group was similar to that of the whole study population [[13931]]; posthoc analysis of data from FREEDOMS, FREEDOMS II, TRANSFORMS, and their extensions indicated that disease severity at baseline, and new disease activity during the studies, correlated with the rate of brain volume loss during these trials [[16634]]; an analysis of 992 participants showed that the treatment effect on the number of relapses during the first year and the yearly percentage brain volume change over 2 years independently predict the treatment effect on progression of disability [[17014]]; analysis of 36 participants showed reduced median levels of neurofilament light chain subunit (a marker of axonal injury) in the cerebrospinal fluid for fingolimod but not placebo at 12 months, and this reduction correlated with better relapse and MRI results [[17840]]; analysis of FREEDOMS and FREEDOMS II data showed that, over 2 years, individuals with highly-active relapsing disease (who had been previously treated with an injectable drug) in the fingolimod group were 6 times more likely than those in the placebo group to show no evidence of disease activity on the basis of 4 measures (no relapses, MRI lesions, progression of disabilty, or MS-related brain volume loss) [[18346]]; posthoc analysis of FREEDOMS and its extension indicated that there is a relationship between the categorical change in the T2 lesion volume (T2LV) and disability over 24 and 48 months, such that participants with increased T2LV display greater changes in the Expanded Disability Status Scale score and the MS Functional Composite score and less time to confirmed disability progression; fingolimod treatment was associated with stable or decreased LV more so than placebo [[18408]]; posthoc subgroup analysis indicated that the efficacy of fingolimod was similar regardless of previous treatment [[18440]]; posthoc analysis of data from FREEDOMS and FREEDOMS II indicated that fingolimod was effective in individuals with highly active RRMS despite previous disease-modifying therapy, such that fingolimod was associated with a reduction in (i) the ARR by 48%, (ii) the risk of 3-month and 6-month confirmed disability progression by 34% and 45%, and (iii) brain volume loss by 46%, in this group [[19899]]; analysis of pooled data from FREEDOMS, FREEDOMS II, and their extensions indicated that during year 1, 27.1% of participants receiving fingolimod exhibited no evidence of disease activity over 4 measures versus 9.1% on placebo; switching to fingolimod from placebo after year 2 increased the frequency of such participants from 12.7% to 27.4% [[22568]]; posthoc analysis of pooled data from FREEDOMS and FREEDOMS II from individuals receiving 0.5 mg fingolimod or placebo showed that fingolimod's effects on relapses, MRI, cognition, brain volume loss, and disability were apparent within 6 months after initiation; at 3 months, effects on ARR were apparent (0.32 versus 0.52) and from day 48 onwards, a delay in time to first relapse was apparent [[24595]] Trial name: Efficacy and Safety of FTY720 in Patients With Relapsing Multiple Sclerosis (publ 2006) [[478]] Phase: Phase II trial [[304]] Study Design: Industry-sponsored, double-blind, placebo-controlled, proof-of-concept trial to test the effects of daily oral fingolimod (5.0 mg or 1.25 mg dose) on the number of gadolinium-enhanced lesions and on the annualized relapse rate (ARR) [[304]] Disease Stage: RRMS [[304]] Enrollment/Number of Patients: 281 (with 255 completing core study and 227 completing extension study) [[304]] Duration: 6-month core study and 6-month extension study [[304]] Status/Outcome: Both doses of fingolimod reduced in the number of gadolinium-enhanced lesions and the ARR compared with placebo (ARR for 1.25 mg dose, 0.35; for 5.0 mg dose, 0.36; for placebo, 0.77) [[304]] Trial name: Kahan et al., N. Engl. J. Med., Oct 2003 trial [[304]] Phase: Phase I trial [[304]] Study Design: Randomized, multicenter, double-blind, placebo-controlled trial to examine safety, pharmacodynamics, and pharmacokinetics of daily oral dose (0.125, 0.25, 0.5, 1.0, 2.5, or 5.0 mg) [[330]] Disease Stage: Not MS; stable renal transplant patients [[330]] Enrollment/Number of Patients: 65 [[330]] Duration: 28 days [[330]] Status/Outcome: Drug doses greater or equal to 1.0 mg caused a reversible reduction in the number of peripheral blood lymphocytes, with no major increase in adverse events [[330]]
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Firategrast |
Trial name: Miller et al., Lancet Neurol 2012 trial [[1338]] Phase: Phase II [[1338]] Study Design: Company-sponsored, multicenter, multinational, randomized, double-blind, placebo-controlled dose-ranging study examining efficacy at four doses (150mg, 600mg, 900mg, 1200mg) as measured by cumulative number of new gadolinium-enhancing lesions (primary endpoint) [[1338]] Disease Stage: RRMS [[1338]] Enrollment/Number of Patients: 343 patients with RRMS who had not previously received immunosuppressant or immunomodulatory therapies enrolled; 286 completed trial [[1338]] Duration: 24 weeks treatment and 12 weeks core follow-up, plus 12 months extended follow-up [[1338]] Status/Outcome: Reduction in lesion number (49%; 2.69, compared to 5.31 with placebo) in patients given 900mg and 1200mg drug; no effect at lower doses [[1338]] |
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Flupirtine |
Trial name: Flupirtine as Oral Treatment in Multiple Sclerosis (FLORIMS) (terminated as of 2014) [[1500]] Phase: Phase II trial [[1500]] Study Design: Investigator-run, multicenter, double-blind, randomized, placebo controlled pilot study assessing effect of flupirtine, added to interferon beta therapy, on neurodegeneration, with the primary endpoint the cumulative number of new T2 hypertensive lesions visualized with MRI [[1500]] Disease Stage: RRMS [[1500]] Enrollment/Number of Patients: Estimated enrollment, 80 individuals [[1500]] Duration: 12 months [[1500]] Status/Outcome: Study has been terminated as of February 2014 [[1500]] Trial name: Fleckenstein et al., J. Transl. Med., February 2013 trial [[1501]] [[13175]] Phase: Phase I trial [[1501]] [[13175]] Study Design: University-sponsored, randomised, double-blind, placebo-controlled, two-way, crossover trial to investigate the effect of flupirtine on the electrical excitability of myelinated peripheral axons in vivo (dose, 200 mg orally) in conjunction with studies to examine the effects on biopsy-derived myelinated axons in vitro (dose, 3 to 30 microM) [[1501]] [[13175]] Disease Stage: Healthy volunteers [[1501]] [[13175]] Enrollment/Number of Patients: 20 [[1501]] [[13175]] Duration: Two weeks [[1501]] [[13175]] Status/Outcome: Flupirtine reduced the excitability of myelinated peripheral axons [[13175]] |
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Glatiramer acetate |
Trial name: A Combination Trial of Copaxone plus Estriol in Relapsing Remitting Multiple Sclerosis (meeting report, April 2014; publ December 2015) [[864]] [[868]] [[10842]] [[24356]] Phase: Phase II trial [[868]] [[24356]] Study Design: Investigator-initiated, institute-funded, randomized, double-blind, placebo-controlled, multicenter, US-based trial to compare the efficacy of oral estriol (8 mg per day) and injectable glatiramer acetate (20 mg per day) versus placebo and glatiramer acetate, with the annualised relapse rate (ARR) after 24 months as the primary endpoint [[868]] [[10842]] [[24356]] Disease Stage: RRMS [[868]] [[24356]] Enrollment/Number of Patients: 164 women [[24356]] Duration: 2 years [[868]] [[24356]] Status/Outcome: Estriol plus glatiramer acetate was associated with a 47% decrease (statistically significant) in the ARR at 12 months as compared with placebo plus glatiramer acetate, and a 32% decrease at 24 months [[10842]]; estriol plus glatiramer acetate was associated with an ARR of 0.25 relapses per year versus 0.37 for the glatiramer acetate alone group; similar proportions in the two groups exhibited serious adverse events; irregular menses occurred more frequently, but vaginal infections less frequently, in the estriol and glatiramer acetate group versus the glatiramer acetate alone group [[24356]]; independent analyses of trial results by two different organizations did not show differences that were statistically significant between estriol and glatiramer acetate versus glatiramer acetate alone for either clinical or MRI results at either 12 or 24 months; the ARR at 12 months was 0.13 versus 0.19 for the estriol plus glatiramer acetate group versus the glatiramer acetate alone group, and at 24 months was 0.17 versus 0.25 (February 2016) [[26483]] Trial name: Fox et al., Neurology, April 2014 study (RESTORE) [[10354]] [[24814]] Phase: Exploratory study [[10354]] Study Design: Industry-funded, randomized, partially placebo-controlled exploratory study to examine disease activity in individuals who had been treated with natalizumab (with no relapse activity during the previous year and no gadolinium-enhancing lesions at the time of screening) during an interruption of natalizumab treatment; participants received either natalizumab, interferon beta-1a, glatiramer acetate, methylprednisolone, or placebo during the interruption [[10354]] [[24814]] Disease Stage: RRMS [[10354]] Enrollment/Number of Patients: 175 [[10354]] Duration: 24 weeks (length of interruption) [[10354]] Status/Outcome: Interruption in natalizumab treatment was associated with an increased risk of MRI and relapse activity even when other therapies were used; relapses occurred in 4% of participants receiving natalizumab versus 15% to 29% of participants in other arms of the study [[10354]]; during the randomized treatment period, gadolinium-enhancing lesions were observed in 0% of individuals receiving natalizumab, 48% of those receiving other treatments, and 61% of those on placebo; such lesions were primarily observed at week 16 or later [[24814]] Trial name: Glatiramer Acetate Clinical Trial to Assess Equivalence With Copaxone (GATE) (press release, March 2014; publ October 2015) [[10368]] [[10369]] [[22531]] Phase: Phase III trial [[10368]] [[10369]] [[22531]] Study Design: Company-sponsored, multinational, randomized, double-blind, active- and placebo-controlled trial to compare the efficacy and safety of GTR [a generic version of glatiramer acetate produced by Synthon (daily injected dose, 20 mg)] to that of Copaxone [(glatiramer acetate produced by Teva (daily injected dose, 20 mg)] or placebo; the primary outcome is the number of gadolinium-enhancing lesions detected by MRI during months 7, 8, and 9 [[10368]] [[10369]] [[22531]] Disease Stage: RRMS [[10368]] [[10369]] [[22531]] Enrollment/Number of Patients: 794 [[22531]] Duration: 9 months (followed by a 15-month open-label extension) [[10368]] [[10369]] [[22531]] Status/Outcome: GTR and Copaxone reduced the number of gadolinium-enhancing lesions during months 7, 8, and 9 to an equivalent degree and were associated with a comparable incidence, severity, and range of adverse reactions (including injection site reactions) [[10368]] [[22531]] Trial name: Glatiramer Acetate Low-Frequency Administration (GALA) (press releases, June 2012 and October 2012, publ May 2013, December 2014) [[2158]] [[3588]] [[6074]] [[16156]] [[21838]] Phase: Phase III trial [[2158]] Study Design: Company-sponsored, multinational, randomized, double-blind, placebo-controlled trial to study the safety and effect of glatiramer acetate injection (40 mg/1 ml, administered 3 times weekly) on reducing the number of confirmed relapses (primary endpoint) [the dose in this study is higher but less frequent than the marketed dose (20 mg/1 ml daily) at the time of this press release] [[2158]] Disease Stage: RRMS [[2158]] Enrollment/Number of Patients: 1404 [[6074]] Duration: 12 months [[2158]] Status/Outcome: Drug at the 40 mg, 3 times a week dose reduced the annualized relapse rate by 34.0% as compared with placebo (mean annualized relapse rate for patients receiving the drug was 0.331 versus 0.505 for those on placebo) [[6074]]; additionally, the drug reduced the cumulative number of new and enlarging T2 lesions by 34.7% and the cumulative number of gadolinium-enhancing lesions by 44.8% as compared with placebo [[6074]], but the drug did not affect the percent change of brain volume at 12 months [[3588]]; posthoc analysis of MRI data showed that glatiramer acetate reduced the conversion of new active lesions (identified 6 months after the trial began) to "black holes" (at month 12), such that both the mean number (0.31 for glatiramer acetate versus 0.45 for placebo) and proportion (15.8% versus 19.6%) of new lesions converting decreased [[16156]]; glatiramer acetate was found to reduce the number of both new or enlarging T1H total lesions and T1H non-enhancing lesions [[21838]] Trial name: Comparator and aN oral Fumarate In RRMS (CONFIRM) (publ September 2012 and June 2013, press release April 2012) [[1793]] [[3222]] [[6366]] Phase: Phase III trial [[1793]] [[3222]] Study Design: Company-sponsored, global, randomized, double-blind, placebo-controlled, dose-comparison study to determine the safety and efficacy of oral BG-12 (dimethyl fumarate) (240 mg given either twice a day or three times a day) or glatiramer acetate (20 mg subcutaneous injection each day) in reducing the annualized relapse rate (ARR) (primary endpoint) and the proportion of patients who relapse at two years and the number of T2-hyperintense lesions (secondary endpoints); study was not designed to test whether dimethyl fumarate is superior or noninferior to glatiramer acetate [[1793]] [[3222]] Disease Stage: RRMS [[1793]] [[3222]] Enrollment/Number of Patients: 1430 [[1793]] [[3222]] Duration: 2 years [[1793]] [[3222]] Status/Outcome: Dimethyl fumarate reduced the ARR by 44% (twice a day dose; ARR=0.22) or 51% (three times a day dose; ARR=0.20) and glatiramer acetate reduced this rate by 29% (ARR=0.29) as compared to placebo (ARR=0.40); dimethyl fumarate reduced the proportion of patients who relapsed at two years by 34% (twice a day dose) or 45% (three times a day dose) and glatiramer acetate reduced this rate by 29% as compared to placebo; dimethyl fumarate also had a significant effect on brain lesions [[1793]] [[3222]]; additional analyses of patient subgroups (based on demographics and disease characteristics) showed that the ARR was reduced across subgroups by dimethyl fumarate, with reductions ranging from 34% to 53% (twice a day dose) and from 13% to 67% (three times a day dose) [[6366]]; glatiramer acetate also reduced the ARR in most subgroups [[6366]]; posthoc analysis of the MRI group indicated that dimethyl fumarate reduced inflammatory disease activity (measured by the presence of relapses and MRI lesions) relative to glatiramer acetate, such that 36% of individuals on dimethyl fumarate were free of such activity during weeks 0-24 versus 29% of those on glatiramer acetate [[22564]] Trial name: Early GA Treatment in Delaying Conversion to Clinically Definite Multiple Sclerosis in Subjects Presenting With a Clinically Isolated Syndrome (CIS) (PreCISe) (publ 2009; further analyses publ 2013) [[343]] [[360]] [[5629]] Phase: Phase III trial [[491]] Study Design: Randomized, double-blind, multicenter trial to study the effect of early glatiramer acetate (20 mg per day) on the time to clinically definite MS from clinically isolated syndrome (primary outcome measure) [[360]] Disease Stage: CIS [[360]] Enrollment/Number of Patients: 481 [[360]] Duration: Up to 36 months [[360]] Status/Outcome: Drug reduced the risk of CIS converting to clinically definite MS by 45% as compared to placebo [[360]]; in a substudy (involving 34 patients, 20 of whom did not relapse and were in the study through 12 months of followup), the drug (versus placebo) appeared to exert a neuroprotective effect in a large central brain volume, based on measurements of the ratio of a marker of neuronal integrity (N-acetylaspartate) relative to creatine [[5629]] Trial name: Metz et al., Mult. Scler., Oct 2009 trial [[361]] Phase: Phase II trial [[361]] Study Design: Double-blind, placebo-controlled study to compare the effects of glatiramer acetate plus minocycline (100 mg twice daily) versus glatiramer acetate plus placebo on the total number of T1 gadolinium-enhanced lesions [[361]] Disease Stage: RRMS [[361]] Enrollment/Number of Patients: 44, with 40 completing study [[361]] Duration: 9 months [[361]] Status/Outcome: Glatiramer acetate plus minocycline reduced the number of T1 gadolinium-enhanced lesions by 63% as compared to glatiramer acetate alone [[361]] Trial name: PROMiSe Trial [[381]] Phase: Phase III trial [[955]] Study Design: Multinational, multicenter, double-blind, placebo-controlled trial to test whether glatiramer acetate (20 mg per day) results in a delay in time to sustained progression of accumulated disability in PPMS (primary outcome) [[381]] Disease Stage: PPMS [[381]] Enrollment/Number of Patients: 943 [[381]] Duration: 3 years [[381]] Status/Outcome: Study was stopped prematurely when an interim analysis (at which time 757 patients had completed 2 or more years of the study or had ended participation prematurely) showed that there was no discernible effect of glatiramer acetate on the primary outcome [[381]] Trial name: Comi et al., Ann. Neurol., Mar 2001 trial [[400]] Phase: Phase of trial not stated in article [[400]] Study Design: Multicenter, double-blind, randomized, placebo-controlled European/Canadian trial to study the effects of glatiramer acetate (20 mg per day) on disease activity (primary outcome, the number of enhancing lesions on T1-weighted images), as measured with monthly MRI scans and clinical assessments [[400]] Disease Stage: RRMS [[400]] Enrollment/Number of Patients: 239 [[400]] Duration: 9 months [[400]] Status/Outcome: Drug was associated with a reduction in the total number of enhancing lesions (-10.8) as compared to placebo (primary outcome), as well as a reduction in the relapse rate (33%) in the treatment versus placebo group [[400]] Trial name: Johnson et al., Neurology, July 1995 trial [[412]] Phase: Phase III trial [[412]] Study Design: Multicenter, double-blind, randomized, placebo-controlled trial to determine whether glatiramer acetate (20 mg per day) caused a difference in the relapse rate (primary end point) [[412]] Disease Stage: RRMS [[412]] Enrollment/Number of Patients: 251 [[412]] Duration: 2 years [[412]] Status/Outcome: Drug was associated with a reduction in the relapse rate (primary outcome measure) (1.19 versus 1.68 over 2 years in the treatment versus placebo group) [[412]] Trial name: Bornstein et al., N. Engl. J. Med., Aug 1987 trial [[414]] Phase: Pilot trial; phase II trial [[414]] Study Design: Single-center, double-blind, randomized, placebo-controlled trial to test the effects of glatiramer acetate (20 mg per day) on the number of exacerbations [[414]] Disease Stage: Exacerbating-remitting MS [[414]] Enrollment/Number of Patients: 50 [[414]] Duration: 2 years (2) Status/Outcome: Drug was associated with a reduction in the number of exacerbations (0.6 versus 2.7 average per patient in treatment versus placebo group over 2 years) [[414]] |
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GNbAC1 |
Trial name: Curtin et al., MAbs, March 2016 trial [[28682]] Phase: Phase I trial [[28682]] Study Design: Industry-funded, randomized, placebo-controlled, dose-escalation trial to examine the pharmacokinetics and safety of a single intravenous infusion of GNbAC1 (doses of 6, 18, and 36 mg per kg); concentrations in the cerebrospinal fluid (CSF) were determined after lumbar punctures on days 2, 15, or 29 [[28682]] Disease Stage: Healthy volunteers [[28682]] Enrollment/Number of Patients: 21 [[28682]] Duration: 29 days [[28682]] Status/Outcome: Dose-linear pharmacokinetics were observed in serum, with mean CSF:serum ratios of 0.12%, 0.39%, and 0.42% on days 2, 15, and 29, respectively; GNbAC1 was well tolerated [[28682]] Trial name: Clinical trial assessing the HERV-W Env ANtagonist GNbAC1 for Efficacy in Multiple Sclerosis (CHANGE-MS) (launched December 2015) [[24962]] Phase: Phase IIb trial [[24962]] Study Design: Industry-sponsored, multicenter, randomized, double-blind, placebo-controlled, dose-escalation, proof-of-concept trial to examine the effects of GNbAC1 on MRI measures [[24962]] [[24963]] Disease Stage: RRMS [[24962]] Enrollment/Number of Patients: 260 (planned) [[24962]] Duration: 6 months, followed by a 6-month open-label extension [[24962]] [[24963]] Status/Outcome: Expected date for preliminary results, end of 2017 [[24962]] Trial name: Derfuss et al., Mult. Scler., November 2014 trial [[10315]] [[15278]] [[21641]] Phase: Phase IIa trial [[10315]] [[15278]] Study Design: Industry-sponsored, randomized, double-blind, placebo-controlled trial to investigate the safety and tolerability of a single ascending dose (2 mg/kg or 6 mg/kg), and repeated doses (5 infusions at 4-week intervals of 2 mg/kg or 6 mg/kg) in an open-label extension, of intravenous GNbAC1 (primary outcome measure) as well as GNbAC1 pharmacokinetics and immunogenecity (secondary outcome measures) [[10315]] [[15278]] Disease Stage: PPMS or SPMS; or RRMS (in cases in which existing therapies cannot be used) [[10315]] Enrollment/Number of Patients: 10 [[10315]] [[15278]] Duration: 177 days [[10315]] Status/Outcome: Final data collection date for primary outcome measure was April 2014 [[10315]]; antibody appeared well tolerated by all participants [[15278]]; 9 participants exhibited stable brain lesions [[15278]]; no anti-GNbAC1 antibodies were detected [[15278]]; MSRV transcripts declined after therapy began [[15278]]; GNbAC1 did not display any immunosuppressive effect, on the basis of analysis of immune cell subsets and the response to viral and vaccine antigens, although was associated with a slight decrease in monocyte activation [[21641]] Trial name: Curtin et al., Clin. Ther., December 2012 trial [[8947]] Phase: Phase I trial [[8947]] Study Design: Industry-sponsored, first-in-human, randomized, double-blind, placebo-controlled, dose-escalation study to examine the safety profile, pharmacokinetics, and immunogenecity of a single intravenous infusion of GNbAC1 (0.0025, 0.025, 0.15, 0.6, 2, or 6 mg/kg) [[8947]] Disease Stage: Healthy male volunteers [[8947]] Enrollment/Number of Patients: 33 [[8947]] Duration: Followup over 64 days postinfusion [[8947]] Status/Outcome: GNbAC1 was well tolerated in all participants in each cohort; the 2 and 6 mg/kg doses resulted in the maintenance of therapeutically relevant concentrations over 4 weeks; anti-GNbAC1 antibodies were not detected in any participant over 64 days [[8947]] |
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Idebenone |
Trial name: Idebenone in Patients With Primary Progressive Multiple Sclerosis (IPPoMS) [[8693]] Phase: Phase I/II trial [[8693]] Study Design: Government institute-sponsored (with industry-supplied drug), randomized, double-blind, placebo-controlled trial to assess the safety and effectiveness of idebenone [2250 mg orally per day (750 mg dose, 3 times per day)]; the primary outcome measure is an inhibition on the development of brain atrophy [[8693]] [[8764]] Disease Stage: PPMS [[8693]] Enrollment/Number of Patients: 80 (estimated) [[8693]] Duration: 3 years (1 year to establish the pretreatment baseline and 2 years of treatment) [[8693]] Status/Outcome: Recruiting as of November 2013; estimated study completion date, September 2016 [[8693]] |
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Imilecleucel-T |
Trial name: Study of Tcelna (Imilecleucel-T) in Secondary Progressive Multiple Sclerosis (Abili-T) (in progress as of December, 2013) [[7755]] [[8423]] [[9101]] Phase: Phase IIb trial [[7755]] [[11094]] Study Design: Company-sponsored, randomized, double-blind, placebo-controlled, multicenter trial to study the effects of imilecleucel-T on brain atrophy (primary outcome measure) and disease progression (secondary outcome measure); cells are given in 2 annual courses of 5 subcutaneous doses per year, given at 0, 4, 8, 12, and 24 weeks; the total number of cells in a 2 ml dose is 30 to 45 million [[7755]] Disease Stage: SPMS [[7755]] Enrollment/Number of Patients: 180 (estimated) [[7755]] Duration: 2 years [[7755]] Status/Outcome: Recruiting as of August 2013; estimated study completion date is December 2015 [[7755]]; has enrolled 100 individuals as of 6 November 2013 [[8423]] and 126 as of 16 December 2013 (to reach 70% of the enrollment target of 180) [[9101]]; reached enrollment target of 180 as of 13 May 2014 [[11094]] Trial name: Autologous T Cell Vaccine (TCV) for Multiple Sclerosis (TERMS) (publ June 2012) [[7707]] [[7759]] Phase: Phase IIb trial [[7707]] [[7759]] Study Design: Company-sponsored, randomized, double-blind, placebo-controlled, multicenter trial to examine the efficacy, safety, and tolerability of Tovaxin autologous T cell therapy, given subcutaneously at weeks 0, 4, 8, 12, and 24, and consisting of 30 to 45 million autologous myelin-reactive T cells; these T cells were manufactured against as many as six peptides from three myelin proteins [[7707]] [[7759]] Disease Stage: CIS or RRMS [[7707]] [[7759]] Enrollment/Number of Patients: 150 [[7707]] [[7759]] Duration: 1 year [[7759]] Status/Outcome: Immunotherapy was not associated with a statistically significant beneficial clinical or radiological outcome in general, but was associated with a lower annual relapse rate in individuals naïve for disease-modifying therapy, especially those with active baseline disease [[7707]] |
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Interferon beta-1a |
Trial name: Sørensen et al., Eur. J. Neurol., February 2016 trial (RECYCLINE) [[26409]] Phase: Phase II trial [[26576]] Study Design: Industry-sponsored, double-blind, randomized, multicenter, placebo-controlled trial to compare the effects of a combination of minocycline (100 mg twice a day) and subcutaneous interferon beta-1a (44 microg 3 times a week) versus interferon beta-1a and placebo on the time to first relapse (primary endpoint) and the annualized relapse rate and MRI measures (secondary endpoints) [[26409]] [[26576]] Disease Stage: RRMS [[26409]] Enrollment/Number of Patients: 304 [[26409]] Duration: 96 weeks [[26409]] Status/Outcome: Minocycline did not affect the time to first relapse or other efficacy measures in a statistically significant manner; more participants in the minocycine versus placebo groups discontinued because of adverse events [[26409]] Trial name: Fox et al., Neurology, April 2014 study (RESTORE) [[10354]] [[24814]] Phase: Exploratory study [[10354]] Study Design: Industry-funded, randomized, partially placebo-controlled exploratory study to examine disease activity in individuals who had been treated with natalizumab (with no relapse activity during the previous year and no gadolinium-enhancing lesions at the time of screening) during an interruption of natalizumab treatment; participants received either natalizumab, interferon beta-1a, glatiramer acetate, methylprednisolone, or placebo during the interruption [[10354]] [[24814]] Disease Stage: RRMS [[10354]] Enrollment/Number of Patients: 175 [[10354]] Duration: 24 weeks (length of interruption) [[10354]] Status/Outcome: Interruption in natalizumab treatment was associated with an increased risk of MRI and relapse activity even when other therapies were used; relapses occurred in 4% of participants receiving natalizumab versus 15% to 29% of participants in other arms of the study [[10354]]; during the randomized treatment period, gadolinium-enhancing lesions were observed in 0% of individuals receiving natalizumab, 48% of those receiving other treatments, and 61% of those on placebo; such lesions were primarily observed at week 16 or later [[24814]] Trial name: ADVANCE (press releases, 2013, 2014; publ 2014) [[4731]] [[5316]] [[7871]] [[13745]] [[11033]] [[13745]] [[16063]] Phase: Phase III trial [[4731]] Study Design: Company-sponsored, global, multicenter, randomized, double-blind, parallel-group, placebo-controlled trial to test the safety and efficacy of peginterferon beta-1a, a form of interferon beta-1a that is pegylated to increase its half-life, given subcutaneously at a dose of 125 microg either once every 2 weeks or once every 4 weeks; the primary endpoint is the annualized relapse rate (ARR) at 1 year [[4731]]; trial was placebo-controlled for the first year [[13745]] Disease Stage: RRMS [[4731]] Enrollment/Number of Patients: 1516 [[4731]] Duration: 2 years [[4731]] Status/Outcome: Peginterferon beta-1a was associated with a significant reduction in ARR at one year (35.6% for the two-week dosing and 27.5% for the four-week dosing) as compared to placebo [[4731]]; also at 1 year, peginterferon beta-1a decreased the percentage of patients who relapsed (by 39%), the number of new T2-hyperintense lesions (by 67%), and the risk of 12-week confirmed disability progression (by 38%) as compared to placebo [[5316]]; from baseline to week 48, peginterferon beta-1a increased the percentage of patients who displayed no measured disease activity (33.9% for the 2-week dose and 21.5% for the 4-week dose versus 15.1% for placebo) [[16063]] and, at 48 weeks, reduced the number of new T1-hypointense lesions (by 53% and 18% for the 2- and 4-week doses) and new active lesions (by 67% and 35% for the 2- and 4-week doses) [[7871]]; at 2 years, the ARR was 0.221 for the 2-week dose (a reduction relative to the ARR from year 1), 0.291 for the 4-week dose, and 0.351 for placebo [[11033]] [[11034]]; post-hoc analysis showed that the peginterferon beta-1a's effects on disease activity and disability were maintained at 2 years; additionally, individuals who received peginterferon beta-1a for both years exhibited better clinical and MRI results after 2 years than did those who switched to drug after a year of placebo [[13745]]; pharmacokinetic and pharmacodynamic profiles established during this trial provide a potential rationale for the increased efficacy of dosing every 2 weeks [[14064]] Trial name: Safety and Efficacy of Natalizumab in Combination with Interferon Beta-1a in Patients with Relapsing Remitting Multiple Sclerosis (SENTINEL) (publ 2006) [[390]] Phase: Phase III trial [[390]] Study Design: Industry-sponsored, multinational, randomized, double-blind, placebo-controlled, parallel-group trial to determine if natalizumab (300 mg intravenously every 4 weeks) together with interferon beta-1a (30 microg intramuscularly every week) is more effective than interferon beta-1a alone in reducing breakthrough disease activity in patients who had received interferon beta-1a treatment for at least 12 months before randomization in study (with at least one relapse in the 12 months before randomization), with the rate of clinical relapse at 1 year and the cumulative probabilty of disability progression at 2 years the primary end points [[390]] Disease Stage: RRMS [[390]] Enrollment/Number of Patients: 1171, with 1003 completing the study [[390]] Duration: 2 years [[390]] Status/Outcome: Combination therapy was associated with a 23% cumulative probability of sustained disability progression at 2 years versus 29% with interferon beta-1a alone; combination therapy reduced the risk of sustained disability progression by 24% and reduced the annualized rate of relapse by 54% (at 1 year) and 55% (at 2 years) as compared to interferon beta-1a alone; trial was stopped 1 month early because of two cases of progressive multifocal leukoencephalopathy, one of which was fatal [[390]]; retrospective analysis of AFFIRM (natalizumab), SENTINEL (natalizumab and interferon beta-1a), and IMPACT (interferon beta-1a) trial data showed that 20% to 25% decreases in speed in the timed 25-foot walk correspond to clinically-meaningful reductions in physical component summary scores [[13561]] Trial name: Cohen et al., Neurology, September 2002 trial [International MS Secondary Progressive Avonex Controlled Trial (IMPACT)] [[13559]] Phase: Phase III trial [[13560]] Study Design: Industry-sponsored, randomized, double-blind, placebo-controlled, two-arm, multinational trial to examine the effects of interferon beta-1a (60 microg, given intramuscularly once per week) on changes in the MS Functional Composite (MSFC), a clinical outcome measure encompasing a timed 25-foot walk and tests of arm function and cognition (primary outcome measure) [[13559]] [[13560]] Disease Stage: SPMS [[13559]] Enrollment/Number of Patients: 436 [[13559]] Duration: 2 years [[13559]] Status/Outcome: Interferon beta-1a was associated with reduced MSFC progression (primarily through an effect on measures of arm function and cognition), reduced relapses, and improved quality of life; the drug was not associated with benefits to Expanded Disability Status Scale scores (which primarily reflect walking ability in these individuals) [[13559]]; retrospective analysis of AFFIRM (natalizumab), SENTINEL (natalizumab and interferon beta-1a), and IMPACT (interferon beta-1a) trial data showed that 20% to 25% decreases in speed in the timed 25-foot walk correspond to clinically-meaningful reductions in physical component summary scores [[13561]] Trial name: Secondary Progressive Efficacy Clinical Trial of Recombinant Interferon Beta-1a in MS (SPECTRIMS) trial (publ 2001) [[1080]] [[1081]] Phase: Phase III trial [[1080]] Study Design: Randomized, placebo-controlled, multicenter parallel-group study to determine whether interferon beta-1a (subcutaneous, 22 or 44 micrograms 3x weekly) increased time to confirmed progression of disability (primary endpoint) [[1080]] Disease Stage: SPMS [[1080]] Enrollment/Number of Patients: 618 [[1080]] Duration: 3 years [[1080]] Status/Outcome: No significant effect on disability progression, although there appeared to be greater benefit in women; caused significant improvement on MRI measures, particularly in patients who had experienced relapses in the past two years [[1080]] [[1081]] Trial name: Controlled High Risk Avonex Multiple Sclerosis (CHAMPS) trial (publ 2001) [[1082]] Phase: Phase III trial [[1082]] Study Design: A randomized, double-blind, placebo-controlled, multicenter trial to determine whether weekly injections of drug (intramuscular) in patients experiencing a single demyelinating event lowered the incidence of MS (primary endpoint) [[1082]] Disease Stage: CIS [[1082]] Enrollment/Number of Patients: 383 individuals who had experienced a first demyelinating event and showed MRI evidence of two or more clinically silent lesions of the brain [[1082]] Duration: 3 years [[1082]] Status/Outcome: After 3 years of treatment, the probability that patients had developed clinically defined MS was 35% for the interferon group and 50% for the placebo group; patients on interferon also showed a relative reduction in the volume of brain lesions, fewer new or enlarging lesions, and fewer gadolinium-enhancing lesions [[1082]]; high levels of MRI activity (≥2 new T2 and/or ≥2 gadolinium-enhancing lesions) 6 months after initiation of treatment was found to predict nonresponse to interferon beta-1a [[18403]] Trial name: Prevention of Relapses and Disability by Interferon beta-1a Subcutaneously in Multiple Sclerosis (PRISMS) trial (publ 1998) [[1083]] Phase: Phase III trial [[1083]] Study Design: Randomized, double-blind, placebo-controlled, multicenter study to test the efficacy of two doses (22 micrograms and 44 micrograms) of subcutaneous interferon beta-1a therapy, with the primary endpont the relapse rate [[1083]] Disease Stage: RRMS [[1083]] Enrollment/Number of Patients: 560 patients [[1083]] Duration: 2 years [[1083]] Status/Outcome: Treatment significantly reduced relapse rate (mean number per patient: 1.82 at 22 micrograms; 1.73 at 44 micrograms; 2.56 for placebo); time to first relapse was extended by 3 (22 micrograms) and 5 (44 micrograms) months [[1083]] Trial name: Multiple Sclerosis Collaborative Research Group, Ann. Neurol., March 1996 trial [[1084]] Phase: Phase III trial [[1084]] Study Design: Randomized, placebo-controlled, multicenter trial examining whether interferon beta-1a (30 micrograms/week, intramuscularly) could delay time to sustained sustained disability progression of at least one point on the Kurtzke Expanded Disability Status Scale (primary endpoint) [[1084]] Disease Stage: RRMS [[1084]] Enrollment/Number of Patients: 301 patients enrolled; because the study was stopped prematurely, just 282 completed 1 year, 172 completed 2 years [[1084]] [[1063]] Duration: 2 years [[1084]] Status/Outcome: 34.9% of patients progressed on placebo, whereas 21.9% progressed on drug; annual exacerbation rate was 0.90 with placebo and 0.61 with drug [[1084]] |
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Interferon beta-1b |
Trial name: Betaferon in Newly Emerging Multiple Sclerosis for Initial Treatment (BENEFIT) (publ 2006, 2014, 2015) [[1131]] [[1137]] [[9378]] [[22490]] Phase: Phase III trial [[1131]] [[1137]] Study Design: Multicenter, randomized, double-blind, placebo-controlled trial to determine the effects of interferon beta-1b (250 microg, given subcutaneously every other day) on delaying conversion to clinically definite MS [[1137]] Disease Stage: CIS [[1137]] Enrollment/Number of Patients: 468 [[1137]] Duration: 2 years, or until MS was diagnosed [[1137]] Status/Outcome: Interferon beta-1b reduced the risk of conversion to clinically definite MS (from 45% in the placebo group to 28% in the interferon beta-1b group) [[1131]] [[1137]]; low levels of a marker of vitamin D status in the first 12 months of the study were found to be a strong risk factor for increased MS disease activity and faster progression over 5 years among individuals primarily treated with interferon beta-1b [[9378]]; among participants, neither higher Epstein-Barr virus antibody levels nor higher cotinine levels (an indicator of tobacco use) correlated with a higher risk of conversion to MS, and over a 5-year followup, were not correlated with MS progression or activity [[22490]] Trial name: Barkhof et al., Arch. Neurol., September 2007 trial [[1142]] Phase: Phase III trial [[1142]] Study Design: Industry-sponsored, double-blind, placebo-controlled, randomized, parallel-group, multicenter study to examine detailed MRI findings from participants in the BENEFIT trial, in which patients received interferon beta-1b (250 microg, given subcutaneously every other day) or placebo [[1137]] [[1142]] Disease Stage: CIS [[1142]] Enrollment/Number of Patients: 404 [[1142]] Duration: 2 years, or until MS was diagnosed [[1142]] Status/Outcome: Drug was associated with a 60% relative reduction in the median cumulative number of newly active lesions (2 versus 5), with lower cumulative numbers of new T2 lesions (1 versus 3) and new gadolinium-enhancing lesions (0 versus 1) [[1131]] [[1142]] Trial name: Panitch et al., Neurology, November 2004 (North American SPMS) trial [[1141]] Phase: Phase III trial [[1141]] Study Design: Multicenter, double-blind, placebo-controlled, randomized trial to test the effects of interferon beta-1b (250 microg or 160 microg per m2 of body surface area, given subcutaneously every other day) on time to progression [at least 1.0 point increase on the Expanded Disability Status Scale (EDSS), or 0.5 point increase if the baseline was 6.0 or 6.5] (primary outcome) and on mean change in EDSS score, measures related to relapse, MRI activity, and results of a neuropsychological test (secondary outcomes) [[1141]] Disease Stage: SPMS [[1141]] Enrollment/Number of Patients: 939 [[1141]] Duration: 3 years [[1141]] Status/Outcome: Drug (at either dose) was not associated with a significant change in the time to confirmed progression of EDSS scores, but both doses were associated with benefits to relapse- and MRI-related measures [[1141]]; retrospective combined analyses of the results of the European SPMS trial (1998) and the North American SPMS trial (2004) to determine reasons for the discrepancy in outcomes determined that the the European SPMS trial included patients with an earlier stage of SPMS and with more active disease, which might be relevant to the different results of the two studies [[1140]] [[1141]] [[1192]] Trial name: European Study Group, Lancet, November 1998 (European SPMS) trial [[1140]] Phase: Phase III trial [[1140]] Study Design: Multicenter, double-masked, randomized, placebo-controlled trial to test the effects of interferon beta-1b [8 million IU (250 microg), given subcutaneously every other day] on the time to confirmed progression of disability [1.0 point increase on the Expanded Disability Status Scale (EDSS), or a 0.5 point increase if the baseline was 6.0 or 6.5] [[1131]] [[1140]] Disease Stage: SPMS [[1140]] Enrollment/Number of Patients: 718, with 661 undergoing followup [[1140]] Duration: 2 to 3 years [[1140]] Status/Outcome: Drug was associated with a reduced time to confirmed progression of disability, such that disability was delayed by 9 to 12 months during the study period of 2 to 3 years [[1140]]; retrospective combined analyses of the results of the European SPMS trial (1998) and the North American SPMS trial (2004) to determine reasons for the discrepancy in outcomes determined that the the European SPMS trial included patients with an earlier stage of SPMS and with more active disease, which might be relevant to the different results of the two studies [[1140]] [[1141]] [[1192]] Trial name: The IFNB Multiple Sclerosis Study Group, Neurology, April 1993 trial [[1136]] Phase: Phase II trial [[1136]] Study Design: Multicenter, randomized, double-blind, placebo-controlled trial to test the effects of interferon beta-1b (50 microg or 250 microg, administered subcutaneously every other day) on the annual exacerbation rate and on the proportion of exacerbation-free patients (primary endpoints) [[1131]] [[1136]] Disease Stage: RRMS [[1136]] Enrollment/Number of Patients: 372, with efficacy analysis based on data from 338 [[1131]] [[1136]] Duration: 2 years [[1136]] Status/Outcome: 250 microg interferon beta-1b was associated with a lower annual exacerbation rate (0.84) than was 50 microg interferon beta-1b (1.17) or placebo (1.27); a larger fraction of patients in the 250 microg group (31%) were exacerbation free at 2 years as compared to those in the 50 microg group (21%) or placebo group (16%); the 250 microg dose significantly reduced the median time to first relapse; the 250 microg dose also reduced the number of new lesions per year and MRI-detected burden of disease (in a cohort of 52 patients undergoing frequent MRIs) [[1131]] [[1136]] [[1156]] Trial name: The IFNB Multiple Sclerosis Study Group and The University of British Columbia MS/MRI Analysis Group, Neurology, July 1995 trial (extension of IFNB 1993 trial) [[1136]] [[1157]] Phase: Phase II trial [[1157]] Study Design: Double-blind extension of a multicenter, randomized, double-blind, placebo-controlled trial to test the effects of interferon beta-1b (50 microg or 250 microg, administered subcutaneously every other day) on the exacerbation rate and the MRI burden of disease [[1136]] [[1157]] Disease Stage: RRMS [[1136]] [[1157]] Enrollment/Number of Patients: 372 in original study, with 218 completing this study [[1157]] Duration: 5 years [[1157]] Status/Outcome: 250 microg interferon beta-1b caused a one-third reduction in the annual exacerbation rate compared to placebo in each of 5 years, but the difference was not statistically significant after the second year [[1136]] [[1157]] Trial name: Knobler et al., J. Interferon Res., October 1993 study [[1159]] Phase: Pilot study [[1159]] Study Design: Placebo-controlled pilot study to test the safety and determine the side effects of recombinant human interferon beta-1b, in which patients were treated with interferon beta-1b [0.8, 4, 8, or 16 million units (mU), given subcutaneously 3 times per week] or placebo [[1159]] Disease Stage: RRMS [[1159]] Enrollment/Number of Patients: 30 enrolled; 15 patients remained in the study for over 6 years [[1159]] Duration: 6 years [[1159]] Status/Outcome: Dose-related trend in reduction of the exacerbation frequency was seen and the 8 mU dose was selected for further study at 24 weeks (such that 15 patients received the 8 mU dose for over 6 years); side effects decreased over time [[1159]] |
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Laquinimod |
Trial name: A Randomized Placebo-controlled Trial Evaluating Laquinimod in PPMS, Gauging Gradations In MRI and Clinical Outcomes (ARPEGGIO) (press releases, 2014-2016) [[14927]] [[18497]] [[25304]] Phase: Phase II trial [[14927]] Study Design: Industry-sponsored, multinational, randomized, double-blind, parallel-group, placebo-controlled, proof-of-concept trial to examine the safety and efficacy of laquinimod [0.6 or 1.5 mg (discontinued as of January 2016) per day], with the primary endpoint the percent brain volume change and secondary endpoints that include the time to confirmed disability [[14927]] Disease Stage: PPMS [[14927]] Enrollment/Number of Patients: 191 [[25304]] Duration: 48 weeks [[14927]] Status/Outcome: Estimated completion, 2017 [[14927]]; first participant has been enrolled (April 2015) [[18497]]; 1.5 mg dose has been discontinued after a nonfatal cardiovascular event occurred in 1 individual at this dose (4 January 2016) [[25304]] Trial name: CONCERTO (press releases, 2012, 2013, 2015, 2016) [[2768]] [[5223]] [[19918]] [[25304]] Phase: Phase III trial [[2768]] Study Design: Company-sponsored, multinational, randomized, double-blind, placebo-controlled trial to evaluate the effects of laquinimod [either 0.6 mg or 1.2 mg oral dose (discontinued as of January 2016 [[25304]]), once daily] on confirmed disability progression as measured by the Expanded Disability Status Scale (primary outcome measure); the protocol has been granted a Special Protocol Assessment agreement by the US Food and Drug Administration [[2768]] [[5223]] Disease Stage: RRMS [[2768]] Enrollment/Number of Patients: 2199 [[25304]] Duration: 24 months [[2768]] Status/Outcome: Plans to initiate this trial have been announced (8 August 2012) [[2768]]; first participant enrolled (6 March 2013) [[5223]]; participant enrollment completed (25 June 2015) [[19918]]; 1.2 mg dose has been discontinued after nonfatal cardiovascular events occurred in 7 individuals at this dose (4 January 2016) [[25304]] Trial name: Assessment of OraL Laquinimod in PrEventing ProGRession in Multiple SclerOsis (ALLEGRO) (publ 2012, 2013; press releases 2010, 2011, 2013) [[809]] [[883]] [[819]] [[820]] [[7572]] [[7849]] Phase: Phase III trial [[883]] Study Design: Company-sponsored, randomized, double-blind, multicenter, placebo-controlled study to test the effects of laquinimod (0.6 mg oral dose, once daily) on the relapse rate (primary outcome) and other secondary outcomes [[809]] [[883]] Disease Stage: RRMS [[883]] Enrollment/Number of Patients: 1106 [[883]] Duration: 2 years [[883]] Status/Outcome: Laquinimod was associated with a 23% reduction in the annualized relapse rate (0.30 versus 0.39) and a reduction in the risk of confirmed disease progression (11.1% versus 15.7%) [[883]] [[819]] [[820]]; analysis of MRI data (from months 0, 12, and 24) showed that laquinimod was associated with lower rates of white matter and thalamic atrophy at months 12 and 24, lower rates of gray matter atrophy at month 12, and a trend toward reduced grey matter atrophy at month 24, among other effects [[7572]]; posthoc analysis of pooled results from ALLEGRO and BRAVO showed that the drug was associated with less progression of disease in both relapsing and relapse-free participants, such that disease progression occurred in 19% (laquinimod) versus 22% (placebo) of relapsing participants and in 4.8% (laquinimod) versus 7.6% (placebo) of relapse-free participants [[7849]] Trial name: Comi et al., Lancet, June 2008 trial; also referred to as LAQ/5062 trial [[823]] Phase: Phase IIb trial [[823]] Study Design: Company-sponsored, randomized, double-blind, multicenter, placebo-controlled trial to test the effects of laquinimod (0.3 mg or 0.6 mg daily oral dose) on the number of brain lesions in the last four months of the study (primary outcome) [[823]] [[821]] Disease Stage: RRMS [[823]] Enrollment/Number of Patients: 306 [[823]] Duration: 36 weeks [[823]] Status/Outcome: Drug (0.6 mg per day) was associated with a 40.4% reduction in the mean cumulative number of gadolinium enhancing lesions, whereas the 0.3 mg dose was not associated with significant effects [[823]] Trial name: Polman et al., Neurology, March 2005 trial [[564]] Phase: Phase II trial [[564]] Study Design: Company-supported, randomized, double-blind, multicenter placebo-controlled trial to test the effects of laquinimod (0.3 mg or 0.1 mg as three tablets once daily) on the number of active brain lesions (primary outcome) [[564]] Disease Stage: RRMS or SPMS [[564]] Enrollment/Number of Patients: 209 [[564]] Duration: 24 weeks [[564]] Status/Outcome: Drug was associated with a 44% reduction in the mean cumulative number of active lesions (5.24 for the 0.3 mg dose versus 9.44 for placebo); no differences in relapses or disability were found between treatment groups [[564]] |
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Masitinib |
Trial name: Masitinib in Patients with Progressive or Relapse-Free Secondary Multiple Sclerosis [[1382]] Phase: Phase III trial [[1381]] [[1382]] Study Design: Company-sponsored, prospective, multicenter, randomized, double-blind, placebo-controlled trial to examine the safety and efficacy of masitinib (6 mg per kg per day), as judged by changes in the MS functional composite score (primary outcome) [[1382]] [[20505]] Disease Stage: PPMS or relapse-free SPMS [[1381]] [[1382]] [[20505]] Enrollment/Number of Patients: 600 [[20505]] Duration: 96 weeks [[1381]] [[1382]] [[20505]] Status/Outcome: Results expected after December 2014 [[1382]]; Data Safety Monitoring Board has recommended continuation of the trial because safety concerns have not been observed (6 October 2014) [[14439]]; Independent Data Safety Monitoring Committee recommends trial continuation because of a successful non futility analysis (i.e., indicating that the study is not futile) (23 July 2015) [[20505]] Trial name: Masitinib in Patients with Primary Progressive Multiple Sclerosis (PPMS) or Relapse-Free Secondary Multiple Sclerosis (SPMS) (publ June, 2012) [[1383]] [[2122]] Phase: Phase II trial [[1383]] [[2122]] Study Design: Company-sponsored, randomized, placebo-controlled trial to test the safety and efficacy of two doses of masitinib (3 or 6 mg per kg per day), as measured by changes in the MS functional composite score (primary outcome) [[1383]] [[2122]] Disease Stage: PPMS or SPMS [[1383]] [[2122]] Enrollment/Number of Patients: 35 [[1383]] [[2122]] Duration: 12 months [[1383]] [[2122]] Status/Outcome: A clinical response to treatment was reported in some participants, but the response was not statistically significant; masitinib was also associated with a higher incidence of severe adverse events than was placebo [[1383]] [[2122]] |
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MEDI-551 |
Trial name: N-MOmentum trial (recruiting is ongoing as of October 2015) [[24768]] [[24762]] Phase: Phase II, Phase III trial [[24768]] Study Design: Industry-sponsored, multinational, double-blind, randomized, placebo-controlled trial, followed by an open-label extension, to examine whether intravenous MEDI-551 reduces the risk of an neuromyelitis optica/neuromyelitis optica spectrum disorder (NMO/NMOSD) attack, with the primary outcome measure the time to onset of an attack [[24768]] Disease Stage: NMO/NMOSD [[24768]] Enrollment/Number of Patients: 212 (estimated) [[24768]] Duration: 197 days (maximum time for randomized-controlled portion) [[24768]] Status/Outcome: Estimated primary completion date, January 2018 [[24768]] Trial name: A Phase 1 Randomized Study of MEDI-551 in Subjects With Relapsing Forms of Multiple Sclerosis (recruiting as of December 2013) [[11917]] Phase: Phase I trial [[11917]] Study Design: Industry-sponsored, multicenter, multinational, randomized, double-blinded, placebo-controlled, dose-escalation study to examine the safety and tolerability of ascending intravenous and subcutaneous doses of MED-551 (primary outcome measure), as well as the pharmacokinetics, pharmacodynamic effects (measured by changes in the B cell count), and immunogenicity of MED-551 (secondary outcome measures) [[11917]] Disease Stage: RRMS [[11917]] Enrollment/Number of Patients: 28 (estimated) [[11917]] Duration: 169 days [[11917]] Status/Outcome: Estimated study completion date, October 2014 [[11917]] |
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Minocycline |
Trial name: Sørensen et al., Eur. J. Neurol., February 2016 trial (RECYCLINE) [[26409]] Phase: Phase II trial [[26576]] Study Design: Industry-sponsored, double-blind, randomized, multicenter, placebo-controlled trial to compare the effects of a combination of minocycline (100 mg twice a day) and subcutaneous interferon beta-1a (44 microg 3 times a week) versus interferon beta-1a and placebo on the time to first relapse (primary endpoint) and the annualized relapse rate and MRI measures (secondary endpoints) [[26409]] [[26576]] Disease Stage: RRMS [[26409]] Enrollment/Number of Patients: 304 [[26409]] Duration: 96 weeks [[26409]] Status/Outcome: Minocycline did not affect the time to first relapse or other efficacy measures in a statistically significant manner; more participants in the minocycine versus placebo groups discontinued because of adverse events [[26409]] Trial name: Minocycline in Clinically Isolated Syndromes (CIS) and Early Single Relapse Multiple Sclerosis (MS) (meeting report, October 2015) [[6986]] [[22575]] Phase: Phase III trial [[6986]] Study Design: Investigator-initiated, double-blind, randomized, placebo-controlled, multicenter trial to test whether oral minocycline (100 mg given twice daily) can reduce the conversion of CIS to MS by 25% over 6 months (primary outcome measure) and to determine whether that early benefit is maintained at 2 years (secondary outcome measure) [[6986]] Disease Stage: CIS [[6986]] Enrollment/Number of Patients: 200 (estimated) [[6986]] Duration: 2 years [[6986]] Status/Outcome: Recruiting participants as of March, 2012; estimated study completion date is December, 2015 [[6986]]; minocycline reduced the risk of progressing to MS within 6 months, such that the risk was 34% for the minocycline group and 61.4% for the placebo group, a 44.6% relative reduction or 27.4% absolute risk reduction (meeting report, October 2015) [[22575]] Trial name: Metz et al., Mult. Scler., October 2009 trial [[361]] Phase: Phase II trial [[6987]] [[361]] Study Design: Industry-sponsored, double-blind, randomized, placebo-controlled, multicenter study to compare the effects of glatiramer acetate (20 mg, given subcutaneously daily) plus oral minocycline (100 mg twice daily) versus glatiramer acetate plus placebo on the total number of T1 gadolinium-enhanced lesions (primary outcome measure) and safety and tolerability (secondary outcome measure) [[6987]] [[361]] Disease Stage: RRMS [[361]] Enrollment/Number of Patients: 44, with 40 completing study [[361]] Duration: 9 months [[361]] Status/Outcome: Glatiramer acetate plus minocycline reduced the number of T1 gadolinium-enhanced lesions by 63% as compared to glatiramer acetate alone; the combination therapy was well tolerated and safe [[361]] |
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MIS416 |
Trial name: Safety and Efficacy Study of MIS416 to Treat Secondary Progressive Multiple Sclerosis (fully enrolled as of April 2016) [[13757]] [[29277]] Phase: Phase IIb trial [[13757]] Study Design: Industry-sponsored, randomized, double-blind, placebo-controlled, parallel-assignment trial to examine the safety and effects of MIS416 (500 microg MIS416 500 given intravenously weekly) on neuromuscular function (primary outcome) and disability and health status and other measures [[13757]] Disease Stage: SPMS [[13757]] Enrollment/Number of Patients: 93 [[29277]] Duration: 12 months [[13757]] Status/Outcome: Final data collection date, December 2015 [[13757]]; patient dosing has started (November 2014) [[15221]]; trial is fully enrolled (April 2016) [[29277]] |
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Mitoxantrone |
Trial name: Hartung et al., Lancet, December 2002 trial [[515]] Phase: Phase III trial [[515]] Study Design: Randomized, double-blind, placebo-controlled, multicenter trial to test the efficacy of mitoxantrone (5mg/m² or 12mg/m² intravenously every 3 months for 24 months), with the primary outcome a multivariate analysis of five clinical measures (change in expanded disability status scale, change in ambulation index, adjusted total number of treated relapses, time to first treated relapse, and change in standardised neurological status), comparing the 12mg/m² and placebo groups [[515]] Disease Stage: Worsening RRMS (also known as progressive relapsing MS) or SPMS [[515]] Enrollment/Number of Patients: 194 enrolled, with 184 in the final analysis [[515]] Duration: 2 years [[515]] Status/Outcome: Drug (12mg/m² dose) was associated with an overall benefit in the multivariate analysis of five clinical measures (0.30 difference overall) [[515]] Trial name: Millefiorini et al., J. Neurol., March 1997 trial [[517]] Phase: Phase II trial [[517]] Study Design: Randomized, placebo-controlled, multicenter trial to determine the clinical efficacy of mitoxantrone (intravenous infusion of 8 mg/m² every month for 1 year), with the primary outcome disease progression and the secondary endpoints the growth and appearance of new brain lesions [[517]] Disease Stage: RRMS [[517]] Enrollment/Number of Patients: 51 enrolled, with 42 completing the MRI examinations [[517]] Duration: 2 years [[517]] Status/Outcome: Drug decreased the proportion of patients who showed confirmed disease progression, defined as a one point increase on the Kurtzke expanded disability scale (EDSS), but was not associated with a statistically significant benefit in the mean EDSS progression; drug reduced the mean number of brain lesions [[517]] |
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Mycophenolate mofetil |
Trial name: Safety Study of Combination Therapy with Intramuscular Avonex and Oral CellCept in Patients with Multiple Sclerosis (TIME-MS) (publ January 2010) [[425]] [[599]] Phase: Phase II trial [[425]] [[599]] Study Design: Company-sponsored, randomized, double-blind, placebo-controlled trial to characterize the adverse events (primary endpoint) associated with combining mycophenolate mofetil with interferon beta-1a [[425]] [[599]] Disease Stage: RRMS [[425]] [[599]] Enrollment/Number of Patients: 24 treatment-naïve patients [[425]] [[599]] Duration: 1 year [[425]] [[599]] Status/Outcome: No differences were observed between experimental and control groups in terms of patient-reported adverse events, MRI metrics, or laboratory abnormalities; there was a trend toward a therapeutic effect [[425]] [[599]] |
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Naltrexone |
Trial name: Cree et al., Ann. Neurol., August 2010 trial [[9935]] Phase: Pilot trial [[9935]] Study Design: Patient-funded, single-center, double-blind, placebo-controlled, crossover study to examine the efficacy of naltrexone (4.5 mg each night) on self-reported quality of life (primary outcome) [[9935]] [[9938]] Disease Stage: Clinically definite MS [[9935]] Enrollment/Number of Patients: 80, with 60 completing the trial [[9935]] Duration: 8 weeks [[9935]] Status/Outcome: Naltrexone was associated with improvements in a number of mental health quality of life indices, but not in physical quality of life indices [[9935]] Trial name: Sharafaddinzadeh et al., Mult. Scler., August 2010 trial [[9936]] Phase: Phase II trial [[9936]] Study Design: Randomized, double-blind, placebo-controlled, parallel-group, crossover trial to examine the effect of low-dose naltrexone on measures of physical and mental health, including overall quality of life (primary outcome) [[9936]] Disease Stage: RRMS or SPMS [[9936]] Enrollment/Number of Patients: 96 [[9936]] Duration: 17 weeks [[9936]] Status/Outcome: Naltrexone was not associated with any changes in a variety of quality of life measures [[9936]] |
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Natalizumab |
Trial name: TOFINGO (meeting report, October 2013; publ May 2015) [[7941]] [[19230]] Phase: Phase IV trial [[19230]] Study Design: Company-sponsored, multicenter, randomized, double-blind, placebo-controlled trial to determine the optimum timing for beginning fingolimod treatment after discontinuation of natalizumab; individuals who had been treated with natalizumab for at least 6 months (and had reason to discontinue such as positive JC virus antibody status, a risk for progressive multifocal leukoencephalopathy) were randomized to the following regimens: a washout period of 8 weeks followed by 24 weeks of fingolimod, a washout period of 12 weeks (no therapy for 8 weeks followed by 4 weeks of placebo) followed by 20 weeks of fingolimod, or a washout period of 16 weeks (no therapy for 8 weeks followed by 8 weeks of placebo) followed by 16 weeks of fingolimod; the primary outcome was the number of active T2 lesions during the washout and first 8 weeks of fingolimod; brain MRIs were obtained at baseline and weeks 8, 12, 16, 20, and 24 [[7941]] [[19230]] Disease Stage: RRMS [[19230]] Enrollment/Number of Patients: 142, with 112 completing the trial [[7941]] [[19230]] Duration: 32 weeks from the last natalizumab infusion [[19230]] Status/Outcome: 8- and 12-week washout periods were associated with fewer active T2 lesions during washout and the first 8 weeks of fingolimod (2.1 and 1.7 versus 8.2 for the 16-week washout) and a higher percentage of relapse-free individuals (88% and 91% versus 84% for the 16-week washout) during the 24 weeks since the last natalizumab treatment [[7941]] [[19230]] Trial name: Fox et al., Neurology, April 2014 study (RESTORE) [[10354]] [[24814]] Phase: Exploratory study [[10354]] Study Design: Industry-funded, randomized, partially placebo-controlled exploratory study to examine disease activity in individuals who had been treated with natalizumab (with no relapse activity during the previous year and no gadolinium-enhancing lesions at the time of screening) during an interruption of natalizumab treatment; participants received either natalizumab, interferon beta-1a, glatiramer acetate, methylprednisolone, or placebo during the interruption [[10354]] [[24814]] Disease Stage: RRMS [[10354]] Enrollment/Number of Patients: 175 [[10354]] Duration: 24 weeks (length of interruption) [[10354]] Status/Outcome: Interruption in natalizumab treatment was associated with an increased risk of MRI and relapse activity even when other therapies were used; relapses occurred in 4% of participants receiving natalizumab versus 15% to 29% of participants in other arms of the study [[10354]]; during the randomized treatment period, gadolinium-enhancing lesions were observed in 0% of individuals receiving natalizumab, 48% of those receiving other treatments, and 61% of those on placebo; such lesions were primarily observed at week 16 or later [[24814]] Trial name: A Clinical Study of the Efficacy of Natalizumab on Reducing Disability Progression in Subjects with Secondary Progressive Multiple Sclerosis (ASCEND in SPMS) (press release, October 2015) [[9639]] [[23070]] Phase: Phase IIIb trial [[9639]] Study Design: Industry-sponsored, multinational, randomized, double-blind, placebo-controlled study to examine the efficacy of intravenous natalizumab (300 mg every 4 weeks) on slowing disability accumulation that is not related to relapses, as measured by the Expanded Disability Status Scale or other tests (primary outcome measure) [[9639]] Disease Stage: SPMS [[9639]] Enrollment/Number of Patients: 889 [[23070]] Duration: Up to 96 weeks (to measure disability progression); after this point, participants can enroll in a 2-year open-label extension (to evaluate safety profile) [[9639]] Status/Outcome: The trial did not achieve its primary or secondary endpoints, but natalizumab was associated with an improvement in upper limb function (press release, October 2015) [[23070]] Trial name: Natalizumab Safety and Efficacy in Relapsing Remitting Multiple Sclerosis (AFFIRM) (publ 2006; additional analyses publ 2011, 2013-2015; press releases, 2013, 2014) [[391]] [[4545]] [[4443]] [[7845]] [[11036]] [[15843]] [[22950]] Phase: Phase III trial [[391]] Study Design: Industry-sponsored, multinational, randomized, placebo-controlled trial to study the efficacy and safety of natalizumab (300 mg, intravenous infusion every 4 weeks), with the primary endpoint at one year being the rate of clinical relapse and the primary endpoint at two years the cumulative probability of sustained progression of disability, measured by the Expanded Disability Status Scale (EDSS) score [[391]] Disease Stage: RRMS [[391]] Enrollment/Number of Patients: 942 [[391]] Duration: More than 2 years [[391]] Status/Outcome: Natalizumab reduced the rate of clinical relapse by 68% at one year, the risk of sustained progression of disabilty by 42% over two years, and the accumulation of lesions over two years by 83% [[391]]; posthoc analysis showed that natalizumab increased the cumulative probability of improvement in EDSS scores (which correlated with quality of life measurements) by 69% [[4545]]; additional analysis showed that natalizumab rapidly reduced the annualized relapse rate (within 3 months) overall (0.30 versus 0.71 for placebo), even in patients with highly active disease (0.30 versus 0.94) [[4443]]; posthoc analysis showed that the drug increased the probability of a lack of evident disease activity (clinically or detected by MRI) in all individuals, but this effect was greater in individuals with an EDSS score <3.0 versus those with a score ≥3.0 at baseline; additional posthoc analysis showed that natalizumab reduced the severity of relapses [[7845]]; additional posthoc analysis showed that at 2 years, natalizumab increased the proportion of participants with confirmed improvement in walking speed relative to placebo [[11036]]; retrospective analysis of AFFIRM (natalizumab), SENTINEL (natalizumab and interferon beta-1a), and IMPACT (interferon beta-1a) trial data showed that 20% to 25% decreases in speed in the timed 25-foot walk correspond to clinically-meaningful reductions in physical component summary scores [[13561]]; >20% of participants exhibited loss of visual function, especially low-contrast visual acuity, during AFFIRM; such loss occurred even in individuals without worsening EDSS scores [[14977]]; retrospective analysis of treated versus control individuals showed that natalizumab was associated with an increase in the proportion of individuals who exhibited ≥20% improvement in timed 25-foot walk speed at year 2 [[15843]]; posthoc analysis showed that natalizumab decreased relapse severity (with a mean increase in the EDSS score of 0.77 for the natalizumab group and 1.09 for the placebo group at relapse) and improved recovery from relapse-associated disability, as measured by changes in the EDSS score [[22950]] Trial name: Safety and Efficacy of Natalizumab in Combination with Interferon Beta-1a in Patients with Relapsing Remitting Multiple Sclerosis (SENTINEL) (publ 2006) [[390]] Phase: Phase III trial [[390]] Study Design: Industry-sponsored, multinational, randomized, double-blind, placebo-controlled, parallel-group trial to determine if natalizumab (300 mg intravenously every 4 weeks) together with interferon beta-1a (30 microg intramuscularly every week) is more effective than interferon beta-1a alone in reducing breakthrough disease activity in patients who had received interferon beta-1a treatment for at least 12 months before randomization in study (with at least one relapse in the 12 months before randomization), with the rate of clinical relapse at 1 year and the cumulative probabilty of disability progression at 2 years the primary end points [[390]] Disease Stage: RRMS [[390]] Enrollment/Number of Patients: 1171, with 1003 completing the study [[390]] Duration: 2 years [[390]] Status/Outcome: Combination therapy was associated with a 23% cumulative probability of sustained disability progression at 2 years versus 29% with interferon beta-1a alone; combination therapy reduced the risk of sustained disability progression by 24% and reduced the annualized rate of relapse by 54% (at 1 year) and 55% (at 2 years) as compared to interferon beta-1a alone; trial was stopped 1 month early because of two cases of progressive multifocal leukoencephalopathy, one of which was fatal [[390]]; retrospective analysis of AFFIRM (natalizumab), SENTINEL (natalizumab and interferon beta-1a), and IMPACT (interferon beta-1a) trial data showed that 20% to 25% decreases in speed in the timed 25-foot walk correspond to clinically-meaningful reductions in physical component summary scores [[13561]] Trial name: Miller et al., N. Engl. J. Med., Jan 2003 trial [[397]] Phase: Phase II trial [[397]] [[4535]] Study Design: Company-sponsored, multinational, randomized, placebo-controlled trial to test the efficacy of natalizumab (3 mg or 6 mg per kg of body weight every 28 days, by intravenous infusion) in reducing the number of new gadolinium-enhancing brain lesions (primary end point) [[397]] Disease Stage: RRMS or SPMS [[397]] Enrollment/Number of Patients: 213 [[397]] Duration: 6 months [[397]] Status/Outcome: Drug reduced the mean number of new inflammatory brain lesions per patient [such that there were 0.7 (3 mg dose) and 1.1 (6 mg dose) versus 9.6 (placebo)] and reduced the number of relapses [[397]] Trial name: Tubridy et al., Neurology, Aug 1999 trial [[405]] Phase: Phase II trial [[405]] Study Design: Randomized, double-blind, placebo-controlled trial to study the effect of natalizumab (two intravenous infusions 4 weeks apart) on brain lesions (followed up for 24 weeks), as measured by MRI [[405]] Disease Stage: RRMS and SPMS [[405]] Enrollment/Number of Patients: 72 [[405]] Duration: 28 weeks [[405]] Status/Outcome: Drug was associated with fewer new active lesions per patient (mean 1.8 versus 3.6 for placebo) in the first 12 weeks of followup, but no difference was seen in the second 12 weeks [[405]] Trial name: Sheremata et al., Neurology, Mar 1999 trial (publ 1999) [[406]] Phase: Phase I trial [[406]] Study Design: Randomized, placebo-controlled, five-level dose escalation study to examine the safety, tolerability, and pharmacokinetics of a single intravenous dose of natalizumab (0.03 to 3.0 mg per kg) [[406]] Disease Stage: RRMS and SPMS [[406]] Enrollment/Number of Patients: 28 [[406]] Duration: 8 weeks [[406]] Status/Outcome: All doses were found to be safe and serum concentrations of drug (after infusion of 1 to 3 mg per kg) were detectable for 3 to 8 weeks [[406]] |
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Ocrelizumab |
Trial name: A Study of Ocrelizumab in Patients with Primary Progressive Multiple Sclerosis (ORATORIO) (press release, September 2015; meeting abstract, February 2016) [[655]] [[879]] [[22070]] [[27255]] Phase: Phase III trial [[655]] Study Design: Company-funded, randomized, parallel-group, multicenter, multinational placebo-controlled study evaluating the efficacy and safety of ocrelizumab [600 mg (two 300 mg doses two weeks apart) via intravenous infusion every six months] on delaying the progression of disability (primary endpoint) [[655]] [[22070]] Disease Stage: PPMS [[655]] Enrollment/Number of Patients: 732 [[22070]] Duration: 120 weeks to 5.5 years [[655]] Status/Outcome: Recruitment began September 2011 [[655]]; ocrelizumab delayed the progression of disability (an increase in the Expanded Disability Status Scale score that is sustained for ≥12 weeks), indicating that the trial met its primary endpoint (press release, September 2015) [[22070]]; ocrelizumab reduced the risk of 12-week and 24-week confirmed disability progression by 24% and 25%, respectively; in individuals with T1 gadolinium-enhancing lesions at baseline, ocrelizumab reduced the risk of 12-week and 24-week confirmed disability progression by 35% and 33%, respectively, and in those without such lesions at baseline, the drug reduced the risk by 16% and 19% (meeting abstract, February 2016) [[27255]] |
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Ofatumumab |
Trial name: Ofatumumab Subcutaneous Administration in Subjects With Relapsiing-Remitting Multiple Sclerosis (MIRROR) (press release, 2013; meeting report, 2014) [[651]] [[8042]] [[10841]] Phase: Phase II trial [[651]] Study Design: Company-funded, randomized, double-blind, parallel-group, placebo-controlled, multinational study to evaluate whether subcutaneous ofatumumab (3 mg, 30 mg, or 60 mg given every 12 weeks; 60 mg every 4 weeks; or placebo followed by 3 mg at week 12) reduces the number of new gadolinium-enhancing brain lesions over 12 weeks (primary endpoint) [[651]] [[8042]] Disease Stage: RRMS [[651]] Enrollment/Number of Patients: 231 [[10841]] Duration: 24 weeks of treatment and at least 24 weeks of followup [[8042]] Status/Outcome: All doses were associated with an estimated 65% reduction in the cumulative number of new lesions (based on analysis of data from weeks 0 to 12); all cumulative doses of at least 30 mg were associated with an estimated ≥90% reduction (based on data from weeks 4 to 12) [[8042]]; reduction of B cell concentration to 32 to 64 cells per microliter led to a reduction in disease activity (as assessed by the appearance of new lesions in the brain), such that the annualized rate of new brain lesions per year was <1 versus 16 without treatment [[10841]] Trial name: Ofatumumab Dose-finding in RRMS Patients, part A (interim data reported September 2010) [[648]] [[649]] [[650]] Phase: Phase I/ II trial [[648]] Study Design: Company-funded, randomized, parallel-group, multi-center, multi-national placebo-controlled study evaluating effect of three doses (100 mg, 300 mg, and 700 mg) of ofatumumab on lesion number (primary endpoint) [[648]] [[649]] [[650]] Disease Stage: RRMS [[648]] [[649]] [[650]] Enrollment/Number of Patients: 38 patients in part A; 288 patients expected in part B [[648]] [[649]] [[650]] Duration: 24 weeks part A; 48 weeks part B [[648]] [[649]] [[650]] Status/Outcome: The drug was associated with reduction in gadolinium-enhancing lesions and raised no dose-related or other safety concerns in patients followed for 48 weeks (Part A) [[649]]; part B data expected in September, 2012 [[648]]
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ONO-4641 |
Trial name: Drug Research Evaluation for Multiple Sclerosis (DreaMS) trial (reported April 2012) [[626]] [[627]] Phase: Phase II trial [[627]] [[2754]] Study Design: Company-sponsored, randomized, double-blind, placebo-controlled, multicenter, multinational study examining the effect of three doses of ONO-4641 on total the number of gadolinium-enhanced lesions, as measured every 4 weeks (primary endpoint) [[627]] Disease Stage: RRMS [[627]] [[2754]] Enrollment/Number of Patients: 407 patients [[2754]] Duration: 26 weeks [[627]] [[2754]] Status/Outcome: Doses of 0.05, 0.10, or 0.15 mg reduced the number of gadolinium-enhanced lesions by 82%, 92%, and 77%, respectively, compared to placebo; adverse events appeared to be dose related [[2754]] |
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Ozanimod |
Trial name: Cohen et al., Lancet Neurol., February 2016 trial (also referred to as RPC01-201 and RADIANCE) [[3775]] [[3776]] [[8354]] [[8906]] [[11609]] [[13754]] [[26787]] Phase: Phase II portion of a Phase II/III trial [[3775]] [[3776]] [[26787]] Study Design: Industry-sponsored, randomized, parallel assignment, double-blind, placebo-controlled trial to study whether an oral, daily dose (0.5 mg or 1.0 mg) of ozanimod can effectively reduce the cumulative number of total gadolinium enhancing lesions (primary outcome measure); initially, the dose was increased from 0.25 mg to either 0.5 mg or 1.0 mg over 8 days to reduce cardiac effects [[3775]] [[3776]] [[26787]] Disease Stage: Relapsing MS [[3775]] [[3776]] [[26787]] Enrollment/Number of Patients: 258, with 252 completing the trial [[13754]] [[26787]] Duration: 24 weeks [[3775]] [[3776]] [[26787]] Status/Outcome: Administered to first patient (22 October 2012) [[3775]]; enrollment completed (30 October 2013) [[8354]]; continuation of trial is approved by the Data Monitoring Committee on the basis of interim analysis of results (5 December 2013) [[8906]]; both doses were associated with a reduction in the cumulative number of total gadolinium enhancing lesions [[11609]] [[9243]], with a mean cumulative number of 1.5 gadolinium enhancing lesions in both treatment groups versus 11.1 for the placebo group at weeks 12 to 24 [[13754]] [[26787]]; neither serious cardiac side effects nor macular edema were observed [[15077]] [[26787]] Trial name: Thorough QT/QTc Study of RPC1063 (press releases, 2013) [[6334]] [[7872]] Phase: Phase I trial [[6334]] Study Design: Study to determine if ozanimod causes prolongation of the mean corrected QT interval (which would increase the risk of ventricular arrhythmia and ultimately sudden death) relative to placebo (the primary objective); participants received either the intended therapeutic dose (1 mg per day) or a supra-therapeutic dose (2 mg per day), such that dosage was titrated (from 0.25 mg to 2.0 mg) over 14 days, or placebo [[6334]] Disease Stage: Healthy volunteers [[6334]] Enrollment/Number of Patients: 124 [[6334]] Duration: 14 days [[6334]] Status/Outcome: A relevant QTc effect was not found for either of the ozanimod doses; therefore, the study was "negative" and the primary objective was met [[6334]]; therapeutic and supratherapeutic doses did not adversely affect cardiac repolarization; dose titration apparently attenuated effects on the heart rate [[7872]] |
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Phenytoin |
Trial name: Neuroprotection With Phenytoin in Optic Neuritis (meeting report, April 2015; publ January 2016) [[10400]] [[18344]] [[26174]] Phase: Phase II trial [[10400]] [[26174]] Study Design: University- and non-profit organization-funded, randomized, double-blind, placebo-controlled trial to examine whether phenytoin protects nerve fibers and prevents vision loss after optic neuritis; the dosage was 15 mg/kg, divided into 3 equal doses given once per day for 3 days, and then 4 or 6 mg/kg per day (depending on randomization date), with a maximum dose of 300 mg, given for 13 weeks; the primary outcome measure was the mean retinal nerve fiber layer thickness in the affected eye at the 6 month time point [[10400]] [[26174]] Disease Stage: Acute optic neuritis, which is often associated with MS [[10400]] [[26174]] Enrollment/Number of Patients: 86, with 81 assessed during followup [[18344]] [[26174]] Duration: 6 months [[10400]] [[26174]] Status/Outcome: Phenytoin was associated with preservation of retinal nerve fiber layer thickness and macular volume (such that there was a 30% reduction in the degree of retinal nerve fiber layer loss and 34% higher macular volume in the phenytoin versus the placebo group), but not with improved visual function [[18344]] [[26174]] |
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Raltegravir |
Trial name: Blocking Integrase in Treatment Experienced Patients with a Novel Compound against HIV, Merck (BENCHMRK-1 and BENCHMRK-2) trials (publ 2008, 2013) [[9200]] [[9201]] Phase: Phase III trials [[9200]] Study Design: Two industry-supported, double-blind, randomized, placebo-controlled trials of identical design (with BENCHMRK-1 in Europe, Asia, Australia, and Peru and BENCHMRK-2 in North and South America) to assess the safety and efficacy of raltegravir (400 mg tablet, twice daily) (combined with other, optimized HIV therapy) in suppressing HIV-1 [[9200]]; after week 156, open-label raltegravir was available to all participants [[9201]] Disease Stage: Individuals who were infected with HIV-1 and in whom other types of antiretroviral therapy were not successful [[9200]] Enrollment/Number of Patients: 699 (in combined trials) [[9200]] Duration: 156 weeks (placebo-controlled), followed by an open-label extension until week 240 [[9200]] [[9201]] Status/Outcome: At week 16, HIV-1 RNA concentrations were reduced to <50 copies per milliliter in 61.8% of the raltegravir recipients versus 34.7% of placebo recipients [[9200]]; at week 156, viral load was <50 per milliliter in 51% of the raltegravir recipients versus 22% of placebo recipients; at week 240, viral load was <50 per milliliter in 42% of recipients who initially received raltegravir [[9201]]; NOTE: These trials formed the basis of approval by the US Food and Drug Administration [[8955]] Trial name: Markowitz et al., J. Acquir. Immune Defic. Syndr., December 2006 trial [[9198]] Phase: Phase II trial [[9198]] Study Design: Multicenter, double-blind, randomized, placebo-controlled trial, such that participants received one of four doses (100, 200, 400, or 600 mg) or placebo twice a day, to examine pharmacokinetic parameters, safety, and antiretroviral effects [[9198]] Disease Stage: Individuals infected with HIV-1 who were naïve to antiretroviral therapy [[9198]] Enrollment/Number of Patients: 35 [[9198]] Duration: 10 days [[9198]] Status/Outcome: Drug was generally well tolerated and displayed antiretroviral effects at all doses tested [[9198]] |
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Riluzole |
Trial name: Multiple Sclerosis-Secondary Progressive Multi-Arm Randomisation Trial (MS-SMART) (Study start date, October 2013) [[12584]] Phase: Phase IIB trial [[12584]] Study Design: University-, institute-, and society-sponsored, multicenter, multi-arm, randomized, double-blind, placebo-controlled trial to compare the effects of three repurposed, candidate neuroprotective drugs [amiloride (5 mg once per day for 4 weeks, then 5 mg twice per day), riluzole (50 mg once per day for 4 weeks, then 50 mg twice per day), and ibudilast (50 mg once per day for 4 weeks, then 50 mg twice per day), each versus matched placebo] on the rate of brain volume loss as assessed by MRI (primary outcome measure) and other measures [[12584]] Disease Stage: SPMS [[12584]] Enrollment/Number of Patients: 440 (estimated) [[12584]] Duration: 96 weeks [[12584]] Status/Outcome: Not yet recruiting as of July 2013; estimated study completion date, September 2016 [[12584]] Trial name: Waubant et al., Ann. Clin. Transl. Neurol., May 2014 study [[12914]] [[14874]] Phase: Phase II trial [[12914]] [[14874]] Study Design: University- and society-sponsored, monocenter, randomized, double-blind, placebo-controlled trial to examine the effects of riluzole (50 mg once per day for 1 month followed by 50 mg twice per day if the first dose was well tolerated) on the percent brain volume change as assessed by MRI (primary outcome measure) and other measures; all participants also began interferon beta-1a therapy (Avonex; 30 microg intramuscularly once per week) 3 months after starting riluzole or placebo if liver function was normal [[12914]] [[14874]] Disease Stage: CIS/early MS (within 12 months of onset) [[12914]] [[14874]] Enrollment/Number of Patients: 43 [[12914]] [[14874]] Duration: Up to 3 years [[14874]] Status/Outcome: Riluzole did not reduce the progression of brain atrophy; although a trend for faster brain atrophy was seen in the riluzole group, imbalances in baseline characteristics between the riluzole and placebo groups are likely responsible for this trend [[14874]]; further analysis indicated that riluzole was associated with increased fatigue; the Modified Fatigue Impact Scale score became worse by 4.6 points per year in the riluzole group as compared with the placebo group [[23594]] Trial name: Effect of Riluzole as a Symptomatic Approach in Patients With Chronic Cerebellar Ataxia (study completed as of February 2014) [[12915]] Phase: Phase II trial [[12915]] Study Design: Hospital-sponsored, randomized, double-blind, placebo-controlled trial to examine the effects of riluzole (50 mg twice per day) on ataxia rating scale scores (primary outcome measure) [[12915]] Disease Stage: Probable or definite MS with chronic cerebellar ataxia; cerebellar degeneration [[12915]] Enrollment/Number of Patients: 40 [[12915]] Duration: 8 weeks [[12915]] Status/Outcome: Study completion date, August 2008 [[12915]] |
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Rituximab |
Trial name: Double Blind Combination of Rituximab by Intravenous and Intrathecal Injection Versus Placebo in Patients With Low-Inflammatory Secondary Progressive Multiple Sclerosis (RIVITaLISe) (publ March 2016) [[9531]] [[28805]] Phase: Phase I/Phase II trial [[9531]] Study Design: Government institute-sponsored, double-blind, placebo-controlled trial to examine the effects of combined systemic and intrathecal rituximab (to ensure that the drug reaches the central nervous system) on brain atrophy (primary outcome measure) [[9531]] Disease Stage: SPMS [[9531]] Enrollment/Number of Patients: 80 (estimated) [[9531]] Duration: 3 years (1 year of pretreatment visits followed by 2 years of treatment) [[9531]] Status/Outcome: Recruiting as of January 2014, estimated completion date, September 2016 [[9531]]; rituximab did not exhibit adequate effect on biomarkers in the cerebrospinal fluid to reach criteria needed for trial continuation; B cell depletion from the central nervous system was insufficient and the trial would be underpowered for measuring clinical effects (reported March 2016) [[28805]] Trial name: Hawker et al., Ann. Neurol., Oct 2009 trial [[359]] Phase: Phase II/III trial [[359]] Study Design: Randomized, double-blind, placebo-controlled, multicenter trial to evaluate the effects of rituximab (two 1000 mg infusions or placebo every 24 weeks) on time to confirmed disease progression (primary endpoint) and T2 lesion volume and total brain volume (secondary endpoints) [[359]] Disease Stage: PPMS [[359]] Enrollment/Number of Patients: 439 [[359]] Duration: 96 weeks [[359]] Status/Outcome: Drug was not associated with a decrease in time to confirmed disease progression (but there was a suggestion of a potential decrease in younger patients, especially those with inflammatory lesions) [[359]] [[484]] Trial name: Hauser et al., N. Engl. Med., Feb 2008 trial [[376]] Phase: Phase II trial [[376]] Study Design: Double-blind, placebo-controlled trial to evaluate the effects of intravenous rituximab (1000 mg or placebo on weeks 1 and 15) on the total count of gadolinium-enhancing lesions (primary endpoint) and on the proportion of patients with relapses [[376]] Disease Stage: RRMS [[376]] Enrollment/Number of Patients: 104 [[376]] Duration: 48 weeks [[376]] Status/Outcome: Drug was associated with a reduced number of inflammatory brain lesions and a reduced number of relapses (14.5% vs 34.3% at week 24 and 20.3% vs 40% at week 48) [[376]] |
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RTL1000 |
Trial name: Phase 1 Safety Study of RTL1000-(Recombinant T Cell Receptor Ligand) in Subjects With Multiple Sclerosis (published February, 2011) [[427]] [[624]] Phase: Phase I [[427]] Study Design: Company-sponsored, randomized, placebo-controlled, escalating dose study to examine safety, laboratory, and disease parameters (primary outcome measures) at 6 dosage levels (20 to 200 mg) [[427]] [[624]] Disease Stage: RRMS and SPMS; patients with the HLA-DR2 gene [[427]] [[624]] Enrollment/Number of Patients: 34 [[427]] [[624]] Duration: 3 months [[427]] Status/Outcome: All subjects tolerated the 2 to 60 mg doses but doses of ≥100 mg caused hypotension and diarrhea; the percentage of participants with gadolinium-positive lesions did not increase; data suggested a decrease in disease activity with increasing dose [[427]] |
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Secukinumab |
Trial name: Efficacy and Safety of AIN457 (Secukinumab) in Patients With Relapsing Multiple Sclerosis [[8243]] Phase: Phase II trial [[8243]] Study Design: Industry-sponsored, multicenter, placebo-controlled, randomized, double-blind, parallel group, adaptive dose-ranging trial to study the safety and effects of secukinumab on the cumulative number of new gadolinium-enhancing lesions (primary outcome measure) and the annualized relapse rate (a secondary outcome measure [[8243]] Disease Stage: RRMS [[8243]] Enrollment/Number of Patients: 380 (estimated) [[8243]] Duration: 6 months [[8243]] Status/Outcome: Recruiting as of September 2013; estimated study completion date is October 2015 [[8243]] Trial name: Effect of Multiple Infusions of AIN457 on Disease Activity in Relapsing-remitting Multiple Sclerosis (meeting report, October 2012) [[8245]] [[8246]] Phase: Phase II trial [[8245]] Study Design: Industry-sponsored, multicenter, placebo-controlled, randomized, double-blind, proof-of-concept trial to study the effects of secukinumab [10 mg per kg infused intravenously, once every 2 weeks (first 3 doses) and then once every 4 weeks (through week 20)] on the number of combined unique activity brain lesions (a combination of new gadolinium-enhancing T1 lesions and new or growing T2 lesions) (primary outcome) [[8245]] [[8246]] Disease Stage: RRMS [[8245]] Enrollment/Number of Patients: 73 [[8245]] Duration: 24 weeks [[8245]] Status/Outcome: Final data collection date for the primary outcome measure was April 2012 [[8245]]; over weeks 12 to 24, secukinumab was associated with a 63% reduction in the number of cumulative combined unique activity lesions relative to placebo (but over weeks 4 to 24, the difference was not statistically significant); secukinumab was associated with more moderately serious infections than placebo [[8246]] |
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Simvastatin |
Trial name: Chataway et al., Lancet, March 2014 trial (MS-STAT) [[11149]] [[11150]] Phase: Phase II trial [[11149]] [[11150]] Study Design: Foundation- and university-funded, multicenter, double-blind, placebo-controlled trial to examine the effects of simvastatin (80 mg per day) on the annualized rate of whole-brain atrophy (primary outcome measure) [[11149]] Disease Stage: SPMS [[11149]] [[11150]] Enrollment/Number of Patients: 140 [[11149]] Duration: 2 years [[11150]] Status/Outcome: Simvastatin was associated with a lower mean annualized atrophy rate than placebo (0.288% versus 0.584% per year), representing a 43% reduction [[11149]] Trial name: Tsakiri et al., Mult. Scler., January 2012 trial [[11284]] Phase: Phase III trial [[11285]] Study Design: University-sponsored (with industry collaboration), double-blind, randomized, placebo-controlled trial to examine whether simvastatin (80 mg per day) (i) improves visual function and (ii) affects cerebral MRI results; an additional aim was to examine whether, in individuals with monosymptomatic acute optic neuritis, simvastatin decreases the risk of developing MS [[11284]] [[11285]] Disease Stage: Optic neuritis [[11284]] Enrollment/Number of Patients: 64 [[11284]] Duration: 6 months [[11284]] Status/Outcome: Simvastatin had a positive effect on visual evoked potentials (both latency and amplitude), but did not have an effect on cerebral MRI results or on relapse rates [[11284]] Trial name: Simvastatin as an Add-on Treatment to Interferon-beta-1a for the Treatment of Relapsing-Remitting Multiple Sclerosis (SIMCOMBIN) (publ 2011) [[11148]] [[11146]] Phase: Phase IV trial [[11146]] Study Design: Industry-sponsored, multicenter, double-blind, randomized, parallel-group, placebo-controlled trial to examine whether simvastatin (80 mg per day), when used as an add-on therapy to interferon beta-1a (30 microg per week), can improve the efficacy of interferon beta-1a alone; the annual rate of documented relapses was the primary outcome measure [[11148]] Disease Stage: RRMS [[11148]] Enrollment/Number of Patients: 307 [[11148]] Duration: 1 to 3 years [[11148]] Status/Outcome: Simvastatin plus interferon beta-1a was associated with an annual relapse rate of 0.19 whereas placebo plus interferon beta-1a was associated with a rate of 0.14; when used as an add-on therapy to interferon beta-1a, simvastatin was not found to have any beneficial effects [[11148]] Trial name: Togha et al., Mult. Scler., July 2010 trial [[11145]] Phase: Phase III trial [[11147]] Study Design: University-sponsored, double-blind, randomized, placebo-controlled trial to examine the effect of simvastatin (40 mg per day) as an adjuvant therapy to interferon beta-1a (30 microg once per week); outcome measures included the relapse rate, Expanded Disability Status Scale (EDSS) score, and MRI lesions [[11145]] [[11147]] Disease Stage: RRMS [[11145]] [[11147]] Enrollment/Number of Patients: 85 [[11145]] Duration: 1 year [[11145]] [[11147]] Status/Outcome: The addition of simvastatin was associated with a lower number of relapses as compared with the addition of placebo, but simvastatin-associated reductions in the EDSS score and MRI lesion number were not significant; the combination therapy appeared safe and well tolerated [[11145]] |
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Siponimod |
Trial name: EXploring the efficacy and safety of siponimod in PAtients with SeconDary Progressive Multiple Sclerosis (EXPAND trial) (meeting abstracts, February 2013, November 2014) [[7174]] [[18446]] Phase: Phase III trial [[7174]] [[18446]] Study Design: Industry-sponsored, multicenter, randomized, double-blind, parallel-group, placebo-controlled variable treatment duration study to examine the safety, tolerability, and efficacy of siponimod (oral dose of 2 mg, given daily after an initial 6-day dose titration (0.25, 0.25, 0.5, 0.75, 1.25, and 2 mg) in delaying the time to 3-month confirmed disability progression (primary objective) [[7174]] [[18446]] Disease Stage: SPMS [[7174]] [[18446]] Enrollment/Number of Patients: 1530 (estimated) [[7174]] [[18446]] Duration: 23 to 42 months (anticipated) [[7174]] [[18446]] Status/Outcome: Recruiting participants as of July, 2013 [[7172]] Trial name: Selmaj et al., Lancet Neurol., August 2013 trial (BOLD trial) [[6418]] Phase: Phase II trial [[6418]] Study Design: Industry-sponsored, multicenter, randomized, double-blind, placebo-controlled, adaptive, dose-ranging trial to examine the dose-response relation of siponimod [oral dose of 10 mg, 2 mg, 0.5 mg, or placebo daily for 6 months (cohort 1) or 1.25 mg, 0.25 mg, or placebo daily for 3 months (cohort 2)] with MRI measures, with the primary endpoint the percentage reduction in the number of active lesions at 3 months [[6418]] Disease Stage: RRMS [[6418]] Enrollment/Number of Patients: 297 [[6418]] Duration: 6 months [[6418]] Status/Outcome: A dose-response relation was found for all doses of siponimod, with reductions in combined unique active lesions at 3 months ranging from 35% (0.25 mg dose) to 82% (10 mg dose) [[6418]] Trial name: Legangneux et al., Br. J. Clin. Pharmacol., March 2013 trial [[7171]] Phase: Phase I trial [[7171]] Study Design: Industry-sponsored, randomized, placebo-controlled study to determine if dose titration of siponimod reduces the transient decrease in heart rate that has been observed after an initial dose; the effects of two dose titration regimens (0.25 to 10 mg over 9 to 10 days) were compared with no titration (10 mg starting dose) or placebo [[7171]] Disease Stage: Healthy individuals [[7171]] Enrollment/Number of Patients: 56 [[7171]] Duration: 12 days [[7171]] Status/Outcome: Titration regimens attenuated the drug-associated effects on heart rate, such that more favorable outcomes were observed in the titration groups on each day of the study versus the non-titration group day 1; in the titration groups, minor decreases in heart rate occurred on days 3 to 7 (as compared with the placebo group) and no decreases occurred on day 1; heart rates were similar in the placebo and titration groups on days 9 to 12 [[7171]] Trial name: Gergely et al., Br. J. Pharmacol., November 2012 trial [[7168]] Phase: Phase I trial [[7168]] Study Design: Industry-sponsored, randomized, parallel, double-blind, placebo-controlled trial to test the safety and tolerability of siponimod (a daily oral dose of 0.3, 1, 2.5, 10, or 20 mg) (primary objective), as well as its effects on lymphocyte counts and pharmacokinetic effects (secondary objectives) [[7168]] Disease Stage: Healthy individuals [[7168]] Enrollment/Number of Patients: 48 [[7168]] Duration: 28 days of treatment; 49 days including follow-up period [[7168]] Status/Outcome: Drug was well tolerated; it was associated with a decline in the peripheral absolute lymphocyte count (ALC) [with declines ranging from 32.8% (0.3 mg dose) to 76.1% (20 mg dose)], with the greatest reduction occurring 4 to 6 hours after the dose; the drug affected leukocyte subsets differently, such that monocytes were largely unaffected and B and T cells strongly affected (with a greater effect on CD4+ T cells versus CD8+ T cells); the ALC returned to normal levels within 7 days after treatment ended (for the 0.3 to 10 mg doses); drug caused a transient, dose-dependent reduction in mean ventricular heart rate after the initial dose, which did not occur on subsequent days; no signs of macular edema were observed [[7168]] |
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Teriflunomide |
Trial name: Teriflunomide Versus Placebo in Patients With First Clinical Symptom of Multiple Sclerosis (TOPIC) (press releases, 2013; publ 2014) [[5801]] [[5802]] [[7870]] [[13550]] Phase: Phase III trial [[5801]] [[13550]] Study Design: Company-sponsored, international, multicenter, randomized, double-blind, placebo-controlled, parallel group trial to study the safety and effects of teriflunomide (7 mg or 14 mg once a day) on the time to relapse defining the conversion of CIS to clinically definite MS (primary endpoint) [[5801]] [[5802]] [[13550]] Disease Stage: CIS [[5801]] [[5802]] [[13550]] Enrollment/Number of Patients: 618 [[5801]] [[5802]] [[13550]] Duration: Up to 108 weeks (placebo-controlled period) [[5801]] [[13550]] Status/Outcome: Relative to placebo, the drug reduced the risk of relapse (which defined clinically definite MS) with hazard ratios of 0.574 (14 mg dose) and 0.628 (7 mg dose) [[13550]]; the 14 mg dose was associated with a 43% reduction in risk of conversion to clinically definite MS over 2 years, and the 7 mg dose with a 37% reduction in the risk, relative to placebo [[5802]]; relative to placebo, 14 mg dose reduced the risk of a new MRI lesion or clinical relapse by 35%, and gadolinium-enhancing lesions by 59%, over 2 years [[7870]] Trial name: Teriflunomide Oral in people With relapsing remitting multiplE scleRosis (TOWER) trial (press releases, 2012; publ 2014) [[2006]] [[3593]] [[9460]] [[12032]] Phase: Phase III trial [[2006]] Study Design: Company-sponsored, multinational, double-blind, placebo-controlled trial to test the efficacy and safety of oral teriflunomide (7 mg or 14 mg once daily), with the primary endpoint the reduction in the annualized relapse rate (ARR) and the main secondary endpoint the reduction in the risk of 12-week sustained accumulation of disability [[2006]] [[9460]] Disease Stage: RRMS [[2006]] [[9460]] Enrollment/Number of Patients: 1169 [[2006]] [[9460]] Duration: Average duration of drug exposure was 18 months; patients were followed from 48 to 173 weeks [[2006]] Status/Outcome: 14 mg dose was associated with a 36.3% reduction in ARR (0.319 versus 0.501 for placebo) and a 31.5% reduction in the risk of 12-week sustained accumulation of disability (as measured by the Expanded Disability Status Scale), whereas the 7 mg dose was associated with a 22.3% reduction in ARR (0.389) but did not affect the risk of 12-week sustained accumulation of disability [[2006]] [[3593]] [[9460]]; post hoc analysis to evaluate the effects of teriflunomide on severe relapses showed that the drug had positive effects [for example, the 14 mg dose reduced the annualized rate of (i) relapses with sequelae (defined by an increase in the Expanded Disability Status Scale) by 36.6%, (ii) relapses with sequelae (defined by the investigator) by 53.5%, and (iii) relapses resulting in hospitalization by 33.6%], suggesting that teriflunomide may reduce relapse-associated healthcare costs [[12032]] Trial name: Freedman et al., Neurology, May 2012 trial [[1880]] Phase: Phase II trial [[1880]] Study Design: Randomized, placebo-controlled trial to test the safety of oral teriflunomide (7 or 14 mg, once daily) as an add-on therapy to interferon-beta (primary objective); the effects on disease activity were also tested (secondary objectives) [[1880]] Disease Stage: RRMS [[1880]] Enrollment/Number of Patients: 118, with 86 entering the 24-week extension [[1880]] Duration: 24 weeks, with a 24-week extension [[1880]] Status/Outcome: Teriflunomide was generally well tolerated and safe when added to ongoing interferon-beta treatment, such that 4.9%, 8.1%, and 7.9% of patients in the placebo, 7 mg, and 14 mg groups discontinued treatment because of treatment-emergent adverse events; the addition of teriflunomide was also associated with a reduction in the number of gadolinium-enhancing T1 lesions as compared to treatment with interferon-beta alone [[1880]] Trial name: Teriflunomide in Reducing the Frequency of Relapses and Accumulation of Disability in Patients With Multiple Sclerosis (TEMSO) (publ 2011, 2013) [[341]] [[339]] [[5095]] [[6770]] [[22563]] Phase: Phase III trial [[341]] [[339]] Study Design: Industry-sponsored, randomized, double-blind, placebo-controlled trial to test the effects of teriflunomide (7 mg or 14 mg once per day) on the annualized relapse rate (primary endpoint) and the confirmed progression of disability for at least 12 weeks (key secondary endpoint) [[339]]; change in total lesion volume was the principal MRI outcome [[5095]] Disease Stage: RRMS [[339]] Enrollment/Number of Patients: 1088 [[339]] Duration: 108 weeks [[339]] Status/Outcome: Teriflunomide reduced the annualized relapse rate by 31% (at either dose), disability progression (at 14 mg dose), and lesion load (assayed by MRI) relative to placebo [[341]] [[339]]; additional analysis showed that the positive effects of the drug were consistent across a variety of patient subgroups [[2194]]; 14 mg and 7 mg doses were associated with 67.4% and 39.4% lower increases in total lesion volume as compared to placebo [[5095]]; posthoc analysis showed that the 7 mg and 14 mg doses reduced the annualized rate of relapses with neurological sequelae by 32% and 36%, respectively, the relapses that led to hospitalization by 36% and 59%, and relapses that required steroid treatment by 29% and 34%, suggesting that the drug's effects might result in lower healthcare expenses [[6770]]; individuals who completed this study were given the option to participate in an extension study with a total duration about about 6 years (from the time the first patient enrolled), to continue receiving 7 mg or 14 mg drug or, if received placebo, to be randomized to receive 7 mg or 14 mg [[581]]; additional analysis indicated that teriflunomide slows brain atrophy, such that at month 12, the median percent reduction in brain volume was 0.39 (14 mg dose) or 0.40 (7 mg dose) versus 0.61 (placebo) and at month 24, the reduction was 0.90 (14 mg dose) or 0.94 (7 mg dose) versus 1.29 (placebo) (meeting report, 2015) [[22563]] Trial name: O'Connor et al., Neurology, Mar 2006 trial [[389]] Phase: Phase II trial [[389]] Study Design: Randomized, double-blind, placebo-controlled trial to study the safety and effects of teriflunomide (7 mg or 14 mg per day) on the number of unique and active lesions per MRI scan (primary endpoint) [[389]] Disease Stage: RRMS and SPMS [[389]] Enrollment/Number of Patients: 179 (157 with RRMS and 22 with SPMS) [[389]] Duration: 36 weeks [[389]] Status/Outcome: Drug at either dose was associated with a reduced number of active lesions per MRI scan and was well tolerated [[389]] |
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Ustekinumab |
Trial name: Segal et al., Lancet Neurol., September 2008 trial [[625]] Phase: Phase II trial [[625]] Study Design: Company-sponsored, randomized, double-blind, placebo-controlled, multicenter trial testing the efficacy of 4 doses of ustekinumab on the cumulative number of gadolinium-enhancing T1 lesions (primary endpoint) [[625]] Disease Stage: RRMS [[625]] Enrollment/Number of Patients: 249 patients enrolled in and completed the study [[625]] Duration: 37 weeks [[625]] Status/Outcome: The treatment was well-tolerated but did not decrease the number of gadolinium-enhancing T1 lesions [[625]] |