From: A perspective on therapies for amyotrophic lateral sclerosis: can disease progression be curbed?
Clinical trial identifier | Phase /subjects | Drug | Treatment | Duration | Primary outcome measure | Main findings |
---|---|---|---|---|---|---|
Oxidative stress | ||||||
 NCT00330681/ [18] | Phase III 206 participants | Edaravone (MCI-186) | Placebo (n = 104) or edaravone (n = 102) i.v. infusion over 60 min for the first 14 days in cycle 1, and for 10 of the first 14 days during cycles 2 to 6. | 2006.05-2008.09 | ALSFRS-R | Small reduction of ALSFRS-R scores was observed in the edaravone group. |
 NCT01492686/ [19] | Phase III 137 participants | Edaravone (MCI-186) | Placebo (n = 69) or edaravone (n = 68) i.v. infusion over 60 min for the first 14 days in cycle 1, and for 10 of the first 14 days during cycles 2 to 6. | 2011.12–2014.9 | ALSFRS-R | Edaravone improved ALSFRS-R scores in a small subset of people. |
Autophagy | ||||||
 UMIN000036295/ [20] | Phase I | Bosutinib | Three to six patients with ALS were enrolled at each of the four bosutinib dose levels (100, 200, 300 or 400 mg/day). | 2019.03–2021.03 | DLT | Undergoing. |
 NCT02166944/ [21] | Phase I/II 20 participants | Tamoxifen | Tamoxifen 40 mg (n = 10) or riluzole (n = 8) daily for 1 year. | 2014.04–2019.09 | ALSFRS-R | Tamoxifen exerted only a modest effect in attenuating progression for 6 months. |
Cell therapy | ||||||
 NCT01640067/ [22] | Phase I 18 participants | HSSCs | Three received 3 unilateral injections of hNSCs into the lumbar cord tract, while the others received bilateral injections. A total of 750,000 cells per injection site (15 μ). | 2011.12–2015.12 | Treatment-related mortality, AEs, neuroradiological and neurophysiological variables | Transplantation of hNSCs was confirmed to be a safe cell therapy approach with good reproducibility. Transient improvement in ALSFRS-R and MRC was observed in some patients. |
 NCT01348451/ [23] | Phase I 18 participants | HSSCs | Ten microliters were delivered at a rate of 5 μl/min over 2 min by unilateral cervical injections, for a total of 500,000 cells (NSI-566RSC HSSC line) in the 5 injections. | 2009.01–2016.12 | AEs | Safety and feasibility of cervical and dual-targeting approaches (both lumbar and cervical injection) was demonstrated. |
 NCT01730716/ [24] | Phase II 18 participants | HSSCs | Three participants in each group. The numbers of injection (site: C3-C5 or L2-L4 bilateral injections) ranged from 10 to 40, and the numbers of cells (HSSCs) injected ranged from 2 million to 16 million. | 2013.05–2016.11 | AEs | Intraspinal transplantation of HSSCs was safe at high doses (20 injections, 400,000 cells/injection), including successive lumbar and cervical injections. |
 NCT01640067/ [25] | Phase I 18 participants | hNSCs | Participants were divided into 3 groups with monolateral or bilateral injections (C3-C5 or T8-T11) of a total of 750,000 cells (15 μ hNSCs) per injection. | 2011.12–2015.12 | Treatment-related mortality, AEs, neuroradiological and neurophysiological variables | Safety of hNSC transplantation was confirmed. A transitory decrease in progression of ALSFRS-R was observed, starting within the first month after surgery and up to 4 months after transplantation. |
Phase I/II 72 participants | BM- MSCs | Each participant received 2 intrathecal injections of autologous BM-MSCs (1 × 106 cells/kg) 26 days apart. Control group (n = 31, riluzole 100 mg alone). | 2011.02–2013.08 | ALSFRS-R | Two repeated intrathecal injections were safe and feasible throughout the 12-month duration. | |
 NCT01051882/ [28] | Phase I/II 12 participants | NurOwn® | Six patients in each group received i.m. or i.t. injection of NurOwn®. | 2011.06–2013.03 | Safety evaluation and tolerability. | Safe and well-tolerated. |
 NCT01777646/ [28] | Phase IIa 14 participants | NurOwn® | Fourteen patients received combined i.t. and i.m. delivery. (IM at 24 sites to the biceps and triceps (1 × 106 cells/site); i.t. of 1 × 106 cells/kg) | 2012.12–2015.09 | Safety evaluation and tolerability | Improvement in the decrease rate of progression of the FVC and ALSFRS-R was demonstrated in the i.t. (or i.t. + i.m.)–treated groups. |
 NCT02017912/ [29] | Phase II 48 participants | MSC-NTF cells | MSC group (n = 36): MSC-NTF cells. Placebo (n = 12): Dulbecco Modified Eagle Medium. Combination of i.t. (125 × 106 cells) and 24 i.m. (48 × 106 cells) injections of NurOwn® at 24 sites to the biceps and triceps | 2014.05–2016.07 | AEs | In a prespecified rapid progressor subgroup (n = 21), the rate of disease progression was improved at early time points. |
 NCT02286011/ [30] | Phase I 20 participants | MNC of BM | Experimental group: an intramuscular infusion of autologous MNC of bone BM in TA muscle of one of the lower limbs (100–1200 million) diluted in 2 ml saline. | 2014.11–2017.12 | AEs | The intramuscular injection of BMMCs was safe and had an effect on the D50 index. |
 NCT03241784/ [31] | Phase I 4 participants | Autologous T-regulatory lymphocytes | A total of 8 infusions of autologous Tregs (1 × 106 cells/kg) with concomitant subcutaneous IL-2 injections (3 times /week, 2 × 105 IU/m2/injection). | 2016.05–2018.02 | AEs | The numbers of Tregs and suppressive function increased after infusion and the increased suppressive function of Tregs correlated with slowing of progression rate. |
Gene modification | ||||||
 NCT01041222/ [32] | Phase I 33 participants | ISIS 333611 | Four cohorts of eight patients received intrathecal infusion of ISIS 333611 at dose of 0.15 mg, 0.5 mg, 1.5 mg, 3 mg, respectively (randomized 6 drugs: 2 placebo/cohort). | 2010.01–2012.01 | Safety, pharmacokinetics tolerability | No dose-limiting toxicity was found at doses up to 3.0 mg. Dose-dependent CSF and plasma concentrations were observed. |
 NCT02623699/ [33] | Phase I/II 84 participants | Tofersen (BIIB067) | In each dose cohort (20, 40, 60, or 100 mg), participants were randomly assigned in a 3:1 ratio to receive five doses of tofersen or placebo, administered intrathecally for 12 weeks. | 2016.01–2019.01 | AEs | CSF SOD1 concentrations decreased at the highest concentration of tofersen administered intrathecally over a period of 12 weeks. |
Excitotoxicity | ||||||
 NCT00444613/ [34] | Phase II/III 373 participants | Mecobalamin (E0302) | Placebo (n = 124), 25 mg (n = 124) or 50 mg methylcobalamin (n = 125) administered intra-muscularly twice a week for 182 weeks. | 2007.04–2014.03 | Survival rate, ALSFRS-R | No significant efficacy was seen in the whole cohort. The treatment may prolong survival and retard symptomatic progression if started early (≤12 months’ duration). |
Mitochondrial defects and apoptosis | ||||||
 NCT01786603/ [35] | Phase II 80 participants | Rasagiline | Rasagiline group (n = 60): rasagiline 2 mg P.O. once a day for 12 months. Placebo group (n = 20): placebo 2 mg once a day for 12 months. | 2013.11–2016.07 | ALSFRS-R | Rasagiline was well tolerated with no serious adverse events. No improvement in the ALSFRS-R slope was observed in the rasagiline group. |
 NCT01879241/ [36] | Phase II 252 participants | Rasagiline | Rasagiline group (n = 127): 100 mg riluzole plus 1 mg rasagiline P.O.Placebo group (n = 125): 100 mg riluzole plus placebo P.O. per day for 18 months. | 2013.06–2016.08 | Survival | Disease progression might be modified by rasagiline in patients with normal to fast progression rate, despite no efficacy in survival. |
Immunomodulatory | ||||||
 NCT02588677/ [37] | Phase II/III 394 participants | Masitinib | 394 patients were randomly assigned (1:1:1) to receive riluzole (100 mg/d) plus placebo or masitinib at 4.5 or 3.0 mg/kg per day. | 2013.04–2018.03 | ALSFRS-R | Masitinib showed significant benefits over placebo with a between-group difference in △ALSFRS-R, corresponding to 27% slowing in the rate of functional decline. |