Table 1.

Clinical trials in recent 10 years

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.
NCT01363401/ [26, 27]	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.

AEs adverse events, ALSFRS-R revised ALS functional rating scale, DLT dose-limiting toxicity, i.v. intravenous, HSSC human spinal stem cells, hNSCs fetal human neural stem cells from natural in utero death, BM-derived MSCs bone marrow-derived mesenchymal stem cells; i.m. intramuscular, i.t. intrathecal, MSC-NTF mesenchymal stem cells-neurotrophic factors, VC vital capacity, CSF cerebrospinal fluid, ISIS 333611 an antisense oligonucleotide designed to inhibit SOD1 expression, MNC mononuclear cells, BM bone marrow