Efficacy and Safety of Masitinib Versus Placebo in the Treatment of ALS Patients

Sponsor

AB Science (Industry)

Overall Status

Recruiting

CT.gov ID

NCT03127267

Collaborator

(none)

495

Enrollment

Locations

Arms

33.9

Anticipated Duration (Months)

11.3

Patients Per Site

0.3

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The objective is to compare the efficacy and safety of masitinib in combination with riluzole versus matched placebo in combination with riluzole for the treatment of Amyotrophic Lateral Sclerosis (ALS).

Condition or Disease	Intervention/Treatment	Phase
Amyotrophic Lateral Sclerosis	Drug: Masitinib (6.0) Drug: Riluzole Drug: Placebo Drug: Masitinib (4.5)	Phase 3

Detailed Description

Masitinib is a selective, oral tyrosine kinase inhibitor with neuroprotective capability demonstrated via numerous preclinical studies. Two of masitinib's main cellular targets are the mast cell and microglia cell. It is well-established that mast cells play a prominent role in neuroinflammatory processes. Microglia, resident immune cells of the central nervous system (CNS), also constitute an important source of neuroinflammatory mediators and may have fundamental roles in numerous neurodegenerative disorders. The development of masitinib in ALS is therefore based on the pharmacological action of masitinib in microglia cells and mast cells, thereby slowing microglial-related disease progression, reducing neuro-inflammation, and modulating the neuronal microenvironment in both central and peripheral nervous systems. This is a multicenter, double-blind, randomized, placebo-controlled, parallel-group (two ascending dose titrations of masitinib and matching placebo), comparative study of oral masitinib in the treatment of patients with amyotrophic lateral sclerosis (ALS).

Study Design

Study Type:

Interventional

Anticipated Enrollment :

495 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Double (Participant, Investigator)

Primary Purpose:

Treatment

Official Title:

Phase 3 Study to Compare the Efficacy and Safety of Masitinib in Combination With Riluzole Versus Placebo in Combination With Riluzole in the Treatment of Patients Suffering From Amyotrophic Lateral Sclerosis (ALS)

Actual Study Start Date :

Feb 2, 2021

Anticipated Primary Completion Date :

Dec 1, 2023

Anticipated Study Completion Date :

Dec 1, 2023

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Masitinib (4.5) & Riluzole Participants receive masitinib (3.0 mg/kg/day), given orally twice daily, with a dose escalation to 4.5 mg/kg/day after 4 weeks of treatment. Each ascending dose titration is subjected to a safety control. Masitinib will be administered as an add-on to riluzole at 50 mg b.i.d	Drug: Riluzole Riluzole 50 mg tablet, treatment per os Other Names: Rilutek Drug: Masitinib (4.5) Masitinib (titration to 4.5 mg/kg/day) Other Names: AB1010
Experimental: Masitinib (6.0) & Riluzole Participants receive masitinib (3.0 mg/kg/day), given orally twice daily, with a dose escalation to 4.5 mg/kg/day after 4 weeks of treatment, followed by dose escalation to 6.0 mg/kg/day after 4 weeks of treatment. Each ascending dose titration is subjected to a safety control. Masitinib will be administered as an add-on to riluzole at 50 mg b.i.d.	Drug: Masitinib (6.0) Masitinib (titration to 6.0 mg/kg/day) Other Names: AB1010 Drug: Riluzole Riluzole 50 mg tablet, treatment per os Other Names: Rilutek
Placebo Comparator: Placebo & Riluzole Participants receive a matched dose placebo, given orally twice daily, in combination with riluzole at 50 mg b.i.d.	Drug: Riluzole Riluzole 50 mg tablet, treatment per os Other Names: Rilutek Drug: Placebo treatment per os Other Names: Placebo Oral Tablet

Arm

Intervention/Treatment

Experimental: Masitinib (4.5) & Riluzole

Participants receive masitinib (3.0 mg/kg/day), given orally twice daily, with a dose escalation to 4.5 mg/kg/day after 4 weeks of treatment. Each ascending dose titration is subjected to a safety control. Masitinib will be administered as an add-on to riluzole at 50 mg b.i.d

Drug: Riluzole

Riluzole 50 mg tablet, treatment per os

Other Names:

Rilutek

Drug: Masitinib (4.5)

Masitinib (titration to 4.5 mg/kg/day)

Other Names:

AB1010

Experimental: Masitinib (6.0) & Riluzole

Participants receive masitinib (3.0 mg/kg/day), given orally twice daily, with a dose escalation to 4.5 mg/kg/day after 4 weeks of treatment, followed by dose escalation to 6.0 mg/kg/day after 4 weeks of treatment. Each ascending dose titration is subjected to a safety control. Masitinib will be administered as an add-on to riluzole at 50 mg b.i.d.

Drug: Masitinib (6.0)

Masitinib (titration to 6.0 mg/kg/day)

Other Names:

AB1010

Drug: Riluzole

Riluzole 50 mg tablet, treatment per os

Other Names:

Rilutek

Placebo Comparator: Placebo & Riluzole

Participants receive a matched dose placebo, given orally twice daily, in combination with riluzole at 50 mg b.i.d.

Drug: Riluzole

Riluzole 50 mg tablet, treatment per os

Other Names:

Rilutek

Drug: Placebo

treatment per os

Other Names:

Placebo Oral Tablet

Outcome Measures

Primary Outcome Measures

ALSFRS-R [48 weeks]
Change in Amyotrophic Lateral Sclerosis functional rating scale (ALSFRS)-Revised.

Secondary Outcome Measures

ALSAQ-40 [48 weeks]
Change in ALS quality of life patient questionnaire (ALSAQ-40)
PFS [From day of randomization to disease progression or death, assessed for a maximum of 36 months]
Progression free survival (PFS) is defined as the time from randomization to progression (decline of more than 9 points in ALSFRS-R score from baseline) or death
FVC [48 weeks]
Change in Forced Vital Capacity (FVC)
HHD [48 weeks]
Change in evaluation of upper- and lower-limb muscle strength using hand-held dynamometry (HHD)
Change in the Combined Assessment of Function and Survival (CAFS) score from baseline to week 48 [48 weeks]
CAFS ranks patients' clinical outcomes based on survival time and change in the ALS Functional Rating Scale-Revised (ALSFRS-R) score. Each patient's outcome is compared to every other patient's outcome, assigned a score, and the summed scores are ranked. The mean rank score for each treatment group can then be calculated. A higher mean CAFS score indicates a better group outcome.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 81 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Main inclusion criteria include:

Patients diagnosed with laboratory supported probable, clinically probable or definite ALS according to the World Federation of Neurology Revised El Escorial criteria
Patient with a familial or sporadic ALS
ALS disease duration from diagnosis no longer than 24 months at the screening visit
Patient treated with a stable dose of riluzole (100 mg/day) for at least 12 weeks days prior to the baseline visit
Patient with an ALSFRS-R score progression between onset of the disease and screening of > 0.3 per month, confirmed with an ALSFRS-R score progression of ≥ 1 point during a 12-week run-in period between screening and randomization.
Patient with a score, at screening, of at least 26 overall, including a score of at least 3 on item #3 and at least 2 on each of the 12 ALSFRS-R individual component items and with a score, at randomization, of at least 2 on each of the 12 ALSFRS-R individual component items

Main exclusion criteria include:

Patient with dementia or significant neurological, psychiatric, systemic or organic disease, uncontrolled or that may interfere with the conduct of the trial or its results
Patient with a FVC < 60% predicted normal value for gender, height, and age at screening and baseline
Pregnant, or nursing female patient

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Alabama at Birmingham, Department of Neurology, Division of Neuromuscular Disease	Birmingham	Alabama	United States	35294
2	University of Southern California	Los Angeles	California	United States	90007
3	University of California, Irvine - ALS & Neuromuscular Center	Orange	California	United States	92868
4	Northwestern University Feinberg School of Medicine	Chicago	Illinois	United States	60611
5	University of Chicago Neurology	Chicago	Illinois	United States	60637
6	University of Kentucky	Lexington	Kentucky	United States	40506
7	Johns Hopkins Medicine Brain Science Institute	Baltimore	Maryland	United States	21205
8	Lahey Hospital and Medical Center	Burlington	Massachusetts	United States	01805
9	Mount Sinai Downtown Union Square	New York	New York	United States	10003
10	Temple University	Philadelphia	Pennsylvania	United States	19122
11	Bispebjerg Hospital	Copenhagen		Denmark
12	CHU de Angers	Angers		France
13	Groupe Hospitalier Pellegrin Tripode	Bordeaux		France
14	Hôpital neurologique Pierre Wertheimer	Bron		France
15	CHU Gabriel Montpied	Clermont Ferrand		France
16	CHU de Lille - Hopital Roger Salengro	Lille		France
17	CHU de Limoges - Hôpital Dupuytren	Limoges		France
18	CHU de Marseille - Hôpital de la Timone	Marseille		France
19	CHRU de Montpellier - Gui de Chauliac	Montpellier		France
20	CHU de Nancy - Hopital Central	Nancy		France
21	Hôpital Pasteur 2 Centre de Reference SLA et autres maladies du Neurone Moteur Pole Neurosciences Cliniques	Nice		France
22	CHRU de Tours - Hopital Bretonneau	Tours		France
23	Department of Neurology, University of Ulm	Ulm		Germany	89081
24	Hadassah University Hospital	Jerusalem		Israel
25	Tel-Aviv Medical Center Hôpital Sourasky (ICHILOV)	Tel Aviv		Israel
26	ASST degli Spedali Civili di Brescia	Brescia		Italy
27	Centro Clinico NeMO Fondazione Serena Onlus	Gussago		Italy
28	Istituti Clinici Scientifici Maugeri IRCCS	Milano		Italy
29	Istituto Auxologico Ospedale San Luca	Milano		Italy
30	Azienda Ospedaliero-Universitaria di Modena	Modena		Italy
31	Oslo University Hospital HF Ullevål	Oslo		Norway
32	Centrum Medyczne Neuromed	Bydgoszcz		Poland
33	Moscow city clinical Hospital after V.M. Buyanov	Moscow		Russian Federation
34	Scientific Practical Medical Center "Innovation and Health"	Novosibirsk		Russian Federation
35	Klinicni center Ljubljana	Ljubljana		Slovenia
36	Hospital Universitari de Bellvitge	Barcelona		Spain
37	Hospital Carlos III	Madrid		Spain
38	Hospital San Rafael	Madrid		Spain
39	Clinical Hospital Santiago de Compostela	Santiago De Compostela		Spain
40	Hospital Universitario y Politecnico La Fe	Valencia		Spain
41	Norrlands universitetssjukhus	Umeå		Sweden
42	The State Institution of Neurology, Psychiatry and Narcology of NAMS of Ukraine	Kharkiv		Ukraine
43	Medical Center of LLC Medical Center Dopomoga Plus	Kyiv		Ukraine
44	Communal Non-Profit Enterprise of Lviv Regional Council, Lviv Regional Clinical Hospital, Neurological Department	Lviv		Ukraine