Effect of MD1003 in Amyotrophic Lateral Sclerosis

Study Overview
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Brief Summary
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This is a 6-month double blind randomized 2:1 placebo-controlled study with two arms (placebo, biotin 300 mg/day). The study will be followed by a 6-month extension phase during which all patients will receive biotin 300 mg/day.

Official Title
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Effect of MD1003 in Amyotrophic Lateral Sclerosis: a Randomized Double Blind Placebo Controlled Pilot Study

Conditions
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ALS, Amyotrophic Lateral Sclerosis, Motor Neuron Disease

Intervention / Treatment
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* Drug: MD1003
* Drug: Placebo oral capsule


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age: 25 to 80 years, inclusive Male or female subjects with probable or confirmed ALS (revised international El Escorial criteria, Forbes et al., 2001). Patients presenting first motor deficits due to ALS for a maximum of three years at the first consultation in an ALS centre. Patients monitored for at least 6 months in an ALS centre or for whom the previous monitoring parameters are available (excepted for MIP and SNIP). Patients who have lost at least 5 points on the ALSFRS-R (ALS functional rating scale) during the last 12 months or at least 2 points during the preceding 6 months Patients who have been treated with riluzole for at least 3 months at a stable dose. In case of intolerance to this product or refusal for this treatment, patients who have not been treated with riluzole for at least 1 month before inclusion For patients with spinal form (onset of the disease affecting limbs) or respiratory form, slow vital capacity > 60% of predicted value. For patients with a bulbar form, slow vital capacity > 60% of theoretical value or, if spirometry not assessable (severe bulbar disability), patient should not have significant abnormality in both nocturnal capnography and nocturnal oximetry (median pCO2 (carbon dioxide partial pressure ) < 52 mmHg, SaO2 (arterial oxygen saturation ) < 90% less than 5% of the time during night) less than 3 months prior inclusion. Patients who are willing to give written consent (or oral consent in the presence of a trusted person if the patient is no longer able to write) Patients likely to be able to participate in all scheduled evaluation and complete all required study procedures (except for spirometry in bulbar patients with severe disability). Exclusion Criteria: Patients on non-invasive ventilation for respiratory insufficiency due to ALS for more than 10 hours a day Patients with an ALSFRS-R score at inclusion of < 20 (maximum score without disability = 48) Patients who have lost less than 5 points on the ALSFRS-R during the last year or less than 2 points during the preceding 6 months Patients with a gastrostomy Patients who have lost more than 15% of their reference weight (defined as weight before disease onset) Patient with dyspnoea at rest or with the least effort (score < 3 on the dyspnoea item of the ALSFRS-R) Patients with dementia Patient with severe or rapidly progressive form of ALS for whom the investigator estimates the life expectancy less than 3 months Patients with another progressive disease that has not been stabilized at the time of inclusion Patients with cancer, except basal cell carcinoma, for less than 5 years, or who require continuous treatment for cancer even if it is older Pregnant women. Subject who are not covered by a social security scheme. Subject under temporary or permanent Judicial Protection. Contraception: Both male subjects, and female subjects who are not either surgically sterile (tubal ligation/obstruction or removal of ovaries or uterus) or post-menopausal (no spontaneous menstrual periods for at least one year confirmed by a negative hormone panel), must commit to using two highly effective method of birth control for the duration of the study and for two months after the treatment termination.

Ages Eligible for Study
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Minimum Age: 25 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: The primary objective of the study is to evaluate the safety of biotin at 300 mg/day over placebo in patients with amyotrophic lateral sclerosis. This is a 6-month double blind randomized 2:1 placebo-controlled study with two arms (placebo, biotin 300 mg/day). The study will be followed by a 6-month extension phase during which all patients will receive biotin 300 mg/day.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: MD1003<br>The investigational drug will consist in capsules of 100 mg biotin and excipients (lactose, magnesium stearate, croscarmellose sodium, Silica) tid during 12 months | Drug: MD1003<br>* capsules 100mg 3 times per day<br>* Other names: BIOTIN;|
| Placebo Comparator: PLACEBO<br>This formulation consists in lactose powder and other excipients (magnesium stearate, croscarmellose sodium, Silica) as placebo, tid during 6 months and then switch to MD1003 tid during 6 additional months. | Drug: MD1003<br>* capsules 100mg 3 times per day<br>* Other names: BIOTIN;Drug: Placebo oral capsule<br>* capsules 100mg lactose 3 times per day<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Recording of adverse events | All adverse events in two groups will be recorded. | 6 months | 
| Laboratory testing (haematology and biochemistry panel) | RBC (red blood cell), WBC (white blood cell ), platelets Ferritin, CPK (creatine phosphokinase ) Electrolytes, creatinine, glycaemia AST (aspartate aminotransferase ), ALT (alanine aminotransferase) , bilirubin, GGT (gamma-glutamyltransferase), alkaline phosphatase Triglyceride, cholesterol Haemostasis: APPT (activated partial thromboplastin time), PT (prothrombin time ) | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Motor disability | this is evaluated using the ALSFRS-R scale (score of 48 points). Among the criteria used to evaluate the severity of ALS, the rate of the decline in the ALSFRS-R is the one that correlates most closely with the risk of death (Kimura et al., 2006). | 6 months | 
| Severity | The severity of the disease defined as the ratio between the number of points lost on the ALSFRS-R score and the number of months that have elapsed (Kollewe et al., 2008). | 6 months | 
| Slow vital capacity (SVC) | in liters | 6 months | 
| Maximal inspiratory pressure (MIP) | in cm H2O | 6 months | 
| Sniff nasal inspiratory pressure (SNIP) | in cm H20 | 6 months | 
| Weight | weight in kg | 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Biotin, MD1003, ALSFRS-R