Safety and Efficacy of TRO19622 as add-on Therapy to Riluzole Versus Placebo in Treatment of Patients Suffering From ALS

Study Overview
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Brief Summary
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The purpose of the assay is to assess the safety and the efficacy of TRO19622 330 mg QD as add-on therapy to riluzole 50 mg bid in the treatment of patients suffering from ALS, as compared to placebo, assessed by the 18-month survival rate.

Detailed Description
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A stand alone treatment with TRO19622 is not acceptable for ethical reasons. Riluzole is an approved and widely used ALS treatment in the European community, in Japan and in the USA. Therefore, in this study, TRO19622 will be assessed as add-on to riluzole in patients suffering from ALS. At the start of the study, patients will be randomized to one of two groups : TRO19622 (330 mg QD or placebo (once a day). Each treatment will be administered for 18 months under double-blind conditions. The product under evaluation will be administered to patients receiving the standard of care for ALS, including riluzole. Riluzole dosage (50 mg bid) must be stable and well tolerated for at least one month prior to inclusion into the study. After the double-blind period, open-label administration of TRO19622 will be allowed for safety and survival assessments and until efficacy results are available. A separate open-label protocol will be written 6 months after the randomization of the last patient into the study.

Official Title
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Phase II/III, Multicenter, Randomized, Parallel Group, Double-blind, Placebo Controlled Study to Assess Safety and Efficacy of TRO19622 in Amyotrophic Lateral Sclerosis (ALS) Patients Treated With Riluzole

Conditions
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Amyotrophic Lateral Sclerosis

Intervention / Treatment
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* Drug: Olesoxime
* Drug: Placebo Comparator
* Drug: Riluzole


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with sporadic or familial Amyotrophic Lateral Sclerosis Patients with a clinical diagnosis of laboratory-supported probable, probable, or definite ALS according to the modified El Escorial criteria8. Have signed an Informed Consent to participate to the trial before any study related procedure has taken place. Be of age >18 (exclusive) and < 80 years (inclusive). If a female, not lactating, has a negative pregnancy test and agrees to use an effective method of birth control. Onset of ALS Symptoms (weakness) for more than 6 months (inclusive) and less than 36 months(inclusive). Slow vital capacity (SVC), measured three times, one of the measure being >/= 70% of that predicted. Treated with riluzole at the stable dose of 50 mg bid for at least 30 days before enrolment. Exclusion Criteria: Tracheostomy, invasive ventilation, or non invasive positive pressure ventilation (NIPPV). Gastrostomy. Evidence of major psychiatric disorder or clinically evident dementia. Diagnosis of a neurodegenerative disease in addition to ALS. Have a current medication that could interfere with TRO19622 pharmacokinetics: tamoxifene. Have current medications that could interfere with TRO19622 absorption such as ezetimibe, bile salts chelators (cholesteramine), fibrates, phytosterols, niacin (vitamin B3),fish oils. Have a current medication of lipid lowering agents other than statins. Known hypersensitivity to any component of the study drug. Patients with known intolerance or contra-indication to riluzole. Have a recent history (within the previous 6 months) or current evidence of alcohol or drug abuse. Have concurrent unstable disease involving any system eg, carcinoma other than basal cell carcinoma, any cardiac dysrhythmia, myocardial infarction, clinical or ECG signs of myocardial ischemia, cardiac insufficiency, angina symptoms, current symptoms of Coronary Artery Disease, or any other condition that in the opinion of the Investigator would make the patient unsuitable for study participation. . In Germany: Have any cardiac dysrhythmia, myocardial infarction, clinical or ECG signs of myocardial ischemia, cardiac insufficiency, angina symptoms, current symptoms of Coronary Artery Disease or any cardiovascular illness known or identified at the screening or inclusion visits, or have concurrent unstable disease involving any system eg, carcinoma other than basal cell carcinoma or any other condition that in the opinion of the Investigator would make the patient unsuitable for study participation. Having a baseline QTc (Bazett) > 450 msec for males and > 470 msec for females. Patients with known hepatitis B/C or HIV positive serology. Be pregnant female or lactating. Have renal impairment defined as blood creatinine > 1:5 X upper limit of normal. Have hepatic impairment and/or liver enzymes (ALAT or ASAT) > 3 X ULN. Hemostasis disorders or current treatment with oral anticoagulants. Be possibly dependent on the Investigator or the Sponsor (eg, including, but not limited to, affiliated employee). Participated in any other investigational drug or therapy study with a non approved medication, within the previous 3 months. Patients without Social Security Insurance (France).

Ages Eligible for Study
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Minimum Age: 18 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
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Olesoxime<br>2 Capsules of TRO19622 (330mg) once a day with the noon meal as add-on therapy to riluzole 50mg bid | Drug: Olesoxime<br>* 2 capsules of TRO19622 (330mg) once a day with the noon meal as add-on therapy to riluzol 50mg bid<br>* Other names: TRO19622;Drug: Riluzole<br>* Riluzole given as add-on therapy 50mg bid<br>* Other names: Rilutek;|
| Placebo Comparator: Placebo Comparator<br>2 Capsules of Placebo once a day with the noon meal as add-on therapy to riluzole 50mg bid | Drug: Placebo Comparator<br>* 2 capsules of Placebo once a day with the noon meal as add-on therapy to riluzole 50mg bid<br>* Other names: Placebo;Drug: Riluzole<br>* Riluzole given as add-on therapy 50mg bid<br>* Other names: Rilutek;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival Rate at 18 Months | Overall survival was defined from the date of randomization until the date of death (event) or last known alive date (censored). If the death date was after 18 months, the participant was censored at 18 months (548 days). Participants still alive at or after 18 months were censored at 18 months/ 548 days. All data over the 18-month follow-up period after randomization, and participant survival status at the 18-month follow-up visit for participants who withdrew prematurely from the study for reasons other than death were included. | From the date of randomization until the date of death or last follow-up censored at 18 months (548 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Failure Over 18 Months | Time to failure was defined as the time from randomization to the time of the first event to consider (Tracheostomy, invasive ventilation [IV] or non invasive ventilation [NIV]) | From randomization to the time of the first event to consider at 18 months (548 days) | 
| Amyotrophic Lateral Sclerosis Functional Rating Scale - Revised (ALSFRS-R) | The ALSFRS-R is an ordinal rating scale (0 through 4) used to determine the ALS participant's self assessment of their ability and need for assistance in 12 activities or functions. This is a validated scale, both in person and by phone, which provides a total score from four sub-scores which assess speech and swallowing, (bulbar function), use of upper extremities (cervical function), gait and turning in bed (lumbar function), and breathing (respiratory function). Total scores range from 0 (most impaired) to 48 (normal ability). | Inclusion, Month 1, Month 2, Month 3, Month 6, Month 9, Month 12, Month 15 and Month 18 | 
| Percentage of Participants With a Global ALS FRS-R Score of <30 or Death | Percentage of participants with a global ALS FRS-R score of < 30 or death was estimated using the Kaplan-Meier method in the ITT, with a two-tailed log-rank, both stratified by site of onset (bulbar or spinal) and non-stratified. The ALSFRS-R is an ordinal rating scale (0 through 4) used to determine the ALS participant's self assessment of their ability and need for assistance in 12 activities or functions. This is a validated scale, both in person and by phone, which provides a total score from four sub-scores which assess speech and swallowing, (bulbar function), use of upper extremities (cervical function), gait and turning in bed (lumbar function), and breathing (respiratory function). Total scores range from 0 (most impaired) to 48 (normal ability). | Month 18 (548 days) | 
| Slow Vital Capacity (SVC) Percent Predicted | SVC as a percent of the predicted value was evaluated and reported. | Baseline, Inclusion, Month 1, Month 3, Month 6, Month 9, Month 12, Month 15 and Month 18 | 
| Percentage of Participants With SVC Percent Predicted <70% or Had Died Over 18 Months |  | Month 18 (548 days) | 
| Global Score of Manual Muscle Testing (MMT) of 34 Muscle Groups | MMT score involved the examination of 30 items. These 30 items are scored from 0 (no trace of contraction) to 5 (normal power at first try). The global score is the sum of the item scores and can range from 0 to 150. Higher score indicates some power. | Inclusion, Month 3, Month 6, Month 9, Month 12, Month 15 and Month 18 | 
| The Single-Item Mc Gill Quality of Life Scale | The single-item McGill quality of life scale evaluated the following question Considering all parts of my life - physical, emotional, social, spiritual, and financial - over the past two (2) days, the quality of my life has been…as a score of 1 to 10 on a visual analog scale where 0 is very bad and 10 is excellent. | Inclusion, Month 1, Month 3, Month 6, Month 9, Month 12, Month 15 and Month 18 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Amyotrophic Lateral Sclerosis, TRO19622, Trophos