MitoTarget Clinical Trial for Physicians

Study title:

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.

Principal Investigator:

Pr V. Meininger, Hôpital de La Pitié-Salpétrière, Paris.

Study sites:

15 sites in Belgium (1), France (6), Germany (4), UK (2). Spain (1)

Studied period:

Expected first enrolment: Q2 2009 - Expected completion date: Q2 2011

Phase of Development:

II/III

Objectives:

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.

Methodology:

Double-blind, randomized, placebo controlled, parallel group, multicenter study.

Study duration:

24.75 Months including a three-week screening period, a 3 to 6 month enrolment period and an 18-month treatment period.

Total number of subjects: 470 patients (235/group).

Diagnosis and main criteria for inclusion:

Inclusion criteria:

1. Patients with sporadic or familial Amyotrophic Lateral Sclerosis
2. Patients with a clinical diagnosis of laboratory-supported probable, probable, or definite ALS according to the modified El Escorial criteria.
3. Have signed an Informed Consent to participate to the trial before any study related procedure has taken place.
4. Be of age >18 (exclusive) and < 80 years (inclusive).
5. If female, not lactating or have a negative pregnancy test. Male and female partners must agree to use an effective method of birth control during their participation in the trial and for at least 15 days after the last IMP dose. Both partners must use reliable methods of contraception with 2 independent methods. The following measures are acceptable: Hormone contraceptives (e.g. oral contraceptives or comparable methods), intrauterine device, condoms with spermicidal coating or in combination with spermicidal creams, total abstinence or sterilisation performed in the past.
6. Onset of ALS Symptoms (weakness) for more than 6 months (inclusive) and less than 36 months (inclusive).
7. Slow vital capacity (SVC), measured three times, one of the measure being 70% of that predicted.
8. Treated with riluzole at the stable dose of 50 mg bid for at least 30 days before enrolment.

Exclusion criteria:

1. Tracheostomy, invasive ventilation, or non invasive positive pressure ventilation (NIPPV).
2. Gastrostomy.
3. Evidence of major psychiatric disorder or clinically evident dementia.
4. Diagnosis of a neurodegenerative disease in addition to ALS.
5. Have a current medication that could interfere with TRO19622 pharmacokinetics: tamoxifene.
6. 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.
7. Known hypersensitivity to any component of the study drug.
8. Patients with known intolerance or contra-indication to riluzole.
9. Have a recent history (within the previous 6 months) or current evidence of alcohol or drug abuse.
10. Have a concurrent unstable disease involving any system e.g. 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.
11. Have a baseline QTc (Bazett) > 450 msec for males and > 470 msec for females.
12. Patients with known hepatitis B/C or HIV positive serology.
13. Be a lactating or pregnant female.
14. Have renal impairment defined as blood creatinine > 1.5× upper limit of normal.
15. Have hepatic impairment and/or liver enzymes (ALAT or ASAT) > 3× ULN.
16. Hemostasis disorders or current treatment with oral anticoagulants.
17. Be possibly dependent on the Investigator or the Sponsor (e.g. including, but not limited to, affiliated employee).
18. Participated in any other investigational drug or therapy study with a non-approved medication, within the previous 3 months.
19. Patients without Social Security Insurance (France).

Investigated Medicinal Product (IMP), dose and mode of administration:

TRO19622, two soft capsules of 165 mg orally, once daily. Total daily dose of 330 mg QD. The IMP will be taken with the noon meal.

Reference therapy, dose and mode of administration:

Placebo, two soft capsules orally, once daily.

Add-On treatment:

All patients will receive the IMP as add-on to riluzole 50 mg bid orally, 50 mg morning and evening on an empty stomach i.e. at least 20 min before the meal.

Duration of treatment:

18 months. If the expected number of events is not met trial duration may be prolonged for 3 months. Patients having completed the study will have the opportunity to be enrolled in an open-label TRO19622 safety study at the end of the double-blind period.

Assessment criteria:

Primary outcome measure:

Overall 18-month survival rate. Survival will be calculated from the date of randomization until the date of death or last follow-up censored at 18 months (548 days).

Secondary outcome measures:

• Survival without the occurrence of tracheostomy, chronic invasive ventilation or non invasive ventilation (NIV) defined as >23 h of NIV daily for 14 consecutive days. Time to failure will be defined as the time from randomization to the time of the first event to consider (Tracheostomy, Invasive Ventilation, NIV)
• Total score of the 48-point ALS Functional Rating Scale Revised, with a focus on the 9-month assessment
• Slow Vital Capacity (SVC) as a percentage of predicted SVC and survival with SVC>50%
• Total score of Manual Muscle Testing of 34 muscle groups
• The single-item McGill quality of life scale

Safety

1. Occurrence of AEs,
2. Physical examination,
3. Laboratory tests,
4. Vital signs and ECG.