Safety and Efficacy of TRO19622 as add-on Therapy to Riluzole Versus Placebo in Treatment of Patients Suffering From Amyotrophic Lateral Sclerosis (ALS) (MITOTARGET)

Study Description

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Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Amyotrophic Lateral Sclerosis	Drug: Olesoxime; Drug: Placebo Comparator	Phase 2; Phase 3

Detailed Description:

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.

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	512 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Official 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
Study Start Date :	April 2009
Actual Primary Completion Date :	September 2011
Actual Study Completion Date :	September 2011

Arms and Interventions

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Arm	Intervention/treatment
Experimental: TRO19622; 2 Capsules of TRO19622 (330mg) once a day with the noon meal as add-on therapy to riluzole 50mg bid	Drug: Olesoxime; 2 capsules of TRO19622 (330mg) once a day with the noon meal as add-on therapy to riluzol 50mg bid
Placebo Comparator: Control; 2 Capsules of Placebo once a day with the noon meal as add-on therapy to riluzole 50mg bid	Drug: Placebo Comparator; 2 capsules of Placebo once a day with the noon meal as add-on therapy to riluzole 50mg bid

Outcome Measures

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Primary Outcome Measures :

1. The primary outcome measure will be the overall 18-month survival rate. [ Time Frame: 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 :

1. Survival without occurrence of tracheostomy, chronic IV or NIV defined as >23h of NIV daily for 14 consecutive days. [ Time Frame: Time to failure will be defined as the time from randomization to the time of the first event to consider (Tracheostomy, IV or NIV) ]
2. Total score of the 48-point ALS Functional Rating Scale Revised, with a focus on the 9-month assessment [ Time Frame: Inclusion, Month 1, Month 2, Month 3, Month 6, Month 9, Month 12, Month 15 and Month 18 ]
3. Slow Vital Capacity (SVC) as a percentage of predicted SVC and survival with SVC >50% [ Time Frame: Screening, Inclusion, Month 1, Month 3, Month 6, Month 9, Month 12, Month 15 and Month 18 ]
4. Total Score of Manual Muscle Testing of 34 muscle groups [ Time Frame: Inclusion, Month 3, Month 6, Month 9, Month 12, Month 15 and Month 18 ]
5. The single-item Mc Gill Quality of life scale [ Time Frame: Inclusion, Month 1, Month 3, Month 6, Month 9, Month 12, Month 15 and Month 18 ]

Eligibility Criteria

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Ages Eligible for Study:	18 Years to 80 Years (Adult, Senior)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

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).

Contacts and Locations

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Locations

Belgium
University Hospital Gasthuisberg - Dept Neurology - Herestraat 49
Leuven, Belgium, 3000
France
HCL Hôpital Neurologique et Neurochirurgical Pierre Wertheimer - Neurologie C et Laboratoire d'électromyographie - 59, boulevard Pinel
Bron Cedex, France, 69677
CHRU de LILLE - Hôpital Roger Salengro - Centre SLA-MMN - Sce de Neurologie et Pathologie du Mouvement
Lille, France, 59037
Centre SLA Limoges - Service de Neurologie
Limoges, France, 87042
Hôpital La Timone - Service Neurologie et Maladies Neuromusculaires
Marseille, France, 13005
Clinique du Motoneurone - Sce d'Explorations Neurologiques - Hôpital Gui de Chauliac
Montpellier, France, 34295
CHU de Nice - Hôpital de l'Archet 1 - Centre de Référence pour les Maladies Neuromusculaires et la SLA
Nice, France, 06202
Groupe Hospitalier PITIE-SALPETRIERE - Fédération des Maladies du Système Nerveux
Paris, France, 75013
Germany
Charité Universitätsmedizin Berlin, Campus Virchow-Klinikum, Neurologische Poliklinik Ambulanz für ALS und andere Motoeneuronenerkrankungen
Berlin, Germany, 13353
Universitätsklinik und Poliklinik für Neurologie - Martin-Luther-Universität Halle-Wittenberg
Halle, Germany, 06097
Neurologische Klinik Medizinische Hochschule
Hannover, Germany, D-30623
Universitäts- und Rehabilitationskliniken Ulm (RKU) - Neurologische Universitätsklinik
Ulm, Germany, 89081
Spain
Hospital Carlos III - Unidad de ELA - Sinesio Delgado, 10
Madrid, Spain, 28029
United Kingdom
King's MND Care and Research Center - Academic Neurosciences Building PO Box 41 Institute of Psychiatry
London, United Kingdom, SE58AF
Academic Neurology Unit - University of Sheffield - Section of Neuroscience - Division of Genomic Medicine - School of Medicine and Biomedical Sciences
Sheffield, United Kingdom, S10 2RX

Sponsors and Collaborators

Trophos

European Commission

Investigators

Principal Investigator:	Vincent Meininger, MD, PhD	Groupe Hospitalier Pitie-Salpetriere

More Information

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Responsible Party:	Trophos
ClinicalTrials.gov Identifier:	NCT00868166 History of Changes
Other Study ID Numbers:	TRO19622 CL E Q 1015-1; EudraCT Number:2008-007320-25
First Posted:	March 24, 2009
Last Update Posted:	March 28, 2012
Last Verified:	March 2012

Keywords provided by Trophos:

Amyotrophic Lateral Sclerosis; TRO19622; Trophos

Additional relevant MeSH terms:

Sclerosis; Motor Neuron Disease; Amyotrophic Lateral Sclerosis; Pathologic Processes; Neurodegenerative Diseases; Nervous System Diseases; Neuromuscular Diseases; Spinal Cord Diseases; Central Nervous System Diseases; TDP-43 Proteinopathies; Proteostasis Deficiencies	Metabolic Diseases; Riluzole; Anticonvulsants; Excitatory Amino Acid Antagonists; Excitatory Amino Acid Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Physiological Effects of Drugs; Neuroprotective Agents; Protective Agents