Clinical trial NCT00868166: Safety and Efficacy of TRO19622 as add-on Therapy to Riluzole Versus Placebo in Treatment of Patients Suffering From ALS
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 type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Amyotrophic Lateral Sclerosis
Keywords: Amyotrophic Lateral Sclerosis
TRO19622
Trophos
Lead sponsor: Hoffmann-La Roche
Sponsor class: INDUSTRY
Collaborators: name: European Commission
First posted: 2009-03-24
Enrollment: 512
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: OTHER

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.

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.

Eligibility 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).

Primary outcomes:
measure: Overall Survival Rate at 18 Months
timeFrame: From the date of randomization until the date of death or last follow-up censored at 18 months (548 days)
Secondary outcomes:
measure: Percentage of Participants With Failure Over 18 Months
timeFrame: From randomization to the time of the first event to consider at 18 months (548 days)
measure: Amyotrophic Lateral Sclerosis Functional Rating Scale - Revised (ALSFRS-R)
timeFrame: Inclusion, Month 1, Month 2, Month 3, Month 6, Month 9, Month 12, Month 15 and Month 18
measure: Percentage of Participants With a Global ALS FRS-R Score of <30 or Death
timeFrame: Month 18 (548 days)
measure: Slow Vital Capacity (SVC) Percent Predicted
timeFrame: Baseline, Inclusion, Month 1, Month 3, Month 6, Month 9, Month 12, Month 15 and Month 18
measure: Percentage of Participants With SVC Percent Predicted <70% or Had Died Over 18 Months
timeFrame: Month 18 (548 days)
measure: Global Score of Manual Muscle Testing (MMT) of 34 Muscle Groups
timeFrame: Inclusion, Month 3, Month 6, Month 9, Month 12, Month 15 and Month 18
measure: The Single-Item Mc Gill Quality of Life Scale
timeFrame: Inclusion, Month 1, Month 3, Month 6, Month 9, Month 12, Month 15 and Month 18
Other outcomes:
Locations:
city: Leuven
country: Belgium
facility: University Hospital Gasthuisberg - Dept Neurology - Herestraat 49
city: Bron Cedex
country: France
facility: HCL Hôpital Neurologique et Neurochirurgical Pierre Wertheimer - Neurologie C et Laboratoire d'électromyographie - 59, boulevard Pinel
city: Lille
country: France
facility: CHRU de LILLE - Hôpital Roger Salengro - Centre SLA-MMN - Sce de Neurologie et Pathologie du Mouvement
city: Limoges
country: France
facility: Centre SLA Limoges - Service de Neurologie
city: Marseille
country: France
facility: Hôpital La Timone - Service Neurologie et Maladies Neuromusculaires
city: Montpellier
country: France
facility: Clinique du Motoneurone - Sce d'Explorations Neurologiques - Hôpital Gui de Chauliac
city: Nice
country: France
facility: CHU de Nice - Hôpital de l'Archet 1 - Centre de Référence pour les Maladies Neuromusculaires et la SLA
city: Paris
country: France
facility: Groupe Hospitalier PITIE-SALPETRIERE - Fédération des Maladies du Système Nerveux
city: Berlin
country: Germany
facility: Charité Universitätsmedizin Berlin, Campus Virchow-Klinikum, Neurologische Poliklinik Ambulanz für ALS und andere Motoeneuronenerkrankungen
city: Halle
country: Germany
facility: Universitätsklinik und Poliklinik für Neurologie - Martin-Luther-Universität Halle-Wittenberg
city: Hannover
country: Germany
facility: Neurologische Klinik Medizinische Hochschule
city: Ulm
country: Germany
facility: Universitäts- und Rehabilitationskliniken Ulm (RKU) - Neurologische Universitätsklinik
city: Madrid
country: Spain
facility: Hospital Carlos III - Unidad de ELA - Sinesio Delgado, 10
city: London
country: United Kingdom
facility: King's MND Care and Research Center - Academic Neurosciences Building PO Box 41 Institute of Psychiatry
city: Sheffield
country: United Kingdom
facility: Academic Neurology Unit - University of Sheffield - Section of Neuroscience - Division of Genomic Medicine - School of Medicine and Biomedical Sciences
Study officials:
affiliation: Hoffmann-La Roche
name: Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Witzel S, Frauhammer F, Steinacker P, Devos D, Pradat PF, Meininger V, Halbgebauer S, Oeckl P, Schuster J, Anders S, Dorst J, Otto M, Ludolph AC. Neurofilament light and heterogeneity of disease progression in amyotrophic lateral sclerosis: development and validation of a prediction model to improve interventional trials. Transl Neurodegener. 2021 Aug 26;10(1):31. doi: 10.1186/s40035-021-00257-y.
citation: Devos D, Moreau C, Kyheng M, Garcon G, Rolland AS, Blasco H, Gele P, Timothee Lenglet T, Veyrat-Durebex C, Corcia P, Dutheil M, Bede P, Jeromin A, Oeckl P, Otto M, Meininger V, Danel-Brunaud V, Devedjian JC, Duce JA, Pradat PF. A ferroptosis-based panel of prognostic biomarkers for Amyotrophic Lateral Sclerosis. Sci Rep. 2019 Feb 27;9(1):2918. doi: 10.1038/s41598-019-39739-5.