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

Primary Purpose

Amyotrophic Lateral Sclerosis

Status
Completed
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
Olesoxime
Placebo Comparator
Riluzole
Sponsored by
Hoffmann-La Roche
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional other trial for Amyotrophic Lateral Sclerosis focused on measuring Amyotrophic Lateral Sclerosis, TRO19622, Trophos

Eligibility Criteria

18 Years - 80 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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).

Sites / Locations

  • University Hospital Gasthuisberg - Dept Neurology - Herestraat 49
  • HCL Hôpital Neurologique et Neurochirurgical Pierre Wertheimer - Neurologie C et Laboratoire d'électromyographie - 59, boulevard Pinel
  • CHRU de LILLE - Hôpital Roger Salengro - Centre SLA-MMN - Sce de Neurologie et Pathologie du Mouvement
  • Centre SLA Limoges - Service de Neurologie
  • Hôpital La Timone - Service Neurologie et Maladies Neuromusculaires
  • Clinique du Motoneurone - Sce d'Explorations Neurologiques - Hôpital Gui de Chauliac
  • CHU de Nice - Hôpital de l'Archet 1 - Centre de Référence pour les Maladies Neuromusculaires et la SLA
  • Groupe Hospitalier PITIE-SALPETRIERE - Fédération des Maladies du Système Nerveux
  • Charité Universitätsmedizin Berlin, Campus Virchow-Klinikum, Neurologische Poliklinik Ambulanz für ALS und andere Motoeneuronenerkrankungen
  • Universitätsklinik und Poliklinik für Neurologie - Martin-Luther-Universität Halle-Wittenberg
  • Neurologische Klinik Medizinische Hochschule
  • Universitäts- und Rehabilitationskliniken Ulm (RKU) - Neurologische Universitätsklinik
  • Hospital Carlos III - Unidad de ELA - Sinesio Delgado, 10
  • King's MND Care and Research Center - Academic Neurosciences Building PO Box 41 Institute of Psychiatry
  • Academic Neurology Unit - University of Sheffield - Section of Neuroscience - Division of Genomic Medicine - School of Medicine and Biomedical Sciences

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Olesoxime

Placebo Comparator

Arm Description

2 Capsules of TRO19622 (330mg) once a day with the noon meal as add-on therapy to riluzole 50mg bid

2 Capsules of Placebo once a day with the noon meal as add-on therapy to riluzole 50mg bid

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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])
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).
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).
Slow Vital Capacity (SVC) Percent Predicted
SVC as a percent of the predicted value was evaluated and reported.
Percentage of Participants With SVC Percent Predicted <70% or Had Died Over 18 Months
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.
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.

Full Information

First Posted
March 23, 2009
Last Updated
February 22, 2020
Sponsor
Hoffmann-La Roche
Collaborators
European Commission
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1. Study Identification

Unique Protocol Identification Number
NCT00868166
Brief Title
Safety and Efficacy of TRO19622 as add-on Therapy to Riluzole Versus Placebo in Treatment of Patients Suffering From ALS
Acronym
MITOTARGET
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

2. Study Status

Record Verification Date
February 2020
Overall Recruitment Status
Completed
Study Start Date
April 30, 2009 (Actual)
Primary Completion Date
September 30, 2011 (Actual)
Study Completion Date
September 30, 2011 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Hoffmann-La Roche
Collaborators
European Commission

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Amyotrophic Lateral Sclerosis
Keywords
Amyotrophic Lateral Sclerosis, TRO19622, Trophos

7. Study Design

Primary Purpose
Other
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
512 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Olesoxime
Arm Type
Experimental
Arm Description
2 Capsules of TRO19622 (330mg) once a day with the noon meal as add-on therapy to riluzole 50mg bid
Arm Title
Placebo Comparator
Arm Type
Placebo Comparator
Arm Description
2 Capsules of Placebo once a day with the noon meal as add-on therapy to riluzole 50mg bid
Intervention Type
Drug
Intervention Name(s)
Olesoxime
Other Intervention Name(s)
TRO19622
Intervention Description
2 capsules of TRO19622 (330mg) once a day with the noon meal as add-on therapy to riluzol 50mg bid
Intervention Type
Drug
Intervention Name(s)
Placebo Comparator
Other Intervention Name(s)
Placebo
Intervention Description
2 capsules of Placebo once a day with the noon meal as add-on therapy to riluzole 50mg bid
Intervention Type
Drug
Intervention Name(s)
Riluzole
Other Intervention Name(s)
Rilutek
Intervention Description
Riluzole given as add-on therapy 50mg bid
Primary Outcome Measure Information:
Title
Overall Survival Rate at 18 Months
Description
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.
Time Frame
From the date of randomization until the date of death or last follow-up censored at 18 months (548 days)
Secondary Outcome Measure Information:
Title
Percentage of Participants With Failure Over 18 Months
Description
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])
Time Frame
From randomization to the time of the first event to consider at 18 months (548 days)
Title
Amyotrophic Lateral Sclerosis Functional Rating Scale - Revised (ALSFRS-R)
Description
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).
Time Frame
Inclusion, Month 1, Month 2, Month 3, Month 6, Month 9, Month 12, Month 15 and Month 18
Title
Percentage of Participants With a Global ALS FRS-R Score of <30 or Death
Description
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).
Time Frame
Month 18 (548 days)
Title
Slow Vital Capacity (SVC) Percent Predicted
Description
SVC as a percent of the predicted value was evaluated and reported.
Time Frame
Baseline, Inclusion, Month 1, Month 3, Month 6, Month 9, Month 12, Month 15 and Month 18
Title
Percentage of Participants With SVC Percent Predicted <70% or Had Died Over 18 Months
Time Frame
Month 18 (548 days)
Title
Global Score of Manual Muscle Testing (MMT) of 34 Muscle Groups
Description
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.
Time Frame
Inclusion, Month 3, Month 6, Month 9, Month 12, Month 15 and Month 18
Title
The Single-Item Mc Gill Quality of Life Scale
Description
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.
Time Frame
Inclusion, Month 1, Month 3, Month 6, Month 9, Month 12, Month 15 and Month 18

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
80 Years
Accepts Healthy Volunteers
No
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).
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Clinical Trials
Organizational Affiliation
Hoffmann-La Roche
Official's Role
Study Director
Facility Information:
Facility Name
University Hospital Gasthuisberg - Dept Neurology - Herestraat 49
City
Leuven
ZIP/Postal Code
3000
Country
Belgium
Facility Name
HCL Hôpital Neurologique et Neurochirurgical Pierre Wertheimer - Neurologie C et Laboratoire d'électromyographie - 59, boulevard Pinel
City
Bron Cedex
ZIP/Postal Code
69677
Country
France
Facility Name
CHRU de LILLE - Hôpital Roger Salengro - Centre SLA-MMN - Sce de Neurologie et Pathologie du Mouvement
City
Lille
ZIP/Postal Code
59037
Country
France
Facility Name
Centre SLA Limoges - Service de Neurologie
City
Limoges
ZIP/Postal Code
87042
Country
France
Facility Name
Hôpital La Timone - Service Neurologie et Maladies Neuromusculaires
City
Marseille
ZIP/Postal Code
13005
Country
France
Facility Name
Clinique du Motoneurone - Sce d'Explorations Neurologiques - Hôpital Gui de Chauliac
City
Montpellier
ZIP/Postal Code
34295
Country
France
Facility Name
CHU de Nice - Hôpital de l'Archet 1 - Centre de Référence pour les Maladies Neuromusculaires et la SLA
City
Nice
ZIP/Postal Code
06202
Country
France
Facility Name
Groupe Hospitalier PITIE-SALPETRIERE - Fédération des Maladies du Système Nerveux
City
Paris
ZIP/Postal Code
75013
Country
France
Facility Name
Charité Universitätsmedizin Berlin, Campus Virchow-Klinikum, Neurologische Poliklinik Ambulanz für ALS und andere Motoeneuronenerkrankungen
City
Berlin
ZIP/Postal Code
13353
Country
Germany
Facility Name
Universitätsklinik und Poliklinik für Neurologie - Martin-Luther-Universität Halle-Wittenberg
City
Halle
ZIP/Postal Code
06097
Country
Germany
Facility Name
Neurologische Klinik Medizinische Hochschule
City
Hannover
ZIP/Postal Code
D-30623
Country
Germany
Facility Name
Universitäts- und Rehabilitationskliniken Ulm (RKU) - Neurologische Universitätsklinik
City
Ulm
ZIP/Postal Code
89081
Country
Germany
Facility Name
Hospital Carlos III - Unidad de ELA - Sinesio Delgado, 10
City
Madrid
ZIP/Postal Code
28029
Country
Spain
Facility Name
King's MND Care and Research Center - Academic Neurosciences Building PO Box 41 Institute of Psychiatry
City
London
ZIP/Postal Code
SE58AF
Country
United Kingdom
Facility Name
Academic Neurology Unit - University of Sheffield - Section of Neuroscience - Division of Genomic Medicine - School of Medicine and Biomedical Sciences
City
Sheffield
ZIP/Postal Code
S10 2RX
Country
United Kingdom

12. IPD Sharing Statement

Citations:
PubMed Identifier
34433481
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.
Results Reference
derived
PubMed Identifier
30814647
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. Erratum In: Sci Rep. 2020 Feb 19;10(1):3312.
Results Reference
derived

Learn more about this trial

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

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