E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Amyotrophic Lateral Sclerosis (ALS) |
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E.1.1.1 | Medical condition in easily understood language |
Amyotrophic lateral sclerosis, or ALS, is a disease of the nerve cells in the brain and spinal cord that control voluntary muscle movement. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10002026 |
E.1.2 | Term | Amyotrophic lateral sclerosis |
E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The primary objective is to assess the effect of tirasemtiv versus placebo on respiratory function in patients with ALS. |
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E.2.2 | Secondary objectives of the trial |
Secondary objectives include: • Evaluation of alternative methods to assess the effect of tirasemtiv versus placebo on percent predicted SVC in patients with ALS • Assessment of the effect of tirasemtiv versus placebo on other clinical measures related to the progressive decline in respiratory function in patients with ALS • Assessment of the effect of tirasemtiv versus placebo on measures of skeletal muscle function in patients with ALS |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Biomarker Sample Collection Biomarkers are objective measures or indicators of normal biological processes, pathological processes or pharmacological responses to a therapeutic intervention. Biomarker development may be useful in developing markers to identify disease subtypes, to guide therapy, or predict disease severity. Where authorized by the applicable IRB/EC/REB approved informed consent, blood samples for biomarker development will be collected at the time points below: - Day 1 - Week 8 - Week 16 - Week 24 - Week 32 - Week 40 - Week 48 Plasma samples will be stored for future biomarker analyses and will NOT be used for pharmacogenomic testing. |
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E.3 | Principal inclusion criteria |
1. Able to comprehend and willing to sign an Informed Consent Form (ICF) 2. Male or female 18 years of age or older 3. A diagnosis of familial or sporadic ALS (defined as meeting the possible, laboratory-supported probable, probable, or definite criteria for a diagnosis of ALS according to the World Federation of Neurology El Escorial criteria) ≤ 24 months prior to screening 4. Upright SVC ≥ 70 % of predicted for age, height and sex 5. Able to swallow tablets without crushing, and in the opinion of the Investigator, is expected to continue to be able to do so during the trial 6. A caregiver if one is needed 7. Clinical laboratory findings within the normal range or, if outside the normal range, deemed not clinically significant by the Investigator 8. Male patients must agree for the duration of the study and 10 weeks after the end of the study to use a condom during sexual intercourse with female partners who are of childbearing potential (i.e., following menarche until post-menopausal if not anatomically and physiologically incapable of becoming pregnant) and to have female partners use an additional effective means of contraception (e.g., diaphragm plus spermicide, or oral contraceptives) or the male patient must agree to abstain from sexual intercourse during and for 10 weeks after the end of the study, unless the male patient has had a vasectomy and confirmed sperm count is zero 9. Female patients must be post-menopausal (≥ 1 year) or sterilized, or, if of childbearing potential, not be breastfeeding, have a negative pregnancy test, have no intention to become pregnant during the course of the study, and use effective contraceptive drugs or devices while requiring male partner to use a condom for the duration of the study and for 10 weeks after the end of the study 10. Patients must be either on a stable dose of riluzole 50 mg twice daily for at least 30 days prior to screening or have not taken riluzole for at least 30 days prior to screening and are willing not to begin riluzole use until they complete study drug dosing
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E.4 | Principal exclusion criteria |
1. At the time of screening, any use of non-invasive positive pressure ventilation (NIPPV, e.g. continuous positive airway pressure [CPAP] or bi-level positive airway pressure [BiPAP]) for any portion of the day, or mechanical ventilation via tracheostomy, or on any form of oxygen supplementation 2. Patients with a diaphragm pacing system (DPS) at study entry or who anticipate DPS placement during the course of the study 3. BMI of 20.0 kg/m2 or lower 4. Unwilling or unable to discontinue tizanidine and theophylline-containing medications during study participation 5. Serum chloride outside the normal reference range 6. Neurological impairment due to a condition other than ALS, including history of transient ischemic attack within the past year 7. Presence at screening of any medically significant cardiac, pulmonary, GI, musculoskeletal, or psychiatric illness that might interfere with the patient’s ability to comply with study procedures or that might confound the interpretation of clinical safety or efficacy data, including, but not limited to: a. Poorly controlled hypertension b. NYHA Class II or greater congestive heart failure c. Chronic obstructive pulmonary disease or asthma requiring daily use bronchodilator medications d. GI disorder that might impair absorption of study drug e. History of significant liver disease defined by bilirubin > 2 times the upper limit of normal (ULN) or ALT or AST > 3 times the ULN on repeat testing f. Poorly controlled diabetes mellitus g. History of vertigo within three months of study entry h. History of syncope without an explainable or treated cause i. History of untreated intracranial aneurysm or poorly controlled seizure disorder j. Amputation of a limb k. Cognitive impairment, related to ALS or otherwise, sufficient to impair the patient’s ability to give informed consent and to understand and/or comply with study procedures l. Cancer with metastatic potential (other than basal cell carcinoma, carcinoma in situ of the cervix, or squamous cell carcinoma of the skin excised with clean margins) diagnosed and treated within the last two years m. Any other condition, impairment or social circumstance that, in the opinion of the Investigator, would render the patient not suitable to participate in the study n. Patient judged to be actively suicidal or a suicide risk by the Investigator 8. Has taken any investigational study drug within 30 days or five half-lives of the prior agent, whichever is greater, prior to dosing 9. Prior participation in any form of stem cell therapy for the treatment of ALS 10. Previously received tirasemtiv in any previous clinical trial |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint is the change from baseline to Week 24 of the double-blind, placebo-controlled phase in percent predicted SVC. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
The following secondary endpoints will be analyzed in a closed testing procedure if the primary efficacy analysis is met as defined in the protocol. • Change from baseline in the ALSFRS-R score of the three respiratory items of the ALSFRS-R (i.e., the sum of items 10, 11 and 12) at the end of 48 weeks of double-blind, placebo-controlled treatment • Slope of mega-score of muscle strength during the 48 weeks of double-blind, placebo-controlled treatment • Time to the first occurrence of a decline from baseline in percent predicted SVC ≥20 percentage points or the onset of respiratory insufficiency or death at the end of the 48 weeks of double-blind, placebo-controlled treatment • Time to the first occurrence of a decline in SVC to ≤50% predicted or the onset of respiratory insufficiency or death at the end of the 48 weeks of double-blind, placebo-controlled treatment • Change from baseline in the ALSFRS-R total score to the end of 48 weeks of the double-blind, placebo-controlled treatment • Time to the first use of mechanical ventilatory assistance or death during all 48 weeks of double-blind, placebo-controlled treatment |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 4 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 24 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Belgium |
Canada |
France |
Germany |
Ireland |
Italy |
Netherlands |
Portugal |
Spain |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 5 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 9 |
E.8.9.2 | In all countries concerned by the trial days | 0 |