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 |
ALS (also known Lou Gehrig’s disease or motor neuron disease) is a progressive and fatal degeneration of the nervous system. |
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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 | 21.1 |
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 |
To assess the effect of reldesemtiv versus placebo on functional outcomes in ALS. To assess the safety and tolerability of reldesemtiv compared to placebo. |
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E.2.2 | Secondary objectives of the trial |
• To assess the effect of reldesemtiv versus placebo on combined functional and survival outcomes in ALS • To assess the effect of reldesemtiv versus placebo on ventilatory function • To assess the effect of reldesemtiv versus placebo on quality of life • To assess the effect of reldesemtiv versus placebo on handgrip strength
Exploratory Objective To assess the effect of reldesemtiv versus placebo on the progression of ALS |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Key Inclusion Criteria • Males or Females between the ages of 18 and 80 years of age, inclusive • Diagnosis of familial or sporadic ALS (defined as meeting the laboratory-supported probable, probable, or definite criteria for ALS according to the World Federation of Neurology El Escorial criteria published in 2000 [Brooks 2000]). Patients who meet the possible criteria are eligible if they have lower motor neuron findings; those who have purely upper motor neuron findings are ineligible. • First symptom of ALS ≤ 24 months prior to screening. The qualifying first symptoms of ALS are limited to manifestations of weakness in extremity, bulbar, or respiratory muscles. Cramps, fasciculations, or fatigue should not be taken in isolation as a first symptom of ALS. • ALSFRS-R total score ≤ 44 at screening. Patients with a total score of 45 or higher may be rescreened 60±7 days following the original screening date and be deemed eligible if their ALSFRS-R total score is ≤ 44 or if their score is 2 or more points less than at initial screening. Such patients must continue to meet all other inclusion/exclusion criteria at the time of rescreening. • Upright FVC ≥ 65.0% of predicted for age, height, sex and ethnicity at screening according to Global Lung Initiative equation • Able to perform reproducible pulmonary function tests defined as being able to perform FVC at screening with variability of the 2 highest raw values of less than 10% with a maximum of 5 trials permitted. Screening FVC results must be reviewed and approved by the central review process prior to randomization. • Must be either on riluzole for ≥ 30 days prior to screening or have not taken it for at least 30 days prior to screening • Must have completed at least 2 cycles of edaravone at the time of screening or have not received it for at least 30 days prior to screening • Able to swallow whole tablets • Clinical laboratory findings within the normal range, or if outside the normal range, not deemed clinically significant by the Investigator, except as specifically indicated as laboratory exclusion |
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E.4 | Principal exclusion criteria |
• eGFRCysC < 45.0 mL/min/1.73 m2 at screening • Urine protein/creatinine ratio > 1 mg/mg (113 mg/mmol) at screening • Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥ 3-times the upper limit of normal (ULN) • Total bilirubin (TBL), direct or indirect bilirubin above the ULN. • Cognitive impairment, related to ALS or otherwise that impairs the patient’s ability to understand and/or comply with study procedures and provide informed consent • Other medically significant neurological conditions that could interfere with the assessment of ALS symptoms, signs or progression. • Presence at screening of any medically significant cardiac, pulmonary, gastrointestinal, 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 • Has a tracheostomy |
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E.5 End points |
E.5.1 | Primary end point(s) |
• Change from baseline to Week 24 in ALSFRS-R total score. |
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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) |
• Combined assessment of change in ALSFRS-R total score, time to onset of respiratory insufficiency, and survival time up to Week 24 • Change from baseline to Week 24 in the percent predicted FVC • Change from baseline to Week 24 in the ALSAQ-40 total score • Change from baseline to Week 24 in handgrip strength (average of both hands)
Exploratory Endpoints • Time to first receipt, time to first use, time to daily use, time to dependence and number used of any of the following durable medical equipment items (manual wheelchair, power wheelchair, augmentative and alternative communication device, noninvasive ventilation (NIV) and/or gastrostomy tube) from randomization to the end of the 24-week doubleblind, placebo-controlled period or to the end of the study • Change from baseline to Week 24 in the four subdomain scores of the ALSFRS-R • Time spent in each MiToS stage and number of patients to transition stages from baseline to Week 24 • Change from baseline to Week 48 in ALSFRS-R total score • Change from baseline to Week 48 in forced vital capacity (FVC) • Combined assessment of change in ALSFRS-R total score, time to onset of respiratory insufficiency, and survival time up to Week 48 • Change from baseline to Week 24 in the megascore of muscle strength measured by hand-held dynamometry (HHD) in bilateral first dorsal interosseous muscles, abductor pollicus brevis muscles, and abductor digiti minimi muscles • Change from baseline to Week 24 and Week 48 in the EQ-5D-5L • Change from baseline to Week 24 and Week 48 in the EQ-Visual Analogue Scale (VAS) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
24 weeks for secondary objectives 48 weeks for exploratory objectives |
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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 | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
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 | No |
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 | 2 |
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 |
Australia |
Canada |
United States |
Belgium |
France |
Germany |
Ireland |
Italy |
Netherlands |
Poland |
Portugal |
Spain |
Sweden |
Switzerland |
United Kingdom |
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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 | 2 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 6 |
E.8.9.2 | In all countries concerned by the trial days | 0 |