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 |
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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 |
• To assess the effect of CK-2127107 versus placebo on respiratory function in patients with ALS. |
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E.2.2 | Secondary objectives of the trial |
• To assess the effect of CK-2127107 versus placebo on measures of skeletal muscle function
• To assess the effect of CK-2127107 versus placebo on global function
• To evaluate the safety and tolerability of CK-2127107 administered orally to patients with ALS
• To evaluate the exposure of CK-2127107 and its metabolites, when administered orally in tablet form to patients with ALS in the fed state
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Able to comprehend and willing to sign an Informed Consent Form (ICF)
2. Males or females between the ages of 18 and 80 years of age, inclusive
3. 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 published in 2000 (Brooks, Miller et al. 2000) ≤ 24 months prior to screening
4. Upright SVC ≥ 60% of predicted for age, height and sex at screening
5. Able to swallow tablets
6. A caregiver (if one is needed)
7. Able to perform reproducible pulmonary function tests
8. Pre-study clinical laboratory findings within the normal range or, if outside the normal range, deemed not clinically significant by the Investigator
9. Male patients, who have not had a vasectomy and a confirmed zero sperm count, must agree after receiving the first dose of study drug until 10 weeks after the last dose to do either of the following:
• use a condom during sexual intercourse with female partners who are of reproductive potential AND to have female partners use an additional highly effective means of contraception. Highly effective birth control methods include:
– combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation:
• oral
• intravaginal
• transdermal
– progestogen-only hormonal contraception associated with inhibition of ovulation:
• oral
• injectable
• implantable
– intrauterine device (IUD)
– intrauterine hormone-releasing system (IUS)
− bilateral tubal occlusion
OR
− practice true abstinence when this is in line with the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods), declaration of abstinence for the duration of a trial, and withdrawal are not acceptable methods of contraception.
10. Female patients must be post-menopausal (≥ 1 year) OR sterilized, OR if of childbearing potential (i.e., females who have had their first period unless they are anatomically and physiologically incapable to become pregnant), must:
• not be breastfeeding,
• have a negative pregnancy test,
• have no intention of becoming pregnant during the course of the study, AND do either of the following:
- use contraceptive drugs or devices as detailed in item number 9 from Screening until 10 weeks after the last dose of study drug AND require male partners to use a condom during sexual intercourse
OR
- practice true abstinence from Screening until 10 weeks after the last dose of study drug
11. Patients must be either on riluzole for at least 30 days prior to screening or have not taken riluzole for at least 30 days prior to screening and not planning to start riluzole during the course of the study.
12. Patients on edaravone must have completed at least 2 cycles of dosing with edaravone at the time of screening or have not taken edaravone for at least 30 days prior to screening and not planning to start edaravone during the course of the study. Two cycles of dosing are defined as having completed Cycle 1 infusion, which is 14 consecutive days of intravenous (IV) edaravone followed by 14 days off edaravone, and Cycle 2, which is 10 out of 14 days of IV edaravone.
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E.4 | Principal exclusion criteria |
1. At the time of screening, any use of non-invasive ventilation, e.g. continuous positive airway pressure, noninvasive bi-level positive airway pressure or noninvasive volume ventilation, for any portion of the day, or mechanical ventilation via tracheostomy, or on any form of oxygen supplementation
2. Neurological impairment due to a condition other than ALS
3. 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, including, but not limited to:
a. A pulse <40 or >100 bpm; mean systolic blood pressure >180 mm Hg; mean diastolic blood pressure >100 mm Hg (based on measurements taken after rest for 3 minutes) that persist on 3 successive measurements taken at least 2 minutes apart.
b. Clinically significant ECG abnormalities that require medical attention (i.e., persistent atrioventricular conduction block >first degree, or acute myocardial ischemic changes)
c. New York Heart Association Class II or greater congestive heart failure
d. Chronic obstructive pulmonary disease or asthma requiring daily use of bronchodilator medications
e. Gastrointestinal disorder that is likely to impair absorption of study drug from the gastrointestinal tract
f. ALT or aspartate aminotransferase (AST) greater than or equal to 3-times the upper limit of normal (ULN) or has total bilirubin (TBL) greater than or equal to 2-times the ULN at screening. These assessments may be repeated at the Investigator’s discretion (within the screening window).
g. Poorly controlled or brittle diabetes mellitus
h. Amputation of a limb
i. Cognitive impairment, related to ALS or otherwise, sufficient to impair the patient’s ability to understand and/or comply with study procedures and provide informed consent
j. 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 five years
k. 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
l. Patient judged to be actively suicidal or a suicide risk by the Investigator
m. Patient has estimated glomerular filtration rate (eGFR) less than 40 mL/min/1.73 m2 calculated by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) cystatin equation based on a cystatin C measurement at baseline
4. Has taken any investigational study drug within 30 days or five half-lives of the prior agent, whichever is longer, prior to dosing
5. Known to have received CK-2127107 or tirasemtiv in any previous clinical trial
6. Has received or is considering receiving during the course of the study any form of stem cell therapy for the treatment of ALS
7. Has received or is considering receiving during the course of the study any form of gene therapy for the treatment of ALS
8. Has received or is considering obtaining during the course of the study a diaphragmatic pacing system
9. History of substance abuse within the past 2 years
10. Use of a strong cytochrome P450 (CYP) 3A4 inhibitor within 7 days prior to first dose of study drug or a strong CYP3A4 inducer within 14 days prior to first dose of study drug
11. Use of a medication that is an OCT1/OCT2 substrate within 7 days
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E.5 End points |
E.5.1 | Primary end point(s) |
The change from baseline to Visit Week 12 in the percent predicted slow vital capacity (SVC). |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
At different time points throughout the study. Please refer to Appendix A within the study protocol for schedule of events. |
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E.5.2 | Secondary end point(s) |
• Slope from baseline to Visit Week 12 in the mega-score of muscle strength measured by hand held dynamometry (HHD) and handgrip dynamometry
• Change from baseline to Visit Week 12 in the ALS Functional Rating Scale – Revised (ALSFRS-R)
• The incidence and severity of treatment-emergent adverse events (TEAEs)
• Plasma concentrations of CK-2127107 at the sampled time points during the study
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
At different time points throughout the study. Please refer to Appendix A within the study protocol for schedule of events. |
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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) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
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 | 3 |
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 |
Ireland |
Netherlands |
Spain |
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 | 0 |
E.8.9.1 | In the Member State concerned months | 4 |
E.8.9.1 | In the Member State concerned days | 20 |
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 | 4 |
E.8.9.2 | In all countries concerned by the trial days | 6 |