E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Mitochondrial myopathy as evidenced by the following 2 criteria (must meet both):
a. Have a history of exercise intolerance with or without weakness and/or progressive exercise intolerance (in which modest exercise typically provokes heaviness, weakness, aching of active muscles, or tachycardia).
b. Have a known primary mitochondrial DNA mutation of a nuclear DNA defect that is associated with reduced activity of at least 1 mitochondrially encoded respiratory chain complex |
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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] - Musculoskeletal Diseases [C05] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 18.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10027710 |
E.1.2 | Term | Mitochondrial myopathy |
E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic 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 |
Primary:
• To evaluate the change in peak work during maximal exercise testing
• To evaluate the safety and tolerability of RTA 408
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E.2.2 | Secondary objectives of the trial |
Secondary:
• To evaluate the change in 6-minute walk test (6MWT) distance
Exploratory:
• To evaluate the change in peak oxygen utilization during maximal exercise testing
• To evaluate the change in peak serum lactate and pyruvate, peak heart rate, and rating of perceived exertion during submaximal exercise testing
• To evaluate the change in Fatigue Severity Scale score
• To evaluate the change in SF-36® Health Survey Update (SF-36) score
• To evaluate the change in pharmacodynamic (PD) markers of activity in blood and muscle samples
• To characterize the pharmacokinetics of RTA 408 and potential metabolites after oral administration of RTA 408 Capsules
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Inclusion criteria:
Patients must:
1. Have mitochondrial myopathy as evidenced by the following 2 criteria (must meet both):
a. Have a history of exercise intolerance with or without weakness and/or progressive exercise intolerance (in which modest exercise typically provokes heaviness, weakness, aching of active muscles, or tachycardia)
b. Have a known primary mitochondrial DNA mutation or a nuclear DNA defect that is associated with reduced activity of at least 1 mitochondrially encoded respiratory chain complex
2. Be male or female and ≥18 years of age and ≤75 years of age
3. Have no changes to their exercise regimen within 30 days prior to Study Day 1 and be willing to remain on the same exercise regimen during the 16-week study period
4. Have the ability to complete maximal exercise testing
5. Have peak work during maximal exercise testing of ≤1.5 W/kg
6. Have adequate kidney function defined as an estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m2 using the Modification of Diet in Renal Disease (MDRD) 4-variable formula
7. Be able to swallow capsules
8. Be willing and able to cooperate with all aspects of the protocol
9. Be willing to practice the medically acceptable methods of birth control
10. Provide written informed consent for study participation, approved by the appropriate Institutional Review Board
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E.4 | Principal exclusion criteria |
Exclusion criteria:
Patients must not:
1. Have uncontrolled diabetes (HbA1c >11.0%)
2. Have B-type natriuretic peptide level >200 pg/mL
3. Have a history of clinically significant left-sided heart disease and/or clinically significant cardiac disease, including but not limited to any of the following:
a. Clinically significant congenital or acquired valvular disease
b. Pericardial constriction (based on echocardiogram performed at Screening Visit or within 30 days prior to Screening Visit)
c. Restrictive or congestive cardiomyopathy (based on echocardiogram performed at Screening Visit or within 30 days prior to Screening Visit)
d. Symptomatic coronary disease (prior myocardial infarction, percutaneous coronary intervention, coronary artery bypass graft surgery, or angina)
e. Evidence of left ventricular diastolic dysfunction
f. History of atrial fibrillation
g. History of unstable arrhythmias
h. Cardiac insufficiency, defined as New York Heart Association Class >2
4. Have known active fungal, bacterial, and/or viral infection, including human immunodeficiency virus or hepatitis virus (B or C)
5. Have known or suspected active drug or alcohol abuse, as per investigator judgment
6. Have clinically significant abnormalities of clinical hematology or biochemistry, including but not limited to elevations greater than 1.5 times the upper limit of normal of aspartate aminotransferase, alanine aminotransferase or creatinine. Levels above this threshold are allowable if attributable to muscle injury.
7. Have any abnormal laboratory test value or clinically significant pre-existing medical condition that, in the opinion of the investigator, would put the patient at risk by study enrollment
8. Have taken any of the following drugs within 7 days prior to Study Day 1 or plan to take any of these drugs during the time of study participation:
a. Sensitive substrates for cytochrome P450 2C8 or 3A4 (e.g., repaglinide, midazolam, sildenafil)
b. Moderate or strong inhibitors or inducers of cytochrome P450 3A4 (e.g., carbamazepine, phenytoin, ciprofloxacin, grapefruit juice)
c. Substrates for p-glycoprotein transporter (e.g., ambrisentan, digoxin)
9. Have a history of clinically significant liver disease (e.g., fibrosis, cirrhosis, hepatitis), or has, at screening, clinically relevant deviations in laboratory tests including any one of the following:
a. alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) > 1.5-fold ULN,
b. bilirubin > 1.2-fold ULN,
c. alkaline phosphatase (ALP) > 2-fold ULN,
d. kidney insufficiency as defined by creatinine level > 1.5 mg/dL,
e. albumin < lower limit of normal (LLN)
10. Have participated in any other interventional clinical study within 30 days prior to Study Day 1
11. Have a cognitive impairment that may preclude ability to comply with study procedures
12. Be unable to comply with the requirements of the study protocol or be unsuitable for the study for any reason, in the opinion of the investigator
13. Have used antioxidant supplements, including but not limited to idebenone, coenzyme Q10, nicotinamide, and vitamin E above the recommended daily allowance, within 14 days prior to Study Day 1 or plan to take any of these supplements during the time of study participation
14. Have taken chronic treatment with corticosteroids within 30 days prior to Study Day 1
15. Have had significant suicidal ideation within 1 month prior to Screening Visit as per investigator judgment or any history of suicide attempts
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E.5 End points |
E.5.1 | Primary end point(s) |
Change from baseline in peak work (W/kg) during maximal exercise testing using a bicycle ergometer. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Screening, week 4, week 12 |
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E.5.2 | Secondary end point(s) |
Efficacy: Parameters collected during maximal exercise testing (including peak work and peak oxygen utilization) and submaximal exercise testing; 6MWT distance; Fatigue Severity Scale results; and SF-36 test results
Safety: Results of echocardiogram, electrocardiogram, vital sign measurements, weight, body mass index, physical examinations, adverse events, serious adverse events, concomitant medications, and laboratory test results (clinical chemistry, hematology, urinalysis, microscopy, and pregnancy tests [as indicated])
Pharmacokinetic: RTA 408 plasma concentration data
Pharmacodynamic: Parameters assessed from serum lactate and serum pyruvate during submaximal exercise testing, muscle needle biopsy biomarkers |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Screening, week 4, week 12 (some end points are also assessed at week 16 or at timepoints during the 12-week treatment period) |
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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 | 3 |
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 | No |
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 |
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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 | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 2 |