| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Primary mitochondrial myopathy |
|
| E.1.1.1 | Medical condition in easily understood language |
| Primary mitochondrial myopathy |
|
| 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 | 20.0 |
| 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 |
|
| 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 evaluate the safety and tolerability of REN001 in subjects with PMM, during 12 weeks of treatment |
|
| E.2.2 | Secondary objectives of the trial |
1. To evaluate the safety and tolerability of REN001 in subjects with PMM, during 48 weeks of treatment.
2. To investigate pharmacokinetics of REN001 in subjects with PMM treated for 12 weeks with REN001, administered as a capsule, using a population pharmacokinetic methodology.
3. To investigate the pharmacodynamic effects of REN001 in subjects with PMM treated for 12 weeks |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Subjects must meet all of the following inclusion criteria to be eligible for inclusion in the study:
1. Males or females aged 16 years or older.
2. Established diagnosis of PMM according to the 2016 Rome Consensus recommendations (Mancuso, McFarland, Klopstock, & Hirano, 2017).
3. A score of 2-4 on Question 5 Section III of NMDAS from subject's medical history or at screening whichever is most relevant.
4. Either a confirmed m.3243A>G mutation or other mtDNA defects, with myopathy.
5. Have no changes to their exercise regimen within 30 days prior to Day 1 and be willing to remain on the same exercise regimen for the duration of the study.
6. Subjects must be ambulatory and able to perform the study exercise tests independently.
7.Subjects must be able to remain on stable medication through the study and specifically must not commence or have changes in medication for diabetes.
8. Have adequate kidney function defined as an estimated glomerular filtration rate (eGFR) ≥ 60 mL/min/1.73 m2 using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine equation (Levey, et al., 2009) at Screening and Baseline.
9. Be able to swallow capsules.
10. Females should be either of non-child-bearing potential or must agree to use a highly effective method of contraception from Screening. Males with partners who are WOCBP must also use contraception from Baseline.
11. Evidence of a personally signed and dated informed consent document indicating that the subject has been informed of all pertinent aspects of the study. |
|
| E.4 | Principal exclusion criteria |
Subjects presenting with any of the following will not be included in the study:
1. Participation in a prior REN001 (previously known as HPP-593) study.
2. Employee of the study site or of the Sponsor’s company or delegates.
3. Documented evidence of ongoing rhabdomyolysis.
4. Currently taking or anticipated to need a PPAR agonist during the study.
5. Subjects with motor abnormalities other than related to the mitochondrial disease that may interfere with the outcome measures.
6. Treatment with an investigational drug within 3 months prior to Day 1.
7. Currently taking or anticipated to need a prescription and/or non-prescription drug that might interfere with the study endpoints.
8. Evidence of significant concomitant clinical disease that may need a change in management during the study or could interfere with the conduct or safety of this study (Stable well-controlled chronic conditions such hypercholesterolemia, gastroesophageal reflux, or depression under control with medication (other than tricyclic antidepressants), are acceptable provided the symptoms and medications would not be predicted to compromise safety or interfere with the tests and interpretations of this study).
9. Subjects with diabetes who require treatment with insulin who are unwilling to undertake glucose monitoring for at least the first 12 weeks of dosing or in the Investigators opinion will not be able to adequately maintain glucose homeostasis.
10. Subjects with a history of cancer. A history of in situ basal cell carcinoma in the skin is allowed.
11. Have been hospitalised within the 3 months prior to Screening for any major medical condition (as deemed by the Principal Investigator).
12. Clinically significant cardiac disease or ECG abnormalities that in the opinion of the Principal Investigator should exclude the subject from enrolment into the study.
13. Any condition possibly reducing drug absorption (e.g., gastrectomy or serious GI dysmotility).
14. Subjects who have poor nutritional status as determined by the Investigator.
15. History of clinically significant liver disease and/or liver function tests (AST, ALT, total Bilirubin) >1.5 x ULN. Subjects with LFTs >1.5 x ULN and <2 x ULN at Screening may be retested once. Subjects with an isolated elevated bilirubin (e.g.< 2 x ULN) may be included after discussion with the Medical Monitor if the cause is due to a benign hereditary disorder of metabolism such as Gilbert’s syndrome.
16. Evidence of clinically significant muscle damage tests (CPK > 3 x ULN). Subjects with CPK > 3 x ULN and < 5 x ULN at Screening may be retested once.
17. Subjects with positive hepatitis B surface antigen (HBsAg), hepatitis B core antibody (HBcAb) or hepatitis C or human immunodeficiency virus (HIV) at Screening.
18. Pregnant or nursing females.
19. History of sensitivity to PPAR agonists.
20. Subjects who are taking anticoagulants that would preclude muscle biopsy.
21. Donation or intent to donate blood, or blood components during the study or within one month after completion of the study.
22. Subjects with a history of drug abuse or with a positive urine drug screen at Screening. Positive results for opiates and/or benzodiazepines will only be allowed if supported by a corresponding prescription from a medically qualified person.
23. History of regular alcohol consumption exceeding 14 units/week (1 unit = 75 mL of wine or 250 mL of beer or 25 mL of spirits) within 6 months of Screening.
24. Inability to comprehend or unwilling to follow the study requirements including restrictions on treatments, attendance at clinic visits, completion of questionnaires and participation in laboratory testing as called for by the protocol.
25. Any other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the Investigator in discussion with the Medical Monitor, would make the subject inappropriate for entry into this study.
26. Subjects who are not eligible or have a contraindication for cataract surgery. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| • Number and severity of adverse events |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Baseline to follow-up visit |
|
| E.5.2 | Secondary end point(s) |
Safety
Absolute values, changes from baseline (at 12 and 48 weeks if
applicable) and incidence of clinically significant changes in:
• Laboratory safety tests
• Electrocardiograms
• Supine vital signs
Pharmacokinetic
• REN001 plasma concentrations using population pharmacokinetic
methodology
• Identification of metabolites using pooled plasma
Pharmacodynamic
Absolute values and changes from baseline in serum biomarkers:
• FGF-21 (Baseline and Week 12)
• GDF-15 (Baseline and Week 12)
Absolute values and changes from baseline in acylcarnitine panel
(Baseline and Week 12)
Changes from baseline in muscle histopathology (Week 12) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Safety
Baseline and weeks 1, 2, 4, 8, 12, 16, 20, 24, 36 and 48 (Weeks 16 to 48 apply only to subjects who take part in optional part B), and follow-up
Pharmacokinetic
Baseline to Week 12
Pharmacodynamic
Baseline and Week 12 |
|
| 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 | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | No |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| 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) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
|
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| 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 | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| 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 | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| 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 | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| 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
|
|
| 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 | 6 |
| E.8.9.1 | In the Member State concerned days | |
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