| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| 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 | 10017374 |
| E.1.2 | Term | Friedreich's ataxia |
| 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 |
Part1
• To evaluate the change in peak work during maximal exercise testing
• To evaluate the safety and tolerability of RTA 408
Part 2
• To evaluate the change in the modified Friedreich’s ataxia rating scale (mFARS) score at Week 48
• To evaluate the safety and tolerability of RTA 408 |
|
| E.2.2 | Secondary objectives of the trial |
Part 1
• To evaluate the change in the modified Friedreich’s ataxia rating scale (FARS) score
Part 2
• To evaluate the change in peak work during maximal exercise testing at Week 48
• To evaluate the Patient Global Impression of Change at Week 48
• To evaluate the Clinical Global Impression of Change at Week 48 |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Part 1 and Part 2
Patients must:
1. Have genetically confirmed Friedreich’s ataxia
2. Have a modified FARS score ≥20 and ≤80. The average of the two mFARS values collected at Screening and Day 1 visits must fall within the allowable range, and they must be within 4.5 points of each other
3. Be male or female and ≥16 years of age and ≤40 years of age
4. 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
5. Have the ability to complete maximal exercise testing
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. Have a left ventricular ejection fraction ≥40% (based on echocardiogram performed at Screening Visit or within 90 days prior to Screening Visit)
8. Be able to swallow capsules
9. Be willing and able to cooperate with all aspects of the protocol
10. Be willing to practice medically acceptable methods of birth control (Section 9.7.2)
11. Provide written informed consent for study participation, approved by the appropriate Institutional Review Board
Extension eligibility:
Patients must complete 12 weeks of treatment in Part 1 or 24 weeks of treatment in Part 2, have no major protocol deviations, and meet inclusion criteria as follows:
1. 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
2. Have a left ventricular ejection fraction ≥ 40% (based on echocardiogram performed at Screening Visit or within 90 days prior to Screening Visit)
3. Be able to swallow capsules
4. Be willing and able to cooperate with all aspects of the extension
5. Be willing to practice medically acceptable methods of birth control
6. Provide written informed consent for study participation, approved by the appropriate Institutional Review Board (IRB)
7. Have been enrolled in Part 1 or Part 2 and completed assessments through the follow-up visit with no major protocol deviations. |
|
| E.4 | Principal exclusion criteria |
Part 1 and Part 2:
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, with the exception of mild to moderate cardiomyopathy associated with Friedreich’s ataxia, 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 90 days prior to Screening Visit)
c. Restrictive or congestive cardiomyopathy (based on echocardiogram performed at Screening Visit or within 90 days prior to Screening Visit)
d. Symptomatic coronary disease (prior myocardial infarction, percutaneous coronary intervention, coronary artery bypass graft surgery, or angina)
e. History of hospitalization for heart failure in the last five years
f. Cardiac insufficiency, defined as New York Heart Association Class >2
g. History of atrial fibrillation
h. History of unstable arrhythmias
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, or alanine aminotransferase. 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. 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 previously documented mitochondrial respiratory chain disease
15. Have a history of thromboembolic events within the past 5 years
16. Have taken anticoagulant therapy within 30 days prior to Study Day 1
17. Have scheduled surgical treatment for scoliosis or foot deformity during the study
18. Have had significant suicidal ideation within 1 month prior to Screening Visit as per investigator judgment or any history of suicide attempts
19. Be pregnant or breastfeeding
20. Prior participation in a trial with RTA 408
Extension eligibility:
Patients must not:
• Have uncontrolled diabetes (HbA1c > 11.0%)
• Have B-type natriuretic peptide (BNP) level > 200 pg/mL
• Have a history of clinically significant left-sided heart disease and/or clinically significant cardiac disease, with the exception of mild to moderate cardiomyopathy associated with Friedreich’s ataxia
• Have a history of clinically significant liver disease or has, at screening, clinically relevant deviations in laboratory tests
• Have a cognitive impairment that may preclude ability to comply with study procedures
• 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
• Have a history of thromboembolic events within the past 5 years
• Have taken anticoagulant therapy within 30 days prior to Extension Day 1
• Be pregnant or breastfeeding
• Have an ongoing SAE from a clinical study that is assessed by the investigator as related to RTA 408
• Have discontinued treatment early in Part 1 or Part 2. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Part 1
Change in peak work during maximal exercise testing
Part 2
Change in the modified Friedreich's ataxia rating scale (mFARS) score |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Part 1
screening, day 1, week 4, week 12
Part 2
screening, day 1, week 4, week 12, week 18, week 24, week 36, week 48 |
|
| E.5.2 | Secondary end point(s) |
Part 1
Change in the modified Friedreich's ataxia rating scale (FARS) score
Part 2
• Change in peak work during maximal exercise testing
• Changes in the Patient and Clinical Global Impression of Change |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Part 1
screening, day 1, week 4, week 8, week 12
Part 2
peak work during maximal exercise testing:
screening, day 1, week 4, week 12, week 18, week 24, week 36, week 48
Patient and Clinical Global Impression of Change:
week 12, week 24, week 36, week 48 |
|
| 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 | 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 | 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 |
| United States |
| United Kingdom |
|
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 8 |
| E.8.9.1 | In the Member State concerned months | 2 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 11 |
| E.8.9.2 | In all countries concerned by the trial months | 3 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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