RTA 408 Capsules in Patients With Mitochondrial Myopathy - MOTOR

Study Overview
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Brief Summary
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Mitochondrial myopathies are a multisystemic group of disorders that are characterized by a wide range of biochemical and genetic mitochondrial defects and variable modes of inheritance. Currently there are no effective treatments for this disease. Despite the heterogeneous myopathy phenotypes, a unifying feature of mitochondrial myopathies is that the pathogenic mtDNA mutations and/or nuclear mutations of the electron transport chain invariably lead to dysfunctional mitochondrial respiration. This reduction in mitochondrial respiration leads to a reduced ability to produce cellular adenosine triphosphate (ATP), often resulting in muscle weakness, exercise intolerance, and fatigue in patients with mitochondrial myopathies. RTA 408 is a potent activator of Nrf2 and inhibitor of NF κB (nuclear factor kappa-light-chain-enhancer of activated B cells), and thus induces an antioxidant and anti-inflammatory phenotype. Several lines of evidence suggest that Nrf2 activation can increase mitochondrial respiration and biogenesis. Collectively, available data suggest that the ability of RTA 408 to activate Nrf2 and induce its target genes could potentially improve muscle function, oxidative phosphorylation, antioxidant capacity, and mitochondrial biogenesis in patients with mitochondrial myopathies. This study will be a randomized, placebo-controlled, double-blind, dose-escalation study to evaluate the safety of omaveloxolone (RTA 408) at various doses in patients with mitochondrial myopathies.

Detailed Description
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This study was previously posted by Reata Pharmaceuticals. In September 2023, sponsorship of the trial was transferred to Biogen.

Official Title
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A Phase 2 Study of the Safety, Efficacy, and Pharmacodynamics of RTA 408 in the Treatment of Mitochondrial Myopathy (MOTOR)

Conditions
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MItochondrial Myopathies

Intervention / Treatment
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* Drug: Omaveloxolone capsules, 2.5 mg
* Drug: omaveloxolone capsules, 5 mg
* Drug: omaveloxolone capsules, 10 mg
* Drug: Placebo capsules
* Drug: omaveloxolone capsules, 20 mg
* Drug: omaveloxolone capsules, 40 mg
* Drug: omaveloxolone capsules, 80 mg
* Drug: omaveloxolone capsules, 160 mg


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Have mitochondrial myopathy as evidenced by the following 2 criteria (must meet both): 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) 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 Be male or female and ≥18 years of age and ≤75 years of age Have no changes to 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 Have the ability to complete maximal exercise testing Have a peak workload during maximal exercise testing of ≤ 1.5 W/kg Be able to swallow capsules Exclusion Criteria: Have uncontrolled diabetes (HbA1c >11.0%) Have B-type natriuretic peptide level >200 pg/mL Have a history of clinically significant left-sided heart disease and/or clinically significant cardiac disease Have known active fungal, bacterial, and/or viral infection, including human immunodeficiency virus or hepatitis virus (B or C) Have known or suspected active drug or alcohol abuse 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 Have any abnormal laboratory test value or serious pre-existing medical condition that, in the opinion of the investigator, would put the patient at risk by study enrollment 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: Sensitive substrates for cytochrome P450 2C8 or 3A4 (e.g., repaglinide, midazolam, sildenafil) Substrates for p-glycoprotein transporter (e.g., ambrisentan, digoxin) Have participated in any other interventional clinical study within 30 days prior to Study Day 1 Have a cognitive impairment that may preclude ability to comply with study procedures

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: omaveloxolone Capsules 2.5 mg and 5 mg<br>omaveloxolone (RTA 408) Capsules, 2.5 mg taken orally once daily for 2 weeks, then 5 mg taken orally once daily for 10 weeks | Drug: Omaveloxolone capsules, 2.5 mg<br> <br> * Other names: RTA 408 Capsules 2.5 mg;Drug: omaveloxolone capsules, 5 mg<br> <br> * Other names: RTA 408 capsules, 5 mg;|
| Experimental: omaveloxolone Capsules 10 mg<br>omaveloxolone (RTA 408) capsules, 10 mg taken orally once daily for 12 weeks | Drug: omaveloxolone capsules, 10 mg<br> <br> * Other names: RTA 408, 10 mg;|
| Placebo Comparator: Placebo Capsules<br>Placebo capsules taken orally once daily for 12 weeks | Drug: Placebo capsules<br> <br> |
| Experimental: omaveloxolone Capsules 20 mg<br>omaveloxolone (RTA 408) Capsules, 20 mg taken orally once daily for 12 weeks. | Drug: omaveloxolone capsules, 20 mg<br> <br> * Other names: RTA 408 capsules, 20 mg;|
| Experimental: omaveloxolone Capsules 40 mg<br>omaveloxolone (RTA 408) Capsules, 40 mg taken orally once daily for 12 weeks. | Drug: omaveloxolone capsules, 40 mg<br> <br> * Other names: RTA 408 capsules, 40 mg;|
| Experimental: omaveloxolone Capsules 80 mg<br>omaveloxolone (RTA 408) Capsules, 80 mg taken orally once daily for 12 weeks. | Drug: omaveloxolone capsules, 80 mg<br> <br> * Other names: RTA 408 capsules, 80 mg;|
| Experimental: omaveloxolone Capsules 160 mg<br>omaveloxolone (RTA 408) Capsules, 160 mg taken orally once daily for 12 weeks. | Drug: omaveloxolone capsules, 160 mg<br> <br> * Other names: RTA 408 capsules, 160 mg;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change of Peak Workload (in Watts/kg) During Exercise Testing | Cycle ergometry using a stationary recumbent bike was used to conduct maximal exercise testing. Peak work is defined as the workload at which patients reach maximal volition (defined as an inability to continue to exercise due to exhaustion). Change of peak workload during exercise testing was measured at baseline, Week 4, and Week 12. Change from baseline at Week 12 reported. | 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in 6-minute Walk Test (6MWT) Distance | Patients were instructed to walk as far as they could along a marked path for 6 minutes. Distance walked was measured. If patients used a cane or walking assist device at Screening, the same walking assist device was to be used for all 6MWT assessments. | 6MWT was assessed at Week 4, Week 8, and Week 12 and compared to baseline | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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omaveloxolone, RTA 408 capsules, mitochondrial myopathies