A Phase 2 Study of the Safety, Efficacy, and Pharmacodynamics of RTA 408 in the Treatment of Mitochondrial Myopathy (MOTOR)
Overview
- Phase
- Phase 2
- Intervention
- Omaveloxolone capsules, 2.5 mg
- Conditions
- MItochondrial Myopathies
- Sponsor
- Biogen
- Enrollment
- 53
- Locations
- 9
- Primary Endpoint
- Change of Peak Workload (in Watts/kg) During Exercise Testing
- Status
- Completed
- Last Updated
- 11 months ago
Overview
Brief Summary
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
Study Sponsor, originally Reata Pharmaceuticals, Inc., is now Reata Pharmaceuticals, Inc., a wholly owned subsidiary of Biogen.
Investigators
Eligibility Criteria
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)
Arms & Interventions
omaveloxolone Capsules 2.5 mg and 5 mg
omaveloxolone (RTA 408) Capsules, 2.5 mg taken orally once daily for 2 weeks, then 5 mg taken orally once daily for 10 weeks
Intervention: Omaveloxolone capsules, 2.5 mg
omaveloxolone Capsules 2.5 mg and 5 mg
omaveloxolone (RTA 408) Capsules, 2.5 mg taken orally once daily for 2 weeks, then 5 mg taken orally once daily for 10 weeks
Intervention: omaveloxolone capsules, 5 mg
omaveloxolone Capsules 10 mg
omaveloxolone (RTA 408) capsules, 10 mg taken orally once daily for 12 weeks
Intervention: omaveloxolone capsules, 10 mg
Placebo Capsules
Placebo capsules taken orally once daily for 12 weeks
Intervention: Placebo capsules
omaveloxolone Capsules 20 mg
omaveloxolone (RTA 408) Capsules, 20 mg taken orally once daily for 12 weeks.
Intervention: omaveloxolone capsules, 20 mg
omaveloxolone Capsules 40 mg
omaveloxolone (RTA 408) Capsules, 40 mg taken orally once daily for 12 weeks.
Intervention: omaveloxolone capsules, 40 mg
omaveloxolone Capsules 80 mg
omaveloxolone (RTA 408) Capsules, 80 mg taken orally once daily for 12 weeks.
Intervention: omaveloxolone capsules, 80 mg
omaveloxolone Capsules 160 mg
omaveloxolone (RTA 408) Capsules, 160 mg taken orally once daily for 12 weeks.
Intervention: omaveloxolone capsules, 160 mg
Outcomes
Primary Outcomes
Change of Peak Workload (in Watts/kg) During Exercise Testing
Time Frame: 12 weeks
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.
Secondary Outcomes
- Change in 6-minute Walk Test (6MWT) Distance(6MWT was assessed at Week 4, Week 8, and Week 12 and compared to baseline)