RTA 408 Capsules in Patients With Mitochondrial Myopathy - MOTOR
Condition: MItochondrial Myopathies
MeSH terms: Muscular Diseases; Mitochondrial Myopathies
Intervention: Omaveloxolone capsules, 2.5 mg; omaveloxolone capsules, 5 mg; omaveloxolone capsules, 10 mg; Placebo capsules; omaveloxolone capsules, 20 mg; omaveloxolone capsules, 40 mg; omaveloxolone capsules, 80 mg; omaveloxolone capsules, 160 mg
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Sequential Assignment
Masking: Double (Participant, Investigator)
Enrollment: 53.0
Sex: All
Minimum age: 18 Years
Maximum age: 75 Years
Healthy volunteers: No
Keywords: omaveloxolone; RTA 408 capsules; mitochondrial myopathies

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.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Have mitochondrial myopathy as evidenced by the following 2 criteria (must meet both):

               1. 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)

               2. 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 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 a peak workload during maximal exercise testing of ≤ 1.5 W/kg

          6. Be able to swallow capsules

        Exclusion Criteria:

          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

          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

          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

          7. 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

          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:

               1. Sensitive substrates for cytochrome P450 2C8 or 3A4 (e.g., repaglinide,
                  midazolam, sildenafil)

               2. Substrates for p-glycoprotein transporter (e.g., ambrisentan, digoxin)

          9. Have participated in any other interventional clinical study within 30 days prior to
             Study Day 1

         10. Have a cognitive impairment that may preclude ability to comply with study procedures