RTA 408 Capsules in Patients With Friedreich's Ataxia - MOXIe
Condition: Friedreich Ataxia
MeSH terms: Ataxia; Cerebellar Ataxia; Friedreich Ataxia
Intervention: Omaveloxolone Capsules, 2.5 mg; Omaveloxolone Capsules, 5 mg; Omaveloxolone Capsules, 10 mg; Placebo; Omaveloxolone Capsules, 20 mg; Omaveloxolone Capsules, 40 mg; Omaveloxolone Capsules, 80 mg; Omaveloxolone Capsules, 160 mg; Omaveloxolone Capsules, 300 mg; Omaveloxolone Capsules, 150 mg
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 172.0
Sex: All
Minimum age: 16 Years
Maximum age: 40 Years
Healthy volunteers: No
Keywords: RTA 408; RTA 408 Capsules; Oxidative Stress; Mitochondrial dysfunction; omaveloxolone

Summary:

      Friedreich's ataxia is an autosomal recessive cerebellar ataxia caused by triplet-repeat
      expansions. The causative mutation is a trinucleotide (GAA) repeat expansion in the first
      intron of the frataxin gene, leading to impaired transcription of frataxin. The pathological
      consequences of frataxin deficiency include a severe disruption of iron-sulfur cluster
      biosynthesis, mitochondrial iron overload coupled to cellular iron dysregulation, and an
      increased sensitivity to oxidative stress.

      A hallmark of Friedreich's ataxia is impairment of antioxidative defense mechanisms, which
      play a major role in disease progression. Studies have demonstrated that nuclear factor
      erythroid-derived 2-related factor 2 (Nrf2) signaling is grossly impaired in patients with
      Friedreich's ataxia. Therefore, the ability of omaveloxolone (RTA 408) to activate Nrf2 and
      induce antioxidant target genes is hypothesized to be therapeutic in patients with
      Friedreich's ataxia.

      This 2-part study will evaluate the efficacy, safety, and pharmacodynamics of omaveloxolone
      (RTA 408) in the treatment of patients with Friedreich's ataxia.

      Part 1: The first part of 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 Friedreich's ataxia.

      Part 2: The second part of this study is a randomized, placebo-controlled, double-blind,
      parallel-group study to evaluate the safety and efficacy of omaveloxolone (RTA 408) 150 mg in
      patients with Friedreich's ataxia. Patients enrolled in Part 2 will be randomized 1:1 to
      receive omaveloxolone (RTA 408) 150 mg or placebo.

      Extension: The extension will assess long-term safety and tolerability of omaveloxolone (RTA
      408) in qualified patients with Friedreich's ataxia following completion of Part 1 or Part 2.
      Patients will not be unblinded to study treatment in Part 1 or Part 2 upon entering the
      extension study. Patients will receive open-label omaveloxolone (RTA 408) at 150 mg once
      daily.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Have genetically confirmed Friedreich's ataxia

          2. Have a modified FARS score ≥20 and ≤80

          3. Be male or female and ≥16 years of age and ≤40 years of age

          4. 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

          5. Have the ability to complete maximal exercise testing

          6. Be able to swallow capsules

        Exclusion Criteria:

          1. Have uncontrolled diabetes (HbA1c >11.0%)

          2. Have B-type natriuretic peptide value >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, or alanine aminotransferase

          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. Moderate or strong inhibitors or inducers of cytochrome P450 3A4 (e.g.,
                  carbamazepine, phenytoin, ciprofloxacin, grapefruit juice)

               3. 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

         11. Prior participation in a trial with omaveloxolone (RTA 408)