RTA 408 Capsules in Patients With Friedreich's Ataxia - MOXIe

Study Overview
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Brief Summary
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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.

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 Friedreich's Ataxia (MOXIe)

Conditions
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Friedreich Ataxia

Intervention / Treatment
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* Drug: Omaveloxolone Capsules, 2.5 mg
* Drug: Omaveloxolone Capsules, 5 mg
* Drug: Omaveloxolone Capsules, 10 mg
* Drug: Placebo
* Drug: Omaveloxolone Capsules, 20 mg
* Drug: Omaveloxolone Capsules, 40 mg
* Drug: Omaveloxolone Capsules, 80 mg
* Drug: Omaveloxolone Capsules, 160 mg
* Drug: Omaveloxolone Capsules, 300 mg
* Drug: Omaveloxolone Capsules, 150 mg


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

Ages Eligible for Study
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Minimum Age: 16 Years
Maximum Age: 40 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: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1 Omaveloxolone Capsules 2.5 and 5 mg<br>omaveloxolone (RTA 408) Capsules, 2.5 mg administered orally one 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: Part 1 Omaveloxolone Capsules 10 mg<br>omaveloxolone (RTA 408) Capsules, 10 mg administered orally once daily for 12 weeks | Drug: Omaveloxolone Capsules, 10 mg<br> <br> * Other names: RTA 408 capsules, 10 mg;|
| Experimental: Part 1 Omaveloxolone Capsules 20 mg<br>Omaveloxolone (RTA 408) Capsules, 20 mg administered orally once daily for 12 weeks | Drug: Omaveloxolone Capsules, 20 mg<br> <br> * Other names: RTA 408 capsules, 20 mg;|
| Experimental: Part 1 Omaveloxolone Capsules 40 mg<br>Omaveloxolone (RTA 408) Capsules, 40 mg administered orally once daily for 12 weeks | Drug: Omaveloxolone Capsules, 40 mg<br> <br> * Other names: RTA 408 capsules, 40 mg;|
| Experimental: Part 1 Omaveloxolone Capsules 80 mg<br>Omaveloxolone (RTA 408) Capsules, 80 mg administered orally once daily for 12 weeks | Drug: Omaveloxolone Capsules, 80 mg<br> <br> * Other names: RTA 408 capsules, 80 mg;|
| Experimental: Part 1 Omaveloxolone Capsules 160 mg<br>Omaveloxolone (RTA 408) Capsules, 160 mg administered orally once daily for 12 weeks | Drug: Omaveloxolone Capsules, 160 mg<br> <br> * Other names: RTA 408 capsules, 160 mg;|
| Experimental: Part 1 Omaveloxolone Capsules 300 mg<br>Omaveloxolone (RTA 408) Capsules, 300 mg administered orally once daily for 12 weeks | Drug: Omaveloxolone Capsules, 300 mg<br> <br> * Other names: RTA 408 capsules, 300 mg;|
| Placebo Comparator: Part 1 Placebo Capsules<br>Placebo capsules administered orally once daily for 12 weeks | Drug: Placebo<br> <br> |
| Placebo Comparator: Part 2 Placebo Capsules<br>Placebo capsules administered orally once daily for 48 weeks | Drug: Placebo<br> <br> |
| Experimental: Part 2 Omaveloxolone Capsules 150 mg<br>Omaveloxolone (RTA 408) Capsules, 150 mg administered orally once daily for 48 weeks | Drug: Omaveloxolone Capsules, 150 mg<br> <br> * Other names: RTA 408 capsules, 150 mg;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Peak Work (in Watts/kg) During Exercise Testing at Week 12 in Part 1 | Peak work attained during maximal exercise testing. Cycle ergometry using a recumbent stationary bicycle was used, and workload was increased incrementally. Peak work is defined as the workload at which patients reach maximal volition (defined as an inability to continue to exercise due to exhaustion). | Baseline through 12 weeks after participant receives the first dose in Part 1. | 
| Change in the Modified Friedreich's Ataxia Rating Scale (mFARS) at Week 48 in Part 2 | The mFARS includes 4 of the 5 sections of the Friedreich's Ataxia Rating Scale (FARS): bulbar (score 0 to 11), upper limb coordination (score 0 to 36), lower limb coordination (score 0 to 16), and upright stability (score 0 to 36). The minimum score is 0 and the maximum score is 99. A lower score indicates better neurological function. | 48 weeks after participant receives the first dose in Part 2 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in the Modified Friedreich's Ataxia Rating Scale (mFARS) at Week 12 in Part 1 | The mFARS includes 4 of the 5 sections of the Friedreich's Ataxia Rating Scale (FARS): bulbar (score 0 to 11), upper limb coordination (score 0 to 36), lower limb coordination (score 0 to 16), and upright stability (score 0 to 36). The minimum score is 0 and the maximum score is 99. A lower score indicates better neurological function. | 12 weeks after participant receives the first dose in Part 1 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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RTA 408, RTA 408 Capsules, Oxidative Stress, Mitochondrial dysfunction, omaveloxolone