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

• ClinicalTrials.gov Identifier: NCT02255435
• Recruitment Status: Active, not recruiting
• First Posted: October 2, 2014
• Results First Posted: November 29, 2022
• Last Update Posted: February 5, 2024
• Sponsor: Reata, a wholly owned subsidiary of Biogen
• Collaborators: AbbVie; Friedreich's Ataxia Research Alliance
• Information provided by (Responsible Party): Biogen ( Reata, a wholly owned subsidiary of Biogen )

Study Description

Brief 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.

Condition or disease	Intervention/treatment	Phase
Friedreich Ataxia	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	Phase 2

Detailed Description:

Study Sponsor, originally Reata Pharmaceuticals, Inc., is now Reata Pharmaceuticals, Inc., a wholly owned subsidiary of Biogen.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 172 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Phase 2 Study of the Safety, Efficacy, and Pharmacodynamics of RTA 408 in the Treatment of Friedreich's Ataxia (MOXIe)
• Actual Study Start Date: January 31, 2015
• Actual Primary Completion Date: October 31, 2019
• Estimated Study Completion Date: December 1, 2024

Arms and Interventions

Arm	Intervention/treatment
Experimental: Part 1 Omaveloxolone Capsules 2.5 and 5 mg; 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; Other Name: RTA 408 Capsules 2.5 mg; Drug: Omaveloxolone Capsules, 5 mg; Other Name: RTA 408 capsules, 5 mg
Experimental: Part 1 Omaveloxolone Capsules 10 mg; omaveloxolone (RTA 408) Capsules, 10 mg administered orally once daily for 12 weeks	Drug: Omaveloxolone Capsules, 10 mg; Other Name: RTA 408 capsules, 10 mg
Experimental: Part 1 Omaveloxolone Capsules 20 mg; Omaveloxolone (RTA 408) Capsules, 20 mg administered orally once daily for 12 weeks	Drug: Omaveloxolone Capsules, 20 mg; Other Name: RTA 408 capsules, 20 mg
Experimental: Part 1 Omaveloxolone Capsules 40 mg; Omaveloxolone (RTA 408) Capsules, 40 mg administered orally once daily for 12 weeks	Drug: Omaveloxolone Capsules, 40 mg; Other Name: RTA 408 capsules, 40 mg
Experimental: Part 1 Omaveloxolone Capsules 80 mg; Omaveloxolone (RTA 408) Capsules, 80 mg administered orally once daily for 12 weeks	Drug: Omaveloxolone Capsules, 80 mg; Other Name: RTA 408 capsules, 80 mg
Experimental: Part 1 Omaveloxolone Capsules 160 mg; Omaveloxolone (RTA 408) Capsules, 160 mg administered orally once daily for 12 weeks	Drug: Omaveloxolone Capsules, 160 mg; Other Name: RTA 408 capsules, 160 mg
Experimental: Part 1 Omaveloxolone Capsules 300 mg; Omaveloxolone (RTA 408) Capsules, 300 mg administered orally once daily for 12 weeks	Drug: Omaveloxolone Capsules, 300 mg; Other Name: RTA 408 capsules, 300 mg
Placebo Comparator: Part 1 Placebo Capsules; Placebo capsules administered orally once daily for 12 weeks	Drug: Placebo
Placebo Comparator: Part 2 Placebo Capsules; Placebo capsules administered orally once daily for 48 weeks	Drug: Placebo
Experimental: Part 2 Omaveloxolone Capsules 150 mg; Omaveloxolone (RTA 408) Capsules, 150 mg administered orally once daily for 48 weeks	Drug: Omaveloxolone Capsules, 150 mg; Other Name: RTA 408 capsules, 150 mg

Outcome Measures

Primary Outcome Measures :

1. Change From Baseline in Peak Work (in Watts/kg) During Exercise Testing at Week 12 in Part 1 [ Time Frame: Baseline through 12 weeks after participant receives the first dose 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).
2. Change in the Modified Friedreich's Ataxia Rating Scale (mFARS) at Week 48 in Part 2 [ Time Frame: 48 weeks after participant receives the first dose 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.

Secondary Outcome Measures :

1. Change in the Modified Friedreich's Ataxia Rating Scale (mFARS) at Week 12 in Part 1 [ Time Frame: 12 weeks after participant receives the first dose 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.

Eligibility Criteria

• Ages Eligible for Study: 16 Years to 40 Years (Child, Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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)

Contacts and Locations

Locations

United States, California

UCLA

Los Angeles, California, United States, 90095

United States, Florida

University of Florida - Neurology

Gainesville, Florida, United States, 32610

USF Ataxia Research Center

Tampa, Florida, United States, 33612

United States, Georgia

Emory University Hospital - Neurology

Atlanta, Georgia, United States, 30329

United States, Iowa

University of Iowa Stead Family Children's Hospital

Iowa City, Iowa, United States, 52242

United States, Ohio

Ohio State University - Neurology

Columbus, Ohio, United States, 43221

United States, Pennsylvania

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, United States, 19104

Australia, Victoria

Murdoch Childrens Research Institute

Parkville, Victoria, Australia, 3052

Austria

Medical University Innsbruck

Innsbruck, Austria, 6020

Italy

Neurological Institute Carlo Besta

Milan, Italy, 20133

United Kingdom

University College of London

London, United Kingdom, WC1E 6BT

Sponsors and Collaborators

Reata, a wholly owned subsidiary of Biogen

AbbVie

Friedreich's Ataxia Research Alliance

  Study Documents (Full-Text)

Documents provided by Biogen ( Reata, a wholly owned subsidiary of Biogen ):

Study Protocol: Main Protocol  [PDF] June 21, 2021

Study Protocol: United Kingdom Protocol  [PDF] June 21, 2021

Statistical Analysis Plan: Part 1  [PDF] May 15, 2017

Statistical Analysis Plan: Part 2  [PDF] September 18, 2019

Statistical Analysis Plan: Part 2 Addendum  [PDF] October 9, 2019

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Lynch DR, Chin MP, Delatycki MB, Subramony SH, Corti M, Hoyle JC, Boesch S, Nachbauer W, Mariotti C, Mathews KD, Giunti P, Wilmot G, Zesiewicz T, Perlman S, Goldsberry A, O'Grady M, Meyer CJ. Safety and Efficacy of Omaveloxolone in Friedreich Ataxia (MOXIe Study). Ann Neurol. 2021 Feb;89(2):212-225. doi: 10.1002/ana.25934. Epub 2020 Nov 5. Erratum In: Ann Neurol. 2023 Dec;94(6):1190.

Lynch DR, Farmer J, Hauser L, Blair IA, Wang QQ, Mesaros C, Snyder N, Boesch S, Chin M, Delatycki MB, Giunti P, Goldsberry A, Hoyle C, McBride MG, Nachbauer W, O'Grady M, Perlman S, Subramony SH, Wilmot GR, Zesiewicz T, Meyer C. Safety, pharmacodynamics, and potential benefit of omaveloxolone in Friedreich ataxia. Ann Clin Transl Neurol. 2018 Nov 10;6(1):15-26. doi: 10.1002/acn3.660. eCollection 2019 Jan.

• Responsible Party: Reata, a wholly owned subsidiary of Biogen
• ClinicalTrials.gov Identifier: NCT02255435
• Other Study ID Numbers: RTA 408-C-1402
• First Posted: October 2, 2014
• Results First Posted: November 29, 2022
• Last Update Posted: February 5, 2024
• Last Verified: February 2024

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: In accordance with Biogen's Clinical Trial Transparency and Data Sharing Policy on https://www.biogentrialtransparency.com/
• URL: https://vivli.org/

Keywords provided by Biogen ( Reata, a wholly owned subsidiary of Biogen ):

RTA 408; RTA 408 Capsules; Oxidative Stress; Mitochondrial dysfunction; omaveloxolone

Additional relevant MeSH terms:

Ataxia; Cerebellar Ataxia; Friedreich Ataxia; Dyskinesias; Neurologic Manifestations; Nervous System Diseases; Cerebellar Diseases; Brain Diseases; Central Nervous System Diseases; Spinocerebellar Degenerations; Spinal Cord Diseases; Heredodegenerative Disorders, Nervous System; Neurodegenerative Diseases; Genetic Diseases, Inborn; Mitochondrial Diseases; Metabolic Diseases