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

Study Description

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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

Study Design

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Study Type :	Interventional (Clinical Trial)
Estimated 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)
Study Start Date :	January 2015
Estimated Primary Completion Date :	January 2020
Estimated Study Completion Date :	December 2022

Arms and Interventions

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Arm	Intervention/treatment
Experimental: Omaveloxolone Capsules 2.5 and 5 mg; omaveloxolone (RTA 408) Capsules, 2.5 mg taken 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: Omaveloxolone Capsules 10 mg; omaveloxolone (RTA 408) Capsules, 10 mg taken orally once daily for 12 weeks	Drug: Omaveloxolone Capsules, 10 mg; Other Name: RTA 408 capsules, 10 mg
Placebo Comparator: Placebo Capsules; Placebo capsules taken orally once daily for 12 weeks	Drug: Placebo
Experimental: Omaveloxolone Capsules 20 mg; omaveloxolone (RTA 408) Capsules, 20 mg taken orally once daily for 12 weeks	Drug: Omaveloxolone Capsules, 20 mg; Other Name: RTA 408 capsules, 20 mg
Experimental: Omaveloxolone Capsules 40 mg; omaveloxolone (RTA 408) Capsules, 40 mg taken orally once daily for 12 weeks	Drug: Omaveloxolone Capsules, 40 mg; Other Name: RTA 408 capsules, 40 mg
Experimental: Omaveloxolone Capsules 80 mg; omaveloxolone (RTA 408) Capsules, 80 mg taken orally once daily for 12 weeks	Drug: Omaveloxolone Capsules, 80 mg; Other Name: RTA 408 capsules, 48 mg
Experimental: Omaveloxolone Capsules 160 mg; omaveloxolone (RTA 408) Capsules, 160 mg taken orally once daily for 12 weeks	Drug: Omaveloxolone Capsules, 160 mg; Other Name: RTA 408 capsules, 160 mg
Experimental: Omaveloxolone Capsules 300 mg; omaveloxolone (RTA 408) Capsules, 300 mg taken orally once daily for 12 weeks	Drug: Omaveloxolone Capsules, 300 mg; Other Name: RTA 408 capsules, 300 mg
Experimental: Omaveloxolone Capsules 150 mg; omaveloxolone (RTA 408) Capsules, 150 mg taken orally once daily for 24 weeks	Drug: Omaveloxolone Capsules, 150 mg; Other Name: RTA 408 capsules, 150 mg

Outcome Measures

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Primary Outcome Measures :

1. Measure the change in the modified Friedreich's ataxia rating scale (FARS) [ Time Frame: 24 weeks ]

Secondary Outcome Measures :

1. Measure the change of peak workload (in watts/kg) during exercise testing [ Time Frame: 24 weeks ]

Eligibility Criteria

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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

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Locations

United States, California
UCLA	Recruiting
Los Angeles, California, United States, 90095
Contact: Aaron Fisher 310-206-8153 adfisher@mednet.ucla.edu
Principal Investigator: Susan Perlman, MD
United States, Florida
University of Florida - Neurology	Recruiting
Gainesville, Florida, United States, 32610
Contact: Amanda Cowsert amanda.cowsert@ufl.edu
Principal Investigator: SH Subramony, MD
USF Ataxia Research Center	Recruiting
Tampa, Florida, United States, 33612
Contact: Daniel Ekbert danielekberg@health.usf.edu
Contact: Jessica Shaw jshaw@helath.usf.edu
Principal Investigator: Theresa Zesiewicz, MD
United States, Georgia
Emory University Hospital - Neurology	Recruiting
Atlanta, Georgia, United States, 30329
Contact: Becky McMurray, RN 404-712-7013 rebecca.s.mcmurray@emory.edu
Principal Investigator: George Wilmot, MD
United States, Iowa
University of Iowa Stead Family Children's Hospital	Recruiting
Iowa City, Iowa, United States, 52242
Contact: Corey McDaniel corey-mcdaniel@uiowa.edu
Principal Investigator: Katherine Mathews, MD
United States, Ohio
Ohio State University - Neurology	Recruiting
Columbus, Ohio, United States, 43221
Contact: Tabitha Alexander 614-685-3030 tabitha.alexander@osumc.edu
Principal Investigator: Chad Hoyle, MD
United States, Pennsylvania
Children's Hospital of Philadelphia	Recruiting
Philadelphia, Pennsylvania, United States, 19104
Contact: Lauren Hauser 267-426-9738 hauserl@email.chop.edu
Principal Investigator: David Lynch, MD
Australia, Victoria
Murdoch Childrens Research Institute	Recruiting
Parkville, Victoria, Australia, 3052
Contact: Geneieve Tai 61 3 8341 6374 geneieve.tai@mcri.edu.au
Principal Investigator: Martin Delatycki, MD
Austria
Medical University Innsbruck	Recruiting
Innsbruck, Austria, 6020
Contact: Wolfgang Nachbauer Wolfgang.Nachbauer@i-med.ac.at
Principal Investigator: Sylvia Boesch, MD
Brazil
University of Campinas	Not yet recruiting
São Paulo, Brazil, 13083
Contact: Maria Fernanda Ribeiro Bittar mafe@fcm.unicamp.br
Principal Investigator: Marcondes Franaca
Italy
Neurological Institute Carlo Besta	Recruiting
Milan, Italy, 20133
Contact: Lorenzo Nanetti Lorenzo.Nanetti@istituto-besta.it
Principal Investigator: Caterina Mariotti
United Kingdom
University College of London	Recruiting
London, United Kingdom, WC1E 6BT
Contact: Mila Resuello-Dauti 0203 4484531 Mila.Resuello-Dauti@nhs.net
Principal Investigator: Paola Giunti, MD

Sponsors and Collaborators

Reata Pharmaceuticals, Inc.

AbbVie

Friedreich's Ataxia Research Alliance

More Information

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Top of Page Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Responsible Party:	Reata Pharmaceuticals, Inc.
ClinicalTrials.gov Identifier:	NCT02255435 History of Changes
Other Study ID Numbers:	RTA 408-C-1402
First Posted:	October 2, 2014
Last Update Posted:	September 11, 2018
Last Verified:	September 2018

Keywords provided by Reata Pharmaceuticals, Inc.:

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; Signs and Symptoms; 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