Clinical trial NCT02255435: RTA 408 Capsules in Patients With Friedreich's Ataxia - MOXIe
Official title: A Phase 2 Study of the Safety, Efficacy, and Pharmacodynamics of RTA 408 in the Treatment of Friedreich's Ataxia (MOXIe)
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Friedreich Ataxia
Keywords: RTA 408
RTA 408 Capsules
Oxidative Stress
Mitochondrial dysfunction
omaveloxolone
Lead sponsor: Biogen
Sponsor class: INDUSTRY
Collaborators: name: AbbVie
name: Friedreich's Ataxia Research Alliance
First posted: 2014-10-02
Enrollment: 172
Sex: ALL
Minimum age (years): 16
Maximum age (years): 40
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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 participants 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 participants with Friedreich's ataxia.

This 2-part study will evaluate the efficacy, safety, and pharmacodynamics of omaveloxolone (RTA 408) in the treatment of participants 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 participants 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 participants with Friedreich's ataxia. Participants 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 participants with Friedreich's ataxia following completion of Part 1 or Part 2. Participants will not be unblinded to study treatment in Part 1 or Part 2 upon entering the extension study. Participants 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)

Primary outcomes:
measure: Change From Baseline in Peak Work (in Watts/kg) During Exercise Testing at Week 12 in Part 1
timeFrame: Baseline through 12 weeks after participant receives the first dose in Part 1.
measure: Change in the Modified Friedreich's Ataxia Rating Scale (mFARS) at Week 48 in Part 2
timeFrame: 48 weeks after participant receives the first dose in Part 2
Secondary outcomes:
measure: Change in the Modified Friedreich's Ataxia Rating Scale (mFARS) at Week 12 in Part 1
timeFrame: 12 weeks after participant receives the first dose in Part 1
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: UCLA
state: California
city: Gainesville
country: United States
facility: University of Florida - Neurology
state: Florida
city: Tampa
country: United States
facility: USF Ataxia Research Center
state: Florida
city: Atlanta
country: United States
facility: Emory University Hospital - Neurology
state: Georgia
city: Iowa City
country: United States
facility: University of Iowa Stead Family Children's Hospital
state: Iowa
city: Columbus
country: United States
facility: Ohio State University - Neurology
state: Ohio
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
city: Parkville
country: Australia
facility: Murdoch Childrens Research Institute
state: Victoria
city: Innsbruck
country: Austria
facility: Medical University Innsbruck
city: Milan
country: Italy
facility: Neurological Institute Carlo Besta
city: London
country: United Kingdom
facility: University College of London
Study officials:
References:
citation: 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.
citation: 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.