A Study to Learn About the Effects and Safety of RTA 408 (Omaveloxolone) in People Aged 16 to 40 With Friedreich's Ataxia

Biogen172 enrolled

Overview

In this study, researchers are learning more about RTA 408, also known as omaveloxolone, BIIB141, or SKYCLARYS®. The main goal of this study is to learn more about the safety of RTA 408 and how it affects physical effort, movement, coordination, and how participants feel in daily life. The main questions researchers want to answer in this study are: * How much physical effort can a participant produce during a cycling test after 12 weeks of treatment? * How do scores on the modified Friedreich's Ataxia Rating Scale (mFARS) change after 48 weeks? Researchers will use the modified Friedreich's Ataxia Rating Scale (mFARS) to measure how FA affects the nervous system. The mFARS looks at movement ability, balance, coordination, speech, and how well the arms and legs work. They will also use a cycling test to measure physical effort, along with questionnaires to learn how participants feel and function in daily life. Safety will also be tested using physical exams, vital sign checks, echocardiograms (ECHO), electrocardiograms (ECG), and blood and urine tests. The study will be done in 2 main parts, followed by an optional Extension period: * In Part 1, participants will be randomly assigned to take different doses of RTA 408 or a placebo by mouth once a day for 12 weeks. A placebo looks like the study drug but contains no real medicine. * Researchers will compare these doses to decide which one to use in Part 2. * In Part 2, a different group of participants will take either the chosen dose of RTA 408 (150 mg) or placebo once a day for 48 weeks. * Participants who complete Part 1 or Part 2 may be able to join an Extension period, where everyone receives RTA 408. * In the Extension period, participants will continue to receive RTA 408 until the drug becomes commercially available or until they leave the study * Participants in Part 1 will have up to 9 study visits and 2 phone calls. If they do not move onto the Extension period, they will stay in the study for up to 20 weeks. * Participants in Part 2 will have up to 10 study visits and 3 phone calls. If they do not move onto the Extension period, they will stay in the study for up to 61 weeks. * Participants in the Extension period will have 2 visits in the first month, followed by visits every 6 months.

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

Sex: ALLMin age: 16 YearsMax age: 40 Years

Medical Language ↔ Plain English

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)

Locations (11)

UCLA

Los Angeles, California, United States

University of Florida - Neurology

Gainesville, Florida, United States

USF Ataxia Research Center

Tampa, Florida, United States

Emory University Hospital - Neurology

Atlanta, Georgia, United States

University of Iowa Stead Family Children's Hospital

Iowa City, Iowa, United States

Ohio State University - Neurology

Columbus, Ohio, United States

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, United States

Murdoch Childrens Research Institute

Parkville, Victoria, Australia

Medical University Innsbruck

Innsbruck, Austria

Neurological Institute Carlo Besta

Milan, Italy

...and 1 more locations

Outcomes

Primary Outcomes

Part 1: Change From Baseline in Peak Work During Maximal Exercise Testing at Week 12

Cycle ergometry using a recumbent stationary bicycle was used to conduct maximal exercise testing and workload was increased incrementally. Peak work is defined as the workload at which participants reach maximal volition (defined as an inability to continue to exercise due to exhaustion). A positive change from baseline suggests an improvement.

Time frame: Baseline, Week 12

Part 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs)

An adverse event (AE) was any unfavorable and unintended sign (including any clinically significant abnormal laboratory test result), symptom, or disease temporally associated with the use of the study drug whether or not it is considered to be study drug related. An SAE was any untoward medical occurrence that at any dose resulted in death, in the view of the Investigator, placed the participant at immediate risk of death, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, resulted in a birth defect. TEAEs were defined as any AEs, regardless of relationship to study drug, that had an onset or worsened in severity on or after the first dose of study drug.

Time frame: From first dose of study drug up to end of Part 1 of the study (up to Week 16)

Part 2: Change From Baseline in the Modified Friedreich's Ataxia Rating Scale (mFARS) at Week 48

The Friedreich Ataxia Rating Scale (FARS) is a neurological-exam-based rating scale with five sections: Bulbar (section A), Upper Limb Coordination (section B), Lower Limb Coordination (section C), Peripheral Nervous System (section D), and Upright Stability (section E). mFARS is the sum of sections A (score 0 to 11), B (score 0 to 36), C (score 0 to 16), and E (score 0 to 36). The minimum score is 0 and the maximum score is 99. A lower score indicates better neurological function.

Time frame: Baseline, Week 48

Part 2: Number of Participants With TEAEs and TESAEs

An AE was any unfavorable and unintended sign (including any clinically significant abnormal laboratory test result), symptom, or disease temporally associated with the use of the study drug whether or not it is considered to be study drug related. An SAE was any untoward medical occurrence that at any dose resulted in death, in the view of the Investigator, placed the participant at immediate risk of death, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, resulted in a birth defect. TEAEs were defined as any AEs, regardless of relationship to study drug, that had an onset or worsened in severity on or after the first dose of study drug.

Time frame: From first dose of study drug up to end of Part 2 of the study (up to Week 52)

Secondary Outcomes

Part 1: Change From Baseline in the mFARS at Week 12

The FARS is a neurological-exam-based rating scale with five sections: Bulbar (section A), Upper Limb Coordination (section B), Lower Limb Coordination (section C), Peripheral Nervous System (section D), and Upright Stability (section E). mFARS is the sum of sections A (score 0 to 11), B (score 0 to 36), C (score 0 to 16), and E (score 0 to 36). The minimum score is 0 and the maximum score is 99. A lower score indicates better neurological function.

Time frame: Baseline, Week 12

Part 2: Number of Participants With Patient Global Impression of Change (PGI-C)

The PGI-C is a 7-point scale that requires participants to assess how much their illness has improved or worsened relative to their baseline state at the beginning of the trial. Participants self-rated their perceived change by completing the following statement: "Since I began trial treatment, my overall status is:" 1=Very much improved, 2=Much improved, 3=Minimally improved, 4=No change, 5=Minimally worse, 6=Much worse and 7=Very much worse. Lower score indicates better improvement. The categories with at least one participant having a PGI-C score are reported.

Time frame: Week 48

Part 2: Number of Participants With Clinical Global Impression of Change (CGI-C)

The CGIC scale is a 7 point scale that requires the clinician to assess how much the participant's illness has improved or worsened relative to a baseline state at the beginning of an intervention. The CGIC was assessed by completing the following statement "Compared to the participant's condition at the start of the trial, this participant's overall status is", where 1=very much improved, 2=much improved, 3=minimally improved, 4=no change, 5=minimally worse, 6=much worse, 7=very much worse. Lower score indicates better improvement. The categories with at least one participant having a CGIC score are reported.

Time frame: Week 48

Part 2: Change From Baseline in Performance on a 9-Hole Peg Test (9-HPT) at Week 48

The 9-HPT is a brief, standardized, quantitative test of upper extremity (arm and hand) function. Both the dominant and nondominant hands were tested twice (2 consecutive trials of the dominant hand, followed immediately by 2 consecutive trials of the nondominant hand). The participant picks up pegs 1 at a time (9 in total), using 1 hand only, and places them into holes on the board as quickly as possible, in any order until all holes are filled. Then, without pausing, the participant removes the pegs 1 at a time and returns them as quickly as possible. The times recorded for the two trials for each hand are averaged, and the reciprocal average value for each hand was used in analyses. Longer test times reflect more impairment on the participant's upper extremity function, thus a negative change from baseline suggests an improvement.

Part 2: Change From Baseline in the Activities of Daily Living (ADL) Score at Week 48

The ADL scale examines the ability of participants to complete everyday tasks (e.g., holding a fork, dressing). The ADL is a 9-question assessment, with the total score being the sum of 9 questions. The ADL survey assesses 9 concepts: (1) speech; (2) swallowing; (3) cutting food and handling utensils; (4) dressing; (5) personal hygiene; (6) falling; (7) walking; (8) quality of sitting position; and (9) bladder function. Each of these is rated on a 5-point scale where 0= normal and 4= severe disability/inability to carry out activity independently, for a total possible score of 0 to 36, with higher scores representing greater disability/dependency. A negative change from baseline indicates improvement.