A Study to Learn About the Effects and Safety of RTA 408 (Omaveloxolone) in People Aged 16 to 40 With Friedreich's Ataxia
- Conditions
- Friedreich Ataxia
- Interventions
- Drug: Placebo
- Registration Number
- NCT02255435
- Lead Sponsor
- Biogen
- Brief Summary
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.
- Detailed Description
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.
Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- All
- Target Recruitment
- 172
- 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
-
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
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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
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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
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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)
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Have participated in any other interventional clinical study within 30 days prior to Study Day 1
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Have a cognitive impairment that may preclude ability to comply with study procedures
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Prior participation in a trial with omaveloxolone (RTA 408)
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Part 1 Omaveloxolone Capsules 80 mg Omaveloxolone Capsules, 80 mg Omaveloxolone (RTA 408) Capsules, 80 mg administered orally once daily for 12 weeks Part 1 Omaveloxolone Capsules 160 mg Omaveloxolone Capsules, 160 mg Omaveloxolone (RTA 408) Capsules, 160 mg administered orally once daily for 12 weeks Part 1 Omaveloxolone Capsules 300 mg Omaveloxolone Capsules, 300 mg Omaveloxolone (RTA 408) Capsules, 300 mg administered orally once daily for 12 weeks Part 1 Placebo Capsules Placebo Placebo capsules administered orally once daily for 12 weeks Part 2 Placebo Capsules Placebo Placebo capsules administered orally once daily for 48 weeks Part 2 Omaveloxolone Capsules 150 mg Omaveloxolone Capsules, 150 mg Omaveloxolone (RTA 408) Capsules, 150 mg administered orally once daily for 48 weeks Part 1 Omaveloxolone Capsules 2.5 and 5 mg Omaveloxolone Capsules, 2.5 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 Part 1 Omaveloxolone Capsules 2.5 and 5 mg Omaveloxolone Capsules, 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 Part 1 Omaveloxolone Capsules 10 mg Omaveloxolone Capsules, 10 mg omaveloxolone (RTA 408) Capsules, 10 mg administered orally once daily for 12 weeks Part 1 Omaveloxolone Capsules 20 mg Omaveloxolone Capsules, 20 mg Omaveloxolone (RTA 408) Capsules, 20 mg administered orally once daily for 12 weeks Part 1 Omaveloxolone Capsules 40 mg Omaveloxolone Capsules, 40 mg Omaveloxolone (RTA 408) Capsules, 40 mg administered orally once daily for 12 weeks
- Primary Outcome Measures
Name Time Method Change From Baseline in Peak Work (in Watts/kg) During Exercise Testing at Week 12 in Part 1 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).
Change in the Modified Friedreich's Ataxia Rating Scale (mFARS) at Week 48 in Part 2 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
Name Time Method Change in the Modified Friedreich's Ataxia Rating Scale (mFARS) at Week 12 in Part 1 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.
Trial Locations
- 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
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