MItochondrial Myopathies
Conditions
Keywords
omaveloxolone, RTA 408 capsules, mitochondrial myopathies
Brief summary
Mitochondrial myopathies are a multisystemic group of disorders that are characterized by a wide range of biochemical and genetic mitochondrial defects and variable modes of inheritance. Currently there are no effective treatments for this disease. Despite the heterogeneous myopathy phenotypes, a unifying feature of mitochondrial myopathies is that the pathogenic mtDNA mutations and/or nuclear mutations of the electron transport chain invariably lead to dysfunctional mitochondrial respiration. This reduction in mitochondrial respiration leads to a reduced ability to produce cellular adenosine triphosphate (ATP), often resulting in muscle weakness, exercise intolerance, and fatigue in patients with mitochondrial myopathies. RTA 408 is a potent activator of Nrf2 and inhibitor of NF κB (nuclear factor kappa-light-chain-enhancer of activated B cells), and thus induces an antioxidant and anti-inflammatory phenotype. Several lines of evidence suggest that Nrf2 activation can increase mitochondrial respiration and biogenesis. Collectively, available data suggest that the ability of RTA 408 to activate Nrf2 and induce its target genes could potentially improve muscle function, oxidative phosphorylation, antioxidant capacity, and mitochondrial biogenesis in patients with mitochondrial myopathies. 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 mitochondrial myopathies.
Interventions
Sponsors
AbbVie
Biogen
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
1. Have mitochondrial myopathy as evidenced by the following 2 criteria (must meet both): 1. Have a history of exercise intolerance with or without weakness and/or progressive exercise intolerance (in which modest exercise typically provokes heaviness, weakness, aching of active muscles, or tachycardia) 2. Have a known primary mitochondrial DNA mutation or a nuclear DNA defect that is associated with reduced activity of at least 1 mitochondrially encoded respiratory chain complex 2. Be male or female and ≥18 years of age and ≤75 years of age 3. 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 4. Have the ability to complete maximal exercise testing 5. Have a peak workload during maximal exercise testing of ≤ 1.5 W/kg 6. Be able to swallow capsules
Exclusion criteria
1. Have uncontrolled diabetes (HbA1c \>11.0%) 2. Have B-type natriuretic peptide level \>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, alanine aminotransferase, or creatinine 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. 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change of Peak Workload (in Watts/kg) During Exercise Testing | 12 weeks | Cycle ergometry using a stationary recumbent bike was used to conduct maximal exercise testing. 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 of peak workload during exercise testing was measured at baseline, Week 4, and Week 12. Change from baseline at Week 12 reported. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in 6-minute Walk Test (6MWT) Distance | 6MWT was assessed at Week 4, Week 8, and Week 12 and compared to baseline | Patients were instructed to walk as far as they could along a marked path for 6 minutes. Distance walked was measured. If patients used a cane or walking assist device at Screening, the same walking assist device was to be used for all 6MWT assessments. |
Countries
Denmark, United States
Participant flow
Recruitment details
First patient enrolled 5-May-2015, last patient completed 30-Nov-2017
Participants by arm
| Arm | Count |
|---|---|
| Placebo Placebo capsules administered orally once daily for 12 weeks | 13 |
| Omaveloxolone Capsules 2.5 and 5 mg Omaveloxolone (RTA 408) 2.5 mg capsules administered orally once daily for 2 weeks then 5 mg administered orally once daily for 10 weeks | 6 |
| Omaveloxolone Capsules 10 mg Omaveloxolone (RTA 408) 10 mg capsules administered orally once daily for 12 weeks | 6 |
| Omaveloxolone Capsules 20 mg Omaveloxolone (RTA 408) 20 mg capsules administered orally once daily for 12 weeks | 6 |
| Omaveloxolone Capsules 40 mg Omaveloxolone (RTA 408) 40 mg capsules administered orally once daily for 12 weeks | 6 |
| Omaveloxolone Capsules 80 mg Omaveloxolone (RTA 408) 80 mg capsules administered orally once daily for 12 weeks | 6 |
| Omaveloxolone Capsules 160 mg Omaveloxolone (RTA 408) 160 mg capsules administered once daily for 12 weeks | 10 |
| Total | 53 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 |
|---|---|---|---|---|---|---|---|---|
| Overall Study | Lost to Follow-up | 0 | 0 | 1 | 0 | 0 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 0 | 0 | 0 | 0 | 2 |
Baseline characteristics
| Characteristic | Placebo | Omaveloxolone Capsules 2.5 and 5 mg | Omaveloxolone Capsules 10 mg | Omaveloxolone Capsules 20 mg | Omaveloxolone Capsules 40 mg | Omaveloxolone Capsules 80 mg | Omaveloxolone Capsules 160 mg | Total |
|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 41.1 Years STANDARD_DEVIATION 11.86 | 52.3 Years STANDARD_DEVIATION 9.61 | 49.8 Years STANDARD_DEVIATION 14.05 | 45.5 Years STANDARD_DEVIATION 14.08 | 45.2 Years STANDARD_DEVIATION 4.71 | 30.7 Years STANDARD_DEVIATION 10.25 | 39.8 Years STANDARD_DEVIATION 15.27 | 42.9 Years STANDARD_DEVIATION 13.01 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 3 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 11 Participants | 6 Participants | 5 Participants | 6 Participants | 6 Participants | 6 Participants | 7 Participants | 47 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Female | 9 Participants | 1 Participants | 3 Participants | 4 Participants | 5 Participants | 4 Participants | 6 Participants | 32 Participants |
| Sex: Female, Male Male | 4 Participants | 5 Participants | 3 Participants | 2 Participants | 1 Participants | 2 Participants | 4 Participants | 21 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk |
|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 13 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 10 |
| other Total, other adverse events | 11 / 13 | 4 / 6 | 6 / 6 | 6 / 6 | 6 / 6 | 4 / 6 | 10 / 10 |
| serious Total, serious adverse events | 1 / 13 | 0 / 6 | 1 / 6 | 0 / 6 | 1 / 6 | 1 / 6 | 1 / 10 |
Outcome results
Primary
Change of Peak Workload (in Watts/kg) During Exercise Testing
Cycle ergometry using a stationary recumbent bike was used to conduct maximal exercise testing. 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 of peak workload during exercise testing was measured at baseline, Week 4, and Week 12. Change from baseline at Week 12 reported.
Time frame: 12 weeks
Population: Three patients out of the 53 total were excluded from the analysis set. One each from the 20 mg arm and the 160 mg arm were excluded because they did not have post-baseline efficacy assessments. One patient from the placebo arm was excluded from analysis because their baseline maximal exercise test duration \< 4 min and was not considered valid.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change of Peak Workload (in Watts/kg) During Exercise Testing | 0.0090 Watts/kg | Standard Error 0.0388 |
| Omaveloxolone Capsules 2.5 and 5 mg | Change of Peak Workload (in Watts/kg) During Exercise Testing | 0.020 Watts/kg | Standard Error 0.0544 |
| Omaveloxolone Capsules 10 mg | Change of Peak Workload (in Watts/kg) During Exercise Testing | -0.0300 Watts/kg | Standard Error 0.0544 |
| Omaveloxolone Capsules 20 mg | Change of Peak Workload (in Watts/kg) During Exercise Testing | 0.1050 Watts/kg | Standard Error 0.0596 |
| Omaveloxolone Capsules 40 mg | Change of Peak Workload (in Watts/kg) During Exercise Testing | -0.0520 Watts/kg | Standard Error 0.0544 |
| Omaveloxolone Capsules 80 mg | Change of Peak Workload (in Watts/kg) During Exercise Testing | -0.0660 Watts/kg | Standard Error 0.0544 |
| Omaveloxolone Capsules 160 mg | Change of Peak Workload (in Watts/kg) During Exercise Testing | 0.0020 Watts/kg | Standard Error 0.0465 |
Comparison: Primary Objective: To evaluate the change in peak work during maximal exercise testingp-value: 0.732195% CI: [-0.1051, 0.0743]Mixed Models Analysis
Secondary
Change in 6-minute Walk Test (6MWT) Distance
Patients were instructed to walk as far as they could along a marked path for 6 minutes. Distance walked was measured. If patients used a cane or walking assist device at Screening, the same walking assist device was to be used for all 6MWT assessments.
Time frame: 6MWT was assessed at Week 4, Week 8, and Week 12 and compared to baseline
Population: Three patients out of the 53 total were excluded from the analysis set. One each from the 20 mg arm and the 160 mg arm were excluded because they did not have post-baseline efficacy assessments. One patient from the placebo arm was excluded from analysis because their baseline maximal exercise test duration \< 4 min and was not considered valid.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change in 6-minute Walk Test (6MWT) Distance | Week 8 | 24.923 Meters | Standard Error 9.9381 |
| Placebo | Change in 6-minute Walk Test (6MWT) Distance | Week 4 | 40.462 Meters | Standard Error 10.0539 |
| Placebo | Change in 6-minute Walk Test (6MWT) Distance | Week 12 | 29.846 Meters | Standard Error 12.9276 |
| Omaveloxolone Capsules 2.5 and 5 mg | Change in 6-minute Walk Test (6MWT) Distance | Week 8 | 12.865 Meters | Standard Error 15.7374 |
| Omaveloxolone Capsules 2.5 and 5 mg | Change in 6-minute Walk Test (6MWT) Distance | Week 4 | 19.333 Meters | Standard Error 14.9658 |
| Omaveloxolone Capsules 2.5 and 5 mg | Change in 6-minute Walk Test (6MWT) Distance | Week 12 | 17.167 Meters | Standard Error 19.6519 |
| Omaveloxolone Capsules 10 mg | Change in 6-minute Walk Test (6MWT) Distance | Week 8 | 33.9170 Meters | Standard Error 15.1418 |
| Omaveloxolone Capsules 10 mg | Change in 6-minute Walk Test (6MWT) Distance | Week 4 | 18.2500 Meters | Standard Error 14.9658 |
| Omaveloxolone Capsules 10 mg | Change in 6-minute Walk Test (6MWT) Distance | Week 12 | 17.7500 Meters | Standard Error 19.6519 |
| Omaveloxolone Capsules 20 mg | Change in 6-minute Walk Test (6MWT) Distance | Week 4 | -9.2000 Meters | Standard Error 16.3942 |
| Omaveloxolone Capsules 20 mg | Change in 6-minute Walk Test (6MWT) Distance | Week 12 | 28.2000 Meters | Standard Error 21.5275 |
| Omaveloxolone Capsules 20 mg | Change in 6-minute Walk Test (6MWT) Distance | Week 8 | 13.8000 Meters | Standard Error 16.587 |
| Omaveloxolone Capsules 40 mg | Change in 6-minute Walk Test (6MWT) Distance | Week 8 | 11.0000 Meters | Standard Error 15.1418 |
| Omaveloxolone Capsules 40 mg | Change in 6-minute Walk Test (6MWT) Distance | Week 4 | -11.6670 Meters | Standard Error 14.9658 |
| Omaveloxolone Capsules 40 mg | Change in 6-minute Walk Test (6MWT) Distance | Week 12 | -7.833 Meters | Standard Error 19.6519 |
| Omaveloxolone Capsules 80 mg | Change in 6-minute Walk Test (6MWT) Distance | Week 4 | 9.9170 Meters | Standard Error 14.9658 |
| Omaveloxolone Capsules 80 mg | Change in 6-minute Walk Test (6MWT) Distance | Week 8 | 17.5830 Meters | Standard Error 15.1418 |
| Omaveloxolone Capsules 80 mg | Change in 6-minute Walk Test (6MWT) Distance | Week 12 | 6.2500 Meters | Standard Error 19.6519 |
| Omaveloxolone Capsules 160 mg | Change in 6-minute Walk Test (6MWT) Distance | Week 8 | 28.9440 Meters | Standard Error 12.3633 |
| Omaveloxolone Capsules 160 mg | Change in 6-minute Walk Test (6MWT) Distance | Week 4 | 10.8330 Meters | Standard Error 12.2195 |
| Omaveloxolone Capsules 160 mg | Change in 6-minute Walk Test (6MWT) Distance | Week 12 | 8.5710 Meters | Standard Error 16.4721 |
Comparison: Secondary Objective: To evaluate the change in 6-minute walk test (6MWT) distance at Week 4p-value: 0.00695% CI: [-56.855, -10.042]Mixed Models Analysis
Comparison: Secondary Objective: To evaluate the change in 6-minute walk test (6MWT) distance at Week 8p-value: 0.732595% CI: [-27.133, 19.207]Mixed Models Analysis
Comparison: Secondary Objective: To evaluate the change in 6-minute walk test (6MWT) distance at Week 12p-value: 0.22195% CI: [-48.739, 11.55]Mixed Models Analysis