Sydämen minuuttitilavuus ja väsymys Friedreichin ataksiassa

In February 2023, omaveloxolone became the first Food and Drug Administration (FDA) approved medication for Friedreich's Ataxia (FRDA). In its pivotal study, named MOXIe, researchers found that omaveloxolone significantly improved neurological function compared to placebo. The primary outcome measure was the modified Friedreich's Ataxia Rating Scale (mFARS), the gold standard for measuring ataxia symptoms in clinical trials for FRDA. However, there are several limitations with the use of mFARS:

• It does not detect subtle disease progression over short time frames. For example, in MOXIe, differences between placebo and omaveloxolone were not detected until 48 weeks.
• Some of the components of mFARS rely on clinical judgment, which can introduce variability between raters.
• The minimal clinical important difference (MCID) for mFARS has not been clearly defined.
• The scale lacks sensitivity to detect changes in individuals with minimal symptoms or advanced disease.

Given these limitations, development of additional outcome measures for clinical trials to determine the impact of drugs like omaveloxolone is desirable. In this study, investigators propose using maximal oxygen consumption (VO2max) as a future primary outcome measure for FRDA clinical trials. VO2max offers several advantages as an outcome measure:

1. It is a direct physiological measure of aerobic capacity, reducing subjectivity compared to clinical scales like mFARS.
2. It can detect subtle changes in aerobic function making it useful for monitoring intervention effects over time.
3. It has a defined MCID, and higher VO2max is associated with better health outcomes making it a clinically meaningful endpoint.
4. It is non-invasive and reproducible.

To examine the utility of VO2max as a primary outcome measure, this study will recruit 30 individuals with FRDA in this pilot study. Twenty individuals will be on omaveloxolone treatment whereas the other 10 individuals will not. Individuals will undergo baseline cardiopulmonary exercise testing (CPET) to determine VO2max. Secondary measures will include cardiac output. All participants will be given a recumbent bicycle for home use. Participants will be expected to cycle 30-minutes per session, 5x per week at 65-75% maximum heart rate (moderate intensity) for 3-months. To track training, individuals will be given a Fitbit Charge 6, and an exercise physiologist will call every two weeks to adjust training as needed. To determine benefits of training with omaveloxolone, repeat assessments will occur at 3- and 6-months.

AIM 1: Acceptability and Feasibility of Home Aerobic Exercise. Individuals with other types of ataxia have been able to train at the above levels safely. We hypothesize that there will be no serious adverse events related to aerobic training, and there will be an acceptable number of minor adverse events. The investigators further hypothesize that drop-out from the trial will be less than 25%.

AIM 2: Impact of Omaveloxolone on VO2max. Omaveloxolone works by activating and preventing the degradation of Nuclear factor-like 2 (Nrf2), which helps prevent oxidative damage within the mitochondria of individuals with FRDA. Improved mitochondrial function should significantly enhance VO2max by increasing ATP production and improving the rate of oxygen consumption. Thus, the investigators hypothesize that individuals on omaveloxolone will have a significantly larger increase in VO2max after the aerobic training when compared to individuals who are not on omaveloxolone.

AIM 3: Impact of Aerobic Training + Omaveloxolone on Fatigue. Omaveloxolone has been shown to cause a transient (12-week) increase in fatigue. Aerobic training, on the other hand, is known to improve fatigue in individuals with other hereditary ataxias. For this aim, the primary outcome measure will be the Fatigue Severity Scale (FSS) with secondary measures of Fatigue Impact Scale (FIS) and 6-minute walk test (6MWT). The investigators hypothesize improved fatigue with the incorporation of aerobic training and that individuals in the omaveloxolone group will have less fatigue than those not on omaveloxolone.

This pilot study will provide the foundation for the use of VO2max as an outcome measure in future FRDA trials. It will also examine the synergistic effect of omaveloxolone and aerobic training which may show greater improvement than either intervention alone, including improvements in fatigue.