Direct utility of natural history data in analysis of clinical trials: Propensity match-based analysis of Omaveloxolone in Friedreich ataxia using the FA-COMS dataset

Rationale The natural history of Friedreich Ataxia (FRDA) is being investigated in a multi-center longitudinal study designated the Friedreich Ataxia Clinical Outcome Measures Study (FA-COMS). To understand the utility of this natural history dataset in analysis of clinical trials, we performed a propensity-matched comparison of the data from the open-label MOXIe Extension (omaveloxolone) with that from FA-COMS. Methods All MOXIe Extension patients who had at least one post-baseline assessment were matched to FA-COMS patients using logistic regression to estimate propensity scores based on multiple covariates: sex, baseline age, age of onset, baseline modified Friedreich Ataxia Rating scale (mFARS) score, and baseline gait score. Selection of covariates was based on clinical relevance (i.e., factors considered prognostic for disease progression) and availability. The change from baseline in mFARS at Year 3 for the MOXIe Extension patients compared to the matched FA-COMS patients was analyzed as the primary efficacy endpoint using mixed model repeated measures analysis. Results Data from the MOXIe Extension show that omaveloxolone provides persistent benefit over three years when compared to an untreated, rigorously matched cohort from FA-COMS. At each year, and in all analysis populations, patients in the MOXIe Extension experienced a smaller change from baseline in mFARS score than the matched FA-COMS patients. In the Primary Pooled Population (136 patients in each group) by Year 3, patients in the FA-COMS matched set progressed 6.6 points whereas patients treated with omaveloxolone in MOXIe Extension progressed 3 points (difference =-3.6; nominal p value =0.0001). Thus, progression in mFARS was slowed by 55% with omaveloxolone treatment. Conclusions These results suggest a clinically meaningful slowing of FRDA progression with omaveloxolone, and consequently details how propensity-matched analysis contributes to the understanding of the effects of therapeutic agents. This demonstrates the direct value of natural history studies in the evaluation of clinical trials. ### Competing Interest Statement In addition to the role of the funder above, CM and AG are employees of Reata Pharmaceutical. The other authors declare no competing interests. ### Clinical Trial NCT03090789 and [NCT02255435][1] ### Funding Statement DRL, SB, MBD, PG, JCH, CM, KDM, WN, SP, SHS, GW, LW and TZ all received individual grants (no number) from Reata Pharmaceuticals to perform the tasks in this study. CM and AG are employees of Reata Pharmaceutical (https://reatapharma.com/home/default.aspx), the funder for the study. In collaboration with these investigators, the sponsor planned the study, supervised its conduct and data collection, and analyzed the data. All authors were involved in the decision to publish and manuscript preparation. JF is an employee of FARA, who funded the FACOMS study, whose data is used in this report after being placed in a public repository. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The protocol was approved by the IRB/ Ethics committees at all Institutions: The Children's Hospital of Philadelphia (lead site), UCLA, University of Iowa, Emory, University of South Florida, University College London, University of Florida, University of Melbourne/Murdoch Research Institute (Australia), Neurological Institute Carlo Besta (Italy), Medical University of Innsbruck (Austria), and Ohio State University. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All files from FACOMS data are held in a public repository at cPATH. (https://c-path.org/programs/rdca-dap/working-group/fa-icd/). Data from the MOXIe extension will not be available. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT02255435&atom=%2Fmedrxiv%2Fearly%2F2022%2F08%2F16%2F2022.08.12.22278684.atom