Antidopaminergic Medications Are Associated with Faster Decline in Measures of Clinical Outcome in HD: Insights from PROOF-HD

BackgroundAntidopaminergic medications (ADMs), including vesicular monoamine transporter-2 (VMAT2) inhibitors and antipsychotics, are frequently-used to manage Huntington disease (HD) symptoms. Prior studies suggest that ADMs may be associated with worsening on measures of outcome in HD clinical trials. The PROOF-HD placebo arm (NCT04556656) provided a controlled, double-blind setting to evaluate ADM impacts on measures of HD progression. ObjectiveAssess the association between ADM exposure and change in clinical outcomes in the placebo arm of PROOF-HD. MethodsPlacebo-arm participants (n=247) were categorized as on- vs off-ADMs. Overall main analyses were corroborated by propensity-score weighting (PSW)-adjusted analyses. Unadjusted analyses examined exposure by ADM class and dose. Outcomes included Total Functional Capacity (TFC), composite Unified Huntingtons Disease Rating Scale (cUHDRS), Stroop Word Reading (SWR), Symbol Digit Modalities Test (SDMT), and Total Motor Score (TMS). ResultsGroup differences ({Delta}) favored off-ADMs in cUHDRS (Weeks 39-78) and TFC (Weeks 26-78); at Week 52, cUHDRS had {Delta}=0.66 (95% CI 0.31-1.01; p=0.0002) and TFC with {Delta}=0.85 (95% CI 0.47-1.22; p<0.0001) as compared with on-ADMs. Other outcomes were significant or directionally-favored off-ADM participants beyond Week 39. All TMS-subdomain scores, except for chorea, directionally-favored off-ADMs at all visits. Antipsychotic-only and higher-dose ADMs were associated with worse cUHDRS and TFC vs off-ADMs. ConclusionsIn this post hoc study, ADM use was associated with greater worsening of measures of global, functional, cognitive, and motor outcomes, versus off-ADMs. Accounting for ADM exposure and dose is essential for the interpretation of results from HD trials.