Trial reportNeurology2026
Antidopaminergic Medications and Clinical Outcomes in Huntington Disease: Evidence From the PROOF-HD Placebo-Controlled Trial.
Trial report in Neurology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT04556656 (A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Parallel Arm, Multicenter Study Evaluating the Efficacy and Safety of Pridopidine in Patients With Early Stage of Huntington Disease), which is not on this map. Not yet cited in PubMed.
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The trial behind it
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A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Parallel Arm, Multicenter Study Evaluating the Efficacy and Safety of Pridopidine in Patients With Early Stage of Huntington Disease
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13 authors.
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Abstract
BACKGROUND AND
objectivesAntidopaminergic medications (ADMs), including vesicular monoamine transporter-2 (VMAT2) inhibitors and antipsychotics, are widely used to manage motor and psychiatric symptoms in Huntington disease (HD). Observational evidence suggests that ADM use may be associated with accelerated worsening of clinical outcome measures used in HD trials, but this relationship has not been examined in a controlled trial setting. We assessed the association between ADM exposure and longitudinal clinical outcomes in the Pridopidine's Outcome On Function in Huntington Disease (PROOF-HD) placebo arm.
methodsThis post hoc analysis included placebo-arm participants from PROOF-HD (NCT04556656), a randomized controlled trial in adults with Total Functional Capacity (TFC) 7-13 and cytosine-adenine-guanine (CAG) ≥36. Participants were categorized as on-ADMs or off-ADMs based on concurrent medication use across the study period. Outcomes included TFC, composite Unified Huntington's Disease Rating Scale (cUHDRS), Symbol Digit Modalities Test (SDMT), Stroop Word Reading (SWR), and Total Motor Score (TMS). Primary analyses used mixed-effects models for repeated measures, corroborated by propensity score weighting (PSW) and time-varying sensitivity analyses.
resultsOf 247 placebo-arm participants (mean age 52.6 years [SD 11.4]; 51% female), 135 (54.7%) were on-ADMs and 112 (45.3%) were off-ADMs. On-ADM participants demonstrated faster clinical decline across multiple outcome measures. Between-group differences in cUHDRS and TFC favored off-ADMs from weeks 39-78; at week 52, the difference in mean change was 0.66 (95% CI 0.31-1.01; DISCUSSION: In this study of the PROOF-HD placebo arm, ADM use was associated with greater worsening across global, functional, cognitive, and motor outcome measures as compared with off-ADM participants. Residual confounding by disease severity cannot be fully excluded, although sensitivity analyses were directionally consistent. Taken together, ADM exposure, class, and dose should be systematically considered when designing and interpreting HD clinical trials. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov Identifier: NCT04556656. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that in patients with HD, the use of ADMs is associated with greater worsening across global, functional, cognitive, and motor outcome measures as compared with patients not on ADMs.
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