Safety and Efficacy of Deutetrabenazine at High versus Lower Daily Dosages in the ARC-HD Study to Treat Chorea in Huntington Disease
Bibliographic record
Abstract
Huntington disease (HD) is a progressive neurodegenerative disease that causes psychiatric and neurological symptoms, including involuntary and irregular muscle movements (chorea). Chorea can disrupt activities of daily living, pose safety issues, and may lead to social withdrawal. The vesicular monoamine transporter 2 inhibitors tetrabenazine, deutetrabenazine, and valbenazine are approved treatments that can reduce chorea. This post hoc analysis was conducted to evaluate safety and efficacy among participants who received high-dosage deutetrabenazine treatment (> 48 mg/d) in ARC-HD, an open-label study that assessed long-term safety and efficacy of deutetrabenazine for the treatment of chorea in HD in adults. ARC-HD was a single-arm, two-cohort, open-label study. Participants either successfully completed the First-HD study or switched overnight from tetrabenazine to deutetrabenazine. Participants were dosed with deutetrabenazine in a response-driven manner (maximum 72 mg/d allowed). For the current analysis, exposure-adjusted incidence rates (EAIRs) for adverse events of interest were analyzed according to daily dosage (≤ 48 mg/d versus > 48 mg/d), and total maximal chorea (TMC) scores were analyzed by cohort during the stable-dose period. In total, 116 of the 119 participants enrolled in ARC-HD entered the stable-dose period, where no apparent differences were seen in EAIRs when receiving deutetrabenazine dosages ≤ 48 mg/d (exposure = 177.7 person-years) compared with > 48 mg/d (exposure = 74.1 person-years). Similar results were found among the subset of participants who received deutetrabenazine dosages > 48 mg/d at least once during the study (n = 49, 42%) when their dosage was ≤ 48 mg/d (exposure = 37.9 person-years) versus > 48 mg/d (74.1 person-years). Efficacy analyses were conducted for participants who had TMC scores available (rollover cohort, n = 77; switch cohort, n = 35). For most participants, the lowest deutetrabenazine dosage needed to achieve a TMC response (≥ 30% improvement from baseline) was between 24 and 48 mg/d in both the rollover (n = 57, 74.0%) and switch (n = 16, 46.0%) cohorts. Whereas the dosage needed for a TMC response was independent of baseline TMC score in the rollover cohort, participants with higher baseline TMC scores in the switch cohort required higher dosages to achieve a TMC response during the trial. In this open-label, long-term study, some participants received deutetrabenazine dosing > 48 mg/d to achieve adequate chorea control. There was no new safety concern or incremental change in the safety profile between dosages of ≤ 48 mg/d and > 48 mg/d. These results include dosages that have not been approved for clinical use, however, they increase our understanding of safety and tolerability of deutetrabenazine doses. ARC-HD (ClinicalTrials.gov identifier: NCT01897896); First-HD (ClinicalTrials.gov identifier: NCT01795859). ARC-HD was a medical study in which participants took a medicine called deutetrabenazine. Deutetrabenazine is used to treat unplanned movements known as chorea, which happen in participants who have Huntington disease. At the start of the ARC-HD study, all participants took 6 milligrams per day (mg/d) of the medicine. Each week, the doctor could give them more medicine, but not more than 72 mg/d. The doctor checked if the medicine helped to lower their chorea and if any safety concerns occurred. The highest amount of the medicine that is allowed in the USA is 48 mg/d. Some participants took more than that. We wanted to learn more about the safety (side effects) and the chorea in participants who took more than 48 mg/d. Participants who took more than 48 mg/d had no new side effects of interest. They also reported the same number of side effects as participants who took 48 mg/d or less. For most participants, the lowest amount of medicine they needed to lower their chorea was between 24 and 48 mg/d.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".