Objective: To evaluate the effect of deutetrabenazine (DTB) on QT interval prolongation in patients with tardive dyskinesia (TD) in the AIM-TD study.

Background: TD is an often-irreversible, drug-induced movement disorder with no approved treatments. Patients with TD often have underlying psychotic and mood disorders, which are typically managed with antipsychotics. These medications can cause QT prolongation, which predisposes patients to life-threatening cardiac arrhythmias. In a thorough QT study in healthy volunteers, single‑dose administration of DTB 24 mg led to a maximum, time-matched, placebo-adjusted increase from baseline in Fridericia-corrected QT interval (ΔΔQTcF) of 4.5 ms, below the level of regulatory concern. AIM-TD assessed the efficacy, safety and tolerability of DTB in TD patients.

Methods: Patients with TD were randomized (1:1:1:1) to one of three fixed-dose regimens of DTB (12 mg/day, 24 mg/day, 36 mg/day) or placebo. The primary efficacy endpoint was change in AIMS scores from baseline to Week 12. Adverse events (AEs) and single 12-lead ECGs that included QTcF were monitored at baseline and Weeks 2, 4, 8, and 12. Subjects with an underlying psychiatric illness were stable with no change in psychoactive therapy for ≥30 days before screening (45 days for antidepressants). Patients with an abnormal QTcF value at screening were excluded.

Results: At baseline, all patients in the intention-to-treat population (n=298) received antipsychotics. The least-squares mean change in AIMS score from baseline to Week 12 improved by –3.3 points for DTB 36 mg/day (treatment difference –1.9, P=0.001), –3.2 points for 24 mg/day (–1.8, P=0.003), and –2.1 points for 12 mg/day (–0.7, P=0.217) compared with –1.4 points in placebo. Mean QTcF values at baseline were similar between the groups. In patients included in the safety population with normal QTcF at baseline (n=279), the incidence of abnormal QTcF values (>450 ms) post-baseline was 13% in placebo compared with 10%, 4%, and 6% in the 12, 24, and 36 mg/day groups, respectively.

Conclusions: Compared with placebo, treatment with DTB did not increase the risk of QTcF prolongation in patients with TD. Drug-induced QTcF prolongation remains a safety concern for new treatment options in TD, especially for patients taking concomitant antipsychotic medications.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/effect-of-deutetrabenazine-on-qtcf-interval-in-the-aim-td-study-a-12-week-phase-iii-randomized-double-blind-placebo-controlled-study/