VANCOUVER—Deutetrabenazine provides clinically significant reductions in involuntary movements of tardive dyskinesia, according to a study described at the 21st International Congress of Parkinson’s Disease and Movement Disorders. The treatment yields benefits regardless of patients’ concomitant use of dopamine-receptor antagonists. In addition, the drug is safe and well tolerated.
Tardive dyskinesia often results from exposure to dopamine-receptor antagonists. Clinicians sometimes manage the disorder by lowering the dose of the causative agent, but this tactic may increase the burden of the underlying disease.
Deutetrabenazine is a novel, highly selective vesicular monoamine transporter type 2 (VMAT2) inhibitor. The drug has been approved for the treatment of Huntington disease chorea and is under investigation as a treatment for tardive dyskinesia. A randomized, double-blind, placebo-controlled trial suggested that deutetrabenazine reduced abnormal involuntary movements, compared with placebo, in patients with tardive dyskinesia.
Comparing Three Doses With Placebo
Karen E. Anderson, MD, Director of the Huntington’s Disease Care, Education, and Research Center at MedStar Georgetown University Hospital in Washington, DC, and colleagues conducted a phase III, double-blind, parallel-group study to evaluate the efficacy, safety, and tolerability of three fixed doses of deutetrabenazine in patients with tardive dyskinesia. Eligible patients had a history of dopamine-receptor antagonist use, stable psychiatric illness on stable psychoactive medication, and an Abnormal Involuntary Movement Scale (AIMS) score of 6 or higher at baseline. Patients with a history of depression or suicidal behavior and those with neurologic conditions that may interfere with the assessment of tardive dyskinesia severity were excluded.
Karen E. Anderson, MD
The investigators randomized patients in equal groups to deutetrabenazine (12 mg/day, 24 mg/day, or 36 mg/day) or placebo. At study initiation, all patients randomized to deutetrabenazine received 12 mg/day. Patients randomized to 24 mg/day or to 36 mg/day underwent a four-week dose-escalation period, at the end of which they reached their assigned doses. An eight-week maintenance period followed for all patients, and the subsequent washout period lasted for one week. Patients were followed up by telephone at week 16.
The study’s primary efficacy end point was change in AIMS score from baseline to week 12. The secondary end point was treatment success, which the investigators defined as the proportion of patients who were “much improved” or “very much improved” on the Clinical Global Impression of Change (CGIC), at week 12.
Benefits Persisted for 10 Weeks
The study included 298 participants. The population’s mean age was 57, and approximately 52% of participants were female. At week 12, AIMS score improved significantly from baseline by 3.2 points for patients receiving 24 mg/day of deutetrabenazine and by 3.3 points for patients receiving 36 mg/day of deutetrabenazine. AIMS score improved by 2.1 points for patients randomized to 12 mg/day of treatment, and by 1.4 points for controls, but these changes were not statistically significant. Clinically meaningful reductions in AIMS score were observed at week 2 and persisted throughout the treatment period for the 24-mg/day and 36-mg/day doses, compared with placebo. AIMS score improved in patients receiving the two higher doses regardless of patients’ use of dopamine-receptor antagonists at baseline.
At week 12, the proportion of patients who had treatment success was greater in those treated with deutetrabenazine, compared with controls. Also, all three doses of deutetrabenazine had clinically meaningful least-squares mean treatment differences on the CGIC at week 12, compared with placebo. The proportion of patients with treatment success was greater for patients who had not received dopamine-receptor antagonists at baseline than for those who had (58% vs 46% for the 24-mg/day dose and 60% vs 34% for the 36-mg/day dose).
The rates of adverse events and discontinuations were similar between the deutetrabenazine and placebo groups. Common adverse events included headache, diarrhea, nausea, nasopharyngitis, and somnolence. Serious adverse events included appendicitis, cardiorespiratory arrest, cellulitis, depression, sudden cardiac death, and psychotic disorders, but none of these was determined to be related to the study drug.
The study was funded by Teva Pharmaceutical Industries.
—Erik Greb
Suggested Reading
Anderson KE, Stamler D, Davis MD, et al. Deutetrabenazine for treatment of involuntary movements in patients with tardive dyskinesia (AIM-TD): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Psychiatry. 2017 Jun 28 [Epub ahead of print].
Fernandez HH, Factor SA, Hauser RA, et al. Randomized controlled trial of deutetrabenazine for tardive dyskinesia: The ARM-TD study. Neurology. 2017;88(21):2003-2010.