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AIM-TD

Deutetrabenazine for treatment of involuntary movements in patients with tardive dyskinesia (AIM-TD): a double-blind, randomised, placebo-controlled, phase 3 trial

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Year of Publication: 2017

Authors: Karen E Anderson, David Stamler, Mat D Davis, ..., Hubert H Fernandez

Journal: The Lancet Psychiatry

Citation: Lancet Psychiatry 2017;4(8):595-604

Link: https://doi.org/10.1016/S2215-0366(17)30236-5

Clinical Question

Is deutetrabenazine (a novel vesicular monoamine transporter-2 inhibitor) effective and safe for treating tardive dyskinesia without disrupting underlying psychiatric treatment regimens?

Bottom Line

Deutetrabenazine 24 mg/day and 36 mg/day provided significant reduction in tardive dyskinesia with favorable safety and tolerability, suggesting dosing regimens could be individualized based on dyskinesia control and tolerability.

Major Points

  • Deutetrabenazine 36 mg/day and 24 mg/day significantly reduced AIMS scores compared to placebo (-3.3 and -3.2 points vs -1.4 points; p=0.001 and p=0.003)
  • 50% improvement in AIMS score achieved in 35% of 24 mg/day group and 33% of 36 mg/day group vs 12% placebo
  • Treatment success on CGIC was 49% for 24 mg/day and 44% for 36 mg/day vs 26% placebo
  • 12 mg/day dose did not show significant improvement vs placebo
  • Efficacy observed both in patients taking and not taking concomitant dopamine receptor antagonists
  • Response observed by week 2 and maintained throughout 12-week treatment period

Design

Study Type: Phase 3, double-blind, randomized, placebo-controlled trial

Randomization: 1

Blinding: Double-blind (patients, investigators, site personnel, and sponsor masked to group assignment). Central video raters masked to treatment assignment.

Enrollment Period: October 2014 to August 2016

Follow-up Duration: 13 weeks (4 weeks dose escalation, 8 weeks maintenance, 1 week washout)

Centers: 75

Countries: USA, Europe

Sample Size: 298

Analysis: Modified intention-to-treat (mITT) population for efficacy. Linear mixed model for repeated measurements. Randomization stratified by baseline dopamine receptor antagonist use.

Inclusion Criteria

  • Age 18-80 years
  • Clinical diagnosis of tardive dyskinesia for ≥3 months before screening
  • History of dopamine receptor antagonist use ≥3 months (or 1 month if age ≥60 years)
  • Total AIMS score (items 1-7) ≥6 at screening and baseline
  • Patients with underlying psychiatric illness: stable with no change in psychoactive medication for ≥30 days before screening

Exclusion Criteria

  • Treatment within 30 days of screening with tetrabenazine, reserpine, metirosine, or medications with strong anticholinergic properties
  • Botulinum toxin within 3 months of screening
  • Neurological condition other than tardive dyskinesia that could interfere with dyskinesia assessment
  • Serious untreated or undertreated psychiatric illness
  • Suicidal ideation or behavior within 6 months of screening
  • HADS depression subscale score ≥11 at screening or baseline

Arms

FieldControlDeutetrabenazine 12 mg/dayDeutetrabenazine 24 mg/dayDeutetrabenazine 36 mg/day
InterventionMatching placebo tablets orally twice dailyDeutetrabenazine 6 mg orally twice daily (total 12 mg/day)Deutetrabenazine 12 mg orally twice daily (total 24 mg/day)Deutetrabenazine 18 mg orally twice daily (total 36 mg/day)
Duration12 weeks12 weeks12 weeks12 weeks

Outcomes

OutcomeTypeControlInterventionHR / OR / RRP-value
Change in Abnormal Involuntary Movement Scale (AIMS) score (items 1-7) from baseline to week 12Primary-1.4 points (SE 0.41)12 mg/day: -2.1; 24 mg/day: -3.2; 36 mg/day: -3.312 mg/day: 0.217; 24 mg/day: 0.003; 36 mg/day: 0.001
Treatment success on CGIC (much/very much improved)Secondary26%24 mg/day: 49%; 36 mg/day: 44%2.7124 mg/day: 0.014; 36 mg/day: 0.059
≥50% improvement in AIMS scoreSecondary12%24 mg/day: 35%; 36 mg/day: 33%3.9624 mg/day: 0.005; 36 mg/day: 0.007
Change in AIMS score at week 2 (early response)SecondaryReference24 mg/day: -1.4; 36 mg/day: -1.1 vs placebo24 mg/day: 0.006; 36 mg/day: 0.032
Any adverse eventAdverse47%12 mg: 49%; 24 mg: 44%; 36 mg: 51%
Serious adverse eventsAdverse6%12 mg: 3%; 24 mg: 8%; 36 mg: 5%
SomnolenceAdverse4%12 mg: 0%; 24 mg: 1%; 36 mg: 4%
DepressionAdverse0%12 mg: 1%; 24 mg: 4%; 36 mg: 1%
Discontinuation due to AEsAdverse3%12 mg: 5%; 24 mg: 3%; 36 mg: 4%

Subgroup Analysis

Efficacy in patients receiving dopamine receptor antagonists at baseline: 36 mg/day showed -3.4 points change (p=0.017); 24 mg/day showed -3.2 points (p=0.036). Greater improvement observed in patients not receiving concomitant dopamine receptor antagonists.

Criticisms

  • Notable placebo response observed (AIMS score reduction of -1.4 points)
  • Large placebo effect noted particularly in patients receiving dopamine receptor antagonists at baseline
  • Patient-reported outcomes (PGIC, mCDQ-24) showed numerically better but non-significant results
  • Short treatment duration (12 weeks) limits assessment of long-term efficacy and safety
  • Fixed-dose design does not reflect individualized titration used in clinical practice

Funding

Teva Pharmaceutical Industries

Based on: AIM-TD (The Lancet Psychiatry, 2017)

Authors: Karen E Anderson, David Stamler, Mat D Davis, ..., Hubert H Fernandez

Citation: Lancet Psychiatry 2017;4(8):595-604

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