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KINECT 3

KINECT 3: A Phase 3 Randomized, Double-Blind, Placebo-Controlled Trial of Valbenazine for Tardive Dyskinesia

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Year of Publication: 2017

Authors: Hauser RA, Factor SA, Marder SR, ..., O'Brien CF

Journal: American Journal of Psychiatry

Citation: Am J Psychiatry 2017;174:476-484

Clinical Question

Is valbenazine effective and safe for treating tardive dyskinesia in patients with schizophrenia, schizoaffective disorder, or mood disorder?

Bottom Line

Once-daily valbenazine at 80 mg/day significantly improved tardive dyskinesia compared to placebo over 6 weeks, with a clinically meaningful effect size of 0.90, and was generally well tolerated with stable psychiatric status.

Major Points

  • First phase 3 trial of valbenazine, a highly selective VMAT2 inhibitor for tardive dyskinesia
  • Valbenazine 80 mg/day met primary endpoint: AIMS score reduction -3.2 vs -0.1 for placebo (p<0.001, effect size 0.90)
  • Valbenazine 40 mg/day also showed improvement (-1.9 vs -0.1, p=0.002) but did not meet fixed-sequence testing threshold
  • Treatment response (≥50% AIMS reduction) achieved in 40% of 80 mg/day group vs 8.7% placebo at week 6
  • Benefits evident as early as week 2 and maintained through week 6
  • Number needed to treat (NNT) of 4 for 80 mg/day dosage
  • No safety signals for psychiatric destabilization or increased suicidality
  • Approximately 85% of participants continued on concomitant antipsychotics

Design

Study Type: Phase 3 randomized, double-blind, placebo-controlled, parallel-group, fixed-dose trial

Randomization: 1

Blinding: Double-blind (participants, investigators, central AIMS video raters, sponsor)

Enrollment Period: October 2014 to September 2015

Follow-up Duration: 6 weeks

Centers: 63

Countries: United States, Canada, Puerto Rico

Sample Size: 234

Analysis: Mixed-effects model for repeated measures (MMRM); intent-to-treat as primary population

Inclusion Criteria

  • Age 18-85 years
  • Medically stable
  • Diagnosis of schizophrenia, schizoaffective disorder, or mood disorder (DSM-IV) for ≥3 months
  • Dopamine receptor blocker-induced tardive dyskinesia (DSM-IV) for ≥3 months
  • Moderate or severe TD based on screening videos
  • Stable psychiatric status
  • Stable treatment regimen for ≥30 days before baseline

Exclusion Criteria

  • BPRS total score ≥50
  • PANSS total score ≥70 (for schizophrenia/schizoaffective disorder)
  • Calgary Depression Scale ≥10 (for schizophrenia/schizoaffective disorder)
  • YMRS total score ≥10 (for mood disorder)
  • MADRS total score >13 (for mood disorder)
  • History of neuroleptic malignant syndrome
  • Significant risk of suicidal or violent behavior
  • Use of prohibited medications without 30-day washout

Arms

FieldControlValbenazine 40 mg/dayValbenazine 80 mg/day
InterventionOnce-daily placeboOnce-daily valbenazine 40 mgOnce-daily valbenazine 80 mg
Duration6 weeks6 weeks6 weeks

Outcomes

OutcomeTypeControlInterventionHR / OR / RRP-value
Change from baseline to week 6 in AIMS dyskinesia score (items 1-7) for valbenazine 80 mg/day vs placeboPrimary-0.1-3.2 (80 mg/day)4<0.001
AIMS dyskinesia score change for valbenazine 40 mg/day vs placeboSecondary-0.1-1.90.002 (not significant by fixed-sequence testing)
AIMS response (≥50% reduction) at week 6Secondary8.7%40.0% (80 mg); 23.8% (40 mg)<0.001 (80 mg); 0.02 (40 mg)
CGI-TD score at week 6Secondary3.22.9 (80 mg); 2.9 (40 mg)0.056 (80 mg); 0.074 (40 mg)
Any adverse eventAdverse43.4%50.6% (80 mg); 40.3% (40 mg)
SomnolenceAdverse3.9%5.1% (80 mg); 5.6% (40 mg)
AkathisiaAdverse1.3%2.5% (80 mg); 4.2% (40 mg)
Serious adverse eventAdverse3.9%7.6% (80 mg); 5.6% (40 mg)
DeathAdverse0%1.3% (80 mg, 1 sudden death, unlikely related)

Subgroup Analysis

Per-protocol analysis showed consistent results. Dose-related improvements across full range of percent improvements (10%-90%).

Criticisms

  • Short 6-week duration limits long-term efficacy/safety evaluation
  • Cannot determine whether masking of TD symptoms contributed to improvements
  • CGI-TD did not reach significance in ITT population (though significant in per-protocol)
  • Fixed-sequence testing prevented formal confirmation of 40 mg/day dosage
  • Minimal clinically important difference not established for AIMS score change
  • 11.4% had undetectable plasma levels at week 6, suggesting adherence issues

Funding

Neurocrine Biosciences, Inc.

Based on: KINECT 3 (American Journal of Psychiatry, 2017)

Authors: Hauser RA, Factor SA, Marder SR, ..., O'Brien CF

Citation: Am J Psychiatry 2017;174:476-484

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