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KINECT 4

A Phase 3, 1-Year, Open-Label Trial of Valbenazine in Adults With Tardive Dyskinesia

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Year of Publication: 2019

Authors: Marder SR, Singer C, Lindenmayer JP, ..., O'Brien CF

Journal: Journal of Clinical Psychopharmacology

Citation: J Clin Psychopharmacol 2019;39:620-627

Clinical Question

Is long-term once-daily valbenazine safe and effective in treating adults with tardive dyskinesia over 48 weeks?

Bottom Line

Once-daily valbenazine (40 or 80 mg/d) for up to 48 weeks was generally well tolerated and resulted in sustained, clinically meaningful improvements in tardive dyskinesia, with approximately 90% of participants achieving ≥50% improvement in AIMS scores by week 48.

Major Points

  • Phase 3, open-label study with 48-week treatment plus 4-week washout in 167 adults with TD
  • Flexible dosing: all started at 40 mg/d, with escalation to 80 mg/d at week 4 based on CGI-TD ≥3 and tolerability
  • Of 163 analyzed: 45 (27.6%) remained on 40 mg/d, 107 (65.6%) escalated to 80 mg/d, 11 (6.7%) reduced from 80 to 40 mg/d
  • After week 4: <15% had serious TEAE (13.7%) or TEAE leading to discontinuation (11.8%)
  • Mean AIMS total score improvement at week 48: -10.2 (40 mg/d) and -11.0 (80 mg/d)
  • At week 48, ~90% of participants achieved ≥50% AIMS improvement
  • CGI-TD and PGIC response rates (much/very much improved) at week 48: 90-96% and 89-90%
  • No apparent dose effect between 40 and 80 mg/d by week 24-36
  • Some loss of effect observed after 4-week washout at week 52
  • 73% had schizophrenia/schizoaffective disorder; 88.3% were taking concomitant antipsychotics

Design

Study Type: Phase 3 open-label single-arm trial with flexible dosing

Randomization:

Blinding: Open-label; central AIMS video raters were blinded to treatment and visit

Enrollment Period: March 2015 to March 2017

Follow-up Duration: 48 weeks treatment + 4-week washout (52 weeks total)

Centers: 45

Countries: United States, Puerto Rico

Sample Size: 167

Analysis: Descriptive analyses of observed cases; all participants with ≥1 dose and postbaseline data included

Inclusion Criteria

  • Adults 18-85 years of age
  • Diagnosis of schizophrenia, schizoaffective disorder, or mood disorder (DSM-IV) for ≥3 months
  • Neuroleptic-induced tardive dyskinesia (DSM-IV) for ≥3 months
  • Moderate or severe TD as assessed by external reviewer at screening
  • Stable psychiatric status
  • Capacity to provide informed consent

Exclusion Criteria

  • BPRS total score ≥50 at screening
  • PANSS total score ≥70 or CDSS ≥10 (for schizophrenia/schizoaffective disorder)
  • YMRS total score >10 or MADRS >13 (for mood disorder)
  • Any clinically significant unstable medical condition
  • Comorbid involuntary movement disorder more prominent than TD
  • Simpson-Angus Scale ≥3 on 2+ items at screening
  • History of neuroleptic malignant syndrome
  • History of long-QT interval or cardiac tachyarrhythmia
  • Significant risk for suicidal or violent behavior

Arms

FieldValbenazine 40 mg/dValbenazine 80 mg/d
InterventionValbenazine 40 mg once daily for 48 weeks (participants who did not escalate or reduced from 80 mg/d)Valbenazine 40 mg/d for 4 weeks, then 80 mg once daily for 44 weeks
Duration48 weeks48 weeks

Outcomes

OutcomeTypeControlInterventionHR / OR / RRP-value
Safety and tolerability assessed by TEAEs, serious TEAEs, and TEAEs leading to discontinuationPrimaryN/A (single-arm study)After week 4: Any TEAE 64.7%, Serious TEAE 13.7%, TEAE leading to discontinuation 11.8%, Death 0.7%
Mean change in AIMS total score (site raters) from baseline to week 48SecondaryN/A40 mg/d: -10.2 ± 1.2; 80 mg/d: -11.0 ± 0.5
AIMS response (≥50% improvement) at week 48 (site raters)SecondaryN/A40 mg/d: 90.0%; 80 mg/d: 89.2%
CGI-TD response (much/very much improved) at week 48SecondaryN/A40 mg/d: 90.0%; 80 mg/d: 95.9%
PGIC response (much/very much improved) at week 48SecondaryN/A40 mg/d: 90.0%; 80 mg/d: 89.2%
Urinary tract infectionAdverseN/A8.5% (weeks 4-48)
HeadacheAdverseN/A5.2% (weeks 4-48)
Suicidal ideationAdverseN/A4.6% (7 participants, 3 led to discontinuation, all resolved)
SomnolenceAdverseN/A3.9% (weeks 4-48)
DeathAdverseN/A1 (0.7%): breast cancer, unrelated to treatment

Subgroup Analysis

Efficacy data presented separately for 40 mg/d and 80 mg/d dose groups. 73% had schizophrenia/schizoaffective disorder, 27% had mood disorder.

Criticisms

  • Open-label design increases risk of bias and expectancy effects
  • Single-arm study with no placebo control
  • Site-rater AIMS scores showed larger improvements than central raters, suggesting potential bias
  • Limited generalizability due to exclusion of psychiatrically unstable patients
  • Central AIMS raters only assessed at baseline, week 8, and week 52
  • High discontinuation rate (38.3% did not complete 48 weeks + washout)
  • 4-week washout may be insufficient to determine reversibility

Funding

Neurocrine Biosciences, Inc.

Based on: KINECT 4 (Journal of Clinical Psychopharmacology, 2019)

Authors: Marder SR, Singer C, Lindenmayer JP, ..., O'Brien CF

Citation: J Clin Psychopharmacol 2019;39:620-627

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