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ARM-TD

Aim to Reduce Movements in Tardive Dyskinesia

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Year of Publication: 2017

Authors: Hubert H Fernandez, Stewart A Factor, Robert A Hauser, ..., Karen E Anderson

Journal: Neurology

Citation: Neurology 2017;88:2003-2010

Link: https://doi.org/10.1212/WNL.0000000000003633

Clinical Question

Is deutetrabenazine effective at reducing the severity of abnormal involuntary movements of tardive dyskinesia as measured by the AIMS score?

Bottom Line

Deutetrabenazine with flexible dosing (mean ~38 mg/day) significantly reduced AIMS scores compared to placebo, with a favorable safety profile including no reports of depression or suicidal ideation. This provides Class I evidence for deutetrabenazine efficacy in TD.

        Major Points
        Phase II/III flexible-dose trial of deutetrabenazine for tardive dyskinesia
Significant reduction in AIMS score vs placebo (-3.0 vs -1.6, p=0.019)
Treatment difference observed by week 4 (p=0.007)
Mean dose at end of titration was 38.8 mg/day
No reports of depression or suicidal ideation in deutetrabenazine group
98.3% of patients had underlying psychiatric comorbidity
80.3% were on concomitant DRAs throughout the study
Provides Class I evidence for deutetrabenazine in TD

      

Design

Study Type: Phase II/III, multicenter, randomized, double-blind, parallel-group, placebo-controlled trial

Randomization: 1

Blinding: Double-blind: patients and site investigators were blinded throughout

Enrollment Period: June 2014 to May 2015

Follow-up Duration: 12 weeks (6-week titration, 6-week maintenance, 1-week washout)

Centers: 46

Countries: United States, Europe

Sample Size: 117

Analysis: Linear mixed model for repeated measurements with fixed effects for treatment, timepoint, and DRA use; Pearson chi-square for proportions; modified intention-to-treat population

Inclusion Criteria

TD diagnosis for >=3 months before screening
History of DRA treatment for >=3 months (>=1 month if age >=60)
AIMS motor score >=6 at screening and baseline
Stable psychoactive medications for >=30 days (>=45 days for antidepressants)

Exclusion Criteria

Treatment with tetrabenazine, reserpine, strong anticholinergics, metoclopramide, dopamine agonists, levodopa, or stimulants within 30 days
Botulinum toxin within 3 months
Neurological condition confounding TD assessment
Serious untreated psychiatric illness
History of suicidal ideation within 6 months or HADS depression >=11
QTcF >450 ms (men) or >460 ms (women)

Arms

Field	Control	Deutetrabenazine
Intervention	Matching placebo, titrated weekly for 6 weeks then maintained	Deutetrabenazine flexible dose, started at 12 mg/day, titrated by 6 mg/day weekly up to 48 mg/day based on dyskinesia control and tolerability; mean dose 38.8 mg/day
Duration	12 weeks	12 weeks

Outcomes

Outcome	Type	Control	Intervention	P-value
Change in AIMS score from baseline to week 12 (central video rating by blinded movement disorder experts)	Primary	-1.6 (SE 0.46)	-3.0 (SE 0.45)	0.019
CGIC treatment success (much/very much improved)	Secondary	40.4%	48.2%	NS
PGIC treatment success	Secondary	29.8%	42.9%	NS
mCDQ-24 change from baseline	Secondary	-8.3 (SE 2.31)	-11.1 (SE 2.14)	NS
Any adverse event	Adverse	61.0%	70.7%
Treatment-related AE	Adverse	35.6%	48.3%
Serious adverse event	Adverse	8.5%	5.2%
Somnolence	Adverse	10.2%	13.8%
Fatigue	Adverse	8.5%	6.9%
Insomnia	Adverse	1.7%	6.9%
Akathisia	Adverse	0%	5.2%
Depression/depressed mood	Adverse	1.7%	1.7%
Suicidal ideation	Adverse	1.7%	0%
Deaths	Adverse	0	0

Subgroup Analysis

Post hoc analysis of patients with central video AIMS >=6 at both screening and baseline (n=97) showed larger treatment difference on CGIC (52.1% vs 34.7%, treatment difference 17.4%)

Criticisms

Notable placebo response on AIMS scores despite central video rating
CGIC and PGIC did not reach statistical significance despite AIMS improvement
Most investigators were psychiatrists who may be less familiar with TD motor nuances
Short 12-week duration
Funded by manufacturer (Teva)
Public announcement of positive First-HD results during study may have affected placebo response

Funding

Teva Pharmaceutical Industries

Based on: ARM-TD (Neurology, 2017)

Authors: Hubert H Fernandez, Stewart A Factor, Robert A Hauser, ..., Karen E Anderson

Citation: Neurology 2017;88:2003-2010

Content summarized and formatted by NeuroTrials.ai.

ARM-TD

(2017)

Objective

To determine the efficacy and safety of deutetrabenazine as a treatment for tardive dyskinesia using a flexible dosing regimen.

Study Summary

• Deutetrabenazine significantly reduced AIMS scores by 3.0 points vs 1.6 with placebo (P=0.019)
• Treatment difference of -1.4 points (95% CI -2.6 to -0.2) favoring deutetrabenazine
• No reports of depression or suicidal ideation with deutetrabenazine; low psychiatric AE rates

Intervention

Deutetrabenazine flexible dose (up to 48 mg/day, mean ~38 mg/day) orally for 12 weeks vs placebo

Inclusion Criteria

Adults with tardive dyskinesia for >=3 months, AIMS score >=6, history of DRA use >=3 months, stable psychiatric illness and medications

Study Design

Arms: Placebo, Deutetrabenazine (flexible dose)

Patients per Arm: Placebo: 59, Deutetrabenazine: 58

Outcome

• Primary: Change in AIMS score at week 12: -1.6 (placebo) vs -3.0 (deutetrabenazine), P=0.019
• CGIC treatment success: 40.4% vs 48.2% (NS)
• Class I evidence for deutetrabenazine efficacy in TD

Bottom Line

Major Points

Phase II/III flexible-dose trial of deutetrabenazine for tardive dyskinesia
Significant reduction in AIMS score vs placebo (-3.0 vs -1.6, p=0.019)
Treatment difference observed by week 4 (p=0.007)
Mean dose at end of titration was 38.8 mg/day
No reports of depression or suicidal ideation in deutetrabenazine group
98.3% of patients had underlying psychiatric comorbidity
80.3% were on concomitant DRAs throughout the study
Provides Class I evidence for deutetrabenazine in TD

Study Design

Study Type: Phase II/III, multicenter, randomized, double-blind, parallel-group, placebo-controlled trial
Randomization: Yes
Blinding: Double-blind: patients and site investigators were blinded throughout
Sample Size: 117
Follow-up: 12 weeks (6-week titration, 6-week maintenance, 1-week washout)
Centers: 46
Countries: United States, Europe

Primary Outcome

Definition: Change in AIMS score from baseline to week 12 (central video rating by blinded movement disorder experts)

Control	Intervention	HR/OR	P-value
-1.6 (SE 0.46)	-3.0 (SE 0.45)	- (-2.6 to -0.2)	0.019

Limitations & Criticisms

Notable placebo response on AIMS scores despite central video rating
CGIC and PGIC did not reach statistical significance despite AIMS improvement
Most investigators were psychiatrists who may be less familiar with TD motor nuances
Short 12-week duration
Funded by manufacturer (Teva)
Public announcement of positive First-HD results during study may have affected placebo response

Citation

Neurology 2017;88:2003-2010

View Original Publication →

ARM-TD

Aim to Reduce Movements in Tardive Dyskinesia

Clinical Question

Bottom Line

Major Points

Design

Inclusion Criteria

Exclusion Criteria

Arms

Outcomes

Subgroup Analysis

Criticisms

Funding

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