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FIRST-HD

Effect of Deutetrabenazine on Chorea Among Patients With Huntington Disease: A Randomized Clinical Trial

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Year of Publication: 2016

Authors: Huntington Study Group

Journal: JAMA

Citation: JAMA. 2016;316(1):40-50. doi:10.1001/jama.2016.8655

Link: https://clinicaltrials.gov/ct2/show/NCT01795859

Clinical Question

Does deutetrabenazine safely and effectively reduce chorea in patients with Huntington disease compared to placebo?

Bottom Line

Among patients with chorea associated with Huntington disease, the use of deutetrabenazine compared with placebo resulted in improved motor signs at 12 weeks, with a mean reduction in total maximal chorea score of 2.5 points (P<0.001).

        Major Points
        Deutetrabenazine significantly improved chorea (mean TMC score: -4.4 vs -1.9, difference -2.5, P<0.001)
Treatment success on PGIC: 51% vs 20% (P=0.002)
Treatment success on CGIC: 42% vs 13% (P=0.002)
SF-36 physical functioning improved (treatment difference 4.3, P=0.03)
UHDRS total motor score improved -4.0 points (P=0.002)
Deutetrabenazine uses deuterium substitution to attenuate CYP2D6 metabolism

      

Design

Study Type: Randomized, double-blind, placebo-controlled, parallel-group trial

Randomization: 1

Blinding: Double-blind (patients, caregivers, investigators, site personnel, data management staff, and steering committee)

Enrollment Period: August 2013 to August 2014

Follow-up Duration: 13 weeks (12 weeks treatment + 1 week washout)

Centers: 34

Countries: United States, Canada

Sample Size: 90

Analysis: Intention-to-treat using ANCOVA model with total maximal chorea score change from baseline as dependent variable, treatment group as factor, and baseline score as covariate

Inclusion Criteria

Ambulatory adults diagnosed with manifest Huntington disease
Characteristic motor examination features and expanded HTT CAG repeat sequence (≥36)
Baseline total maximal chorea score ≥8 at screening and baseline (range 0-28)
UHDRS total functional capacity score ≥5 at screening
Daily contact with a study partner
Patients with more advanced disease (TFC 5-7) required live-in caregiver

Exclusion Criteria

Serious untreated or undertreated psychiatric illness (HADS depression ≥11)
History of significant suicidal thoughts or behavior
Prolonged QTc interval or left bundle-branch block
Hepatic or renal impairment
Score ≥11 on Swallowing Disturbance Questionnaire
Use of tetrabenazine within 6 months
Use of antipsychotics, MAO inhibitors, levodopa, or dopamine agonists within 30 days

Arms

Field	Control	Deutetrabenazine
Intervention	Matching placebo titrated over 8 weeks and maintained for 4 weeks, followed by 1-week washout. Administered in 2 doses daily.	Deutetrabenazine titrated to optimal dose over 8 weeks (starting at 6 mg/d, increased weekly by 6 mg/d up to maximum 48 mg/d), maintained for 4 weeks. Mean dose at end of treatment: 39.7 mg (SD 9.3 mg; range 12-48 mg).
Duration	12 weeks + 1 week washout	12 weeks + 1 week washout

Outcomes

Outcome	Type	Control	Intervention	P-value
Change in total maximal chorea score from baseline (average of screening and day-0 visits) to maintenance therapy (average of week 9 and 12 visits). Scale range 0-28.	Primary	-1.9 (95% CI -2.8 to -1.1)	-4.4 (95% CI -5.3 to -3.6)	<0.001
Patient Global Impression of Change (PGIC) - treatment success	Secondary	9 patients (20%)	23 patients (51%)	0.002
Clinical Global Impression of Change (CGIC) - treatment success	Secondary	6 patients (13%)	19 patients (42%)	0.002
SF-36 physical functioning subscale score	Secondary	Change -3.6	Change 0.7	0.03
UHDRS total motor score	Secondary	Improved -3.4	Improved -7.4	0.002
Percentage change in TMC score	Secondary	-16%	-37%	<0.001
Somnolence	Adverse	2 (4.4%)	5 (11.1%)
Diarrhea	Adverse	0	4 (8.9%)
Dry mouth	Adverse	3 (6.7%)	4 (8.9%)
Depression or agitated depression	Adverse	3 (6.7%)	2 (4.4%)
Serious adverse events	Adverse	1 patient (COPD exacerbation)	1 patient (cholecystitis, agitated depression)
Weight gain (BMI)	Adverse	-0.1	+0.6	0.002

Subgroup Analysis

CYP2D6 genotyping performed. Poor metabolizers (10 patients in deutetrabenazine group) had mean dose of 34.8 mg. Genetic status of CYP2D6 was not associated with dosing; poor metabolizers did not have additional adverse events.

Criticisms

Limited duration of exposure (12 weeks) in a disease that progresses over years to decades
Not powered for detailed safety assessment
Small proportion of patients had prior tetrabenazine exposure
Minimal clinically important difference for UHDRS total maximal chorea score has not been determined
Small number of patients per site prevented stratification by site

Funding

Auspex Pharmaceuticals, a wholly owned subsidiary of Teva Pharmaceutical Industries

Based on: FIRST-HD (JAMA, 2016)

Authors: Huntington Study Group

Citation: JAMA. 2016;316(1):40-50. doi:10.1001/jama.2016.8655

Content summarized and formatted by NeuroTrials.ai.

FIRST-HD

(2016)

Objective

To evaluate the efficacy and safety of deutetrabenazine treatment to control chorea associated with Huntington disease.

Study Summary

• Deutetrabenazine significantly reduced total maximal chorea score by 4.4 points vs 1.9 with placebo (treatment difference -2.5, P<0.001)
• Patient-reported treatment success (PGIC): 51% vs 20% (P=0.002)
• Safety profile similar to placebo including depression, anxiety, and akathisia rates

Intervention

Deutetrabenazine titrated up to 48 mg/day (mean 39.7 mg) in 2 divided doses over 8 weeks, maintained for 4 weeks vs placebo

Inclusion Criteria

Ambulatory adults with manifest Huntington disease (CAG >=36), total maximal chorea score >=8, UHDRS total functional capacity >=5, HADS depression <11

Study Design

Arms: Placebo, Deutetrabenazine

Patients per Arm: Placebo: 45, Deutetrabenazine: 45

Outcome

• Primary: Change in total maximal chorea score: -4.4 (deutetrabenazine) vs -1.9 (placebo), difference -2.5 (P<0.001)
• PGIC treatment success: 51% vs 20% (P=0.002)
• CGIC treatment success: 42% vs 13% (P=0.002)
• SF-36 physical functioning: treatment benefit 4.3 points (P=0.03)

Bottom Line

Major Points

Deutetrabenazine significantly improved chorea (mean TMC score: -4.4 vs -1.9, difference -2.5, P<0.001)
Treatment success on PGIC: 51% vs 20% (P=0.002)
Treatment success on CGIC: 42% vs 13% (P=0.002)
SF-36 physical functioning improved (treatment difference 4.3, P=0.03)
UHDRS total motor score improved -4.0 points (P=0.002)
Deutetrabenazine uses deuterium substitution to attenuate CYP2D6 metabolism

Study Design

Study Type: Randomized, double-blind, placebo-controlled, parallel-group trial
Randomization: Yes
Blinding: Double-blind (patients, caregivers, investigators, site personnel, data management staff, and steering committee)
Sample Size: 90
Follow-up: 13 weeks (12 weeks treatment + 1 week washout)
Centers: 34
Countries: United States, Canada

Primary Outcome

Definition: Change in total maximal chorea score from baseline (average of screening and day-0 visits) to maintenance therapy (average of week 9 and 12 visits). Scale range 0-28.

Control	Intervention	HR/OR	P-value
-1.9 (95% CI -2.8 to -1.1)	-4.4 (95% CI -5.3 to -3.6)	- (-3.7 to -1.3)	<0.001

Limitations & Criticisms

Limited duration of exposure (12 weeks) in a disease that progresses over years to decades
Not powered for detailed safety assessment
Small proportion of patients had prior tetrabenazine exposure
Minimal clinically important difference for UHDRS total maximal chorea score has not been determined
Small number of patients per site prevented stratification by site

Citation

JAMA. 2016;316(1):40-50. doi:10.1001/jama.2016.8655

View Original Publication →

FIRST-HD

Effect of Deutetrabenazine on Chorea Among Patients With Huntington Disease: A Randomized Clinical Trial

Clinical Question

Bottom Line

Major Points

Design

Inclusion Criteria

Exclusion Criteria

Arms

Outcomes

Subgroup Analysis

Criticisms

Funding

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