Efficacy, Safety, and Tolerability of Valbenazine for the Treatment of Chorea Associated With Huntington Disease (KINECT-HD)

• ClinicalTrials.gov Identifier: NCT04102579
• Recruitment Status: Completed
• First Posted: September 25, 2019
• Results First Posted: October 11, 2023
• Last Update Posted: October 11, 2023
• Sponsor: Neurocrine Biosciences
• Collaborator: Huntington Study Group
• Information provided by (Responsible Party): Neurocrine Biosciences

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Chorea, Huntington
• Interventions: Drug: Valbenazine; Drug: Placebo
• Enrollment: 128

Participant Flow

Recruitment Details
Pre-assignment Details

Arm/Group Title	Valbenazine	Placebo
Arm/Group Description	Capsule, administered orally once daily for 12 weeks.	Capsule, administered orally once daily for 12 weeks.
Period Title: Overall Study
Started	64	64
Received at Least 1 Dose of Study Drug	64	63
Completed	57	54
Not Completed	7	10
Reason Not Completed
Withdrawal by Subject	3	4
Lost to Follow-up	0	1
Discontinued Due to COVID-19-related Study Pause	3	4
Other than Specified	1	0
Not Dosed with Study Drug	0	1

Baseline Characteristics

Arm/Group Title		Valbenazine	Placebo	Total
Arm/Group Description		Capsule, administered orally once daily for 12 weeks.	Capsule, administered orally once daily for 12 weeks.	Total of all reporting groups
Overall Number of Baseline Participants		64	63	127
Baseline Analysis Population Description		All participants who received at least 1 dose of study drug.
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	64 participants	63 participants	127 participants
		54.1 (10.1)	53.6 (11.6)	53.8 (10.8)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	64 participants	63 participants	127 participants
	Female	33 51.6%	36 57.1%	69 54.3%
	Male	31 48.4%	27 42.9%	58 45.7%
Ethnicity (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	64 participants	63 participants	127 participants
	Hispanic or Latino	5 7.8%	3 4.8%	8 6.3%
	Not Hispanic or Latino	59 92.2%	60 95.2%	119 93.7%
	Unknown or Not Reported	0 0.0%	0 0.0%	0 0.0%
Race (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	64 participants	63 participants	127 participants
	American Indian or Alaska Native	0 0.0%	0 0.0%	0 0.0%
	Asian	1 1.6%	0 0.0%	1 0.8%
	Native Hawaiian or Other Pacific Islander	0 0.0%	0 0.0%	0 0.0%
	Black or African American	1 1.6%	0 0.0%	1 0.8%
	White	60 93.8%	62 98.4%	122 96.1%
	More than one race	0 0.0%	0 0.0%	0 0.0%
	Unknown or Not Reported	2 3.1%	1 1.6%	3 2.4%
Region of Enrollment; Measure Type: Number; Unit of measure: Participants	Number Analyzed	64 participants	63 participants	127 participants
Canada		2	7	9
United States		62	56	118

Outcome Measures

1. Primary Outcome

Title	Change From Screening Period Baseline to Maintenance Period in the Unified Huntington's Disease Rating Scale (UHDRS) Total Maximal Chorea (TMC) Score.
Description	The TMC is part of the motor assessment of the UHDRS and measures chorea in 7 different body parts including the face, oral-buccal-lingual region, trunk and each limb independently. The TMC score is the sum of the individual scores and ranges from 0 to 28. A decrease in TMC scores indicates improvement in chorea symptoms.
Time Frame	Baseline (average of screening and Day -1), maintenance (average of Weeks 10 and 12)

Outcome Measure Data

Analysis Population Description

All participants who are randomly assigned to a treatment group and who had at least 1 evaluable TMC change from baseline score during the 12-week double-blind treatment period.

Arm/Group Title	Valbenazine	Placebo
Arm/Group Description:	Capsule, administered orally once daily for 12 weeks.	Capsule, administered orally once daily for 12 weeks.
Overall Number of Participants Analyzed	64	61
Least Squares Mean (Standard Error); Unit of Measure: units on a scale
	-4.60 (0.43)	-1.44 (0.44)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Valbenazine, Placebo
	Comments	Results were analyzed using a mixed-effect model repeated measures (MMRM) analysis. The model included the screening period baseline TMC as a covariate, and treatment group, visit, treatment group-by-visit interaction, and baseline-by-visit interaction as fixed effects. Participant was included as a random effect.
	Type of Statistical Test	Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Statistical significance achieved if p-value <0.05.
	Method	MMRM
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Least Squares (LS) Means Difference
	Estimated Value	-3.16
	Confidence Interval	(2-Sided) 95%; -4.37 to -1.95
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.61
	Estimation Comments	LS Means Difference = Valbenazine - Placebo

2. Secondary Outcome

Title	Percent of Clinical Global Impression of Change (CGI-C) Responders at Week 12
Description	The CGI-C is a 7-point scale that rates the overall global change in chorea symptoms since the initiation of study drug dosing, ranging from 1 (very much improved) to 7 (very much worse), as assessed by the investigator or qualified clinician designee. Participants whose CGI-C score was either a 1 (very much improved) or a 2 (much improved) were classified as responders.
Time Frame	Week 12

Outcome Measure Data

Analysis Population Description

All participants who were randomly assigned to a treatment group, and who had at least 1 evaluable TMC change from baseline score and observed data at Week 12.

Arm/Group Title	Valbenazine	Placebo
Arm/Group Description:	Capsule, administered orally once daily for 12 weeks.	Capsule, administered orally once daily for 12 weeks.
Overall Number of Participants Analyzed	56	53
Measure Type: Number; Unit of Measure: percentage of responders
	42.9	13.2

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Valbenazine, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0007
	Comments	Statistical significance achieved if p-value <0.05.
	Method	Fisher Exact
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Percent Difference in Responders
	Estimated Value	29.65
	Confidence Interval	(2-Sided) 95%; 10.77 to 45.37
	Estimation Comments	Percent Difference in Responders (%) = Valbenazine - Placebo

3. Secondary Outcome

Title	Percent of Patient Global Impression of Change (PGI-C) Responders at Week 12
Description	The PGI-C is a 7-point scale that rates the overall global change in chorea symptoms since the initiation of study drug dosing, ranging from 1 (very much improved) to 7 (very much worse), as assessed by the participant. Participants whose PGI-C score was either a 1 (very much improved) or a 2 (much improved) were classified as responders.
Time Frame	Week 12

Outcome Measure Data

Analysis Population Description

All participants who were randomly assigned to a treatment group, and who had at least 1 evaluable TMC change from baseline score and observed data at Week 12.

Arm/Group Title	Valbenazine	Placebo
Arm/Group Description:	Capsule, administered orally once daily for 12 weeks.	Capsule, administered orally once daily for 12 weeks.
Overall Number of Participants Analyzed	55	53
Measure Type: Number; Unit of Measure: percentage of responders
	52.7	26.4

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Valbenazine, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0062
	Comments	Statistical significance achieved if p-value <0.05.
	Method	Fisher Exact
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Percent Difference in Responders
	Estimated Value	26.31
	Confidence Interval	(2-Sided) 95%; 6.32 to 43.74
	Estimation Comments	Percent Difference in Responders (%) = Valbenazine - Placebo

4. Secondary Outcome

Title	Change From Baseline to Week 12 in the Quality of Life in Neurological Disorders (Neuro-QoL) Upper Extremity Function T-Score
Description	The Neuro-QoL Upper Extremity Function Short Form consists of 8 questions about physical abilities, rated from 1 (unable to do) to 5 (without any difficulty). The Neuro-QoL scores were standardized as T-scores with a mean of 50 and standard deviation of 10. Scores below 50 indicated below average upper extremity function. The change from baseline to Week 12 in the Neuro-QoL Upper Extremity Function T-score are presented here. An increase in score indicates increased function.
Time Frame	Baseline, Week 12

Outcome Measure Data

Analysis Population Description

All participants who are randomly assigned to a treatment group and who had at least 1 evaluable TMC change from baseline score during the 12-week double-blind treatment period.

Arm/Group Title	Valbenazine	Placebo
Arm/Group Description:	Capsule, administered orally once daily for 12 weeks.	Capsule, administered orally once daily for 12 weeks.
Overall Number of Participants Analyzed	64	61
Least Squares Mean (Standard Error); Unit of Measure: units on a scale
	-1.58 (1.01)	-3.00 (1.04)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Valbenazine, Placebo
	Comments	LS mean was based on the MMRM model which included corresponding baseline value of the Neuro-QoL Upper Extremity Function T-score as a covariate; treatment group, visit, baseline-by-visit interaction, and treatment group-by-visit interaction as fixed effects; and participant as a random effect.
	Type of Statistical Test	Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.3304
	Comments	Statistical significance achieved if p-value <0.05.
	Method	MMRM
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Means Difference
	Estimated Value	1.42
	Confidence Interval	(2-Sided) 95%; -1.46 to 4.31
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.46
	Estimation Comments	LS Means Difference = Valbenazine - Placebo

5. Secondary Outcome

Title	Change From Baseline to Week 12 in the Neuro-QoL Lower Extremity Function T-Score
Description	The Neuro-QoL Lower Extremity Function Short Form consists of 8 questions about physical abilities, rated from 1 (unable to do) to 5 (without any difficulty). The Neuro-QoL scores were standardized as T-scores with a mean of 50 and standard deviation of 10. Scores below 50 indicated below average upper extremity function. The change from baseline to Week 12 in the Neuro-QoL Upper Extremity Function T-score are presented here. An increase in score indicates better function.
Time Frame	Baseline, Week 12

Outcome Measure Data

Analysis Population Description

All participants who are randomly assigned to a treatment group and who had at least 1 evaluable TMC change from baseline score during the 12-week double-blind treatment period.

Arm/Group Title	Valbenazine	Placebo
Arm/Group Description:	Capsule, administered orally once daily for 12 weeks.	Capsule, administered orally once daily for 12 weeks.
Overall Number of Participants Analyzed	64	61
Least Squares Mean (Standard Error); Unit of Measure: units on a scale
	-0.27 (0.82)	0.61 (0.84)

Adverse Events

Time Frame	Day 1 (after dosing) through Week 14
Adverse Event Reporting Description	All-cause mortality, serious adverse events, and other adverse events were assessed using the safety analysis population which included all participants who were randomly assigned to a treatment group, received at least 1 dose of study treatment, and had any postbaseline safety data. Treatment-emergent adverse events were those that occurred on or after first dose date of study treatment and up to 14 days after the last dose of study treatment.
Arm/Group Title	Valbenazine	Placebo
Arm/Group Description	Capsule, administered orally once daily for 12 weeks.	Capsule, administered orally once daily for 12 weeks.
All-Cause Mortality
	Valbenazine	Placebo
	Affected / at Risk (%)	Affected / at Risk (%)
Total	0/64 (0.00%)	1/63 (1.59%)
Serious Adverse Events
	Valbenazine	Placebo
	Affected / at Risk (%)	Affected / at Risk (%)
Total	1/64 (1.56%)	2/63 (3.17%)
Cardiac disorders
Colon cancer † 1 [1]	0/64 (0.00%)	1/63 (1.59%)
Psychiatric disorders
Psychotic disorder † 1	0/64 (0.00%)	1/63 (1.59%)
Skin and subcutaneous tissue disorders
Angioedema † 1	1/64 (1.56%)	0/63 (0.00%)
1 Term from vocabulary, MedDRA 24.0; † Indicates events were collected by systematic assessment; [1] A serious adverse event of colon cancer in the placebo group resulted in death.
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Valbenazine	Placebo
	Affected / at Risk (%)	Affected / at Risk (%)
Total	35/64 (54.69%)	17/63 (26.98%)
General disorders
Fatigue † 1	9/64 (14.06%)	6/63 (9.52%)
Injury, poisoning and procedural complications
Fall † 1	8/64 (12.50%)	8/63 (12.70%)
Nervous system disorders
Somnolence † 1	10/64 (15.63%)	2/63 (3.17%)
Akathisia † 1	4/64 (6.25%)	3/63 (4.76%)
Skin and subcutaneous tissue disorders
Rash † 1	5/64 (7.81%)	0/63 (0.00%)
Urticaria † 1 [1]	5/64 (7.81%)	0/63 (0.00%)
1 Term from vocabulary, MedDRA 24.0; † Indicates events were collected by systematic assessment; [1] Note: One additional participant in the valbenazine group had an event of urticaria that was coded under the system organ class of immune system disorders.

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Generally, the PI has the right to publish results provided such publication does not violate confidentiality or IP provisions within the contract with the Sponsor. Prior to submission for publication or presentation of results, the PI must provide the Sponsor time for review. The Sponsor can request the PI to withhold or remove information from all publications. For a multi-center study, any publication of results by the PI shall not be made before the first multi-center publication.

Results Point of Contact

• Name/Title: Neurocrine Medical Information Call Center
• Organization: Neurocrine Biosciences
• Phone: 877-641-3461
• EMail: medinfo@neurocrine.com

Publications of Results:

Furr Stimming E, Claassen DO, Kayson E, Goldstein J, Mehanna R, Zhang H, Liang GS, Haubenberger D; Huntington Study Group KINECT-HD Collaborators. Safety and efficacy of valbenazine for the treatment of chorea associated with Huntington's disease (KINECT-HD): a phase 3, randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2023 Jun;22(6):494-504. doi: 10.1016/S1474-4422(23)00127-8. Erratum In: Lancet Neurol. 2023 Sep;22(9):e10. Lancet Neurol. 2023 Sep;22(9):e10.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Rodrigues FB, Wild EJ. Huntington's Disease Clinical Trials Corner: April 2020. J Huntingtons Dis. 2020;9(2):185-197. doi: 10.3233/JHD-200002.

• Responsible Party: Neurocrine Biosciences
• ClinicalTrials.gov Identifier: NCT04102579
• Other Study ID Numbers: NBI-98854-HD3005
• First Submitted: September 23, 2019
• First Posted: September 25, 2019
• Results First Submitted: September 15, 2023
• Results First Posted: October 11, 2023
• Last Update Posted: October 11, 2023