Chorea, Huntington
Conditions
Keywords
Huntington's, Huntington, Chorea, Movement disorder, Valbenazine, HD, Tetrabenazine, VMAT2-Inhibitor
Brief summary
This is a Phase 3, randomized, double-blind, placebo-controlled study to evaluate the efficacy, safety, and tolerability of valbenazine to treat chorea in participants with Huntington disease.
Interventions
DRUGValbenazine
vesicular monoamine transporter 2 (VMAT2) inhibitor
DRUGPlacebo
non-active dosage form
Sponsors
Huntington Study Group
Neurocrine Biosciences
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
1. Have a clinical diagnosis of Huntington Disease (HD) with chorea 2. Be able to walk, with or without the assistance of a person or device 3. Participants of childbearing potential who do not practice total abstinence must agree to use hormonal or two forms of nonhormonal contraception (dual contraception) consistently while participating in the study until 30 days (females) or 90 days (males) after the last dose of the study drug 4. Be able to read and understand English
Exclusion criteria
1. Have a history of previously established therapy with a VMAT2 inhibitor, in the judgement of the investigator 2. Have difficulty swallowing 3. Are currently pregnant or breastfeeding 4. Have a known history of long QT syndrome, cardiac tachyarrhythmia, left bundle-branch block, atrioventricular block, uncontrolled bradyarrhythmia, or heart failure 5. Have an unstable or serious medical or psychiatric illness 6. Have a significant risk of suicidal behavior 7. Have a history of substance dependence or substance (drug) or alcohol abuse, within 1 year of screening 8. If taking antidepressant therapy, be on a stable regimen 9. Have received gene therapy at any time 10. Have received an investigational drug in a clinical study within 30 days of the baseline visit or plan to use such investigational drug (other than valbenazine) during the study 11. Have had a blood loss ≥550 milliliters (mL) or donated blood within 30 days before the baseline visit 12. Had a medically significant illness within 30 days before baseline, or any history of neuroleptic malignant syndrome
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Screening Period Baseline to Maintenance Period in the Unified Huntington's Disease Rating Scale (UHDRS) Total Maximal Chorea (TMC) Score. | Baseline (average of screening and Day -1), maintenance (average of Weeks 10 and 12) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percent of Clinical Global Impression of Change (CGI-C) Responders at Week 12 | Week 12 | 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. |
| Percent of Patient Global Impression of Change (PGI-C) Responders at Week 12 | Week 12 | 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. |
| Change From Baseline to Week 12 in the Quality of Life in Neurological Disorders (Neuro-QoL) Upper Extremity Function T-Score | Baseline, Week 12 | 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. |
| Change From Baseline to Week 12 in the Neuro-QoL Lower Extremity Function T-Score | Baseline, Week 12 | 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. |
Countries
Canada, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Valbenazine Capsule, administered orally once daily for 12 weeks. | 64 |
| Placebo Capsule, administered orally once daily for 12 weeks. | 63 |
| Total | 127 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Discontinued Due to COVID-19-related Study Pause | 3 | 4 |
| Overall Study | Lost to Follow-up | 0 | 1 |
| Overall Study | Not Dosed with Study Drug | 0 | 1 |
| Overall Study | Other than Specified | 1 | 0 |
| Overall Study | Withdrawal by Subject | 3 | 4 |
Baseline characteristics
| Characteristic | Valbenazine | Total | Placebo |
|---|---|---|---|
| Age, Continuous | 54.1 years STANDARD_DEVIATION 10.1 | 53.8 years STANDARD_DEVIATION 10.8 | 53.6 years STANDARD_DEVIATION 11.6 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 5 Participants | 8 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 59 Participants | 119 Participants | 60 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 3 Participants | 1 Participants |
| Race (NIH/OMB) White | 60 Participants | 122 Participants | 62 Participants |
| Region of Enrollment Canada | 2 participants | 9 participants | 7 participants |
| Region of Enrollment United States | 62 participants | 118 participants | 56 participants |
| Sex: Female, Male Female | 33 Participants | 69 Participants | 36 Participants |
| Sex: Female, Male Male | 31 Participants | 58 Participants | 27 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 64 | 1 / 63 |
| other Total, other adverse events | 35 / 64 | 17 / 63 |
| serious Total, serious adverse events | 1 / 64 | 2 / 63 |
Outcome results
Primary
Change From Screening Period Baseline to Maintenance Period in the Unified Huntington's Disease Rating Scale (UHDRS) Total Maximal Chorea (TMC) Score.
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)
Population: 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 | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Valbenazine | Change From Screening Period Baseline to Maintenance Period in the Unified Huntington's Disease Rating Scale (UHDRS) Total Maximal Chorea (TMC) Score. | -4.60 units on a scale | Standard Error 0.43 |
| Placebo | Change From Screening Period Baseline to Maintenance Period in the Unified Huntington's Disease Rating Scale (UHDRS) Total Maximal Chorea (TMC) Score. | -1.44 units on a scale | Standard Error 0.44 |
Comparison: 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.p-value: <0.000195% CI: [-4.37, -1.95]MMRM
Secondary
Change From Baseline to Week 12 in the Neuro-QoL Lower Extremity Function T-Score
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
Population: 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 | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Valbenazine | Change From Baseline to Week 12 in the Neuro-QoL Lower Extremity Function T-Score | -0.27 units on a scale | Standard Error 0.82 |
| Placebo | Change From Baseline to Week 12 in the Neuro-QoL Lower Extremity Function T-Score | 0.61 units on a scale | Standard Error 0.84 |
Secondary
Change From Baseline to Week 12 in the Quality of Life in Neurological Disorders (Neuro-QoL) Upper Extremity Function T-Score
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
Population: 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 | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Valbenazine | Change From Baseline to Week 12 in the Quality of Life in Neurological Disorders (Neuro-QoL) Upper Extremity Function T-Score | -1.58 units on a scale | Standard Error 1.01 |
| Placebo | Change From Baseline to Week 12 in the Quality of Life in Neurological Disorders (Neuro-QoL) Upper Extremity Function T-Score | -3.00 units on a scale | Standard Error 1.04 |
Comparison: 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.p-value: 0.330495% CI: [-1.46, 4.31]MMRM
Secondary
Percent of Clinical Global Impression of Change (CGI-C) Responders at Week 12
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
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| Valbenazine | Percent of Clinical Global Impression of Change (CGI-C) Responders at Week 12 | 42.9 percentage of responders |
| Placebo | Percent of Clinical Global Impression of Change (CGI-C) Responders at Week 12 | 13.2 percentage of responders |
p-value: 0.000795% CI: [10.77, 45.37]Fisher Exact
Secondary
Percent of Patient Global Impression of Change (PGI-C) Responders at Week 12
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
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| Valbenazine | Percent of Patient Global Impression of Change (PGI-C) Responders at Week 12 | 52.7 percentage of responders |
| Placebo | Percent of Patient Global Impression of Change (PGI-C) Responders at Week 12 | 26.4 percentage of responders |
p-value: 0.006295% CI: [6.32, 43.74]Fisher Exact