Reducing Involuntary Movements in Participants With Tardive Dyskinesia

Conditions

Tardive Dyskinesia

Keywords

Dyskinesias, Movement Disorders, Central Nervous System Diseases, Nervous System Diseases, Neurologic Manifestations, Signs and Symptoms

Brief summary

The purpose of this study is to evaluate the long-term safety, tolerability, and efficacy of SD-809 in reducing the severity of abnormal involuntary movements of moderate to severe tardive dyskinesia. The purpose of part B is to establish the durability of effect of SD-809 following 1-week period of randomized withdrawal (SD-809 and placebo), followed by 12 weeks of maintenance with SD-809.

Detailed description

Participants who complete study SD-809-C-18 (NCT02195700), SD-809-C-23 (NCT02291861), or any other SD-809 study will be enrolled in this study. This study include a screening period (Part A), a titration period (Part A), a long-term treatment period (Part A), a double-blind, randomized withdrawal period (Part B), treatment after completion of the randomized withdrawal period (Part B), and a post-treatment safety follow-up period (Part A and Part B). EU participants who complete Part B will be invited to participate in Part C.

Robert A. Hauser, Hadas Barkay, Hubert H. Fernandez, Joohi Jimenez‐Shahed, Stewart A. Factor et al. (12 authors)

Journal of Clinical Psychopharmacology2024-06-20

10.1097/jcp.0000000000001885

Safety of Deutetrabenazine for the Treatment of Tardive Dyskinesia and Chorea Associated with Huntington Disease.

Frank S, Anderson KE, Fernandez HH, Hauser RA, Claassen DO, Stamler D, Factor SA, Jimenez-Shahed J, Barkay H, Wilhelm A, Alexander JK, Chaijale N, Barash S, Savola JM, Gordon MF, Chen M.

2024-04-012 citations

10.1007/s40120-024-00600-1

Long-term safety and efficacy of deutetrabenazine for the treatment of tardive dyskinesia

Hubert H. Fernandez, David Stamler, Mat D. Davis, Stewart A. Factor, Robert A. Hauser et al. (13 authors)

Journal of Neurology Neurosurgery & Psychiatry2019-07-1047 citations

10.1136/jnnp-2018-319918

Interventions

DRUGSD-809

SD-809 will be administered per dose and schedule specified in the arm.

DRUGPlacebo

Placebo matching to SD-809 will be administered per schedule specified in the arm.

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 No maximum

Healthy volunteers

No

Inclusion criteria

* History of using a dopamine receptor antagonist for at least 3 months * Clinical diagnosis of tardive dyskinesia and has had symptoms for at least 3 months prior to screening * Participant has successfully completed a controlled study of SD-809 for treatment of moderate to severe tardive dyskinesia * Participants with underlying psychiatric diagnosis are stable and have no change in psychoactive medications * Have a mental health provider and does not anticipate any changes to treatment regimen in the next 3 months * History of being compliant with prescribed medications * Able to swallow study drug whole * Be in good general health and is expected to attend all study visits and complete study assessments * Female participants must not be pregnant and agree to an acceptable method of contraception

Exclusion criteria

* Currently receiving medication for the treatment of tardive dyskinesia * Have a neurological condition other than tardive dyskinesia that may interfere with assessing the severity of dyskinesias * Have a serious untreated or undertreated psychiatric illness * Have recent history or presence of violent behavior * Have unstable or serious medical illness * Have evidence of hepatic impairment * Have evidence of renal impairment * Have known allergy to any component of SD-809 or tetrabenazine * Has participated in an investigational drug or device trial (other than Study C-18, Study C-23, or any other eligible TEV-50717 parent study) and received study drug within 30 days * Have acknowledged use of illicit drugs * Have a history of alcohol or substance abuse in the previous 12 months

Design outcomes

Primary

Measure	Time frame	Description
Part A, B, and C: Number of Participants With Treatment-Emergent AEs (TEAEs), Serious TEAEs, Severe TEAEs, Drug-Related TEAEs, and TEAEs Leading to Withdrawal	Baseline up to the end of follow-up (4 weeks after the last dose of study drug; mean exposure: up to approximately 866.1 days)	AEs were analyzed as one group combined for parts A and B per planned analysis. An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Severe AE=prevents normal daily activities. Drug-related TEAEs: TEAEs with possible, probable, or definite relationship to study drug. Serious AEs: death, a life-threatening AE, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, a congenital anomaly or birth defect, or an important medical event that jeopardized participant and required medical intervention to prevent 1 of the outcomes listed in this definition. A treatment-emergent AE was defined as an AE that began after the first administration of study medication or existing AEs that worsened after the first dose of study medication. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section.
Part B: Change From Day 1 Visit in Total Motor AIMS Score at Day 7 Visit, as Assessed by Blinded Central Video Rating	Day 1 of Part B, Day 7 of Part B	The AIMS is an assessment tool used to detect and follow the severity of TD over time. The AIMS is composed of 12 clinician-administered and -scored items. A total motor score from Items 1 to 7 (orofacial, extremity, and truncal movements) was calculated. Items 1 through 7 included facial and oral movements (Items 1-4), extremity movements (Items 5-6), and trunk movements (Item 7). Each item was rated on a 5-point anchored scale ranging from 0 (no dyskinesia) to 4 (severe dyskinesia). Total motor AIMS score for Items 1-7 ranged from 0 to 28, with higher scores indicative of more severe dyskinesia.

Secondary

Measure	Time frame	Description
Part A: Percent Change From Baseline in Total Motor AIMS Score at Week 145, as Assessed by the Site Rating	Baseline, Week 145	The AIMS is an assessment tool used to detect and follow the severity of TD over time. The AIMS is composed of 12 clinician-administered and -scored items. A total motor score from Items 1 to 7 (orofacial, extremity, and truncal movements) was calculated. Items 1 through 7 included facial and oral movements (Items 1-4), extremity movements (Items 5-6), and trunk movements (Item 7). Each item was rated on a 5-point anchored scale ranging from 0 (no dyskinesia) to 4 (severe dyskinesia). Total motor AIMS score for Items 1-7 ranged from 0 to 28, with higher scores indicative of more severe dyskinesia.
Part A: Percent Change From Baseline in Total Motor AIMS Score at Week 158, as Assessed by the Site Rating	Baseline, Week 158	The AIMS is an assessment tool used to detect and follow the severity of TD over time. The AIMS is composed of 12 clinician-administered and -scored items. A total motor score from Items 1 to 7 (orofacial, extremity, and truncal movements) was calculated. Items 1 through 7 included facial and oral movements (Items 1-4), extremity movements (Items 5-6), and trunk movements (Item 7). Each item was rated on a 5-point anchored scale ranging from 0 (no dyskinesia) to 4 (severe dyskinesia). Total motor AIMS score for Items 1-7 ranged from 0 to 28, with higher scores indicative of more severe dyskinesia.
Part A: Percentage of Participants Who Had a 50% or Greater Reduction From Baseline in Total Motor AIMS Score, as Assessed by the Site Rating	Baseline to Week 145	The AIMS is an assessment tool used to detect and follow the severity of TD over time. The AIMS is composed of 12 clinician-administered and -scored items. A total motor score from Items 1 to 7 (orofacial, extremity, and truncal movements) was calculated. Items 1 through 7 included facial and oral movements (Items 1-4), extremity movements (Items 5-6), and trunk movements (Item 7). Each item was rated on a 5-point anchored scale ranging from 0 (no dyskinesia) to 4 (severe dyskinesia). Total motor AIMS score for Items 1-7 ranged from 0 to 28, with higher scores indicative of more severe dyskinesia.
Part A: Percentage of Participants Who Had a 70% or Greater Reduction From Baseline in Total Motor AIMS Score, as Assessed by the Site Rating	Baseline to Week 145	The AIMS is an assessment tool used to detect and follow the severity of TD over time. The AIMS is composed of 12 clinician-administered and -scored items. A total motor score from Items 1 to 7 (orofacial, extremity, and truncal movements) was calculated. Items 1 through 7 included facial and oral movements (Items 1-4), extremity movements (Items 5-6), and trunk movements (Item 7). Each item was rated on a 5-point anchored scale ranging from 0 (no dyskinesia) to 4 (severe dyskinesia). Total motor AIMS score for Items 1-7 ranged from 0 to 28, with higher scores indicative of more severe dyskinesia.
Part A: Change From Baseline in Total Motor AIMS Score at Week 145, as Assessed by the Site Rating	Baseline, Week 145	The AIMS is an assessment tool used to detect and follow the severity of tardive dyskinesia (TD) over time. The AIMS is composed of 12 clinician-administered and -scored items. A total motor score from Items 1 to 7 (orofacial, extremity, and truncal movements) was calculated. Items 1 through 7 included facial and oral movements (Items 1-4), extremity movements (Items 5-6), and trunk movements (Item 7). Each item was rated on a 5-point anchored scale ranging from 0 (no dyskinesia) to 4 (severe dyskinesia). Total motor AIMS score for Items 1-7 ranged from 0 to 28, with higher scores indicative of more severe dyskinesia.
Part A: Percentage of Participants Who Were a Treatment Success, Based on the Clinical Global Impression of Change (CGIC)	Baseline up to Week 145	A treatment success was defined as much or very much improved on the CGIC from baseline of this study. The CGIC is a single-item questionnaire that asks the investigator to assess a participant's TD symptoms at specific visits/weeks after initiating therapy. The CGIC uses a 7-point Likert scale, ranging from -3 to +3 (-3 = very much worse, -2 = much worse, -1 = minimally worse, 0 = not changed, 1 = minimally improved, 2 = much improved, 3 = very much improved), to assess overall response to therapy.
Part A: Percentage of Participants Who Were a Treatment Success, Based on the Patient Global Impression of Change (PGIC)	Baseline up to Week 145	A treatment success was defined as much or very much improved on the PGIC from baseline of this study. The PGIC is single-item questionnaire that asks the participant to assess their TD symptoms at specific visits/weeks after initiating therapy. The PGIC uses a 7-point Likert scale, ranging from -3 to +3 (-3 = very much worse, -2 = much worse, -1 = minimally worse, 0 = not changed, 1 = minimally improved, 2 = much improved, 3 = very much improved), to assess overall response to therapy.
Part A: Change From Baseline in Modified CDQ-24 Score at Week 158	Baseline, Week 158	The CDQ-24 is a disease-specific quality of life questionnaire developed for use in participants with craniocervical dystonia, including both cervical dystonia (CD) and blepharospasm (BPS). The CDQ-24 was modified such that the questions focus more directly on the impact of TD (as opposed to CD/BPS) on quality of life. The following domains were evaluated in the mCDQ-24: stigma, emotional well-being, pain, activities of daily living, and social/family life. Each of the 24 questions were rated by participants on a scale of 0 = never or no impairment to 4 = always or very severe impairment. Total score ranged from 0 - 96, with higher score indicative of severe impairment.
Part A: Change From Baseline in AIMS Items 8, 9, and 10 Score at Week 145, as Assessed by the Site Rating	Baseline, Week 145	The AIMS is an assessment tool used to detect and follow the severity of TD over time. The AIMS is composed of 12 clinician-administered and -scored items. Items 8 to 10 deal with global severity as judged by the examiner, and the participant's awareness of the movements and the distress associated with them. Item 8 (used as an overall severity index indicating severity of abnormal movements) was rated on a 5-point anchored scale ranging from 0 (no dyskinetic movements) to 4 (severe dyskinetic movements). Items 9 and 10 (provide additional information with regard to participant's incapacitation due to abnormal movements and participant's awareness of abnormal movements) were rated on a 5-point anchored scale ranging from 0 (none or no awareness) to 4 (severe or aware, severe distress). Higher scores indicated more severe disease.
Part A: Change From Baseline in Total Motor AIMS Score at Week 158, as Assessed by the Site Rating	Baseline, Week 158	The AIMS is an assessment tool used to detect and follow the severity of TD over time. The AIMS is composed of 12 clinician-administered and -scored items. A total motor score from Items 1 to 7 (orofacial, extremity, and truncal movements) was calculated. Items 1 through 7 included facial and oral movements (Items 1-4), extremity movements (Items 5-6), and trunk movements (Item 7). Each item was rated on a 5-point anchored scale ranging from 0 (no dyskinesia) to 4 (severe dyskinesia). Total motor AIMS score for Items 1-7 ranged from 0 to 28, with higher scores indicative of more severe dyskinesia.

Countries

Czechia, Germany, Hungary, Poland, Slovakia, United States

Participant flow

Recruitment details

343 participants who completed previous SD-809 studies, including study SD-809-C-18 (NCT02195700) or SD-809-C-23 (NCT02291861) were enrolled and 337 participants were eligible for analysis. 6 participants were not evaluable and were excluded from the analysis due to site data integrity issues as reported to the United States Food and Drug Administration (US FDA).

Pre-assignment details

Study included 3 parts: A, B, and C. Participants in Part A who were on a stable dose for ≥4 weeks after a 6-week titration, were invited to participate in Part B. Participants who are noted as Completed for Part A: completed the study in Part A plus continued in Part B. EU participants who completed Part B were invited to participate in Part C.

Participants by arm

Arm	Count
SD-809 Participants received SD-809 orally BID starting at 12 mg/day, which was titrated based on dyskinesia control and tolerability up to a maximum total dose of 48 mg/day. Participants who declined to participate in Part B, continued at their stable dose of SD-809 BID up to Week 158.	337
Total	337

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002	FG003
Part A: Open-Label (158 Weeks)	Adverse Event	33	0	0	0
Part A: Open-Label (158 Weeks)	Agreed to continue in Part B	142	0	0	0
Part A: Open-Label (158 Weeks)	Death	8	0	0	0
Part A: Open-Label (158 Weeks)	Lack of Efficacy	9	0	0	0
Part A: Open-Label (158 Weeks)	Lost to Follow-up	24	0	0	0
Part A: Open-Label (158 Weeks)	Noncompliance with study drug	3	0	0	0
Part A: Open-Label (158 Weeks)	Other than specified	5	0	0	0
Part A: Open-Label (158 Weeks)	Protocol deviation	1	0	0	0
Part A: Open-Label (158 Weeks)	Study terminated	1	0	0	0
Part A: Open-Label (158 Weeks)	Withdrawal by Subject	79	0	0	0
Part B: Randomized (13 Weeks)	Lost to Follow-up	0	2	2	0
Part B: Randomized (13 Weeks)	Withdrawal by Subject	0	3	1	0
Part C: Safety Assessment (52 Weeks)	Adverse Event	0	0	0	2
Part C: Safety Assessment (52 Weeks)	Death	0	0	0	2
Part C: Safety Assessment (52 Weeks)	Withdrawal by Subject	0	0	0	3

Baseline characteristics

Characteristic	SD-809
Age, Continuous	56.9 years STANDARD_DEVIATION 10.65
AIMS Individual Items (8-10) Scores Incapacitation due to abnormal movements	2.0 units on a scale STANDARD_DEVIATION 1.07
AIMS Individual Items (8-10) Scores Participant's awareness of abnormal movements	2.2 units on a scale STANDARD_DEVIATION 1.08
AIMS Individual Items (8-10) Scores Severity of abnormal movements	2.6 units on a scale STANDARD_DEVIATION 0.78
Ethnicity (NIH/OMB) Hispanic or Latino	28 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	300 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	9 Participants
Modified Craniocervical Dystonia Questionnaire 24 (CDQ-24) Score	29.2 units on a scale STANDARD_DEVIATION 18.96
Race/Ethnicity, Customized Race American Indian or Alaskan Native	1 Participants
Race/Ethnicity, Customized Race Asian	2 Participants
Race/Ethnicity, Customized Race Black	69 Participants
Race/Ethnicity, Customized Race Other	1 Participants
Race/Ethnicity, Customized Race White	264 Participants
Sex: Female, Male Female	188 Participants
Sex: Female, Male Male	149 Participants
Total Motor Abnormal Involuntary Movement Scale (AIMS) Score	10.7 units on a scale STANDARD_DEVIATION 4.68

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	8 / 337	2 / 80
other Total, other adverse events	172 / 337	5 / 80
serious Total, serious adverse events	68 / 337	5 / 80

Outcome results

Primary

Part A, B, and C: Number of Participants With Treatment-Emergent AEs (TEAEs), Serious TEAEs, Severe TEAEs, Drug-Related TEAEs, and TEAEs Leading to Withdrawal

AEs were analyzed as one group combined for parts A and B per planned analysis. An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Severe AE=prevents normal daily activities. Drug-related TEAEs: TEAEs with possible, probable, or definite relationship to study drug. Serious AEs: death, a life-threatening AE, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, a congenital anomaly or birth defect, or an important medical event that jeopardized participant and required medical intervention to prevent 1 of the outcomes listed in this definition. A treatment-emergent AE was defined as an AE that began after the first administration of study medication or existing AEs that worsened after the first dose of study medication. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section.

Time frame: Baseline up to the end of follow-up (4 weeks after the last dose of study drug; mean exposure: up to approximately 866.1 days)

Population: Safety population included all participants who were administered any study drug.

Arm	Measure	Group	Value (COUNT_OF_PARTICIPANTS)
SD-809	Part A, B, and C: Number of Participants With Treatment-Emergent AEs (TEAEs), Serious TEAEs, Severe TEAEs, Drug-Related TEAEs, and TEAEs Leading to Withdrawal	Serious TEAEs	68 Participants
SD-809	Part A, B, and C: Number of Participants With Treatment-Emergent AEs (TEAEs), Serious TEAEs, Severe TEAEs, Drug-Related TEAEs, and TEAEs Leading to Withdrawal	Drug-Related TEAEs	154 Participants
SD-809	Part A, B, and C: Number of Participants With Treatment-Emergent AEs (TEAEs), Serious TEAEs, Severe TEAEs, Drug-Related TEAEs, and TEAEs Leading to Withdrawal	Severe TEAEs	57 Participants
SD-809	Part A, B, and C: Number of Participants With Treatment-Emergent AEs (TEAEs), Serious TEAEs, Severe TEAEs, Drug-Related TEAEs, and TEAEs Leading to Withdrawal	TEAEs Leading to Withdrawal From Study	42 Participants
SD-809	Part A, B, and C: Number of Participants With Treatment-Emergent AEs (TEAEs), Serious TEAEs, Severe TEAEs, Drug-Related TEAEs, and TEAEs Leading to Withdrawal	Any TEAEs	269 Participants
Part C: SD-809	Part A, B, and C: Number of Participants With Treatment-Emergent AEs (TEAEs), Serious TEAEs, Severe TEAEs, Drug-Related TEAEs, and TEAEs Leading to Withdrawal	TEAEs Leading to Withdrawal From Study	3 Participants
Part C: SD-809	Part A, B, and C: Number of Participants With Treatment-Emergent AEs (TEAEs), Serious TEAEs, Severe TEAEs, Drug-Related TEAEs, and TEAEs Leading to Withdrawal	Any TEAEs	23 Participants
Part C: SD-809	Part A, B, and C: Number of Participants With Treatment-Emergent AEs (TEAEs), Serious TEAEs, Severe TEAEs, Drug-Related TEAEs, and TEAEs Leading to Withdrawal	Serious TEAEs	5 Participants
Part C: SD-809	Part A, B, and C: Number of Participants With Treatment-Emergent AEs (TEAEs), Serious TEAEs, Severe TEAEs, Drug-Related TEAEs, and TEAEs Leading to Withdrawal	Severe TEAEs	3 Participants
Part C: SD-809	Part A, B, and C: Number of Participants With Treatment-Emergent AEs (TEAEs), Serious TEAEs, Severe TEAEs, Drug-Related TEAEs, and TEAEs Leading to Withdrawal	Drug-Related TEAEs	3 Participants

Primary

Part B: Change From Day 1 Visit in Total Motor AIMS Score at Day 7 Visit, as Assessed by Blinded Central Video Rating

The AIMS is an assessment tool used to detect and follow the severity of TD over time. The AIMS is composed of 12 clinician-administered and -scored items. A total motor score from Items 1 to 7 (orofacial, extremity, and truncal movements) was calculated. Items 1 through 7 included facial and oral movements (Items 1-4), extremity movements (Items 5-6), and trunk movements (Item 7). Each item was rated on a 5-point anchored scale ranging from 0 (no dyskinesia) to 4 (severe dyskinesia). Total motor AIMS score for Items 1-7 ranged from 0 to 28, with higher scores indicative of more severe dyskinesia.

Time frame: Day 1 of Part B, Day 7 of Part B

Population: The randomized withdrawal modified intent-to-treat (mITT) population included all participants enrolled in Part B who received study drug during the randomized withdrawal period and had a total motor AIMS score as assessed by blinded central video rating at both the pre-withdrawal visit and the post-withdrawal visit.

Arm	Measure	Group	Value (MEAN)	Dispersion
SD-809	Part B: Change From Day 1 Visit in Total Motor AIMS Score at Day 7 Visit, as Assessed by Blinded Central Video Rating	Pre-withdrawal	5.7 units on a scale	Standard Error 0.55
SD-809	Part B: Change From Day 1 Visit in Total Motor AIMS Score at Day 7 Visit, as Assessed by Blinded Central Video Rating	Change at Post-withdrawal	0.6 units on a scale	Standard Error 0.28
Part C: SD-809	Part B: Change From Day 1 Visit in Total Motor AIMS Score at Day 7 Visit, as Assessed by Blinded Central Video Rating	Pre-withdrawal	5.0 units on a scale	Standard Error 0.49
Part C: SD-809	Part B: Change From Day 1 Visit in Total Motor AIMS Score at Day 7 Visit, as Assessed by Blinded Central Video Rating	Change at Post-withdrawal	0 units on a scale	Standard Error 0.29

Comparison: The statistical model was an analysis of covariance (ANCOVA) with treatment group and dopamine receptor antagonist status at the pre-withdrawal visit as fixed effects and the pre-withdrawal visit value as a covariate.p-value: 0.12195% CI: [-1.42, 0.17]ANCOVA

Secondary

Part A: Change From Baseline in AIMS Items 8, 9, and 10 Score at Week 145, as Assessed by the Site Rating

The AIMS is an assessment tool used to detect and follow the severity of TD over time. The AIMS is composed of 12 clinician-administered and -scored items. Items 8 to 10 deal with global severity as judged by the examiner, and the participant's awareness of the movements and the distress associated with them. Item 8 (used as an overall severity index indicating severity of abnormal movements) was rated on a 5-point anchored scale ranging from 0 (no dyskinetic movements) to 4 (severe dyskinetic movements). Items 9 and 10 (provide additional information with regard to participant's incapacitation due to abnormal movements and participant's awareness of abnormal movements) were rated on a 5-point anchored scale ranging from 0 (none or no awareness) to 4 (severe or aware, severe distress). Higher scores indicated more severe disease.

Time frame: Baseline, Week 145