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Addressing Involuntary Movements in Tardive Dyskinesia (AIM-TD)

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ClinicalTrials.gov Identifier: NCT02291861
Recruitment Status : Completed
First Posted : November 17, 2014
Results First Posted : April 11, 2018
Last Update Posted : May 14, 2018
Sponsor:
Information provided by (Responsible Party):
Teva Pharmaceutical Industries ( Auspex Pharmaceuticals, Inc. )

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Triple (Participant, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition Tardive Dyskinesia
Interventions Drug: SD-809
Drug: Placebo
Enrollment 298

Recruitment Details This study was performed at 75 study centers (38 in the US, 19 in Poland, 7 in Hungary, 6 in the Czech Republic, 3 in Slovakia, and 2 in Germany) by 75 investigators; 298 patients were enrolled.
Pre-assignment Details Participants were randomly assigned in a 1:1:1:1 ratio to receive 1 of 3 fixed-dose regimens of SD-809 (deutetrabenazine) or placebo following a screening period.
Arm/Group Title Placebo SD-809 12 mg/Day SD-809 24 mg/Day SD-809 36 mg/Day
Hide Arm/Group Description Placebo tablets taken twice daily for 12 weeks. SD-809 tablets 6 mg taken twice a day (BID) for 12 weeks. SD-809 tablets dose starting at 6 mg twice a day (BID) and titrated over 4 weeks to 12 mg BID. The total daily dose of 24 mg was maintained for an additional 8 weeks. SD-809 tablets dose starting at 6 mg twice a day (BID) and titrated over 4 weeks to 18 mg BID. The total daily dose of 36 mg was maintained for an additional 8 weeks.
Period Title: Overall Study
Started 74 75 74 75
Safety Population 72 74 73 74
Modified Intent to Treat Pop (mITT) 58 60 49 55
Completed 67 67 65 65
Not Completed 7 8 9 10
Reason Not Completed
Adverse Event             2             4             1             2
Death             0             0             1             1
Protocol Violation             1             0             0             1
Withdrawal by Subject             1             2             1             4
Noncompliance             1             1             2             1
Lost to Follow-up             2             1             4             0
Not specified             0             0             0             1
Arm/Group Title Placebo SD-809 12 mg/Day SD-809 24 mg/Day SD-809 36 mg/Day Total
Hide Arm/Group Description Placebo tablets taken twice daily for 12 weeks. SD-809 tablets 6 mg taken twice a day (BID) for 12 weeks. SD-809 tablets dose starting at 6 mg twice a day (BID) and titrated over 4 weeks to 12 mg BID. The total daily dose of 24 mg was maintained for an additional 8 weeks. SD-809 tablets dose starting at 6 mg twice a day (BID) and titrated over 4 weeks to 18 mg BID. The total daily dose of 36 mg was maintained for an additional 8 weeks. Total of all reporting groups
Overall Number of Baseline Participants 72 74 73 74 293
Hide Baseline Analysis Population Description
The Safety Population was a subset of randomized participants and included all patients who were administered study drug (N=293).
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 72 participants 74 participants 73 participants 74 participants 293 participants
54.6  (12.06) 57.0  (9.95) 55.6  (11.34) 58.3  (11.55) 56.4  (11.27)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 72 participants 74 participants 73 participants 74 participants 293 participants
Female 37 42 41 42 162
Male 35 32 32 32 131
Race/Ethnicity, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 72 participants 74 participants 73 participants 74 participants 293 participants
American Indian or Alaska Native 1 1 0 2 4
Asian 0 0 0 0 0
Black or African American 12 15 19 10 56
Native Hawaiian or Pacific Islander 0 0 0 0 0
White 59 58 54 61 232
Other 0 0 0 1 1
Race/Ethnicity, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 72 participants 74 participants 73 participants 74 participants 293 participants
Hispanic or latino 7 6 3 7 23
Not hispanic or latino 64 64 69 65 262
Not reported 0 3 1 1 5
Unknown 1 1 0 1 3
Weight  
Mean (Standard Deviation)
Unit of measure:  Kg
Number Analyzed 72 participants 74 participants 73 participants 74 participants 293 participants
82.8  (18.51) 80.8  (21.00) 86.8  (18.79) 78.5  (17.56) 82.2  (19.16)
Height  
Mean (Standard Deviation)
Unit of measure:  Cm
Number Analyzed 72 participants 74 participants 73 participants 74 participants 293 participants
168.3  (9.25) 167.7  (10.68) 168.7  (9.39) 167.6  (10.55) 168.1  (9.96)
Body Mass Index  
Mean (Standard Deviation)
Unit of measure:  Kg/m^2
Number Analyzed 72 participants 74 participants 73 participants 74 participants 293 participants
29.18  (6.128) 28.69  (6.814) 30.64  (7.021) 27.99  (6.178) 29.12  (6.587)
Education Level  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 72 participants 74 participants 73 participants 74 participants 293 participants
<= 12 years 40 44 44 39 167
> 12 years 32 30 29 35 126
Time Since Tardive Dyskinesia (TD) Diagnosis  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 72 participants 74 participants 73 participants 74 participants 293 participants
6.03  (5.353) 5.49  (5.426) 4.98  (6.034) 5.89  (5.342) 5.60  (5.532)
Total Motor Abnormal Involuntary Movement Scale (AIMS) Score   [1] 
Mean (Standard Deviation)
Unit of measure:  Units on a scale
Number Analyzed 72 participants 74 participants 73 participants 74 participants 293 participants
8.5  (3.28) 8.6  (3.13) 7.7  (3.51) 8.6  (3.84) 8.4  (3.46)
[1]
Measure Description:

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.

Total Motor assessment sums items 1 through 7 which cover orofacial movements, as well as extremity and truncal dyskinesia. Ratings were based on a 5-point scale of severity from 0 (none), 1 (minimal), 2 (mild), 3 (moderate), to 4 (severe) for a total scale of 0-28.

Modified Craniocervical Dystonia Questionnaire (mCDQ-24)   [1] [2] 
Mean (Standard Deviation)
Unit of measure:  Units on a scale
Number Analyzed 72 participants 73 participants 73 participants 74 participants 292 participants
40.5  (19.88) 37.2  (20.15) 34.4  (19.59) 34.9  (18.34) 36.7  (19.55)
[1]
Measure Description: The CDQ-24 is a disease-specific quality of life questionnaire developed for use in patients 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. Each of the 24 questions was rated by patients on a scale of 0=no impairment to 4=severest impairment for a total scale of 0 – 96.
[2]
Measure Analysis Population Description: One participant in the SD-809 12 mg/day group was missing a baseline mCDQ-24 total score.
Baseline Use of a Dopamine Receptor Antagonist (DRA)   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 72 participants 74 participants 73 participants 74 participants 293 participants
Yes 56 56 57 53 222
No 16 18 16 21 71
[1]
Measure Description: The randomization was stratified by baseline use of DRA (currently taking versus not currently taking a DRA).
1.Primary Outcome
Title Change in Total Motor Abnormal Involuntary Movement Scale (AIMS) Score From Baseline to Week 12 Using a Mixed Model For Repeated Measures (MMRM)
Hide Description

AIMS is an assessment tool used to detect and follow the severity of tardive dyskinesia (TD) over time. AIMS is composed of 12 clinician-administered and scored items. The exam was digitally video recorded using a standard protocol, and independently reviewed by blinded central raters who were experts in movement disorders.

This outcome sums items 1 through 7 which cover orofacial movements, as well as extremity and truncal dyskinesia (the total motor AIMS score). Ratings were based on a 5-point scale of severity from 0 (none), 1 (minimal), 2 (mild), 3 (moderate), to 4 (severe) for a total scale of 0-28. A negative change from baseline score indicates improvement.

MMRM with treatment group, visit, treatment group-by-visit interaction, and baseline use of dopamine receptor antagonist (DRAs) as fixed effects and the baseline value as a covariate. The model was fit using an unstructured covariance structure.

Time Frame Day 0 (Baseline), Weeks 2, 4, 8 and 12
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
The mITT Population (N=222) included all patients in the ITT Population with a baseline AIMS score ≥6 as assessed by central video rating, were randomized to treatment, received study drug, and had at least 1 postbaseline AIMS assessment. For this outcome, participants with baseline readings and during-study readings through Week 12 are included.
Arm/Group Title Placebo SD-809 12 mg/Day SD-809 24 mg/Day SD-809 36 mg/Day
Hide Arm/Group Description:
Placebo tablets taken twice daily for 12 weeks.
SD-809 tablets 6 mg taken twice a day (BID) for 12 weeks.
SD-809 tablets dose starting at 6 mg twice a day (BID) and titrated over 4 weeks to 12 mg BID. The total daily dose of 24 mg was maintained for an additional 8 weeks.
SD-809 tablets dose starting at 6 mg twice a day (BID) and titrated over 4 weeks to 18 mg BID. The total daily dose of 36 mg was maintained for an additional 8 weeks.
Overall Number of Participants Analyzed 56 53 45 52
Least Squares Mean (Standard Error)
Unit of Measure: units on a scale
-1.4  (0.41) -2.1  (0.42) -3.2  (0.45) -3.3  (0.42)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, SD-809 36 mg/Day
Comments

A hierarchical (fixed-sequence) testing approach was used for the analysis of the primary and key secondary endpoints to maintain the experiment-wise type I error rate of 5%.

The primary endpoint compared the change in total motor AIMS score from baseline to week 12 between the SD-809 36 mg/day group and the placebo group.

Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.001
Comments Treatment group, visit, treatment group-by-visit interaction, and baseline use of DRAs as fixed effects and the baseline value as a covariate. The model was fit using an unstructured covariance structure.
Method mixed model for repeated measures
Comments [Not Specified]
Method of Estimation Estimation Parameter LSM difference
Estimated Value -1.9
Confidence Interval (2-Sided) 95%
-3.09 to -0.79
Estimation Comments SD-809 - placebo
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, SD-809 24 mg/Day
Comments

A hierarchical (fixed-sequence) testing approach was used for the analysis of the primary and key secondary endpoints to maintain the experiment-wise type I error rate of 5%.

This key secondary endpoint compared the change in total motor AIMS score from baseline to week 12 between the SD-809 24 mg/day group and the placebo group, and is the third analysis in the fixed-sequence.

Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.003
Comments Treatment group, visit, treatment group-by-visit interaction, and baseline use of DRAs as fixed effects and the baseline value as a covariate. The model was fit using an unstructured covariance structure.
Method mixed model for repeated measures
Comments [Not Specified]
Method of Estimation Estimation Parameter LSM difference
Estimated Value -1.8
Confidence Interval (2-Sided) 95%
-3.00 to -0.63
Estimation Comments SD-809 - placebo
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Placebo, SD-809 12 mg/Day
Comments

A hierarchical (fixed-sequence) testing approach was used for the analysis of the primary and key secondary endpoints to maintain the experiment-wise type I error rate of 5%.

This key secondary endpoint compared the change in total motor AIMS score from baseline to week 12 between the SD-809 12 mg/day group and the placebo group, and is the fifth analysis in the fixed-sequence.

Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.217
Comments Treatment group, visit, treatment group-by-visit interaction, and baseline use of DRAs as fixed effects and the baseline value as a covariate. The model was fit using an unstructured covariance structure.
Method mixed model for repeated measures
Comments [Not Specified]
Method of Estimation Estimation Parameter LSM difference
Estimated Value -0.7
Confidence Interval (2-Sided) 95%
-1.84 to 0.42
Estimation Comments SD-809 - placebo
2.Secondary Outcome
Title Percentage of Patients Considered a Treatment Success at Week 12 as Assessed by the Clinical Global Impression of Change (CGIC)
Hide Description

The CGIC is a single-item questionnaire that asks the investigator to assess a patient’s TD symptoms at specific visits after initiating therapy. The CGIC uses a 7 point Likert Scale, ranging from very much worse (–3) to very much improved (+3), to assess overall response to therapy.

A treatment success was defined as “much improved” or “very much improved” at the week 12 visit.

Patients whose status at week 12 was not known, as well as patients who were not “much improved” or “very much improved” at the week 12 visit, were considered treatment failures.

The success 95% confidence interval (CI) was calculated with the Wilson (score) confidence limits.

Time Frame Week 12
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
The mITT Population (N=222) included all patients in the ITT Population with a baseline AIMS score ≥6 as assessed by central video rating, were randomized to treatment, received study drug, and had at least 1 postbaseline AIMS assessment.
Arm/Group Title Placebo SD-809 12 mg/Day SD-809 24 mg/Day SD-809 36 mg/Day
Hide Arm/Group Description:
Placebo tablets taken twice daily for 12 weeks.
SD-809 tablets 6 mg taken twice a day (BID) for 12 weeks.
SD-809 tablets dose starting at 6 mg twice a day (BID) and titrated over 4 weeks to 12 mg BID. The total daily dose of 24 mg was maintained for an additional 8 weeks.
SD-809 tablets dose starting at 6 mg twice a day (BID) and titrated over 4 weeks to 18 mg BID. The total daily dose of 36 mg was maintained for an additional 8 weeks.
Overall Number of Participants Analyzed 58 60 49 55
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
26
(16.3 to 38.4)
28
(18.5 to 40.8)
49
(35.6 to 62.5)
44
(31.4 to 56.7)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, SD-809 36 mg/Day
Comments

A hierarchical (fixed-sequence) testing approach was used for the analysis of the primary and key secondary endpoints to maintain the experiment-wise type I error rate of 5%.

This key secondary endpoint compared the percentage of patients considered a treatment success at week 12 between the SD-809 36 mg/day group and the placebo group, and is the second analysis in the fixed-sequence.

Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.059
Comments [Not Specified]
Method Cochran-Mantel-Haenszel
Comments The statistical test was a Cochran-Mantel-Haenszel (CMH) test stratified by baseline use of dopamine receptor antagonist (DRAs).
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 2.11
Confidence Interval (2-Sided) 95%
0.960 to 4.645
Estimation Comments SD-809/placebo The odds ratio was the Mantel-Haenszel estimate of the common odds ratio.
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, SD-809 24 mg/Day
Comments

A hierarchical (fixed-sequence) testing approach was used for the analysis of the primary and key secondary endpoints to maintain the experiment-wise type I error rate of 5%.

This key secondary endpoint compared the percentage of patients considered a treatment success at week 12 between the SD-809 24 mg/day group and the placebo group, and is the fourth analysis in the fixed-sequence.

Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.014
Comments [Not Specified]
Method Cochran-Mantel-Haenszel
Comments The statistical test was a CMH test stratified by baseline use of DRAs.
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 2.71
Confidence Interval (2-Sided) 95%
1.211 to 6.052
Estimation Comments SD-809/placebo The odds ratio was the Mantel-Haenszel estimate of the common odds ratio.
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Placebo, SD-809 12 mg/Day
Comments

A hierarchical (fixed-sequence) testing approach was used for the analysis of the primary and key secondary endpoints to maintain the experiment-wise type I error rate of 5%.

This key secondary endpoint compared the percentage of patients considered a treatment success at week 12 between the SD-809 12 mg/day group and the placebo group, and is the sixth (last) analysis in the fixed-sequence.

Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.734
Comments [Not Specified]
Method Cochran-Mantel-Haenszel
Comments The statistical test was a CMH test stratified by baseline use of DRAs.
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 1.15
Confidence Interval (2-Sided) 95%
0.509 to 2.610
Estimation Comments SD-809/placebo The odds ratio was the Mantel-Haenszel estimate of the common odds ratio.
3.Secondary Outcome
Title Change in the Modified Craniocervical Dystonia Questionnaire (mCDQ-24) Total Score From Baseline to Week 12
Hide Description

The CDQ-24 is a disease-specific quality of life questionnaire developed for use in patients 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 are 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 patients on a scale of 0=no impairment to 4=severest impairment for a total scale of 0 – 96. Negative change from baseline scores indicate improvement.

For patients with missing data at week 12, the baseline or last available value was used as the week 12 value.

Time Frame Day 0 (Baseline), Week 12
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
The mITT Population (N=222) included all patients in the ITT Population with a baseline AIMS score ≥6 as assessed by central video rating, were randomized to treatment, received study drug, and had at least 1 postbaseline AIMS assessment. One SD-809 12 mg/day participant was missing a baseline mCDQ-24.
Arm/Group Title Placebo SD-809 12 mg/Day SD-809 24 mg/Day SD-809 36 mg/Day
Hide Arm/Group Description:
Placebo tablets taken twice daily for 12 weeks.
SD-809 tablets 6 mg taken twice a day (BID) for 12 weeks.
SD-809 tablets dose starting at 6 mg twice a day (BID) and titrated over 4 weeks to 12 mg BID. The total daily dose of 24 mg was maintained for an additional 8 weeks.
SD-809 tablets dose starting at 6 mg twice a day (BID) and titrated over 4 weeks to 18 mg BID. The total daily dose of 36 mg was maintained for an additional 8 weeks.
Overall Number of Participants Analyzed 58 59 49 55
Least Squares Mean (Standard Error)
Unit of Measure: units on a scale
-7.1  (2.06) -5.8  (2.03) -10.2  (2.21) -10.7  (2.04)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, SD-809 36 mg/Day
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.207
Comments 5% level of significance (2-sided)
Method ANCOVA
Comments The statistical model was an ANCOVA with treatment group and baseline use of DRAs as fixed effects and the baseline value as a covariate.
Method of Estimation Estimation Parameter LSM difference
Estimated Value -3.6
Confidence Interval (2-Sided) 95%
-9.18 to 2.00
Estimation Comments SD-809 - placebo
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, SD-809 24 mg/Day
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.281
Comments 5% level of significance (2-sided)
Method ANCOVA
Comments The statistical model was an ANCOVA with treatment group and baseline use of DRAs as fixed effects and the baseline value as a covariate.
Method of Estimation Estimation Parameter LSM difference
Estimated Value -3.1
Confidence Interval (2-Sided) 95%
-8.86 to 2.59
Estimation Comments SD-809 - placebo
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Placebo, SD-809 12 mg/Day
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.627
Comments 5% level of significance (2-sided)
Method ANCOVA
Comments The statistical model was an ANCOVA with treatment group and baseline use of DRAs as fixed effects and the baseline value as a covariate.
Method of Estimation Estimation Parameter LSM difference
Estimated Value 1.3
Confidence Interval (2-Sided) 95%
-4.10 to 6.79
Estimation Comments SD-809 - placebo
4.Secondary Outcome
Title Percentage of Patients Considered a Treatment Success at Week 12 as Assessed by the Patient Global Impression of Change (PGIC)
Hide Description

The PGIC is a single-item questionnaire that asks the patient to assess their TD symptoms at specific visits after initiating therapy. The PGIC uses a 7 point Likert Scale, ranging from very much worse (–3) to very much improved (+3), to assess overall response to therapy. A treatment success was defined as “much improved” or “very much improved” at the week 12 visit.

Patients whose status at week 12 was not known, as well as patients who were not “much improved” or

“very much improved” at the week 12 visit, were considered treatment failures. The success 95% CI was calculated with the Wilson (score) confidence limits.

Time Frame Week 12
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
mITT population
Arm/Group Title Placebo SD-809 12 mg/Day SD-809 24 mg/Day SD-809 36 mg/Day
Hide Arm/Group Description:
Placebo tablets taken twice daily for 12 weeks.
SD-809 tablets 6 mg taken twice a day (BID) for 12 weeks.
SD-809 tablets dose starting at 6 mg twice a day (BID) and titrated over 4 weeks to 12 mg BID. The total daily dose of 24 mg was maintained for an additional 8 weeks.
SD-809 tablets dose starting at 6 mg twice a day (BID) and titrated over 4 weeks to 18 mg BID. The total daily dose of 36 mg was maintained for an additional 8 weeks.
Overall Number of Participants Analyzed 58 60 49 55
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
31
(20.6 to 43.8)
23
(14.4 to 35.4)
45
(31.9 to 58.7)
40
(28.1 to 53.2)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, SD-809 36 mg/Day
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.296
Comments 5% level of significance (2-sided)
Method Cochran-Mantel-Haenszel
Comments The statistical test was a CMH test stratified by baseline use of DRAs.
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 1.51
Confidence Interval (2-Sided) 95%
0.694 to 3.285
Estimation Comments SD-809/placebo The odds ratio was the Mantel-Haenszel estimate of the common odds ratio.
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, SD-809 24 mg/Day
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.134
Comments 5% level of significance (2-sided)
Method Cochran-Mantel-Haenszel
Comments The statistical test was a CMH test stratified by baseline use of DRAs.
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 1.82
Confidence Interval (2-Sided) 95%
0.826 to 3.994
Estimation Comments SD-809/placebo The odds ratio was the Mantel-Haenszel estimate of the common odds ratio.
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Placebo, SD-809 12 mg/Day
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.372
Comments 5% level of significance (2-sided)
Method Cochran-Mantel-Haenszel
Comments The statistical test was a CMH test stratified by baseline use of DRAs.
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 0.69
Confidence Interval (2-Sided) 95%
0.302 to 1.563
Estimation Comments SD-809/placebo The odds ratio was the Mantel-Haenszel estimate of the common odds ratio.
5.Secondary Outcome
Title Percentage of Participants Who Had a 50% or Greater Reduction in Total Motor Abnormal Involuntary Movement Scale (AIMS) From Baseline to Week 12
Hide Description

Responders who had a 50% or greater improvement in total motor modified AIMS at Week 12 as compared to baseline were reported as a percentage of participants with an outcome at Week 12. The responder 95% CI is calculated with the Wilson (score) confidence limits.

AIMS is an assessment tool used to detect and follow the severity of TD over time. AIMS is composed of 12 clinician-administered and scored items. The exam was digitally video recorded using a standard protocol, and independently reviewed by blinded central raters who were experts in movement disorders.

This outcome sums items 1 through 7 which cover orofacial movements, as well as extremity and truncal dyskinesia (the total motor AIMS score). Ratings were based on a 5-point scale of severity from 0 (none), 1 (minimal), 2 (mild), 3 (moderate), to 4 (severe) for a total scale of 0-28. A negative change from baseline score indicates improvement.

Time Frame Day 0 (Baseline), Week 12
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
mITT population of participants. Participants with missing Week 12 data were considered non-responders.
Arm/Group Title Placebo SD-809 12 mg/Day SD-809 24 mg/Day SD-809 36 mg/Day
Hide Arm/Group Description:
Placebo tablets taken twice daily for 12 weeks.
SD-809 tablets 6 mg taken twice a day (BID) for 12 weeks.
SD-809 tablets dose starting at 6 mg twice a day (BID) and titrated over 4 weeks to 12 mg BID. The total daily dose of 24 mg was maintained for an additional 8 weeks.
SD-809 tablets dose starting at 6 mg twice a day (BID) and titrated over 4 weeks to 18 mg BID. The total daily dose of 36 mg was maintained for an additional 8 weeks.
Overall Number of Participants Analyzed 58 60 49 55
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
12
(6.0 to 22.9)
13
(6.9 to 24.2)
35
(22.9 to 48.7)
33
(21.8 to 45.9)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, SD-809 36 mg/Day
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.007
Comments 5% level of significance (2-sided)
Method Cochran-Mantel-Haenszel
Comments The statistical test was a CMH test stratified by baseline use of DRAs.
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 3.80
Confidence Interval (2-Sided) 95%
1.395 to 10.359
Estimation Comments SD-809/placebo The odds ratio was the Mantel-Haenszel estimate of the common odds ratio.
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, SD-809 24 mg/Day
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.005
Comments 5% level of significance (2-sided)
Method Cochran-Mantel-Haenszel
Comments The statistical test was a CMH test stratified by baseline use of DRAs.
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 3.96
Confidence Interval (2-Sided) 95%
1.460 to 10.716
Estimation Comments SD-809/placebo The odds ratio was the Mantel-Haenszel estimate of the common odds ratio.
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Placebo, SD-809 12 mg/Day
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.829
Comments 5% level of significance (2-sided)
Method Cochran-Mantel-Haenszel
Comments The statistical test was a CMH test stratified by baseline use of DRAs.
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 1.13
Confidence Interval (2-Sided) 95%
0.383 to 3.316
Estimation Comments SD-809/placebo The odds ratio was the Mantel-Haenszel estimate of the common odds ratio.
6.Secondary Outcome
Title Percent Change in Total Motor Abnormal Involuntary Movement Scale (AIMS) Score From Baseline to Week 12 Using a Mixed Model for Repeated Measures (MMRM)
Hide Description

AIMS is an assessment tool used to detect and follow the severity of TD over time. AIMS is composed of 12 clinician-administered and scored items. The exam was digitally video recorded using a standard protocol, and independently reviewed by blinded central raters who were experts in movement disorders.

This outcome sums items 1 through 7 which cover orofacial movements, as well as extremity and truncal dyskinesia (the total motor AIMS score). Ratings were based on a 5-point scale of severity from 0 (none), 1 (minimal), 2 (mild), 3 (moderate), to 4 (severe) for a total scale of 0-28. A negative change from baseline score indicates improvement.

MMRM with treatment group, visit, treatment group-by-visit interaction, and baseline use of DRAs as fixed effects and the baseline value as a covariate. The model was fit using an unstructured covariance structure.

Time Frame Day 0 (Baseline), Weeks 2, 4, 8 and 12
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
The mITT Population (N=222) included all patients in the ITT Population with a baseline AIMS score ≥6 as assessed by central video rating, were randomized to treatment, received study drug, and had at least 1 postbaseline AIMS assessment. For this outcome, participants with baseline readings and during-study readings through Week 12 are included.
Arm/Group Title Placebo SD-809 12 mg/Day SD-809 24 mg/Day SD-809 36 mg/Day
Hide Arm/Group Description:
Placebo tablets taken twice daily for 12 weeks.
SD-809 tablets 6 mg taken twice a day (BID) for 12 weeks.
SD-809 tablets dose starting at 6 mg twice a day (BID) and titrated over 4 weeks to 12 mg BID. The total daily dose of 24 mg was maintained for an additional 8 weeks.
SD-809 tablets dose starting at 6 mg twice a day (BID) and titrated over 4 weeks to 18 mg BID. The total daily dose of 36 mg was maintained for an additional 8 weeks.
Overall Number of Participants Analyzed 56 53 45 52
Least Squares Mean (Standard Error)
Unit of Measure: percentage of baseline
-11.6  (4.32) -20.0  (4.34) -31.9  (4.73) -33.1  (4.38)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, SD-809 36 mg/Day
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments 5% level of significance (2-sided). Treatment group, visit, treatment group-by-visit interaction, and baseline use of DRAs as fixed effects and the baseline value as a covariate. The model was fit using an unstructured covariance structure.
Method mixed model for repeated measures
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -21.5
Confidence Interval (2-Sided) 95%
-33.44 to -9.52
Estimation Comments SD-809 - placebo
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, SD-809 24 mg/Day
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.001
Comments 5% level of significance (2-sided). Treatment group, visit, treatment group-by-visit interaction, and baseline use of DRAs as fixed effects and the baseline value as a covariate. The model was fit using an unstructured covariance structure.
Method mixed model for repeated measures
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -20.2
Confidence Interval (2-Sided) 95%
-32.57 to -7.92
Estimation Comments SD-809 - placebo
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Placebo, SD-809 12 mg/Day
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.160
Comments 5% level of significance (2-sided). Treatment group, visit, treatment group-by-visit interaction, and baseline use of DRAs as fixed effects and the baseline value as a covariate. The model was fit using an unstructured covariance structure.
Method mixed model for repeated measures
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -8.4
Confidence Interval (2-Sided) 95%
-20.15 to 3.34
Estimation Comments SD-809 - placebo
7.Secondary Outcome
Title Cumulative Percentage of Responders Based on Change in in Total Motor Abnormal Involuntary Movement Scale (AIMS) Score From Baseline to Week 12 Recorded in Incremental Steps of 10 Percentage Points
Hide Description

AIMS is an assessment tool used to detect and follow the severity of TD over time, composed of 12 clinician-administered and scored items. The exam was digitally video recorded using a standard protocol, and independently reviewed by blinded central raters who were experts in movement disorders.

This outcome sums items 1 through 7 which cover orofacial movements, as well as extremity and truncal dyskinesia (the total motor AIMS score). Ratings were based on a 5-point scale of severity from 0 (none), 1 (minimal), 2 (mild), 3 (moderate), to 4 (severe) for a total scale of 0-28. A negative change from baseline score indicates improvement.

Participants with missing data are classified as non-responders. The responder 95% CI is calculated with the Wilson (score) confidence limits. If any of the expected cell counts are < 5, exact Clopper Pearson limits are presented.

Data report the percentage of participants who responded to the percentage improvement indicated in each row.

Time Frame Day 0 (Baseline), Week 12
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
The mITT Population (N=222) included all patients in the ITT Population with a baseline AIMS score ≥6 as assessed by central video rating, were randomized to treatment, received study drug, and had at least 1 postbaseline AIMS assessment.
Arm/Group Title Placebo SD-809 12 mg/Day SD-809 24 mg/Day SD-809 36 mg/Day
Hide Arm/Group Description:
Placebo tablets taken twice daily for 12 weeks.
SD-809 tablets 6 mg taken twice a day (BID) for 12 weeks.
SD-809 tablets dose starting at 6 mg twice a day (BID) and titrated over 4 weeks to 12 mg BID. The total daily dose of 24 mg was maintained for an additional 8 weeks.
SD-809 tablets dose starting at 6 mg twice a day (BID) and titrated over 4 weeks to 18 mg BID. The total daily dose of 36 mg was maintained for an additional 8 weeks.
Overall Number of Participants Analyzed 58 60 49 55
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
10% Improvement
50
(37.5 to 62.5)
62
(49.0 to 72.9)
67
(53.4 to 78.8)
71
(57.9 to 81.2)
20% Improvement
40
(28.1 to 52.5)
47
(34.6 to 59.1)
59
(45.2 to 71.8)
60
(46.8 to 71.9)
30% Improvement
31
(20.6 to 43.8)
32
(21.3 to 44.2)
49
(35.6 to 62.5)
49
(36.4 to 61.9)
40% Improvement
16
(8.4 to 26.9)
23
(14.4 to 35.4)
45
(31.9 to 58.7)
40
(28.1 to 53.2)
50% Improvement
12
(6.0 to 22.9)
13
(6.9 to 24.2)
35
(22.9 to 48.7)
33
(21.8 to 45.9)
60% Improvement
5
(1.8 to 14.1)
7
(2.6 to 15.9)
20
(11.5 to 33.6)
18
(10.2 to 30.3)
70% Improvement
2
(0.0 to 9.2)
3
(0.4 to 11.5)
12
(4.6 to 24.8)
16
(7.8 to 28.8)
80% Improvement
2
(0.0 to 9.2)
2
(0.0 to 8.9)
2
(0.1 to 10.9)
13
(5.3 to 24.5)
90% Improvement
2
(0.0 to 9.2)
0
(0.0 to 6.0)
0
(0.0 to 7.3)
5
(1.1 to 15.1)
8.Secondary Outcome
Title Participants With Adverse Events During the Overall Treatment Period
Hide Description An adverse event was defined as any untoward medical occurrence that develops or worsens in severity during the conduct of a clinical study and does not necessarily have a causal relationship to the study drug. Severity was rated by the investigator on a scale of mild, moderate and severe, with severe= an AE which prevents normal daily activities. Relation of AE to treatment was determined by the investigator and includes possibly, probably and definitely related categories. Serious AEs (SAE) include death, a life-threatening adverse event, 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 the patient and required medical intervention to prevent the previously listed serious outcomes.
Time Frame Day 1 to Week 12
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
The Safety Population was a subset of randomized participants and included all patients who were administered study drug (N=293).
Arm/Group Title Placebo SD-809 12 mg/Day SD-809 24 mg/Day SD-809 36 mg/Day
Hide Arm/Group Description:
Placebo tablets taken twice daily for 12 weeks.
SD-809 tablets 6 mg taken twice a day (BID) for 12 weeks.
SD-809 tablets dose starting at 6 mg twice a day (BID) and titrated over 4 weeks to 12 mg BID. The total daily dose of 24 mg was maintained for an additional 8 weeks.
SD-809 tablets dose starting at 6 mg twice a day (BID) and titrated over 4 weeks to 18 mg BID. The total daily dose of 36 mg was maintained for an additional 8 weeks.
Overall Number of Participants Analyzed 72 74 73 74
Measure Type: Count of Participants
Unit of Measure: Participants
Overall Treatment Period: any AE
34
  47.2%
36
  48.6%
32
  43.8%
38
  51.4%
Overall Treatment Period: SAE
4
   5.6%
2
   2.7%
6
   8.2%
4
   5.4%
Overall Treatment Period: Severe AE
2
   2.8%
2
   2.7%
4
   5.5%
1
   1.4%
Overall Treatment Period: treatment-related AE
19
  26.4%
13
  17.6%
11
  15.1%
18
  24.3%
Dose reduction because of AE
0
   0.0%
0
   0.0%
1
   1.4%
3
   4.1%
Dose suspension because of AE
2
   2.8%
3
   4.1%
1
   1.4%
1
   1.4%
Withdrawn from study because of AE
2
   2.8%
4
   5.4%
2
   2.7%
3
   4.1%
Time Frame Day 1 to Week 12
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Placebo SD-809 12 mg/Day SD-809 24 mg/Day SD-809 36 mg/Day
Hide Arm/Group Description Placebo tablets taken twice daily for 12 weeks. SD-809 tablets 6 mg taken twice a day (BID) for 12 weeks. SD-809 tablets dose starting at 6 mg twice a day (BID) and titrated over 4 weeks to 12 mg BID. The total daily dose of 24 mg was maintained for an additional 8 weeks. SD-809 tablets dose starting at 6 mg twice a day (BID) and titrated over 4 weeks to 18 mg BID. The total daily dose of 36 mg was maintained for an additional 8 weeks.
All-Cause Mortality
Placebo SD-809 12 mg/Day SD-809 24 mg/Day SD-809 36 mg/Day
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   0/72 (0.00%)      0/74 (0.00%)      1/73 (1.37%)      1/74 (1.35%)    
Show Serious Adverse Events Hide Serious Adverse Events
Placebo SD-809 12 mg/Day SD-809 24 mg/Day SD-809 36 mg/Day
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   4/72 (5.56%)      2/74 (2.70%)      6/73 (8.22%)      4/74 (5.41%)    
Cardiac disorders         
Cardio-respiratory arrest  1  0/72 (0.00%)  0 0/74 (0.00%)  0 0/73 (0.00%)  0 1/74 (1.35%)  1
Gastrointestinal disorders         
Abdominal pain  1  1/72 (1.39%)  1 0/74 (0.00%)  0 0/73 (0.00%)  0 0/74 (0.00%)  0
Pancreatic mass  1  1/72 (1.39%)  1 0/74 (0.00%)  0 0/73 (0.00%)  0 0/74 (0.00%)  0
General disorders         
Alcohol interaction  1  0/72 (0.00%)  0 0/74 (0.00%)  0 0/73 (0.00%)  0 1/74 (1.35%)  1
Sudden cardiac death  1  0/72 (0.00%)  0 0/74 (0.00%)  0 1/73 (1.37%)  1 0/74 (0.00%)  0
Infections and infestations         
Appendicitis  1  0/72 (0.00%)  0 0/74 (0.00%)  0 1/73 (1.37%)  1 0/74 (0.00%)  0
Cellulitis  1  0/72 (0.00%)  0 0/74 (0.00%)  0 1/73 (1.37%)  1 0/74 (0.00%)  0
Pneumonia  1  0/72 (0.00%)  0 0/74 (0.00%)  0 1/73 (1.37%)  1 1/74 (1.35%)  1
Injury, poisoning and procedural complications         
Face injury  1  0/72 (0.00%)  0 1/74 (1.35%)  1 0/73 (0.00%)  0 0/74 (0.00%)  0
Head injury  1  1/72 (1.39%)  1 0/74 (0.00%)  0 0/73 (0.00%)  0 0/74 (0.00%)  0
Skeletal injury  1  0/72 (0.00%)  0 1/74 (1.35%)  1 0/73 (0.00%)  0 0/74 (0.00%)  0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)         
Neuroendocrine carcinoma metastatic  1  1/72 (1.39%)  1 0/74 (0.00%)  0 0/73 (0.00%)  0 0/74 (0.00%)  0
Nervous system disorders         
Psychomotor hyperactivity  1  0/72 (0.00%)  0 0/74 (0.00%)  0 0/73 (0.00%)  0 1/74 (1.35%)  1
Psychiatric disorders         
Bipolar disorder  1  1/72 (1.39%)  1 0/74 (0.00%)  0 0/73 (0.00%)  0 0/74 (0.00%)  0
Depression  1  0/72 (0.00%)  0 0/74 (0.00%)  0 1/73 (1.37%)  1 0/74 (0.00%)  0
Psychotic disorder  1  0/72 (0.00%)  0 1/74 (1.35%)  1 0/73 (0.00%)  0 0/74 (0.00%)  0
Suicidal ideation  1  0/72 (0.00%)  0 0/74 (0.00%)  0 1/73 (1.37%)  1 0/74 (0.00%)  0
1
Term from vocabulary, MedDRA (17.0)
Indicates events were collected by systematic assessment
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Placebo SD-809 12 mg/Day SD-809 24 mg/Day SD-809 36 mg/Day
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   14/72 (19.44%)      9/74 (12.16%)      9/73 (12.33%)      10/74 (13.51%)    
Gastrointestinal disorders         
Diarrhoea  1  2/72 (2.78%)  2 1/74 (1.35%)  1 3/73 (4.11%)  4 5/74 (6.76%)  6
Nausea  1  7/72 (9.72%)  8 1/74 (1.35%)  1 1/73 (1.37%)  1 1/74 (1.35%)  1
Infections and infestations         
Nasopharyngitis  1  1/72 (1.39%)  1 4/74 (5.41%)  4 3/73 (4.11%)  3 2/74 (2.70%)  2
Nervous system disorders         
Headache  1  4/72 (5.56%)  4 5/74 (6.76%)  7 2/73 (2.74%)  3 5/74 (6.76%)  5
1
Term from vocabulary, MedDRA (17.0)
Indicates events were collected by systematic assessment
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.
Sponsor has the right 60 days before submission for publication to review/provide comments. If the Sponsor’s review shows that potentially patentable subject matter would be disclosed, publication or public disclosure shall be delayed for up to 90 additional days in order for the Sponsor, or Sponsor’s designees, to file the necessary patent applications. In multicenter trials, each PI will postpone single center publications until after disclosure or publication of multicenter data
Results Point of Contact
Name/Title: Director, Clinical Research
Organization: Teva Branded Pharmaceutical Products, R&D Inc
Phone: 215-591-3000
Responsible Party: Teva Pharmaceutical Industries ( Auspex Pharmaceuticals, Inc. )
ClinicalTrials.gov Identifier: NCT02291861     History of Changes
Other Study ID Numbers: SD-809-C-23
2014-003135-19 ( EudraCT Number )
First Submitted: November 12, 2014
First Posted: November 17, 2014
Results First Submitted: March 15, 2018
Results First Posted: April 11, 2018
Last Update Posted: May 14, 2018