SD-809-C-23

Auspex Pharmaceuticals, Inc.

3333 N. Torrey Pines Court, Suite 400, La Jolla, California, United States, 92037

Director, Clinical Research, Teva Branded Pharmaceutical Products, R&D Inc, 001 2155913000, info.era-clinical@teva.de

Director, Clinical Research, Teva Branded Pharmaceutical Products, R&D Inc, 001 2155913000, info.era-clinical@teva.de

No

No

No

Final

20 Dec 2016

No

Yes

19 Aug 2016

No

The objectives of this study were: - To evaluate the efficacy of fixed doses of SD-809 to reduce the severity of abnormal involuntary movements of TD - To evaluate the safety and tolerability of fixed doses of SD-809 in patients with TD

This study was conducted in full accordance with the International Council on Harmonisation (ICH) Good Clinical Practice (GCP) Consolidated Guideline (E6) and any applicable national and local laws and regulations (eg, Code of Federal Regulations Title 21, Parts 50, 54, 56, 312, and 314; EU Directive 2001/20/EC on the approximation of the laws, regulations and administrative provisions of the Member States relating to the implementation of GCP in the conduct of clinical trials on medicinal products for human use). Each investigator was responsible for performing the study in accordance with the protocol, ICH guidelines, and GCP, and for collecting, recording, and reporting the data accurately and properly. Written and/or oral information about the study was provided to all patients in a language understandable by the patients. The information included an adequate explanation of the aims, methods, anticipated benefits, potential hazards, and insurance arrangements in force. Written informed consent was obtained from each patient before any study procedures or assessments were done. It was explained to the patients that they were free to refuse entry into the study and free to withdraw from the study at any time without prejudice to future treatment. Each patient’s willingness to participate in the study was documented in writing in a consent form that was signed by the patient with the date of that signature indicated. Each investigator kept the original consent forms, and copies were given to the patients.

29 Oct 2014

No

Yes

Czech Republic: 24

Germany: 4

Hungary: 17

Poland: 84

Slovakia: 8

United States: 161

298

137

0

0

0

0

0

0

226

72

0

Overall Study (overall period)

Randomised - controlled

During the treatment period the sponsor, patients, as well as the investigators and their site personnel were blinded to treatment assignment. Active and placebo study drug were identical in appearance and packaged in study drug kits according to the randomization code

Yes

Placebo

Tablet

Oral use

Placebo tablets taken twice daily for 12 weeks. Tablets were swallowed whole with water and taken with food.

SD-809

deutetrabenzine, Austedo

Tablet

Oral use

SD-809 tablets dose titrated for 4 weeks until target randomized dose is reached. The dose is maintained for an additional 8 weeks. Tablets were swallowed whole with water and taken with food.

SD-809

deutetrabenzine, Austedo

Tablet

Oral use

SD-809 tablets dose titrated for 4 weeks until target randomized dose is reached. The dose is maintained for an additional 8 weeks. Tablets were swallowed whole with water and taken with food.

SD-809

deutetrabenzine, Austedo

Tablet

Oral use

SD-809 tablets dose titrated for 4 weeks until target randomized dose is reached. The dose is maintained for an additional 8 weeks. Tablets were swallowed whole with water and taken with food.

Placebo

SD-809 12 mg/day

SD-809 24 mg/day

SD-809 36 mg/day

Placebo

SD-809 12 mg/day

SD-809 24 mg/day

SD-809 36 mg/day

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.

Primary

Day 0 (Baseline), Weeks 2, 4, 8 and 12

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.

Placebo v SD-809 36 mg/day

108

Pre-specified

-1.9

2-sided

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.

Placebo v SD-809 24 mg/day

101

Pre-specified

-1.8

2-sided

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.

Placebo v SD-809 12 mg/day

109

Pre-specified

-0.7

2-sided

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.

Secondary

Week 12

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.

Placebo v SD-809 36 mg/day

113

Pre-specified

2.11

2-sided

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.

Placebo v SD-809 24 mg/day

107

Pre-specified

2.71

2-sided

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.

Placebo v SD-809 12 mg/day

118

Pre-specified

1.15

2-sided

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.

Secondary

Day 0 (Baseline), Week 12

Placebo v SD-809 36 mg/day

113

Pre-specified

-3.6

2-sided

Placebo v SD-809 24 mg/day

107

Pre-specified

-3.1

2-sided

Placebo v SD-809 12 mg/day

117

Pre-specified

1.3

2-sided

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.

Secondary

Week 12

Placebo v SD-809 36 mg/day

113

Pre-specified

1.51

2-sided

Placebo v SD-809 24 mg/day

107

Pre-specified

1.82

2-sided

Placebo v SD-809 12 mg/day

118

Pre-specified

0.69

2-sided

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.

Secondary

Day 0 (Baseline), Week 12

Placebo v SD-809 36 mg/day

113

Pre-specified

3.8

2-sided

Placebo v SD-809 24 mg/day

107

Pre-specified

3.96

2-sided

Placebo v SD-809 12 mg/day

118

Pre-specified

1.13

2-sided

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.

Secondary

Day 0 (Baseline), Weeks 2, 4, 8 and 12

Placebo v SD-809 36 mg/day

108

Pre-specified

-21.5

2-sided

Placebo v SD-809 24 mg/day

101

Pre-specified

-20.2

2-sided

Placebo v SD-809 12 mg/day

109

Pre-specified

-8.4

2-sided

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.

Secondary

Day 0 (Baseline), Week 12

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.

Secondary

Day 1 to Week 12

Day 1 to Week 12

17.0

SD-809 12 mg/day

Placebo

SD-809 24 mg/day

SD-809 36 mg/day