SD-809-C-18

Auspex Pharmaceuticals, Inc

3333 N. Torrey Pines Court, Ste. 400, La Jolla, CA, United States, 92037

Director, Clinical Research, Teva Branded Pharmaceuticals Products, R&D, Inc, 1 215-591-3000, ustevatrials@tevapharm.com

Director, Clinical Research, Teva Branded Pharmaceuticals Products, R&D, Inc, 1 215-591-3000, ustevatrials@tevapharm.com

No

No

No

Final

30 Aug 2016

No

Yes

21 May 2015

No

• To evaluate the efficacy of SD-809 to reduce the severity of abnormal involuntary movements of Tardive Dyskinesia • To evaluate the safety and tolerability of titration and maintenance therapy with SD-809 in subjects with drug-induced Tardive Dyskinesia

This study was conducted in full accordance with the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) Consolidated Guideline (E6) and any applicable national and local laws and regulations (eg, Code of Federal Regulations [CFR] 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). 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.

11 Jun 2014

No

Yes

Slovakia: 4

Poland: 12

Czech Republic: 4

United States: 97

117

20

0

0

0

0

0

0

101

16

0

Overall Trial (overall period)

Randomised - controlled

This was a randomized, double blind, placebo controlled, parallel group study. Patients were randomly assigned to receive treatment with SD 809 or a matching placebo in a 1:1 ratio. Patients were randomly assigned to treatment through an Interactive Technology Response System (ITRS). Using this system ensured a balance across treatment groups; no effort was made to maintain a balance among treatment groups within a study center. No patient’s treatment assignment was unblinded during the study.

Yes

SD-809

deutetrabenazine

Tablet

Oral use

A tablet formulation of SD 809 was administered with food twice daily, approximately 10 hours apart during the day. Starting dose level was 6 mg BID and adjusted over the 6-week titration period. Weekly dose adjustments for insufficient dyskinesia control were limited to increments of 6 mg per day and all dose levels were administered in 2 divided doses. The maximum total daily dose of SD 809 was 48 mg per day, unless the patient was receiving a strong CYP2D6 inhibitor, in which case the maximum total daily dose was 36 mg. Once adequate control of dyskinesia was achieved, the dose of study drug was not to be increased further. The optimal dose was continued for an additional 6 weeks of maintenance therapy.

Placebo

Tablet

Oral use

Placebo-treated patients received tablets identical in appearance to the SD-809 tablets which were administered with food twice daily, approximately 10 hours apart during the day. Doses were adjusted over the 6-week titration period. Once adequate control of dyskinesia was achieved, the dose of study drug was not to be increased further. The optimal dose was continued for an additional 6 weeks of maintenance therapy.

SD-809

Placebo

SD-809

Placebo

SD-809 mITT

Patients underwent dose adjustment of SD-809 over the initial 6 weeks of treatment, starting treatment with SD-809 at 6 mg twice daily and titrating to a maximum total daily dose of 48 mg per day. The optimal dose was continued by a 6-week maintenance period. The modified intention-to-treat (mITT) population was defined as all randomized patients who received study drug and had at least 1 centrally read postbaseline assessment of the AIMS from at least 1 scheduled postbaseline time point.

Placebo mITT

Patients underwent 'dose adjustment' of placebo over the initial 6 weeks of treatment. The optimal dose was continued by a 6-week maintenance period. The modified intention-to-treat (mITT) population was defined as all randomized patients who received study drug and had at least 1 centrally read postbaseline assessment of the AIMS from at least 1 scheduled postbaseline time point.

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. 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. A MMRM analysis with change from baseline in AIMS score as dependent variable was used. The model included fixed effects for treatment, time point, treatment-by-time point interaction, DRA status, and baseline AIMS as a covariate. An unstructured covariance model was used.

Primary

Day 0 (Baseline), Weeks 2, 4, 6, 9 and 12

The linear mixed model for repeated measurements (MMRM) included fixed effects for treatment, each scheduled time point (5 levels: weeks 2, 4, 6, 9, and 12), the treatment-by-time point interaction, and the DRA status. Baseline AIMS score was a covariate. The unstructured covariance model was used, and the primary analysis compared the SD-809 and placebo groups at week 12. This was based on the F-test using the Satterhwaite method to compute the denominator degrees of freedom.

SD-809 mITT v Placebo mITT

103

Pre-specified

-1.4

2-sided

Standard error of the mean

0.6

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.

Secondary

Week 12

The secondary efficacy endpoints were analyzed using a hierarchical testing procedure. If the primary analysis was statistically significant (p<0.05), then the first key secondary endpoint was to be analyzed. If the first key secondary endpoint was statistically significant, then the second key secondary endpoint was to be similarly analyzed. For any analysis that was not statistically significant, all subsequent analyses of key secondary endpoints were exploratory rather than confirmatory.

SD-809 mITT v Placebo mITT

113

Pre-specified

7.9

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.

Secondary

Week 12

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 CDQ-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.

Secondary

Day 0 (Baseline), Week 12 with last observation carried forward

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

Placebo