VA Cooperative Studies Program #576 VA Augmentation and Switching Treatments for Improving Depression Outcomes (VAST-D) STUDY PROTOCOL Version 5.2 March 9, 2015 Co-Principal Proponents: Somaia Mohamed, M.D., Ph.D. Sidney Zisook, M.D. Biostatistician: Gary R. Johnson, M.S. PRIVILEGED AND CONFIDENTIAL Not For Distribution Beyond the Intended Committee Function Downloaded From: https://jamanetwork.com/ on 09/23/2021 [THIS PAGE LEFT INTENTIONALLY BLANK] Downloaded From: https://jamanetwork.com/ on 09/23/2021 Table of Contents Page LETTERS OF SUBMITTAL: ....................................................................................................... 1 A. Principal Proponents ................................................................................................................. 1 B. Acting Director: Cooperative Studies Program Center, West Haven .................................. 3 C. Cooperative Studies Program Clinical Research Pharmacy Coordinating Center ............... 5 EXECUTIVE SUMMARY ......................................................................................................... 11 PLANNING COMMITTEE ........................................................................................................ 15 I. INTRODUCTION AND BACKGROUND ............................................................................ 17 A. Introduction ....................................................................................................................... 17 B. Study Rationale ................................................................................................................. 18 C. Goals of Treatment: Achieving and Maintaining Remission ............................................ 20 D. Why BUP-SR? .................................................................................................................. 24 E. Why aripiprazole? ............................................................................................................. 26 F. Summary ........................................................................................................................... 29 II. PRELIMINARY RESEARCH .............................................................................................. 30 III. STUDY OBJECTIVES ......................................................................................................... 31 A. Primary Objectives ............................................................................................................ 31 B. Secondary Objectives ........................................................................................................ 31 C. Tertiary (Other) Objectives ............................................................................................... 33 IV. STUDY OUTCOME MEASURES .................................................................................. 34 A. Primary Outcome .............................................................................................................. 34 B. Secondary Outcomes ......................................................................................................... 36 C. Additional Outcomes ......................................................................................................... 39 V. SUMMARY OF STUDY DESIGN AND METHODS ......................................................... 41 A. Background and Significance ............................................................................................ 41 B. Study Population ............................................................................................................... 42 C. Treatment Regimens ......................................................................................................... 43 D. Outcome Measures ............................................................................................................ 44 E. Sample Size ....................................................................................................................... 45 F. Study Monitoring .............................................................................................................. 45 VI. RATIONALE FOR OVERALL DESIGN CONSIDERATIONS ......................................... 47 VII. PATIENT POPULATION ................................................................................................ 48 A. Inclusion Criteria ............................................................................................................... 48 B. Exclusion Criteria .............................................................................................................. 48 C. Rationale for Participant Selection .................................................................................... 49 D. Definition and Rationale for “Adequate Treatment Trial” of Index Antidepressant ......... 51 VIII. PATIENT RECRUITMENT AND SCREENING ............................................................ 55 CSP#576 (VAST-D) Protocol Version 5.2 i 03/09/2015 Downloaded From: https://jamanetwork.com/ on 09/23/2021 IX. HUMAN RIGHTS ISSUES AND INFORMED CONSENT ................................................ 57 A. Consent Procedure............................................................................................................. 57 B. Surrogate Consent ............................................................................................................. 58 C. Risks and Benefits ............................................................................................................. 59 D. Informed Consent .............................................................................................................. 59 E. Certificate of Confidentiality ............................................................................................. 59 X. BASELINE ASSESSMENT.................................................................................................. 60 XI. STRATIFICATION AND RANDOMIZATION .................................................................. 62 XII. BLINDING OF THE RANDOMIZATION SCHEME ..................................................... 64 XIII. FOLLOW-UP ASSESSMENT PROCEDURES .............................................................. 65 A. Assessments administered at each visit ............................................................................. 65 B. Assessments administered at baseline, at the end of acute treatment (12 weeks or sooner), at 24 weeks, and at the end of study (36 weeks or sooner) only ...................................... 66 XIV. TREATMENT REGIMENS ............................................................................................. 67 A. General Principles ............................................................................................................. 67 B. Acute Treatment ................................................................................................................ 68 C. Continuation Treatment ..................................................................................................... 72 D. Concomitant Medications and Treatments ........................................................................ 79 XV. DISCONTINUATION OF TREATMENT ....................................................................... 82 XVI. METHODS TO MAXIMIZE ADHERENCE ................................................................... 84 XVII. MONITORING ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS (SAE)... 84 A. Suicide-Related Risks Monitoring .................................................................................... 84 B. Role of the Local Site Investigator in Adverse Event Monitoring .................................... 88 C. Definitions ......................................................................................................................... 88 D. Adverse Events and Serious Adverse Events to be Documented ...................................... 89 E. Adverse Event and Serious Adverse Event Monitoring .................................................... 90 F. Expedited Reporting of Serious Adverse Events to CSP .................................................. 90 G. Reporting of Serious Related and Unexpected Events ...................................................... 91 H. Reporting of Adverse and Serious Adverse Events to the DMC ....................................... 91 I. Reporting Requirements of the VA Central IRB ............................................................... 91 XVIII. COST EFFECTIVENESS ............................................................................................. 92 A. Overview and Perspective ................................................................................................. 92 B. Costs and Other Economic Measures ................................................................................ 93 C. Cost-Effectiveness Analysis .............................................................................................. 95 D. Analysis of Other Economic Outcomes ............................................................................ 97 E. Inflation and Discounting .................................................................................................. 97 F. Sensitivity Analysis ........................................................................................................... 97 XIX. LIMITATIONS OF THE PROTOCOL ...........................................................................