PPCOS II Protocol Reproductive Medicine Network Funded by NICHD PREGNANCY IN POLYCYSTIC OVARY SYNDROME II (PPCOS II): A 25 WEEK DOUBLE-BLIND RANDOMIZED TRIAL OF CLOMIPHENE CITRATE AND LETROZOLE FOR THE TREATMENT OF INFERTILITY IN WOMEN WITH POLYCYSTIC OVARY SYNDROME Protocol Leader: Richard S. Legro, MD Data and Coordination Leader: Heping Zhang, PhD Version 9.0 (Replacing Version 8.0) Prepared by: The RMN Data Coordination Center Collaborative Center for Statistics in Science Yale University School of Medicine 300 George Street, Suite 523 New Haven, CT 06511 (203) 785-5185 Last updated: August 12, 2011 1.1 PPCOS II Protocol Protocol Subcommittee Group email address: [email protected] Member Name Email Address Richard Legro, MD [email protected] Robert Brzyski, MD, PhD [email protected] Peter Casson, MD [email protected] Michael Diamond, MD [email protected] Esther Eisenberg, MD, MPH [email protected] [email protected] Nanette Santoro, MD [email protected] [email protected] Hugh Taylor, MD [email protected] Heping Zhang, PhD [email protected] 1.2 PPCOS II Protocol Table of Contents 1 ACRONYMS ................................................................................................................................................. 7 2 STUDY SYNOPSIS ....................................................................................................................................... 8 2.1 OBJECTIVES ..................................................................................................................................................... 8 2.2 PATIENT POPULATION ...................................................................................................................................... 8 2.3 STUDY DESIGN ................................................................................................................................................. 8 2.4 TREATMENT ..................................................................................................................................................... 8 2.5 PRIMARY EFFICACY PARAMETER ..................................................................................................................... 8 2.6 SECONDARY EFFICACY PARAMETERS .............................................................................................................. 8 2.7 STATISTICAL ANALYSIS ................................................................................................................................... 9 2.8 ANTICIPATED TIME TO COMPLETION ............................................................................................................... 9 2.9 REGULATORY COMPLIANCE ............................................................................................................................. 9 2.10 STUDY DIAGRAM ........................................................................................................................................... 10 3 BACKGROUND AND SIGNIFICANCE .................................................................................................. 11 3.1 OVERVIEW ..................................................................................................................................................... 11 3.2 PATHOGENESIS OF SUBFECUNDITY IN PCOS ................................................................................................. 11 3.3 RISK/BENEFIT ASSESSMENT OF CLOMIPHENE CITRATE IN PCOS .................................................................. 12 3.4 AROMATASE INHIBITORS (AIS) AS OVULATION INDUCTION AGENTS ............................................................ 13 3.5 SUMMARY OF PRELIMINARY DATA ................................................................................................................ 15 4 OBJECTIVES.............................................................................................................................................. 16 4.1 PRIMARY RESEARCH HYPOTHESIS ................................................................................................................. 16 4.1.1 Primary Outcome Measure ...................................................................................................................... 16 4.2 SECONDARY RESEARCH HYPOTHESES ........................................................................................................... 16 4.3 TREATMENT DESIGN, STUDY SUMMARY AND STUDY POPULATION ............................................................... 17 4.3.1 Treatment Design ..................................................................................................................................... 17 4.3.2 Study Summary ......................................................................................................................................... 17 4.3.3 Study Population ...................................................................................................................................... 19 4.3.4 Inclusion Criteria ..................................................................................................................................... 20 4.3.5 Exclusion Criteria .................................................................................................................................... 20 4.3.6 Couple Inclusion Criteria ......................................................................................................................... 21 4.3.7 Specific Exclusion Criteria ....................................................................................................................... 21 5 STUDY DESIGN ......................................................................................................................................... 24 5.1 TYPE OF DESIGN ............................................................................................................................................ 24 5.2 RATIONALE FOR DESIGN ................................................................................................................................ 24 5.3 RECRUITMENT/INFORMED CONSENT PROCESS ............................................................................................... 24 5.4 RECRUITMENT ................................................................................................................................................ 24 5.4.1 Hospital/Local Health Care Referrals ...................................................................................................... 24 5.4.2 Local Publicity Office ............................................................................................................................... 25 5.4.3 Local Advertisements ................................................................................................................................ 25 5.4.4 Local PCOS/Infertility Support Groups ................................................................................................... 25 5.4.5 National Professional Organizations ....................................................................................................... 25 5.4.6 National Support Groups .......................................................................................................................... 25 5.4.7 Web Sites .................................................................................................................................................. 26 5.5 INFORMED CONSENT ...................................................................................................................................... 26 5.6 SCREENING VISIT ........................................................................................................................................... 26 5.7 PHYSICAL EXAM ............................................................................................................................................ 26 5.8 TRANSVAGINAL ULTRASOUND EXAM ............................................................................................................ 28 5.9 LABORATORY EXAM ...................................................................................................................................... 28 5.9.1 Central Core Laboratory .......................................................................................................................... 29 5.9.2 DNA Core Facility .................................................................................................................................... 29 5.9.3 Serum Bank ............................................................................................................................................... 30 1.3 PPCOS II Protocol 5.10 QUALITY OF LIFE MEASURES (QOL) ............................................................................................................. 31 5.11 EXCLUSION OF OTHER INFERTILITY FACTORS ............................................................................................... 31 5.12 PRECONCEPTION COUNSELING ....................................................................................................................... 32 5.12.1 Screen Failures ......................................................................................................................................... 33 5.13 COUNSELING ABOUT MENSTRUAL AND INTERCOURSE DIARIES ....................................................................