Phase II-b Randomized Double-Blind Placebo-Controlled Trial of Lactobacillus crispatus CTV-05 (LACTIN-V) to Prevent the Recurrence of Bacterial Vaginosis A Study of the Sexually Transmitted Infection Clinical Trials Group (STI CTG) DMID Protocol Number: 14-0029 DMID Funding Mechanism: Contract Number: HHSN272201 3000141 Task Order Number: HHSN27200003 Pharmaceutical Support Provided by: Osel, Inc. IND Sponsor: Division of Microbiology and Infectious Diseases National Institute of Allergy and Infectious Diseases National Institutes of Health 5601 Fishers Lane Bethesda, MD 20892 Principal Investigator: Craig R. Cohen, MD, MPH DMID Clinical Project Manager: Jonathan Glock, MPH DMID Medical Monitor: Soju Chang, MD DMID Medical Officer: Jill Long, MD, MPH Version 3.0 19 February 2016 DMID14-0029 Version 3.0 February 19, 2016 ____________________________________________________________________________________________ STATEMENT OF COMPLIANCE The study will be carried out in accordance with Good Clinical Practice (GCP) as required by the following • United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 CFR Part 46; 21 CFR Part 50, 21 CFR Part 56, and 21 CFR Part 312) • ICH E6; 62 Federal Register 25691 (1997) • NIH Clinical Terms of Award All key personnel (all individuals responsible for the design and conduct of this study) have completed Human Subjects Protection Training. ____________________________________________________________________________________________ i DMID14-0029 Version 3.0 February 19, 2016 ____________________________________________________________________________________________ SIGNATURE PAGE The signature below constitutes the approval of this protocol and the attachments, and provides the necessary assurances that this trial will be conducted according to all stipulations of the protocol, including all statements regarding confidentiality, and according to local legal and regulatory requirements and applicable US federal regulations and ICH guidelines. Site Investigator: Signed: Date: Name Title ____________________________________________________________________________________________ ii DMID14-0029 Version 3.0 February 19, 2016 ____________________________________________________________________________________________ TABLE OF CONTENTS Page STATEMENT OF COMPLIANCE ................................................................................................. i SIGNATURE PAGE .................................................................................................................... ii LIST OF ABBREVIATIONS ........................................................................................................ vi PROTOCOL SUMMARY .......................................................................................................... viii SCHEMATIC OF STUDY DESIGN: ........................................................................................... ix 1.0 KEY ROLES .......................................................................................................................1 2.0 BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE ...................................... 4 2.1 Background Information ..........................................................................................4 2.2 Rationale ................................................................................................................6 2.3 Potential Risks and Benefits ................................................................................... 8 2.3.1 Potential Risks ............................................................................................ 8 2.3.2 Known Potential Benefits........................................................................... 11 3.0 OBJECTIVES ................................................................................................................... 12 3.1 Study Objectives ................................................................................................... 12 3.2 Study Outcome Measures .................................................................................... 12 3.2.1 Primary Efficacy Outcome Measure .......................................................... 12 3.2.2 Primary Safety Outcome Measure ............................................................. 12 3.2.3 Secondary Efficacy Outcome Measures .................................................... 13 4.0 STUDY DESIGN .............................................................................................................. 14 5.0 STUDY ENROLLMENT AND WITHDRAWAL .................................................................. 15 5.1 Subject Inclusion Criteria ...................................................................................... 15 5.2 Subject Exclusion Criteria ..................................................................................... 16 5.3 Treatment Assignment Procedures ....................................................................... 17 5.3.1 Randomization Procedures ....................................................................... 17 5.3.2 Masking Procedures .................................................................................. 17 5.3.3 Reasons for Withdrawal ............................................................................ 17 5.3.4 Handling of Withdrawals ............................................................................ 18 5.3.5 Termination of Study ................................................................................. 19 6.0 STUDY PRODUCT .......................................................................................................... 20 6.1 Study Product Description .................................................................................... 20 6.1.1 Acquisition ................................................................................................. 20 6.1.2 Formulation, Packaging, and Labeling....................................................... 20 6.2 Dosage, Preparation, and Administration of Study Product ................................... 22 6.3 Accountability Procedures for the Study Investigational Product ........................... 22 6.4 Assessment of Subject Compliance with Study Product ....................................... 22 6.5 Concomitant Medications/Treatments ................................................................... 22 ____________________________________________________________________________________________ iii DMID14-0029 Version 3.0 February 19, 2016 ____________________________________________________________________________________________ 7.0 STUDY SCHEDULE ......................................................................................................... 24 7.1 Screening Visit 0 (Day -30 to Day -5) .................................................................... 24 7.1.1 Rescreening Visit ...................................................................................... 26 7.2 Enrollment Visit 1 (Day 1) ..................................................................................... 27 7.3 Follow-up Study Visit 2, Week 4, Day 28 (Allowable Days 21-35) ......................... 30 7.4 Follow-up Study Visit 3, Week 8, Day 56 (Allowable Days 49-63) ......................... 31 7.5 Follow-Up Study Visit 4, Week 12, Day 84 (Allowable Days 77-91) ...................... 31 7.6 Telephone Interview, Visit 5, Week 16, Day 112 (Allowable Days 105-119) .......... 33 7.7 Telephone Interview, Visit 6, Week 20, Day 140 (Allowable Days 133-146) .......... 33 7.8 Final Study Visit 7, Week 24, Day 168 (Allowable Days 161-175) ......................... 34 7.9 Study Product Discontinuation/Early Termination Visit .......................................... 35 7.10 Unscheduled Visit ................................................................................................. 36 8.0 STUDY PROCEDURES/EVALUATIONS ......................................................................... 39 8.1 Clinical Evaluations ............................................................................................... 39 8.2 Laboratory Evaluations ......................................................................................... 39 8.2.1 Clinical Laboratory Evaluations ................................................................. 39 8.2.2 Special Assays or Procedures ................................................................... 39 8.2.3 Specimen Preparation, Handling, and Shipping ........................................ 39 9.0 ASSESSMENT OF SAFETY ............................................................................................ 40 9.1 Specification of Safety Parameters ....................................................................... 40 9.2 Methods and Timing for Assessing, Recording, and Analyzing Safety Parameters ........................................................................................................... 40 9.2.1 Adverse Events ......................................................................................... 40 9.2.2 Serious Adverse Events ............................................................................ 41 9.2.3 Procedures to be followed in the Event of Abnormal Laboratory Test Values or Abnormal Clinical Findings ........................................................ 42 9.3 Reporting Procedures ........................................................................................... 42 9.3.1 Serious Adverse