Product:

V501

Protocol/Amendment No.:

015-00

BP4651.DOC VERSION 8.0 APPROVED11-Apr-2002

Worldwide Protocol U.S. IND/Non-U.S. IND

 Restricted Confidential – Limited Access

THIS PROTOCOL AND ALL OF THE INFORMATION RELATING TO IT ARECONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK & CO., INC.,WHITEHOUSE STATION, NJ, U.S.A.THIS PROTOCOL IS FOR WORLDWIDE USE. BOTH U.S. AND NON-U.S.SITES ARE TO FOLLOW THE INSTRUCTIONS IN THIS DOCUMENT ASDIRECTED.

SPONSOR:

Merck & Co., Inc. (hereafter referred to as the

SPONSOR

)One Merck DriveP.O. Box 100Whitehouse Station, NJ, 08889-0100, U.S.A.

TITLE:

A Randomized, Worldwide, Placebo-Controlled, Double-Blind Study to Investigate theSafety, Immunogenicity, and Efficacy on the Incidence of HPV 16/18-Related CIN 2/3 orWorse of the Quadrivalent HPV (Types 6, 11, 16, 18) L1 Virus-Like Particle (VLP)

Vaccine in 16- to 23-Year-Old Women

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The FUTURE II Study (Females United toUnilaterally Reduce Endo/Ectocervical Disease)

INVESTIGATOR(S):

PRIMARY: SECONDARY/SUBINVESTIGATOR:

SITE: INSTITUTIONAL REVIEW BOARD/ETHICS REVIEW COMMITTEE:

 

 

Product:

 V501

Protocol/Amendment No.:

 015-00

CIN 2/3 Efficacy Trial in Women

BP4651.DOC VERSION 8.0 APPROVED11-Apr-2002

Worldwide Protocol U.S. IND/Non-U.S. IND

Restricted Confidential

–

 Limited Access

TABLE OF CONTENTS

PAGEPROTOCOL SYNOPSIS....................................................................................................7STUDY FLOW CHART...................................................................................................17SPONSOR CONTACT INFORMATION

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U.S. SITE(S)...............................................18SPONSOR CONTACT INFORMATION

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NON-U.S. SITE(S).....................................20I.CLINICAL SECTIONS.....................................................................................22A.BACKGROUND AND RATIONALE........................................................221.Epidemiology.........................................................................................222.Merck 

’

s Ongoing HPV Vaccine Clinical Program................................22a.Demographic and Behavioral Characteristics of theStudy Population..............................................................................22b.Tolerability of HPV Vaccines (Preliminary Data)...........................23c.Determination of the Target Immune Responses.............................24d.Immunogenicity of the Quadrivalent HPV Vaccine........................253.Rationale for the Current Study.............................................................26a.Efficacy............................................................................................26b.Safety................................................................................................27c.Immunogenicity...............................................................................28B.OBJECTIVES..............................................................................................281.Primary...................................................................................................282.Secondary...............................................................................................293.Exploratory.............................................................................................29C.HYPOTHESES............................................................................................291.Primary...................................................................................................29D.SUBJECT DEFINITION.............................................................................301.Inclusion Criteria....................................................................................302.Exclusion Criteria..................................................................................31E.STUDY DESIGN.........................................................................................331.Summary of Study Design.....................................................................332.Treatment...............................................................................................36a.Treatment Plan.................................................................................36b.Clinical Material...............................................................................371)Quadrivalent HPV Vaccine........................................................372)Placebo.......................................................................................38

 

Product:

 V501

Protocol/Amendment No.:

 015-00

CIN 2/3 Efficacy Trial in WomenTABLE OF CONTENTS (CONT.)

PAGE

BP4651.DOC VERSION 8.0 APPROVED11-Apr-2002

Worldwide Protocol U.S. IND/Non-U.S. IND

Restricted Confidential

–

 Limited Access

3)Labeling of Material for Injection..............................................384)Subject Unblinding.....................................................................39c.Special Handling Requirements.......................................................40d.Prior and Concomitant Medication(s)/Treatment(s)........................40e.Diet/Activity/Other..........................................................................403.Study Procedures....................................................................................41a.Consent.............................................................................................41b.Study Visit Schedule........................................................................41c.Full Evaluation Visit (Day 1, Month 7, 12, 24, 36,and 48)

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Study Procedures (Including PrevaccinationProcedures on Day 1).......................................................................44d.Vaccination Visit (Day 1, Month 2, and Month 6)..........................46e.Unscheduled Visit............................................................................47f.Status/Retention Visit......................................................................48g.Study Visit Requirements................................................................50h.Collection and Handling of Specimens............................................501)Serum or Urine Specimen for Pregnancy Test...........................512)Urine Specimen for Gonorrhea and ChlamydiaLCR or PCR or SDA..................................................................513)Serum for Antibody Measurements...........................................514)Labial/Vulvar/Perineal and Perianal Swabs forHPV PCR...................................................................................525)HSV Culture (If Indicated).........................................................536)pH, Wet Mount, Whiff Test, KOH (Performed atthe Investigator

’

s Discretion).....................................................547)Endo/Ectocervical Swab for HPV PCR.....................................548)Pap Test for Liquid Cytology (ThinPrep

™

)..............................55i.Assignment of Allocation Number and Vaccine.............................56 j.Vaccine/Placebo Administration......................................................571)Preparation for Administration..................................................572)Guidelines for Vaccinations.......................................................57k.Clinical Follow-Up...........................................................................58l.Biopsy/Colposcopy/Definitive Procedures......................................591)Procedure for External Genital Lesion Biopsy..........................592)Guidelines for Colposcopy.........................................................603)Procedures for Colposcopy........................................................634)Procedures for Cervical Biopsy.................................................645)Procedures for Endocervical Curettage (ECC)(Optional)...................................................................................66