APPENDIX E-1: STUDY PROTOCOL This document is the property of Merck and Merck owns the copyright. Merck’s policy on posting of study protocols on journal websites is described at the following link: http://www.merck.com/research/discovery-and-development/clinical- development/Merck-Guidelines-for-Publication-of-Clinical-Trials-and-Related- Works.pdf For publicly posted protocols, Merck redacts the background and rationale sections because these sections may contain proprietary information. Merck also redacts the names of any individuals due to privacy issues. The appendices are generally not provided because they may be lengthy and contain non-essential information. The publicly posted protocol includes all the key sections that are relevant to evaluating the study, specifically those sections describing the study objectives and hypotheses, the patient inclusion and exclusion criteria, the study design and procedures, the efficacy and safety measures, the statistical analysis plan, and amendments relating to those sections. 1 006-02 A Phase IIb, Multicenter, Randomized, Double-Blind Placebo- Controlled, 2-Period Adaptive Crossover Polysomnography Study to Evaluate the Safety and Efficacy of MK-4305 in Patients with Primary Insomnia 4305, Protocol 006-02 Issue Date: 03-Apr-2009 2 Product: MK-4305 Protocol/Amendment No.: 006-02 THIS PROTOCOL AND ALL OF THE INFORMATION RELATING TO IT ARE CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK & CO., INC., WHITEHOUSE STATION, NJ, U.S.A. THIS PROTOCOL REPLACES THE ORIGINAL PROTOCOL AND ANY SUBSEQUENT AMENDMENTS AND SHOULD BE SIGNED BY ALL INVESTIGATORS SIGNING THE ORIGINAL PROTOCOL. SPONSOR: Merck & Co., Inc. (hereafter referred to as the SPONSOR) One Merck Drive P.O. Box 100 Whitehouse Station, NJ, 08889-0100, U.S.A. Protocol-specific Sponsor Contact information can be found in the Administrative Binder. TITLE: A Phase IIb, Multicenter, Randomized, Double-Blind Placebo-Controlled, 2-Period Adaptive Crossover Polysomnography Study to Evaluate the Safety and Efficacy of MK-4305 in Patients with Primary Insomnia INVESTIGATOR: PRIMARY: CLINICAL PHASE: IIb US IND NUMBER: 101,847 SITE: INSTITUTIONAL REVIEW BOARD/ETHICS REVIEW COMMITTEE: 4305_006-02_ProtTitle VERSION 3.1 APPROVED 03-Apr-2009 Worldwide Restricted Confidential – Limited Access 4305, Protocol 006-02 Issue Date: 03-Apr-2009 3 Product: MK-4305 1 Protocol/Amendment No.: 006-02 SUMMARY OF CHANGES PRIMARY REASON FOR THIS AMENDMENT: The primary reason for this amendment is to clarify that the siDMC review of the interim analyses will involve unblinding of patient level data from the ex-Japan stratum only, e.g. all Japan stratum data will remain blinded until the final data analysis following full study completion. Affected Sections and revised text: 1.4, 2.7, 3.5.1, 3.5.6, 3.5.9.1, 3.5.9.2 OTHER CHANGES INCLUDED IN THE AMENDMENT: Global Clarifications were made to stratification of Japanese patients. Stratification of Japanese patients will be by geographic region (Japan vs. ex-Japan). Affected Sections and revised text: 1.4, 1.6, 2.4.1, 2.4.2, 2.7, 3.2.3.3, 3.2.3.4.3, 3.5.1, 3.5.5.1, 3.5.6, 3.5.9.1 and 3.5.9.2 Modifications to the statistical model for the analysis of primary, secondary and exploratory efficacy endpoints: Section 2.7: Added a term to the model for geographic region (Japan vs. ex- Japan). Section 3.5.5.1: Specified a completely unstructured covariance matrix for the mixed effects model and removed the random subject effect; if this model does not converge then a model with a random subject effect and an unstructured covariance within patient and time will be used. S 3 3 1 12 R yz Cover and Title Pages: Corrected protocol title Summary of Changes 006-01 PRIMARY REASON FOR THIS AMENDMENT (006-01): The primary reason for this amendment is to allow for an extension of the treatment period visit window with dosing beyond 28 days. The global revision consists of changing the original 28 days of treatment to the updated 28 ± 2 days of treatment. Affected Sections and revised text: 1.4, 1.7, 2.4.1, 2.4.2, and 3.2.3.4.3 4305_006-02_ProtSoC VERSION 3.0 APPROVED 03-Apr-2009 Worldwide Restricted Confidential – Limited Access 4305, Protocol 006-02 Issue Date: 03-Apr-2009 4 Product: MK-4305 2 Protocol/Amendment No.: 006-02 OTHER CHANGES INCLUDED IN THE AMENDMENT (006-01): Global Clarifications were made to enrollment and stratification of Japanese patients. Affected Sections and revised text: 1.4, 1.5, 1.6, 2.4.1, 2.4.2, 2.7, 3.2.3.3, 3.2.3.4.3, 3.5.1, and 3.5.7 Sections 1.6, 2.4.1, and 3.2.3.4.2: The time window of 5 to 10 minutes was added to the protocol sections where oral administration of MK-4305 is specified to occur immediately (within 5 to 10 minutes) prior to bedtime on non-PSG nights. Section 1.7 and 3.4.1.5: Footnote § On PSG Visits, weight should be collected at both PM and AM time points, during assessment of vitals. Footnote : Added collection of serum βhCG samples for females of child-bearing potential at Visit 1 in addition to standard urine pregnancy test. Revised text in 3.4.1.5, paragraph 4, Appendix 6.5-footnote † Footnote Clarified procedure for positive alcohol breath tests at Visit 4 and post randomization Revised text in 3.4.1.5, paragraph 5 Footnote †††† and Clarified timing of assessments is consistent for each type of visit, i.e. PSG visit or non-PSG visit. Section 2.2, Prestudy Inclusion Criteria 1p: Changed barrier c c to effective forms of contraception," modified and added additional examples of contraception: status post-vasectomy and hormonal contraceptives; Add a statement to allow a female patient to use 2 effective forms of contraception to meet criteria, if a male partner cannot use an effective form of contraception. Section 2.3 Prestudy Exclusion Criteria 1.h: The specific QTc interval of QTcB (Bazett’s correction), as determined by the ECG reading center, should be used to meet criteria 1.h. Screening PSG Exclusion Criteria 2a: Added an to clarify that patient must meet either 2.a.a. or 2.a.b 4305_006-02_ProtSoC VERSION 3.0 APPROVED 03-Apr-2009 Worldwide Restricted Confidential – Limited Access 4305, Protocol 006-02 Issue Date: 03-Apr-2009 5 Product: MK-4305 3 Protocol/Amendment No.: 006-02 Section 2.4.1, 3.2.2.2, 3.2.3.4.1, 3.2.3.4.2, and 3.3.1.4: Several statements were added to clarify site’s and patient’s responsibility in regards to eDiary reporting, monitoring, and compliance. Section 3.2.1 and Table 3-1: Clarified use of non-prohibited concomitant medication and concurrent medication, and initiation of new medications during the course of the study -1 to be consistent with Table 2-1. Section 3.2.3.4.2 and 3.4.1.5: Corrected the urine pregnancy test collection time point. The urine pregnancy test will not be collected at Visit 2. Section 3.2.3.4.3 and Table 3-4: Corrected the blood sample for genetic analysis (DNA) collection time point. No genetic sample will be collected at V6. Section 3.3.1.2b: Removed 3rd paragraph regarding the timing of PSG electrode calibrations and replaced with: For the timing of electrode calibrations and other PSG activities, refer to the PSG SOP. Section 3.3.1.7: Clarified the scoring of the WRAT-4. A patient should receive a score of 48 out of 70 to meet criteria. Section 3.4.1.8: Amended paragraph to clarify the use of the MCQ to assess a single episode of a patient’s spontaneously-reported cataplexy-like behavior. The MCQ must also be assessed by either the Primary Investigator (PI) or a Sub-PI. Section 3.5.8, Table 3-13: Removed United Kingdom and Australia. Appendix 6.10: Corrected the location to which plasma samples should be shipped. Appendix 6.7: Clarified that blood pressure measurements are collected both in the sitting and standing positions and that the instructions provided in the Appendix are only a guide for sitting blood pressure measurements. 4305_006-02_ProtSoC VERSION 3.0 APPROVED 03-Apr-2009 Worldwide Restricted Confidential – Limited Access 4305, Protocol 006-02 Issue Date: 03-Apr-2009 6 PROTOCOL A Phase IIb, Multicenter, Randomized, Double-Blind Placebo- Controlled, 2-Period Adaptive Crossover Polysomnography Study to Evaluate the Safety and Efficacy of MK-4305 in Patients with Primary Insomnia TABLE OF CONTENTS Application Starting Contents Page Summary of Changes 3 PRIMARY REASON FOR THIS AMENDMENT: 3 OTHER CHANGES INCLUDED IN THE AMENDMENT: 3 PRIMARY REASON FOR THIS AMENDMENT (006-01): 3 OTHER CHANGES INCLUDED IN THE AMENDMENT 4 (006-01): 1. SUMMARY 13 1.1 Title 13 1.2 Indication 13 1.3 Summary of Rationale 13 1.4 Summary of Study Design 13 1.5 Sample 14 1.6 Dosage/Dosage Form, Route, and Dose Regimen 14 1.7 Study Flow Chart 16 2. CORE PROTOCOL 19 2.1 Objectives and Hypotheses 19 2.1.1 Primary 19 2.1.2 Secondary 19 2.1.3 Exploratory Objectives 20 2.2 Subject/Patient Inclusion Criteria 20 2.3 Subject/Patient Exclusion Criteria 22 2.4 Study Design and Duration 27 4305, Protocol 006-02 Issue Date: 03-Apr-2009 7 TABLE OF CONTENTS (CONT.) Application Starting Contents Page 2.4.1 Summary of Study Design 27 2.4.2 Treatment Plan 30 2.5 List of Efficacy/Pharmacokinetic/Immunogenicity, etc., 31 Measurements 2.6 List of Safety Measurements 31 2.7 Data Analysis Summary 32 3.