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ConfidentialCLINICAL PROTOCOLSponsor NameBest Pharmaceutical, IncProtocol TitleMulti-Center, Randomized, Double-Blind, Placebo-Controlled Study Comparing the Safety and Effectiveness of Drug A 20 mg Once Daily Versus Placebo Using 24-Hour Ambulatory Blood Pressure Monitoring In Patients With mild to moderateProtocol NumberABC01Protocol Date27March2007Version NumberFinal 1.0Amendment Number0IND Number999,999NDA NumberNot applicablePrimary AuthorBest Protocol Author, MDContributing AuthorsBest SAP Author, PhDBest CSR Author, MDDrug NameDrug APhase of DevelopmentIIIIndicationMild to moderate hypertensionStudy Sponsor: Best Pharmaceutical, Inc.Wonderful Road, Suite 909Rockville, MA 20850Phone: 999-999-9999Fax: 999-999-8888Web: CONFIDENTIALThis document is a confidential communication of the Sponsor. Acceptance of this document constitutes the agreement by the recipient that no unpublished information contained herein will be published or disclosed without prior written approval.Protocol Signature PageBest Pharmaceutical, IncProtocol ABC01Original Approval Date: March XX, 2007A Multi-Center, Randomized, Double-Blind, Placebo-Controlled Study Comparing the Safety and Effectiveness of Drug A 20 mg Once Daily Versus Placebo Using 24-Hour Ambulatory Blood Pressure Monitoring (ABPM) In Patients with Mild to Moderate HypertensionProtocol Final Version 1.0 ApprovalThis protocol has been verified and approved by:_ _Date_Date_DateTABLE OF CONTENTSProtocol Signature Page2List of Abbreviations51. PROTOCOL SYNOPSIS62. Background Information92.1 Background92.2 Study Rationale92.3 Toxicity and Pre-clinical experience92.4 Clinical experience92.5 Summary of Potential Risks and Benefits93. Study Objectives103.1 Primary objectives103.2 Secondary objectives104.0 Study Design114.1 Study Endpoints114.2 Overall Study Design114.3 Randomization/Blinding Procedure114.4 Stopping Rules114.5 Maintenance of Randomization Codes and Procedure for Breaking Codes125.0 Study Population145.1 Inclusion Criteria145.2 Exclusion Criteria146.0 Investigational Medicine Products166.1 Study Treatment166.2 Concomitant Medications and Prohibited Medications167.0 Study Procedures187.1 Visit 1 (Week -4, Screening)187.2 Visit 2 (Week -3, Placebo Run-in)187.3 Visit 3 (Week -2, Placebo Run-in)197.4 Visit 4 (Week -1, Placebo Run-in)197.5 Visit 5 (Week 0 Baseline) or Visit 4A (Week -1A Placebo Run-In)197.6 Visit 6 (Week 0, Baseline/Randomization)207.7 Visit 7 (Week 2, Double-Blind Treatment)207.8 Visit 8 (Week 4, Double-Blind Treatment)217.9 Visit 9 (Week 6 End of Study/Early Termination)217.10 Visit 10 (Week 6 End of Study/Early Termination)218.0 Clinical Assessment238.1 12-lead Electrocardiogram238.2 Physical Examination238.3 Pregnancy Test and238.4 Laboratory Assessments238.5 Office Blood Pressure and ABPM Measurements249.0 Safety Assessment259.1 Adverse Event and AE reporting2510.0 Statistical Consideration and Analysis2610.1 General Statistical Method2610.2 Analysis Population2610.3 Subject Disposition2610.4 Demographic and Baseline Characteristics2610.5 Protocol Deviation2710.6 Efficacy Analysis2710.7 Safety Analysis2710.8 Sample Size Estimation/Justification2711.0 Ethics2812.0 Data Handling and Record Keeping2913.0 Financing and Insurance3014.0 Publication Policy3115.0 Reference List32APPENDIX A Schedule of Study Evaluations33APPENDIX B Blood Pressure Measurement: Office and Ambulatory Blood Pressure Monitoring34List of AbbreviationsAmbulatory Blood Pressure MonitoringABPMAdverse EventAEBlood PressureBPCase Report FormCRFDiastolic Blood PressureDBPEelectrocardiogramECGLast observation carried forwardLOCFSystolic Blood PressureSBP1. PROTOCOL SYNOPSISProtocol Number:ABC01Title:A Multi-Center, Randomized, Double-Blind, Placebo-Controlled Study Comparing the Safety and Effectiveness of Drug A 20 mg Once Daily Versus Placebo Using 24-Hour Ambulatory Blood Pressure Monitoring (ABPM) In Patients with Mild to Moderate Hypertension. Indication:Mild to moderate hypertension.Objectives:1. The primary objective of the study is to compare the antihypertensive effectiveness using change from Baseline in mean seated office cuff diastolic blood pressure of Drug A 20 mg once daily to placebo.2. The secondary objective is to evaluate the safety of low-dose Drug A compared to placebo and change from Baseline at Week 6 or end of study in mean 24-hour and mean daytime ambulatory Diastolic Blood Presssure (from time of dosing until 8:00PM) as measured by ABPM.Study Design:The study will employ a randomized, double-blind design in patients with mild to moderate hypertension. The study includes a 3- to 4-week single-blind placebo run-in phase and a 6-week double-blind treatment phase. Treatments:All patients will receive placebo tablets once daily for 3 4 weeks during the single-blind, run-in phase. During the double-blind treatment phase, patients will be randomized in a 1:1 ratio to receive either Drug A 20 mg or placebo tablets once daily for 6 weeks.Procedures/Visits:Study visits will be scheduled to fit within the window for trough blood pressure (BP) measurements (i.e., prior to next dose and between 2226 hours after previous dose 242 hours).Study Population:Approximately 300 patients at approximately 10 sites will be enrolled into the placebo run-in phase. It is expected that 20% of patients will not qualify for randomization based on office BP entry criteria and an additional 25% of patients will not qualify based on ABPM entry criteria. The study will randomize approximately 180 patients into the double-blind treatment. The study population will include males and females 18 years of age with mild to moderate hypertension (defined as a seated diastolic blood pressure (DBP) 95 mmHg and 110 mmHg).Efficacy Measures:Primary Endpoint: The primary efficacy endpoint is the change from Baseline in mean seated office cuff DBP (242 hours) at Week 6 or end of study.Secondary Endpoints:l Change from Baseline in seated office systolic blood pressure (SBP) at Weeks 2, 4, 6 or end of study and DBP at Weeks 2 and 4 or end of study,l Change from Baseline to Week 6 or end of study in mean 24-hour and mean daytime ambulatory DBP (time of dose until 8:00 PM) as measured by ABPM,l Change from Baseline to Week 6 or end of study in mean 24-hour and mean daytime (time of dose until 8:00 PM) ambulatory SBP as determined by ABPM,l Proportion of patients with seated office cuff DBP reduced 4 mmHg from baseline at Week 6 or end of study,l Proportion of patients who are normalized by office BP measurements (defined as a trough seated SBP 135 mmHg and/or DBP 10 mmHg from baseline at Week 6 or end of study.Safety Measures:Patient safety will be assessed by monitoring and reporting of adverse events (AE) that occur during the study. Further safety assessments will include physical examinations, 12-lead electrocardiogram (ECG), and clinical laboratory tests.Statistical Analysis:Efficacy analyses will be conducted for two populations: Modified Intent-to-Treat (ITT) and Per Protocol (PP). Descriptive statistics will be presented for the observed blood pressure values, but analysis will be performed on change from baseline. Change from baseline will be calculated as BPt BP0 where BPt is defined as the blood pressure measurement obtained at time = t (Week 2, 4, or 6) and BP0 is the baseline blood pressure (Randomization, Week 0). The primary efficacy endpoint is the change from Baseline in mean seated office cuff DBP (242 hours) at Week 6 or end of study. The primary analysis is the comparison of the two treatment groups using the ITT and PP populations.Secondary efficacy analyses will be conducted for the ITT and PP populations. In addition, analyses for change from baseline for the primary efficacy endpoint will be presented in both ITT and PP populations, examining the effect of race (Caucasian versus Non-Caucasian), gender (male versus female), and age ( 65 years versus 65 years) at Week 6 or end of study. These subgroup analyses by demographics will be performed for the primary efficacy endpoint but not for the secondary efficacy endpoints. For analyses conducted on efficacy results obtained at the various scheduled visits, missing values in the ITT population will be imputed using the last observation carried forward (LOCF) method except for mean ambulatory SBP and DBP by ABPM.Continuous efficacy endpoints (e.g., change from baseline in seated and standing systolic and diastolic office blood pressures) will be compared across treatment groups using a fixed-effect two-way analysis of variance (ANOVA) with center and treatment as factors. Categorical response variables (e.g., proportion of normalized patients with SBP 135 mmHg and/or DBP85 mmHg) will be compared using the Cochran-Mantel-Haenszel test stratified by center.2. Background Information2.1 Background2.2 Study Rationale2.3 Toxicity and Pre-clinical experience2.4 Clinical experience2.5 Summary of Potential Risks and Benefits3. Study ObjectivesThe objective of this study is to evaluate the safety and effectiveness of Drug A 20 mg once daily versus placebo using 24-hour Ambulatory Blood Pressure Monitoring (ABPM) in patients with mild to moderate hypertension. 3.1 Primary objectivesThe primary objective of the study is to compare the antihypertensive effectiveness using change from Baseline in mean seated office cuff diastolic blood pressure of Drug A 20 mg once daily to placebo.3.2 Secondary objectivesThe secondary objective is to evaluate the safety of low-dose Drug A compared to placebo and change from Baseline at Week 6 or end of study in mean 24-hour and mean daytime ambulatory DBP (from time of dosing until 8:00PM) as measured by ABPM.4.0 Study Design4.1 Study Endpoints4.1.1 Efficacy Endpoints4.1.2 Safety Endpoints4.2 Overall Study DesignThe study is a phase III, prospective, randomized, double-blind, placebo-controlled clinical trial to evaluate the safety and effectiveness of Drug A 20 mg once daily versus placebo using 24-hour Ambulatory Blood Pressure Monitoring (ABPM) in patients with mild to moderate hypertension. The study includes a 3- to 4-week single-blind placebo run-in phase and a 6-week double-blind treatment phase.The study will receive approval from the institutional review board (IRB)/ethics committee (EC) at each site and will be conducted in accordance with the principles outlined in the Declaration of Helsinki. Written informed consent will be obtained from all subjects.This study will be at 20 sites in Europe, North America and Asian Pacific. 4.3 Randomization/Blinding ProcedureA centralized, center-blocked randomization procedure will be used for treatment assignment by means of an Interactive Voice Response System (IVRS). Subjects will be randomized 1:1 into 2groups (Drag A n=90, placebo n=90). Subjects and study personnel will be blinded to treatment groups (active study drug vs. placebo).4.4 Stopping Rules4.4.1 Subject WithdrawalA subject (or subjects legal guardian) is free to withdraw consent and discontinue participation in the study at any time, without prejudice to further treatment according to standard practice. If a subject becomes pregnant, or is discovered to be pregnant, during study participation, the Sponsor should be notified. A detailed, comprehensive medical review (for the subject and fetus) will be conducted prior to continuing or discontinuing study participation. Pregnancy will not be considered an SAE.If a subjects participation in the study is terminated early, all available data, including the incidence of AEs and the reason for discontinuation, will be recorded on the Case Report Form (CRF). If a serious adverse event (SAE) occurs within 30 days after the last study dose, the investigator should follow the SAE until the event is resolved or the subject is lost to follow-up. Resolution means the subject has returned to the baseline state of health or the condition is stable and the Investigator does not expect any further improvement or worsening of the adverse event. In all cases, the appropriate information will be recorded on the CRF.4.4.2 Sponsor or Investigator WithdrawalAny of the following are considered reason for the Investigator to remove a subject from the study: The subject is uncooperative/non-compliant and will not or cannot adhere to study responsibilities, including all eligible study visits The subject was erroneously enrolled in the study The subject suffers an intolerable AE The sponsor terminates the study.A subjects participation in the study may be discontinued at any time at the discretion of the Investigator.If the Sponsor, an Investigator, or a regulatory agency discovers a condition during the study to indicate that the study or site should be terminated, this action may be taken after appropriate consultation between the Sponsor and the Investigator. Conditions that might warrant termination of the study include, but are not limited to the following criteria. The discovery of an unexpected, serious, or unacceptable risk to a subject enrolled in the study The decision on the part of the Sponsor to suspend or discontinue testing, evaluation, or development of the study drug Failure of the Investigator to comply with pertinent regulatory authority regulations Submission of knowingly false information from the research facility to the Sponsor, or other regulatory authority Insufficient adherence to protocol requirements4.5 Maintenance of Randomization Codes and Procedure for Breaking CodesUnblinding of treatment assignment during the study is discouraged and should occur only if it is absolutely necessary to identify treatment assignment in an emergency situation due to an adverse event (AE). If the Investigator deems identification of the study medication as necessary for the purpose of providing urgent subject care, unblinding should proceed and the Sponsors Chief Medical Officer and/or PI should be notified. Every effort should be made to contact the Sponsors Chief Medical Officer and/or PI prior to unblinding. If this is not possible, then the Investigator can proceed with determining the study medication assignment by using the Interactive Voice Response System and monitor as soon as possible.Note: Causality should be assessed by the Investigator prior to unblinding of treatment assignment but must not delay treatment in an emergency situation.The date and reason for the unblinding must be recorded in the subjects medical record and on the subjects CRF.5.0 Study PopulationA total of 180 eligible subjects will be randomized to the Drug A or placebo treatment groups.5.1 Inclusion CriteriaPatients will be eligible to participate in this study after the nature and purpose of the protocol have been explained to them and appropriate informed consent has been obtained. The confirmation of the informed consent before the patients participation in the study will be documented in source documents and on the Case Report Form (CRF). The presence of inclusion criteria and the absence of exclusion criteria will be verified on the CRF and patient eligibility for study participation must be documented in source documents.Patients must meet all of the following criteria in order to be randomized into the trial:1. Patients must be males or females 18 years of age.2. Patients must have a history of Stage I to Stage II hypertension (defined as a seated DBP 95 mmHg and 110 mmHg at Baseline-Week 0).3. Patients must be able to communicate effectively with the study personnel. 4. Patients must be adequately informed of the nature and risks of the study and give written informed consent prior to screening.5. Patients must be ambulatory and able to maintain a normal daily activity schedule.6. Patients must have a mean 24-hour ambulatory diastolic blood pressure (DBP) 85 and 105 mmHg as determined by ABPM at the end of the Baseline (Visit 6).7. Patients must have a mean seated diastolic blood pressure 95 and 110 mmHg at the end of the baseline (Visit 6).8. Patients under treatment for hypertension must be willing and able to discontinue all previous anti-hypertensive medications for the duration of the study.9. Women of childbearing potential must be using a medically acceptable form of birth control for the duration of the trial, must have a negative serum pregnancy test at screening, and must have a negative urine pregnancy