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NCT01970982
9.2.2
Baseline Period (Day-1 to Day 0)
9.2.2 Baseline Period (Day-1 to Day 0) [Table 8](#page-104-0) and [Table 9](#page-105-0) show the assessments that will be performed at baseline (Day -1 and Day 0, respectively): The timings given are for the first subject. All subsequent subjects should complete procedures within the time window given in the tables. Z...
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NCT01970982
9.2.3
Exposure Period (Days 1 to 5)
9.2.3 Exposure Period (Days 1 to 5) The tables in this Section show the assessments that will be performed during the confinement period (Day 1 to Day 5). [Table 10](#page-107-0) shows the assessments that will be performed on Day 1: Table 10. Time Schedule – Day 1 | Time | Bloodsample | Procedures | Additional informa...
[ "ZRHR-REXC-04-JP Clinical Study Protocol Confidential Final 2.0/08 July 2013 Page 116 of 171" ]
NCT01970982
9.2.4
Day of Discharge (Day 6)
9.2.4 Day of Discharge (Day 6) [Table 15](#page-117-0) shows the assessments that will be performed on Day 6, prior to Discharge from the study unit: ZRHR-REXC-04-JP Clinical Study Protocol Confidential Final 2.0/08 July 2013 Page 118 of 171 Table 15. Time Schedule – Day 6 | Time | Bloodsample | Procedures | Additional...
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NCT01970982
9.3
Safety Follow-up Period
9.3 Safety Follow-up Period All subjects participating in the product trial on Day -2 and are not enrolled into the study will enter a 7-day safety follow-up period. After subjects have completed the assessments at Day 6 (or if they are prematurely withdrawn from the study), they will enter a 7-day safety follow-up per...
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NCT01970982
9.4
Early Termination Procedures
9.4 Early Termination Procedures The assessments of the Day of Discharge will be performed as early termination procedures (see Section [9.2.4\)](#page-116-0). Final 2.0/08 July 2013 Page 120 of 171
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NCT01970982
10
CONTROL AND QUALITY ASSURANCE
10 CONTROL AND QUALITY ASSURANCE
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NCT01970982
10.1
Monitoring
10.1 Monitoring The Clinical Research Associate ("Monitor") will be responsible for the monitoring of the study. Monitoring will be performed according to CRO's Standard Operating Procedure (SOPs) and as per the agreed monitoring plan with the Sponsor. The Principal Investigator/head of the investigational site shall p...
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NCT01970982
10.2
Training of Study Collaborator
10.2 Training of Study Collaborator A formal meeting (Investigator's meeting) will be conducted prior to site initiation. During this meeting, the Sponsor or its authorized representative will discuss the requirements of the clinical study protocol and related documents and will also provide training in the relevant sy...
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NCT01970982
10.3
Audits and Inspections
10.3 Audits and Inspections Good Clinical Practice regulations require that there are independent inspections of clinical program activities. Such inspections may be performed at any time before, during and/or after the study. Authorized representatives of the Sponsor, regulatory agencies and/or an IRB may perform audi...
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NCT01970982
11
DATA MANAGEMENT ACTIVITIES
11 DATA MANAGEMENT ACTIVITIES All Data Management Activities will be described in detail in the Data Management Plan and documents specified therein.
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NCT01970982
11.1
Data Capture
11.1 Data Capture
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NCT01970982
11.1.1
Case Report Forms and Study Records
11.1.1 Case Report Forms and Study Records With the exception of the subject reported outcome data, all results from the clinical assessments will be recorded in the Source Documents by the Investigator or authorized designee and then captured in the eCRFs at the study site. The subject questionnaires and the VAS will ...
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NCT01970982
11.1.2
Protocol Deviations
11.1.2 Protocol Deviations All protocol deviations will be entered into the Clinical Trial Management System (CTMS) or other approved format. Information from the Source Documents will represent the primary source of protocol deviations. Information following site monitoring and other manual reviews will be documented ...
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NCT01970982
11.2
Data Handling
11.2 Data Handling All study data will be managed by the Data Management Team at the CRO. The overall procedures for quality assurance of clinical study data are described in the SOPs of the CRO Data Management Team. The Data Management Team at CRO will prepare a DMP, to be reviewed and approved by the Sponsor, prior t...
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NCT01970982
11.2.1
Data Validation
11.2.1 Data Validation The data will be validated as defined in the DMP and Data Validation Specifications. Discrepancies will be reported as defined in DMP and Data Validation Plan. Final 2.0/08 July 2013 Page 125 of 171 Data queries will be raised for discrepant or missing data. All changes to data will be captured i...
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NCT01970982
11.2.2
Coding
11.2.2 Coding Adverse events, medical/surgical history, and prior/concomitant medication will be classified according to the terminology of the latest version of the following Dictionaries, at time of coding the first entry: Medical history: Medical Dictionary for Regulatory Activities (MedDRA®) Adverse events: MedDRA®...
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NCT01970982
11.2.3
Database Lock
11.2.3 Database Lock When all outstanding Data Management issues have been resolved and all validation, quality review, and cleaning activities are complete, the database or selected data is/are declared soft locked. Access to change data in the soft-locked database or to change selected data at this time is limited. A...
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NCT01970982
12
PLANNED STATISTICAL METHODS
12 PLANNED STATISTICAL METHODS
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NCT01970982
12.1
General Considerations
12.1 General Considerations Full details of the statistical analysis will be given in a SAP. Any changes to the planned statistical methods will be documented in the CSR. The statistical evaluation will be performed using SAS®, version 9.2 or later.
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NCT01970982
12.1.1
Stratification Criteria
12.1.1 Stratification Criteria For the primary analysis of the BoExp, the following stratification criteria will be used: - 1. Sex (male; female). - 2. Average daily CC consumption over the last 4 weeks as reported during Screening.
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NCT01970982
12.1.2
Definitions for Statistical Data Analysis
12.1.2 Definitions for Statistical Data Analysis In general, baseline is the last available time-point prior to Day 1, 06:30 AM.
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NCT01970982
12.1.3
Descriptive Statistics
12.1.3 Descriptive Statistics All data will be presented in listings, ordered by product arm and subject, unless otherwise specified. Descriptive statistics for continuous variables (number of subjects [n], number and percent of subjects with data, mean, standard deviation [SD], median, first and third quartiles, minim...
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NCT01970982
12.1.4
Handling of Missing Values and of Values outside the Detection Limits
12.1.4 Handling of Missing Values and of Values outside the Detection Limits Missing values for the BoExp will be imputed using the last observation carried forward approach. For questionnaire data, total scores and domain or subscale scores may use a certain degree of imputation by averaging across individual item sco...
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NCT01970982
12.1.5
Significance Level for Inferential Analysis
12.1.5 Significance Level for Inferential Analysis Unless stated otherwise, all statistical tests will be two-sided and conducted at the 5% level, and all quoted confidence intervals (CIs) will be two-sided 95% CIs. The primary endpoints will be tested using a multiple testing procedure to preserve the overall alpha le...
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NCT01970982
12.2
Determination of Sample Size and Power Consideration
12.2 Determination of Sample Size and Power Consideration The following discussion addresses the ability to demonstrate on Day 5 a reduction of at least 50% on 4 selected primary BoExps in smokers switching from CC to THS 2.2 as compared to smokers continuing to smoke CC. [Table 16](#page-128-0) describes the expected ...
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NCT01970982
12.3
Analysis Population
12.3 Analysis Population The main population for non-safety analysis will be the full analysis set (FAS) population. The per-protocol (PP) population will be used only for the analysis of the primary endpoint to examine the robustness of the primary analyses. Safety will be analyzed using the safety population.
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NCT01970982
12.3.1
Full Analysis Set
12.3.1 Full Analysis Set The FAS consists of all the randomized subjects who had at least one post-randomization product use experience, if randomized to THS 2.2 or CC, and have at least one valid nonsafety assessment (THS 2.2, CC, SA arms).
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NCT01970982
12.3.2
Per Protocol Population
12.3.2 Per Protocol Population The PP population is a subset of FAS and includes all randomized subjects who fulfill key compliance criteria of the protocol, and have no major protocol deviation (to be further described in the SAP).
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NCT01970982
12.3.3
Safety Population
12.3.3 Safety Population The safety population consists of all the subjects who had at least one exposure to THS 2.2 (product test at Admission Day). Subjects in the safety population will be analyzed according to actual exposure.
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NCT01970982
12.4
Primary Analysis
12.4 Primary Analysis
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NCT01970982
12.4.1
Primary Endpoint Analysis Variables
12.4.1 Primary Endpoint Analysis Variables The primary endpoints are: - COHb on Day 5. - MHBMA on Day 5. Final 2.0/08 July 2013 Page 133 of 171 - 3-HPMA on Day 5. - S-PMA on Day 5. See section [3.4.1.](#page-38-0) Evaluation Criterion: The study will be considered successful if the study demonstrates a 50% reduction or...
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NCT01970982
12.4.2
Baseline Comparability
12.4.2 Baseline Comparability Not applicable.
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NCT01970982
12.4.3
Descriptive Analysis
12.4.3 Descriptive Analysis Primary endpoints will be summarized as described in Section [12.1.3](#page-125-2) on the FAS. Should more than 20% of the subjects be excluded from the FAS population, the above descriptive analysis will be repeated on the PP population.
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NCT01970982
12.4.4
Confirmatory Analysis
12.4.4 Confirmatory Analysis The hypothesis to be tested for each of the primary and secondary biomarkers of exposure is that the geometric mean level on Day 5 of the biomarker for THS 2.2 is lower relative to CC. Analysis of BoExp will be conducted on the natural log scale. In order to test the following hypothesis Nu...
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NCT01970982
12.5
Secondary Analysis
12.5 Secondary Analysis
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NCT01970982
12.5.1
Secondary Endpoint Analysis Variables
12.5.1 Secondary Endpoint Analysis Variables See section [3.4.2](#page-39-0) More details on derivation rules will be given in the SAP.
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NCT01970982
12.5.2
Baseline Comparability
12.5.2 Baseline Comparability Not applicable.
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NCT01970982
12.5.3
Descriptive Analysis
12.5.3 Descriptive Analysis In general, secondary endpoints will be summarized as described in Section [12.1.3](#page-125-2) on the FAS.
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NCT01970982
12.5.4
Safety Analysis
12.5.4 Safety Analysis In general, all safety data will be listed and tabulated on the safety population by product arm, using the approach described in Section [12.1.3.](#page-125-2) Safety variables collected during exposure periods will also be reported by product exposure. Confidentiality statement: Data and inform...
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NCT01970982
12.6
Exploratory Analysis
12.6 Exploratory Analysis
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NCT01970982
12.6.1
Exploratory Endpoint Analysis Variables
12.6.1 Exploratory Endpoint Analysis Variables See section [3.4.3.](#page-41-0)
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NCT01970982
12.6.2
Baseline Comparability
12.6.2 Baseline Comparability Not applicable.
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NCT01970982
12.6.3
Descriptive Analysis
12.6.3 Descriptive Analysis In general, exploratory endpoints will be summarized as described in Section [12.1.3](#page-125-2) on the FAS. ZRHR-REXC-04-JP Clinical Study Protocol Confidential Final 2.0/08 July 2013 Page 136 of 171
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NCT01970982
12.7
Demographics and Baseline Characteristics
12.7 Demographics and Baseline Characteristics Demographic and other baseline characteristics will be reported for safety population. Summary statistics will be provided by exposure group and stratified by sex and by cigarette consumption. Formal statistical analysis will not be performed on baseline demographic data.
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NCT01970982
12.8
Interim Analysis
12.8 Interim Analysis There are no planned interim analyses.
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NCT01970982
13
ADMINISTRATIVE CONSIDERATIONS
13 ADMINISTRATIVE CONSIDERATIONS
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NCT01970982
13.1
Principal Investigators and Study Administrative Structure
13.1 Principal Investigators and Study Administrative Structure
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NCT01970982
13.1.1
Principal Investigator
13.1.1 Principal Investigator | Principal Investigator: | Takuya Kunito, MD | |-------------------------|------------------------------------------------------------------------------------------------------| | | Daito Bldg., 1-11-3, Okubo, Shinjuku-ku, Tokyo 169-0072 JapanHigashi Shinjuku ClinicTEL: | | | E-mail: |
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NCT01970982
13.1.2
Sponsor
13.1.2 Sponsor | Sponsor: | Philip Morris Products S.A, | |----------------------------------------------|-----------------------------| | | Quai Jeanrenaud 5, | | | 2000 Neuchâtel, | | | Switzerland. | | | Tel: + 41 (58) 242 2111 | | | Fax: + 41 (58) 242 2811 | | , PhD | Phone: +41 | | Manager Clinical Science | Mobil...
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NCT01970982
13.1.3
Other Responsibilities
13.1.3 Other Responsibilities ![](page137Picture6.jpeg) ZRHR-REXC-04-JP Clinical Study Protocol Confidential Final 2.0/08 July 2013 Page 139 of 171 ![](page138Picture4.jpeg) Details of the laboratories conducting the clinical safety laboratory services, biopharmaceutical analyses and the analyses of BoExp are shown in ...
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NCT01970982
13.2
Subject Confidentiality
13.2 Subject Confidentiality All information obtained during the conduct of the study with respect to the subjects' state of health will be regarded as confidential. A statement to this effect will be written in the information provided to the subject. An agreement to disclose any such information will be obtained from...
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NCT01970982
13.3
Access to Source Documentation
13.3 Access to Source Documentation Subjects will be informed that, during the course of the clinical study, the Sponsor, any authorized representatives of the Sponsor, IRB, or regulatory authorities may inspect their medical records to verify the information collected, and ensure that all personal information made ava...
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NCT01970982
13.4
Record Retention
13.4 Record Retention All records of data, source data and source documents (original records or certified copies), in any form (including, but not limited to, written, electronic, magnetic, optical records and scans, X-rays, and ECGs) that describe or record the methods, conduct, and/or results of the study, the facto...
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NCT01970982
13.5
Clinical Study Report
13.5 Clinical Study Report The Sponsor must ensure that a CSR for this study is prepared regardless of whether the study is completed or prematurely terminated. The CSR will be written based on standards of the ICH Guideline for the Structure and Content of Clinical Study Reports. In certain circumstances, an abbreviat...
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NCT01970982
13.6
Financial Disclosure
13.6 Financial Disclosure Investigators are required to provide financial disclosure information to the Sponsor. In addition, the Investigators must provide to the Sponsor a commitment to promptly update this information if any relevant changes occur during the course of the investigation and for 1 year following the c...
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NCT01970982
13.7
Publication and Disclosure Policy
13.7 Publication and Disclosure Policy This document contains data, information and trades secretes that are confidential and proprietary to the Sponsor. This document is being provided solely for the purpose of evaluation and/or conducting this clinical study for the Sponsor. Disclosure of the content of this document...
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NCT01970982
13.8
Insurance
13.8 Insurance Confidentiality statement: Data and information contained in this document are considered to constitute trade secrets and confidential commercial information, and the legal protections provided to such trade secrets and confidential information are hereby claimed under the provisions of applicable law. N...
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NCT01970982
14
REFERENCE LIST
14 REFERENCE LIST Ashley et al., 2008 Ashley DL, Burns D, Djordjevic M, Dybing E, Gray N, Hammond SK, et al. WHO Study Group on Tobacco Product Regulation. The scientific basis of tobacco product regulation. World Health Organ Tech Rep Ser. 2008; (951): 1-277, 1 p following 277. Benowitz et al., 1993 Benowitz NL, Fit...
[ "Ashley et al., 2008", "Benowitz et al., 1993", "Benowitz et al., 2002", "Cappelleri et al., 2007", "Chang and Kam, 1999", "Connolly et al., 2011", "Cox et al., 2001", "Declaration of Helsinki, 2008", "Faber and Fuhr, 2004", "Fagerström et al., 2012", "FDA, 2002", "FDA, 2011", "FDA, 2012a", ...
NCT01975389
1
Visit Schedule:
1 Visit Schedule: Visits should be scheduled by the numbered weeks above. Subjects should be fasting for at least 10 hours prior to all visits during which fasting blood samples will be collected, with the following exceptions. Unscheduled assessments limited to measures of creatine kinase (CK), liver function tests (i...
[ "Informed consent:", "Visit 0, Pre-screening visit:", "Visit 1:", "Lipid, ADA, PK, and PCSK9 testing requirements after randomization:", "Visit windows:", "Dosing windows:", "LIST OF TABLES Table 1. Treatments [................................................................................................
NCT01975389
1
INTRODUCTION
1. INTRODUCTION Bococizumab (previously numbered PF-04950615, RN-316, and J16) is a humanized monoclonal antibody that is a potent and selective inhibitor of proprotein convertase kexin (PCSK9). Bococizumab enhances the expression of LDL receptors on hepatocytes, lowering LDL-C levels substantially, with or without con...
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NCT01975389
1.1
Indication
1.1. Indication In patients at high risk of coronary events due to a history of CV disease (myocardial infarction, ischemic stroke, or arterial revascularization) or in high-risk patients without CV disease (diabetes mellitus, familial hypercholesterolemia, symptomatic peripheral vascular disease, or chronic kidney dis...
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NCT01975389
1.2
Background and Rationale
1.2. Background and Rationale
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NCT01975389
1.2.1
Overview of the Disease State
1.2.1. Overview of the Disease State Cardiovascular disease due to atherosclerosis (CVD), including myocardial infarction and stroke, is currently the leading cause of morbidity and premature mortality worldwide, contributing 17 million (8.6 million among women) deaths annually and 10% of the global disease burden, des...
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NCT01975389
1.2.2
Rationale
1.2.2. Rationale Despite currently available treatments for dyslipidemia, many patients do not reach therapeutic LDL-C goals and others sustain major CV events, even while being treated with adequate doses of medication. LDL-C lowering by inhibiting the action of proprotein convertase subtilisin kexin type 9 (PCSK9) ap...
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NCT01975389
1.2.3
Summary of Safety from Completed Studies with Bococizumab
1.2.3. Summary of Safety from Completed Studies with Bococizumab Bococizumab administered either as a single or multiple doses, either alone or in combination with current lipid lowering agents, was generally well tolerated in completed studies. No subjects in completed studies met the categorical criteria of drug-indu...
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NCT01975389
1.2.4
Benefits and Risks of Participation
1.2.4. Benefits and Risks of Participation The potential benefit of participation, for all subjects in this study, is close monitoring of their medical condition and safety. Those randomized to the active treatment arm may have a benefit of a lower risk of major CV events. Those randomized to the placebo arm are not ex...
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NCT01975389
1.2.5
Interim Analysis from Study B1481015
1.2.5. Interim Analysis from Study B1481015 An interim analysis, for the primary endpoint of the now completed study B1481015, was conducted after subjects completed 12 weeks of treatment, for the purpose of Phase 3 dose selection. The study was a randomized, double-blind, placebo-controlled, parallel-group, dose-rangi...
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NCT01975389
1.2.6
Rationale for Dose Selection
1.2.6. Rationale for Dose Selection The dose selected for Phase 3 is a starting dose of 150 mg administered SC, every two weeks (Q2wks), with a potential modification to a dose of 75 mg Q2wks for subjects with two consecutive low LDL-C concentrations (10 mg/dL or 0.26 mmol/L) at the end of the dosing interval. Addition...
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NCT01975389
2
STUDY OBJECTIVES AND ENDPOINTS
2. STUDY OBJECTIVES AND ENDPOINTS
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NCT01975389
2.1
Objectives
2.1. Objectives
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NCT01975389
2.1.1
Primary Objective
2.1.1. Primary Objective The primary objective of this clinical trial is to demonstrate the superior efficacy of bococizumab compared with placebo in reducing the risk of major CV events, a composite endpoint which includes adjudicated and confirmed CV death, non-fatal MI, non-fatal stroke, and hospitalization for unst...
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NCT01975389
2.1.2
Secondary Objectives
2.1.2. Secondary Objectives
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NCT01975389
2.1.2.1
Clinical Secondary Objectives
2.1.2.1. Clinical Secondary Objectives The key secondary objectives of this clinical trial are to demonstrate in subjects with high or very high risk of major CV events, who are on background lipid lowering treatment and have an LDL-C 100 mg/dL (2.59 mmol/L) or non-HDL-C 130 mg/dL (3.36 mmol/L), the superior efficacy o...
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NCT01975389
2.1.2.2
Circulating Biomarker Secondary Objectives
2.1.2.2. Circulating Biomarker Secondary Objectives
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NCT01975389
2.1.2.2.1
LDL-C
2.1.2.2.1. LDL-C To evaluate, in subjects at high or very high risk of major CV events, who are on background lipid lowering treatment and have an LDL-C 100 mg/dL (2.59 mmol/L) or non-HDL-C 130 mg/dL (3.36 mmol/L), bococizumab compared with placebo, with respect to the circulating lipid biomarker LDL-C (direct measure)...
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NCT01975389
2.1.2.2.2
Other Circulating Lipid Biomarkers
2.1.2.2.2. Other Circulating Lipid Biomarkers To evaluate, in subjects at high or very high risk of major CV events, who are on background lipid lowering treatment, and have an LDL-C 100 mg/dL (2.59 mmol/L) or non-HDL-C 130 mg/dL (3.36 mmol/L), bococizumab compared with placebo, with respect to the following circulatin...
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NCT01975389
2.1.2.2.3
Inflammatory Circulating Biomarker
2.1.2.2.3. Inflammatory Circulating Biomarker To evaluate in subjects at high or very high risk of major CV events, who are on background lipid lowering treatment, and have an LDL-C 100 mg/dL (2.59 mmol/L) or non-HDL-C 130 mg/dL (3.36 mmol/L), bococizumab compared with placebo, with respect to high sensitivity C-reacti...
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NCT01975389
2.1.2.3
Health Care Resource Utilization Objectives
2.1.2.3. Health Care Resource Utilization Objectives To evaluate in subjects at high or very high risk of major CV events, who are on background lipid lowering treatment, and have an LDL-C 100 mg/dL (2.59 mmol/L) or non-HDL-C 130 mg/dL (3.36 mmol/L), the comparison of health care resource utilization (HCRU) associated ...
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NCT01975389
2.1.2.4
Safety Objectives
2.1.2.4. Safety Objectives To describe in subjects at high or very high risk of major CV events, who are on background lipid lowering treatment, and have an LDL-C 100 mg/dL (2.59 mmol/L) or non-HDL-C 130 mg/dL (3.36 mmol/L), the safety, tolerability and immunogenicity of bococizumab or placebo, including the assessment...
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NCT01975389
2.2
Endpoints
2.2. Endpoints This protocol will use an independent endpoint adjudication committee to determine whether certain investigator-reported events meet the definition of disease-related efficacy endpoints, using pre-defined endpoint criteria. For all clinical endpoints listed below, a description of qualifying outcome even...
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NCT01975389
2.2.1
Primary Endpoint
2.2.1. Primary Endpoint The primary endpoint is defined as the time from randomization to the first adjudicated and confirmed occurrence of a major CV event, a composite endpoint that includes CV death, non-fatal MI, non-fatal stroke, and hospitalization for unstable angina needing urgent revascularization.
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NCT01975389
2.2.2
Key Secondary Endpoints
2.2.2. Key Secondary Endpoints Key secondary endpoints are defined as the times from randomization to the first adjudicated and confirmed occurrence of: - A composite endpoint of CV death, non-fatal MI, and non-fatal stroke; - A composite endpoint of all-cause death, non-fatal MI, non-fatal stroke, and hospitalization ...
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NCT01975389
2.2.3
Other Clinical Secondary Endpoints
2.2.3. Other Clinical Secondary Endpoints Other clinical secondary endpoints are defined as the times from randomization to the first adjudicated and confirmed occurrence of: - A composite endpoint of CV death, non-fatal MI, and non-fatal stroke, and hospitalization for unstable angina; - CV death; - Any MI (fatal and ...
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NCT01975389
2.2.3.1
Circulating Biomarker Endpoints
2.2.3.1. Circulating Biomarker Endpoints
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NCT01975389
2.2.3.1.1
LDL-C
2.2.3.1.1. LDL-C The percent change and nominal change, from baseline at Week 14 (Visit -8) and percent change from baseline to the last available post-randomization value, in LDL-C (direct measurement).
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NCT01975389
2.2.3.1.2
Other Circulating Lipid Biomarker Endpoints
2.2.3.1.2. Other Circulating Lipid Biomarker Endpoints The percent change from baseline at Week 14 (Visit 8) in levels of: - Non-HDL-C; - Total cholesterol; - VLDL-C; - RLP-C; - Apo B; - Lp(a); - Triglycerides; - HDL-C; - Apo A-I.
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NCT01975389
2.2.3.1.3
Inflammatory Circulating Biomarker
2.2.3.1.3. Inflammatory Circulating Biomarker The percent change from baseline at Week 14 (Visit 8), in levels of hs-CRP.
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NCT01975389
2.2.3.2
Health Care Resource Utilization Endpoints
2.2.3.2. Health Care Resource Utilization Endpoints The HCRU endpoints include: - The occurrence, primary and secondary discharge diagnoses, overall length of stay, duration of stay in different medical care units, and discharge disposition, of all-cause hospitalizations; - The occurrence, primary and secondary dischar...
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NCT01975389
2.2.4
Safety Endpoints
2.2.4. Safety Endpoints Safety endpoints include investigator reported adverse events, (including Type 1 and 3 hypersensitivity reactions and injection site reactions), serious adverse events, vital signs, examination observations (physical and neurological examinations and cognitive testing), 12-lead ECG recordings, a...
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NCT01975389
2.2.5
Assessment of Clinical Efficacy and Safety Endpoints
2.2.5. Assessment of Clinical Efficacy and Safety Endpoints This protocol will use an independent blinded Adjudication Committee wherein, to maintain scientific integrity, adjudication of disease-related efficacy endpoints will be performed. The Adjudication Committee will adjudicate potential disease-related efficacy ...
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NCT01975389
3
STUDY DESIGN
3. STUDY DESIGN This is an event driven, Phase 3 multi-center, double-blind, randomized parallel group evaluation of the efficacy, safety, and tolerability of bococizumab compared with placebo, in reducing the occurrence of major CV events in subjects at risk, who are on background lipid lowering treatment and have an ...
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NCT01975389
3.1
Number and Location of Study Sites
3.1. Number and Location of Study Sites The study will be conducted in North America, Latin America, Europe, Africa, Asia, and Australia in approximately forty countries.
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NCT01975389
3.2
Study Population
3.2. Study Population Subjects will be men and women with a high risk or very high risk of incurring major CV events based on the study inclusion and exclusion criteria ([Section 4\)](#page-52-0).
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NCT01975389
3.3
Treatment Periods
3.3. Treatment Periods
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NCT01975389
3.3.1
Pre-screening Visit
3.3.1. Pre-screening Visit A pre-screening visit is required for all subjects. Sites will obtain informed consent from potential subjects to evaluate baseline lipids and obtain medical records for review, only, so as to determine if the subject qualifies for this study. The lipid assessments will be done using the cent...
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NCT01975389
3.3.2
Screening Visit
3.3.2. Screening Visit The time interval between the Pre-screening Visit (Visit 0) and the Screening Visit (Visit 1) is a maximum of 30 days. At the screening visit, after obtaining consent for participation in study B1481038, potential subjects will be fully evaluated for eligibility, based on the prescreening lipid v...
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NCT01975389
3.3.3
Run-In Period
3.3.3. Run-In Period After the screening visit, qualified subjects will begin a run-in period of up to six weeks duration during which they will receive SC injections of open-label placebo IP no less than 7 and no more than 14 days apart. The primary objectives of the run-in period are to ensure (1) compliance with the...
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NCT01975389
3.3.4
Active Treatment Period
3.3.4. Active Treatment Period At the randomization visit, the subject will be assigned to either active treatment or placebo IP in a blinded fashion. IP will be administered SC by self-injection, or by a trained caregiver, Q2wks during the course of the study, unless there has been an IP dose modification to a frequen...
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NCT01975389
3.3.5
Safety Follow-up Period
3.3.5. Safety Follow-up Period The safety follow-up period will comprise 40 calendar days after the last administration of the IP.
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NCT01975389
3.4
External Committees
3.4. External Committees
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