Major Extremity Trauma Research Consortium (METRC):

Improving Pain Management and Long Term Outcomes Following High Energy Orthopedic Trauma (Pain Study)

Financial Sponsor: DOD OETRP/CDMRP/NIH

Contract Number: W81XWH1020090

IND# N/A

IDE# N/A

Principal Investigators/Protocol Chairs:

Renan C. Castillo, PhD

Srinivasa N. Raja, MD

Principal Investigators PTOA Pilot Study:

J. Lawrence Marsh, MD

Don Anderson, PhD

Medical Monitor: Marc Swiontkowski, MD

Version # 11.0

DATE: October 20, 2015

This template is adapted from the ICH guidance document E6 (Good Clinical Practices), Section 6.

Confidentiality Statement

This document is confidential and is to be distributed for review only to investigators, potential investigators, consultants, study staff, and applicable independent ethics committees or institutional review boards. The contents of this document shall not be disclosed to others without written authorization from METRC (or others, as applicable), unless it is necessary to obtain informed consent from potential study participants.

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 U.S. federal regulations and ICH guidelines.

The Lead Principal Investigator (Protocol Chair) should sign Signature Page 1. A copy of this Signature Page 1 should be filed with the holder of the Regulatory documents and a copy should be maintained at the site.

Principal Investigator: _______________________________________________

Print/Type

Signed:

Date:

Name/Title

i

Pain Protocol v 11.0 10/20/1580

CONTENTS

Signature PageiiPROTOCOL SUMMARY91. KEY ROLES172. BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE182.1 Background Information182.2 Rationale212.3 Potential Risks and Benefits223. STUDY OBJECTIVES243.1 Primary Objective243.2 Secondary Objectives244. STUDY DESIGN254.1 Description of the Study Design254.2 Study Endpoints275. STUDY POPULATION275.1 Description of the Study Population275.2 Strategies for Recruitment286. STUDY TREATMENTS296.1 Description of the Study Treatment Arms296.2 Study Agent Administration346.3 Concomitant Medications and Procedures346.4 Assessment of Participant Adherence with Study Agent(s)/Intervention(s)346.5 Precautionary and Prohibited Medications and Procedures347. STUDY PROCEDURES/EVALUATIONS347.1 Clinical Evaluation357.2 Laboratory Evaluations377.3 Assessment of Participant Compliance with Study378. STUDY SCHEDULE378.1 Screening378.2 Enrollment/Baseline388.3 Randomization388.4 Follow-up398.5 Final Study Visit398.6 Early Termination Visit N/A408.7 Pregnancy Visit408.8 Unscheduled Visits409. ASSESSMENT OF SAFETY409.1 Definitions409.2 Methods and Timing for Assessing, Recording, and Analyzing, Managing Safety Parameters419.3 Adverse Event Reporting Procedures429.4 Reporting Pregnancy449.5 Type and Duration of the Follow-up of Participants After Adverse Events459.6 Modifications of Study Agent(s)/Intervention(s) for a Participant459.7 Halting Rules for the Protocol459.8 Stopping Rules for an Individual Participant/Cohort459.9 Premature Withdrawal of a Participant469.10 Replacement of a Participant Who Discontinues Study Treatment N/A4610. CLINICAL MONITORING STRUCTURE4610.1 Site Monitoring Plan4610.2 Safety Monitoring Plan4611. STATISTICAL CONSIDERATIONS4711.1 Overview and Study Objectives4711.2 Sample Size Considerations4711.3 Randomization4811.4 Missing Data4811.5 Planned Interim Analysis4911.6 Analysis Plan4912. QUALITY CONTROL AND QUALITY ASSURANCE5013. ETHICS/PROTECTION OF HUMAN SUBJECTS5113.1 IRB/Ethics Committee5113.2 Informed Consent Process51All recruitment materials will be provided in both English and Spanish.5213.2.2 Assessing Capacity to Consent and Consenting a Proxy Respondent5213.3 Exclusion of Women, Minorities, and Children (Special Populations)5213.4 Participant Confidentiality5213.5 Study Discontinuation5314. DATA HANDLING AND RECORD KEEPING5314.1 Data Management Responsibilities5314.2 Data Capture Methods5414.3 Types of Data5414.4 Source Documents and Access to Source Data/Documents5414.5 Timing/Reports5414.6 Study Records Retention5414.7 Protocol Deviations5515. PUBLICATIONS POLICY5516. SCIENTIFIC REFERENCES5517. APPENDICES61APPENDIX A: STUDY CONTACT ROSTER61APPENDIX B: PROTOCOL COMMITTEE62APPENDIX C: DATA COLLECTION SCHEDULE63APPENDIX D: ADVERSE EVENT GRADING TABLE*65APPENDIX E: Common and Infrequent Adverse Events for Study Drugs75APPENDIX F: CONSENT TEMPLATE78APPENDIX G: CONSENT TEMPLATE PILOT STUDY85APPENDIX H: EVALUTION TO GIVE CONSENT91APPENDIX I: STUDY INSERT92APPENDIX J: PATIENT DAILY LOG94

List of General Abbreviations/Terminology

AE

Adverse Event/Adverse Experience

CFR

Code of Federal Regulations

CIB

Clinical Investigators Brochure

CONSORT

Consolidated Standards of Reporting Trials

CRF

Case Report Form

DSMB

Data and Safety Monitoring Board

DSMC

Data and Safety Monitoring Committee

FDA

Food and Drug Administration

FWA

Federal-Wide Assurance

GCP

Good Clinical Practice

HIPAA

Health Insurance Portability and Accountability Act

IB

Investigators Brochure

ICF

Informed Consent Form

ICH

International Conference on Harmonization

IDE

Investigational Device Exemption

IND

Investigational New Drug

IRB

Institutional Review Board

ISM

Independent Safety Monitor

MedDRA

Medical Dictionary for Regulatory Activities

MOP

Manual of Procedures

NDA

New Drug Application

OHRP

Office for Human Research Protections

OHSR

Office for Human Subjects Research

PHI

Protected Health Information

PI

Principal Investigator

PK

Pharmacokinetics

QA

Quality Assurance

QC

Quality Control

SAE

Serious Adverse Event/Serious Adverse Experience

SMC

Safety Monitoring Committee

SOP

Standard Operating Procedure

WHO

World Health Organization

List of METRC Abbreviations/Terminology

CDMRP Congressionally Directed Medical Research Program.

DODDepartment of Defense

DOD HRPODOD Human Research Subject Protection Office.

Master Consent FormTemplate consent form designed for study by the MCC

Master IRB applicationTemplate IRB application designed for study by the MCC

MCCMETRC Coordinating Center

MCC Study ManagerPrincipal site contact for Research Coordinators at sites

MTF Core Clinical SitesMilitary Treatment Facilities Core Clinical

OETRPOrthopaedic Extremity Trauma Research Program

SCCSatellite Clinical Sites

AISite Associate Investigators.

RCSite Research Coordinator

RSSite Research Staff

Study NumberProtocol identification number

Study Principal InvestigatorLead Investigator on a protocol

Study Protocol CommitteeProtocol development

SOPStandard Operating Procedures

REDCapResearch Electronic Data Capture System

USAMRMC United States Army Medical Research and Material Command

PROTOCOL SUMMARY

Title: Improving Pain Management and Long Term Outcomes Following High Energy Orthopedic Trauma

Financial Sponsor: DoD CDMRP / National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)

Type of study: The proposed study is a three arm, double blinded, randomized, placebo controlled multicenter Phase III clinical trial.

Objective: The objective of this study is to definitively resolve questions regarding the use of multimodal pharmacologic pain management for orthopedic trauma patients in the context of a multicenter, randomized clinical trial. We will test whether adjunctive analgesic therapy during the pre and peri-operative period, in addition to standard of care pain management, can improve overall pain control and pain related outcomes without increasing analgesic related side effects.

As a significant proportion of this population develops chronic post traumatic osteoarthritis (PTOA), a sub-objective of this study is to examine the etiology and incidence of chronic pain and PTOA in this population.

Study Groups: Patients will be randomized into three treatment groups. The intervention will begin within 48 hours of admission and continue for no longer than two weeks or up to 48 hours after definitive fixation.

Group 1: standard pain management, plus up to two weeks of oral placebo, plus intravenous and oral placebo for up to 48 hours at each surgical procedure.

Group 2: standard pain management, plus up to two weeks of oral non-steroidal anti-inflammatory drugs (NSAIDs) (meloxicam), plus intravenous NSAIDs (ketorolac) and oral placebo for up to 48 hours at each surgical procedure.

Group 3: standard pain management, plus up to two weeks of oral pregabalin, plus intravenous placebo and oral pregabalin for up to 48 hours at each surgical procedure.

Specific Aim 1: Evaluate the effect of standard pain management (Group 1) vs. standard pain management plus pre and peri-operative NSAIDs (Group 2 meloxicam + ketorolac) in the treatment of s