Final Preparation Date 06/02/08

Multiple Dose Pharmacokinetic Study of Meropenem in Young Infants (

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Table of Contents LIST OF ABBREVIATIONS............................................................................................................ 3 CHAPTER 1: OVERVIEW AND STUDY DESIGN.......................................................................... 6

1.1 INTRODUCTION ................................................................................................................. 6 1.2 OVERVIEW ....................................................................................................................... 6

CHAPTER 2: PROTOCOL.............................................................................................................. 7 CHAPTER 3: ADMINISTRATION................................................................................................... 8

3.1. STUDY ORGANIZATION...................................................................................................... 8 3.2. COMMUNICATION.............................................................................................................. 8 3.3. POINTS OF CONTACT ........................................................................................................ 8 3.4. ROLES AND RESPONSIBILITIES .......................................................................................... 9 3.5. MEROPENEM SUBCOMMITTEE MEMBERSHIP LIST ............................................................. 14

CHAPTER 4 RECRUITMENT....................................................................................................... 15 4.1. IDENTIFYING SUBJECTS................................................................................................... 15

CHAPTER 5 INFORMED CONSENT ........................................................................................... 16 5.1. PROCESS ....................................................................................................................... 16 5.2. REQUIREMENTS ............................................................................................................... 17 5.3. INFORMED CONSENT TEMPLATES ..................................................................................... 17

CHAPTER 6 STUDY SCHEMATIC............................................................................................... 19

6.1. SCHEDULE OF PROCEDURES………………………………………………………………………….19 6.2. PRESUMPTIVE CLINICAL CURE SCORE………………………………………………………………19 CHAPTER 7 SCREENING, ELIGIBILITY AND ENROLLMENT.................................................. 21

7.1. SCREENING.................................................................................................................... 21 7.2. ELIGIBILITY AND ENROLLMENT……………………………………………………………..21 CHAPTER 8 SUBJECT ENROLLMENT AND STATUS UPDATES(IVRS)............................... 22

8.1. INTRODUCTION ................................................................................................................ 22 8.2. STUDY DRUG ORDERING AND DISPENSING .................................................................. 22

CHAPTER 9 STUDY PROCEDURES ......................................................................................... 24 9.1. TIMING OF STUDY DRUG INFUSION................................................................................ 24 9.2. PRE-STUDY DRUG ADMINISTRATION PROCEDURES ..................................................... 24

9.3. PROCEDURES DURING STUDY DRUG ADMINISTRATION………………………………… 24 9.4. STUDY DAY 28: DOCUMENTATION OF CLINICAL RESPONSE… ………………………….25 9.5. PROCEDURES FOLLOWING STUDY DRUG ADMINISTRATION…………………..…………..26

CHAPTER 10 COLLECTION OF BLOOD SAMPLES ................................................................. 27 10.1. BLOOD SAMPLING........................................................................................................... 27

CHAPTER 11 STUDY SAMPLE SHIPMENT LOG ...................................................................... 29 11.1. INSTRUCTIONS FOR COMPLETION OF THE STUDY SPECIMEN SHIPMENT LOG.......................... 29

CHAPTER 12 SAFETY, ADVERSE EVENTS, SERIOUS ADVERSE EVENTS, AND ADVERSE EVENTS OF SPECIAL INTEREST............................................................................................... 30

12.1. RISKS/BENEFITS............................................................................................................. 30 12.2. DATA SAFETY MONITORING PLAN.................................................................................... 30 12.3. ADVERSE EVENTS.......................................................................................................... 31

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12.4. SEIZURES....................................................................................................................... 34 12.5. BLOOD VOLUME FOR PK AND SAFETY LABORATORY TESTS .............................................. 34

12.6. SAE CONTACT INFORMATION………………………………………………..………………………35 CHAPTER 13 DATA COLLECTION AND DATA MANAGEMENT ............................................. 36 13.1. CASE REPORT FORM COMPLETION…………………………………………………………………36 13.2. QUERY PROCESS……………………………… ……………………………………………………….36

CHAPTER 14 STUDY CONDUCT................................................................................................ 37 14.1. PRINCIPLES OF GOOD CLINICAL PRACTICE ........................................................................ 37 14.2. STANDARD OPERATING PROCEDURES (SOPS) ................................................................ 37 14.3. MONITORING .................................................................................................................. 37 14.4. DATA QUALITY CONTROL ................................................................................................ 41

CHAPTER 15 HUMAN SUBJECTS PROTECTION..................................................................... 42 15.1. CONFIDENTIALITY AND HIPAA CONSIDERATIONS ............................................................. 42 15.2. APPROVAL BY INSTITUTIONAL REVIEW BOARDS................................................................ 43 15.3. ANNUAL RENEWALS........................................................................................................ 43

CHAPTER 16 PRIVACY AND CONFIDENTIALITY..................................................................... 44 16.1. ENSURING CONFIDENTIALITY………………………………………………………………………44

CHAPTER 17 PROTOCOL COMPLIANCE AND VIOLATION.................................................... 46 17.1. DEFINITIONS ................................................................................................................ 46

17.2. SIGNIFICANT PV IDENTIFICATION TASKS AND RESPONSIBILITIES………..……………….46 17.3. PVs OTHER THAN THOSE DEFINED ABOVE………………………………………………………46

CHAPTER 18 BPCA-CC WEB PORTAL……………………………………………………………. 47 18.1. DESCRIPTION OF BPCA-CC PORTAL …………………………………………………………… 47 APPENDIX A: STUDY DEFINITIONS AND REFERENCES........................................................48 APPENDIX B: DETERMINATION OF MEROPENEM CONCENTRATION IN PLASMA............52 APPENDIX C: STUDY FORMS .................................................................................................... 56 APPENDIX D: MEROPENEM SAMPLE MEASUREMENT ......................................................... 58 APPENDIX E: BPCA WEB PORTAL WEB USER INFORMATION FORM ................................ 62

APPENDIX F: NICHD DSMB CHARTER AND MEMBER LIST…………………………………….64 APPENDIX G: SRC CHARTER…………………………………………………………………………75

APPENDIX H: SAMPLE CONSENT............................................................................................. 84 APPENDIX I: MEDWATCH FORM............................................................................................... 97 APPENDIX J: PROCEDURES FOR FORMS AND DOCUMENTATION................................... 111 APPENDIX K: CONCOMITANT MEDICATIONS……………………………………………………113 APPENDIX L: STUDY CONTACT INFORMATION…………………………………………………117 APPENDIX M: SUBSTUDIES…………………………………………………………………………121 APPENDIX N: CASE REPORT FORM AND INSTRUCTIONS……………………………………129

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List of Abbreviations A arterial line

AE adverse event

ALT alanine aminotransferase

AST aspartate aminotransferase

BCPA Best Pharmaceuticals for Children Act

BCPA-CC Best Pharmaceuticals for Childrens Act Coordinating Center

BUN blood urea nitrogen

C drug concentration

CBC complete blood count

CFR Code of Federal Regulations

CONS coagulase cegative staphylococccus

CRA clinical research associate

CRF case report form

CRP c-reactive protein

DCRI Duke Clinical Research Institute

DIC disseminated intravascular coagulation

DOL day of life

DSMB Data Safety Monitoring Board

DSMP data safety and monitoring plan

ELBW extremely low birth weight

EEG electroencephalogram

ESBL extended spectrum beta-lactamases

FDA Food and Drug Administration

g/dL grams per deciliter

GA gestational age

GCP good clinical practice

GNR gram negative rod

GPC gram positive cocci

HHS Health and Human Services (US Department of)

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HIPAA Health Insurance Portability and Accountability Act

HS heel stick

ICF informed consent

ICH International Committee on Harmonization

ICU intensive care unit

IEC Independent ethics committee

IRB institutional review board

IVH intraventricular hemorrhage

IVRS interactive voice response system

Kg kilogram

LFT liver function test

Mcg microgram

mg milligrams

MIC minimum inhibitory concentration

Min minute

mL milliter

MPODS Meropenem Off-Patent Drug Studies

MRSA methicillin-resistant staphylococcus aureus

NEC necrotizing enterocolitis

NELSE non epileptic seizure-like events

NICHD National Institute of Child Health and Human Development

NICU Neonatal Intensive Care Unit

NIH National Institutes of Health

P peripheral venous

PD pharmacodynamic

PHI personal health information

PI principal investigator

PK pharmacokinetic

PNA post natal age

PODS Pediatric Off-Patent Drug Studies

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SAE serious adverse event

SNAP score for neonatal acute physiology

V venous line

Vd volume of distribution

WR written request

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Chapter 1: Overview and Study Design 1.1. Introduction This Manual of Procedures (MOP) provides a blueprint for operations for the following study: Multiple Dose Pharmacokinetic Study of Meropenem in Young Infants (

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Chapter 2: Protocol Refer to the protocol version 28 March 2008 located in the Regulatory Binder.

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Chapter 3: Administration 3.1. Study Organization The National Institute of Child Health Development (NICHD) is sponsoring this research. 3.2. Communication Communication and consultation with team members is crucial. This section outlines the approach and strategies for the Meropenem Study. The objective is to provide avenues of contact to enhance communication. 3.3. Points of Contact Detailed contact information can be found in Appendix L.

General Protocol Questions

Debbe Blackwell DCRI CRA

Urgent Clinical Questions

Danny Benjamin, MD Mike Cotton, MD Brian Smith, MD Pager: 919-970-2534

Safety and Protocol Violations/Waivers

Bernard Brownstein, MD BPCA-CC Medical/ Safety Monitor Office: 215-282-5558 After hours emergency: 215-284-4365

Lab Supplies Heather Thomas Wesley Grey 216-844-6950

Investigative Product

Shipment Issues: call Fisher Global HelpDesk at 877-253-3080; General questions: (BPCA-CC: contact Ligia McDonald, Clinical Manager; cc Debbie Rinas, Sr. Project Manager)

Site Payments Katherine Berezny

Contracts Debra Smith 919-668-8913

Start Up Regulatory Documents

Debbe Blackwell Kerri Pullium

ICF Review BPCA-CC: Ligia McDonald, Clinical Manager; cc Debbie Rinas, Sr. Project Manager

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Maintenance of Regulatory Documents

BPCA-CC: John-Paul Caloiero Clinical Trial Associate

General Study Questions

BPCA-CC Site Monitor; or Ligia McDonald, Clinical Manager, or Debbie Rinas, Sr. Project Manager

3.4. Roles and Responsibilities 3.4.1 National Institute of Child Health and Human Development (NICHD) This study is funded by a contract from the National Institute of Health (NIH). The NIH is the steward of medical and behavioral research for the nation. It is an agency under the U.S. Department of Health and Human Services. The NIH comprises the Office of the Director and 27 Institutes and Centers. The Office of Director is responsible for setting policy for NIH planning, managing, and coordinating the programs and activities of all NIH components. The NICHD is one of the 27 Institutes and Centers within the NIH. The mission of the NICHD is to ensure that every person is born healthy and wanted, that women suffer no harmful effects from reproductive processes, and that all children have the chance to achieve their full potential for healthy and productive lives, free from disease or disability, and to ensure the health, productivity, independence, and well-being of all people through optimal rehabilitation. The Project Officer is responsible for: • Monitoring the Contractor's technical progress, including the surveillance and assessment of

performance and recommending to the Contracting Officer changes in requirements; • Interpreting the Statement of Work and any other technical performance requirements; • Performing technical evaluation as required; • Performing technical inspections and acceptance required by this contract; and • Assisting in the resolution of technical problems encountered during performance. The Contracting Officer is the only person with authority to act as agent of the Government under this contract. Only the Contracting Officer has authority to: • Direct or negotiate any changes in the Statement of Work; • Modify or extend the period of performance; • Change the delivery schedule; • Authorize reimbursement to the contractor any costs incurred during the performance of this

contract; or • Otherwise change any terms and conditions of this contract.

3.4.2. Best Pharmaceuticals for Children Act Coordinating Center (BPCA-CC) The BPCA-CC oversees all activities for NICHD trials conducted within the purview of the BPCA. In support of this, the BPCA-CC will:

1. Develop and maintain administrative, clinical, data, safety, regulatory, technical and analytical resources, and communications that integrate and coordinate the operations of all PODS Centers in performing studies of drugs for pediatric indications

2. Insure the quality and accuracy of data gathering and reporting, adherence to study protocols, and to administrative and regulatory requirements across the participating sites

3. Monitor performance of the different PODS Centers and meet with NICHD, the FDA (if needed), and contracting staff on a regular basis to review annual site performance reports

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4. Develop and maintain information systems for specified tasks including establishing and maintaining a database of all studies performed under the BPCA that can be used for research, regulatory, and reporting purposes as directed by the NICHD

5. Develop and maintain an investigational product program to purchase, label, and distribute drugs to the PODS Centers in accordance with FDA and NIH rules and guidelines and other applicable regulations

6. Help identify additional study sites when requested by the NICHD Contracting Officer under specifications defined by the Project Officer

7. Prepare data, analyses, and reports for regulatory submissions

3.4.3. Safety Surveillance

• Submit regulatory reported SAEs to DSMB and NICHD. • Assist in expedited adverse event reporting. • Review SAE reports and database safety information. • Create regulatory documents as needed, as well as provide investigator alerts.

3.4.4. Data Safety Monitoring Board

An independent DSMB established in accordance with the “NIH Policy for Data and Safety Monitoring” will monitor the conduct of the trial for performance (e.g., recruitment, flow and quality control of data, adherence to the protocol), patient safety, and efficacy. The DSMB may review the data at any time. At any time and for any reason, the DSMB may recommend to the NICHD Project Officer that the trial may be interrupted or discontinued. Refer to Appendix F for DSMB Charter and Membership list.

3.4.5. BPCA-CC Web Portal Site

There is a BPCA-CC Web Portal (www.bpca-cc.com) that will provide study personnel with information such as the study protocol and any amendments, ICF template, Meropenem Product Monograph, the DSMB Charter and membership, a team contact list, a study question and answer list, and study template forms and instructions such as those for reporting an SAE. In order to gain access to the web portal, please fill out the “Web User Information” form with instructions in Appendix E.

3.4.6. Almac Clinical Technologies, Inc. Almac Clinical Technologies is the subcontractor for subject enrollment and will provide the following services:

• Maintenance of the Interactive Voice-Response System (IVRS). • Distribution of an IVRS Manual and “quick” reference card to study sites. • Assigning and maintaining unique site ID and pass codes. • Handling centralized subject enrollment and assigning a subject identification number

at time of enrollment. • Site confirmation fax of subject enrollment, dosing regimen and PK sampling time. • Handling subject status updates: Enrollment, Early Termination, or Completion. • Providing technical support for the IVRS.

3.4.7. Monitoring

Monitoring visits are conducted to oversee the progress of the study at the investigative site and to ensure that the investigator and IRB meet their regulatory requirements and responsibilities. Good communication between the monitor and site personnel is important in meeting these goals. Studies are monitored to assure that:

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• They are conducted according to the protocol. • They are conducted according to all applicable regulations. • The resources at the site are adequate to conduct the study. • The required data are collected and recorded accurately.

3.4.8. Investigative Product Investigative product will be distributed to sites by Fisher Clinical Services. The main contact for any shipping issues will be the Fisher Global HelpDesk at phone number: 877-253-3080. For any general questions please contact the BPCA-CC study managers Ligia McDonald (ligia.mcdonald@premier-research.com); or Debbie Rinas (debbie.rinas@premier-research.com). Study drug ordering will be via fax form request sent to # 215-282-5528; Attn. BPCA-CC (refer to section 8.2. for process). It is however, the site’s responsibility for the accountability, dispensing and disposition of test article. Fisher Clinical Services will have product responsibility for:

• Ordering test article • Packaging per protocol • Insuring that product is shipped to sites • Tracking receipt and distribution.

The sites will insure that:

• They account for all test article received • Order test article as needed for subject enrollment • All unused product is returned or disposed of in the appropriate manner.

3.4.9. Responsibilities for Duke Clinical Research Institute Duke Clinical Research Institute has the following responsibilities:

• Development of the study protocol • Facilitation of investigator meetings, site educational and safety visits, and

subcommittee meetings (Clinical Safety Committee, Steering Committee, Pharmacokinetic Committee).

• Serve as a clinical resource for sites and monitors • Execution of site contracts and payments • Participation in preparation of publications

3.4.10. PODS Networks The Principal Investigator (PI) of the PODS Network serves as the main clinical contact for the PODS. This individual is responsible for disseminating information to each of the study sites and for providing copies of this information to the BPCA-CC for inclusion in the trial archives. The PODS PI of the Meropenem study is Danny Benjamin, MD, PhD, MPH at the Duke Clinical Research Institute. Sites in the PODS Network:

Site # Institution Name 01 Albany Medical Center 02 Baylor College of Medicine 03 Case Western 04 Children's Hospital of Oakland 05 Children's Hospital of Philadelphia 06 Duke University Medical Center 07 Indiana University - Riley

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Site # Institution Name 08 Kapiolani Medical Center for Women and Children 09 Buffalo Children's-Wayne State University Children's Hospital 10 University of Alabama at Birmingham 11 University of California-San Diego 12 University of Florida 13 University of Louisville 14 University of Texas Southwestern 15 Vanderbilt Children's Hospital 16 Yale New Haven 17 Kansas City Children's Mercy Hospital 18 Children's National Medical Center 19 Magee-Women's Hospital 20 Akron Children's 21 Evanston Northwestern Healthcare 22 Sharp-Mary Burch Hospital for Women 23 Children's Hospital of Orange County 24 University of Utah 25 University of Michigan

3.4.11. Responsibilities for the Sites in the PODS Network The minimum staff required for the sites to participate in this trial is the physician principal investigator (PI) and the research coordinator. The responsibilities of these individuals are described briefly in this chapter and in more detail in subsequent chapters. The PI, or their designee, is responsible for ensuring the proper conduct of the trial at his or her clinical center, including recruitment and treatment of patients as specified in the protocol, accurate collection of data, and recording of information on the Case Report Forms. Other specific duties include the following, if indicated:

• Applying for IRB approval • Presenting an in-service to his/her physicians • Introducing the study to the parent(s) of prospective infants • Monitoring protocol deviations and assisting in remediation of problem areas when

necessary • Monitoring all adverse experiences for appropriateness and assisting in the

documentation of case information for reporting to appropriate sources The Research Coordinator will be responsible for the day-to-day operation of the study at the clinical center. His or her responsibilities include:

• Presenting in-services to the nursing staff in the NICU detailing the study protocol • Screening for potential study candidates • Recruiting study candidates (center specifics responsibility) • Collecting information necessary for some of the data collection forms and

coordinating data entry • Training and certifying designated research staff in the collection of specimens • Reporting protocol deviations and adverse events • Assuring patient confidentiality is maintained • Completion and maintenance of regulatory documents

3.4.12. PK Committee

The main responsibilities of the PK Committee are as follows: • Provide rational for selected study drug dosing scheme

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• Assist with protocol development • Develop a PK analysis plan • Perform PK analyses

3.4.13. Clinical Safety Committee The main responsibilities of the Clinical Safety Committee are as follows:

• To ensure those patients enrolled, and/or to be enrolled into the trial, do not have an unacceptable balance between risks and benefits through the ongoing review of safety data.

• To review selected adverse events and all serious adverse events occurring during the study.

• To make appropriate recommendations for dose escalation upon review of the safety data to the Steering Committee, BPCA-CC, and NICHD. These recommendations may result in modification or discontinuation of the study.

Refer to Appendix G for the Safety Committee Charter. 3.4.14. Steering Committee

The primary responsibilities of the Steering Committee are listed below. • Serve as consultant regarding the meropenem drug development program for neonates. • Contribute to protocol and study design of NICHD sponsored neonatal Meropenem

clinical trials. • Help to identify critical data points for Case Report Form. • Serve as expert medical consultant in the field of neonatal infectious disease and about

current clinical practice for sites. • Serve as consultant to NICHD for clinical decisions as outlined in the protocol. • Assist in problem solving slow enrollment issues. • Provide clinical input into dose escalation and safety decisions. • Provide clinical input into result interpretation and publications. • Establish publication policy • Provide clinical input into result interpretation and publications. • Review and approve proposed publications

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3.5. Meropenem Subcommittee Membership List

Meropenem Steering Committee* Daniel K. Benjamin Jr, MD, PhD Duke University Edmund Capparelli, PharmD University of California at San Diego Michael Cohen-Wolkoweiz, MD Duke University Robert M. Reed, MD University of Utah Robert L. Schelonka, MD University of Alabama at Birmingham Janice E. Sullivan, MD University of Louisville John van den Anker, MD Children’s National Medical Center Kelly C. Wade, MD, PhD Children’s Hospital of Philadelphia *Additional members may be added upon request

Meropenem Clinical Safety Committee C. Michael Cotten, MD Duke University William Gallentine, MD Duke University Matthew Laughon, MD, MPH University of North Carolina at Chapel Hill Jennifer Li, MD Duke University P. Brian Smith, MD Duke University

Meropenem PK Committee Edmund Capperelli, PharmD University of California at San Diego Kelly C. Wade, MD, PhD Children’s Hospital of Philadelphia Michael Reed Pharm D Akron Children’s Hospital

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Chapter 4: Recruitment 4.1. Identifying Subjects Inpatient neonates and term infants (

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Chapter 5: Informed Consent 5.1. Process After the responsible physicians agree, and in accordance with the local IRB guidelines, the parent or legal guardian can be approached for informed consent for the Meropenem trial. The overall informed consent process should be conducted in privacy, by authorized site personnel in a non-threatening way. The parent or legal guardian and the patient should be reassured that failure to consent to enter the trial will in no way compromise any aspect of their ongoing care. Families should be informed that consent can be withdrawn at any time and for unstated reasons. This information should be balanced with the caution that unless they are truly willing to accept any randomized treatment for which they are eligible, they should be honest at the outset and decline participation. The parent or legal guardian must be provided with sufficient information about the study to give informed consent. Information that must be provided to allow an informed decision includes the following:

• A statement that the study involves research, an explanation of the purposes of the research and the expected duration and responsibilities of the subject's participation, a description of the procedures to be followed, and identification of any procedures that are experimental.

• A description of any reasonably foreseeable risks or discomforts to the subject. • A description of any benefits to the subject or to others which may reasonably be

expected from the research. • A disclosure of appropriate alternative procedures or courses of treatment, if any, that

might be advantageous to the subject. • A statement describing the extent, if any, to which confidentiality of records identifying the

subject will be maintained. • An explanation as to whether any compensation and any medical treatments are

available if injury occurs and, if so, what they consist of, or where further information may be obtained.

• An explanation of whom to contact in the event of a research-related injury to the subject. • A statement of whom to contact with questions regarding the protocol. • A statement that participation is voluntary, refusal to participate will involve no penalty or

loss of benefits to which the subject is otherwise entitled, and the subject may discontinue participation at any time without penalty or loss of benefits to which the subject is otherwise entitled. (45 CFR 46, Section 117).

Additionally, the following information must be provided to the parent.

• Study participation can be declined without compromise to medical care. In addition, consent to participate in the study can be withdrawn at any time and will not affect medical care.

• If information that might affect willingness to continue participation in the study is discovered, the information will be provided to the parent/child in a timely manner.

• The site PI or sponsor can withdraw a participant from the study at any time for safety and/or compliance reasons without the consent of the parent.

• A copy of the signed and dated informed consent will be provided to the parent. If the parents provide consent to participate, the original Informed Consent Form (ICF) should be maintained in the patient’s study file. Note: If a patient is withdrawn after enrollment, the ICF should still be maintained and not destroyed.

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5.2. Requirements The Principal investigator (PI), sub-investigators or designated staff will explain all the aspects of the study, in lay language, and answer all of the parents’/legally authorized guardians’ questions regarding the research study prior to signing the IRB approved informed consent. It is the responsibility of the PI or the designated staff to assure that the parent/legally authorized guardian understands the research study. The PI must be available to answer any questions that from the parent/legally authorized guardians’. No study procedures will take place prior to the signing of the consent by the parent/legally authorized guardians’. The parent/legally authorized guardians’ may consent to the study and at any time withdraw study participation. One copy of the signed consent will be given to the parent/legally authorized guardians’, one will be placed in the subject’s research record and the original will be kept in subject medical record. Informed consent gives the parent/legally authorized guardians’ the opportunity to choose whether they want their infant to participate in a study. The following measures should be considered with conducting the consenting process:

• When offering the study to a subjects’ parents/legally authorized guardian, the consenting process should provide for adequate time for the consent to be read by the subjects’ parents/legally authorized guardian. There should be time for discussion of the nature of the study, study procedures, importance of compliance, potential risks and benefits, and duration of the study. The informed consent process should ensure that there is no penalty for NOT participating in the trial and that the decision to not participate will in no way affect the clinical care and management of the infant.

• There should be adequate time for the parent/ legally authorized guardian to ask questions of the Principal Investigator.

• The subject may withdraw from the study at any time. • The neonatologist may discontinue the subject from the study drug at any time. • The parent/ legally authorized guardian must sign the informed consent

document as well as the witness to the consenting process. (The signature requirements will vary depending on the local IRB recommendations).

• The International Committee on Harmonization (ICH) Good Clinical Practice (GCP) guidelines requires that the subject or legal representative receive a copy of the signed and dated ICF. Additionally, the investigator must maintain the signed original of the informed consent document for each subject in the study. The source documents should indicate the date the informed consent was obtained.

• If there is a change in any of the study procedures that may affect the subject, the informed consent document must be revised and approved by the IRB. The parent or legal guardian of any subject currently ongoing in the study must sign the amended consent form.

A regulatory review of the ICF is to be performed. Each site is to forward an electronic copy of their ICF to Ligia.McDonald@premier-research.com and cc (Debbie.Rinas@premier-research.com) at BPCA-CC prior to submitting to each site’s IRB. The BPCA-CC will review and respond within 48-72 hours. Once the BPCA-CC has provided feedback regarding regulatory compliance of the informed consent, each site should review the feedback to consider any possible revisions. The forms then may be submitted to the sites IRB for review and approval. The IRB must approve the informed consent prior to patient enrollment. 5.3. Informed Consent Templates The Informed Consent template contains language for the main study and 2 substudies. Sites who are not participating in the substudies (all or any portion) should delete IC language pertaining to the substudy (or substudies) and insert their site-specific information and required language. (Refer to Appendix H for ICF template.)

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5.3.1. Date Informed Consent Signed Fill in the date that informed consent was obtained from the parent or legal guardian. (MM/DD/YYYY). The person obtaining the consent must also sign and date the consent form. This date will also be recorded on the CRF.

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Chapter 6: Study Schematic The table below illustrates the schematic representation of assessments: 6.1. Schedule of Procedures Study Day PROCEDURE 0a 1-27 28 29 to end of studya

Informed Consent X Abdominal Radiographic Testsl X X X X Sterile Body Fluid Culturesb,c X X X X Abdominal Surgical Proceduresb X X X X Medical Baseline Conditions X Pertinent Medical History X Physical Exam X X X Concomitant Medicationsd X X Body Weighte X X X Vital Signs, Length, Head Circumferencef X X X Adverse Eventsg X X X X Laboratory Evaluationf X X CRPh X X X PK Evaluationi X Study Drug Administrationj X Clinical Score (see 6.2 below) X X Efficacy Assessmentk X

a) Day 0 refers to time point prior to start of meropenem but may be the same calendar day as Day 1. End of study is 30 days after last administration of study drug. b) Record results from 7 days prior to study drug and 30 days post completion of study drug. c) Record results of sterile body fluid cultures (blood, CSF, urine, peritoneal fluid) as obtained for clinical care. d) Record from 72 hours prior to first dose and until 72 hours after completion of study drug. e) Assess prior to first dose and document daily during therapy if available as local clinical care of infant. f) Assess prior to first dose and document weekly until 7 days following last dose if available as local clinical care of infant. g) Record SAEs until 30 days and non-serious AEs until 72 hours following last dose of study drug. h) CRP will be obtained on 3 occasions: 1) within the 72 hours prior to first dose of meropenem; 2) between study drug days 3-5; and 3) on study day 28. i) Obtain per protocol Appendix 2 and single sample at time of suspicious clinical seizure. j) Treatment for minimum of 3 days and maximum 21 days. k) Obtain at study Day 28; efficacy assessment includes alive, documentation of negative bacterial cultures, and presumptive clinical cure (see clinical score elements listed below). l) Record results from 72 hours prior to fist dose and 30 days post completion of study drug.

6.2. Presumptive Clinical Cure Score The presumptive clinical cure score will be derived by comparing clinical signs and symptoms prior to administration of the first dose of study drug and study Day 28. The clinical, laboratory, and radiographic findings are based on the components of the Score for Neonatal Acute Physiology (SNAP) II and other items listed in the following table. It is acknowledged that the SNAP II has not been validated as a clinical tool beyond the first hours of life, but there is not a clinical tool to predict mortality in serious abdominal infections. The original assessment, efficacy assessment, and resulting efficacy interpretation are listed in the following table:

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Presumptive Clinical Cure Score Initial Assessment Efficacy Assessment Resulting Efficacy Interpretation and Score

Asymptomatic Asymptomatic 1 Asymptomatic Worsening 0 Symptomatic Worsening 0 Symptomatic No Change 0 Symptomatic Improved 1 Symptomatic Asymptomatic 1

If 7 or more of 10 signs received a score of 1, then the infant will be considered a presumptive clinical cure. The elements of the presumptive clinical cure score are:

I. Mean blood pressure II. Temperature III. PaO2 (mmHg)/FiO2 IV. Lowest serum pH V. Presence or absence of seizures

VI. Urine output VII. Cardiovascular inotrope support: Record number and amount of each cardioactive drug. VIII. C-reactive protein (CRP) (prior to study drug, Day 3-5, and Day 28) IX. Abdominal girth X. Findings on abdominal radiograph (to be determined locally)

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Chapter 7: Screening, Eligibility, and Enrollment 7.1. Screening Inpatients in the newborn intensive care units will be screened regularly in order to identify appropriate candidates. 7.1.1. Definition of Subjects Premature and term young infants (1.7 mg/dL c. History of clinical seizures or EEG confirmed seizures d. Concomitant treatment with another carbapenem (ertapenem or imipenem) at the time of

informed consent e. Any condition which would make the subject or the caregiver, in the opinion of the

investigator, unsuitable for the study

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Chapter 8: Subject Enrollment and Status Updates (IVRS) 8.1. Introduction Almac Clinical Technologies Inc. is responsible for administering the IVRS for this study. The Interactive Voice Response System (IVRS) is an automated telephone-based system for enrolling a study subject and confirming their dosage regimen. An IVRS Reference Card and Manual will be provided to each study site.

• The system will repeat all responses made by the caller and ask for confirmation. Any errors can be corrected by the caller at that time.

● Enter all dates into the system using a dd/mm/yyyy format. Study sites will call the IVRS to enroll subjects into the trial by date of birth, gender, post-natal age, gestational age and any other required demographic information; the IVRS will also ask for the enrollment date, if the subject was on Meropenem prior to enrollment, and if an informed consent form was signed by the parent/legal guardian.

IVRS will assign a sequential subject number at the time of enrollment (i.e., 001, 002); if a subject screen fails, that number will not be used again.

A Study Site generated fax report will consist of:

• Confirmation of subject enrollment

• Dosing Regimen based on Gestational and Post-Natal Age (per protocol page 39)

• pK sampling time schedule (per protocol, page 39)

A Subject Status (update) menu will be according to the following categories:

• Screen Fail (SF)- (and reason for)

• Early Termination- (and reason for)

• Completion

8.2. Study Drug Ordering and Dispensing Study drug will be distributed to the site pharmacy or designated drug shipment address by Fisher Clinical Services. The pharmacist at each site will prepare and dispense the study drug. Study drug will be dispensed by the pharmacy in appropriate size syringes and administered via a syringe pump at a rate calculated based on the infants’ body weight in kilograms (kg) per local standard of care, but with a target of infusing the product over 30 minutes. The pharmacy will supply study syringes wrapped in amber plastic to protect the contents from light. A new bottle of study drug should be used for every dose.

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The compatibility of meropenem with other drugs has not been established. Meropenem should not be mixed with or physically added to solutions containing other drugs. Freshly prepared solutions of meropenem should be used whenever possible and should not be frozen. All vials are for single use only. Reconstitute vial as per package insert, shake to dissolve and let stand until clear. Reconstituted infusion vials of meropenem are stable as per the package insert, and per specific diluent used. Refer to the Merrem Product Monograph pages 14-15 for infusion and stability guidelines.

The initial shipment of study drug will be triggered by BPCA-CC based upon IRB and regulatory document approval for each site. BPCA-CC will contact Fisher Clinical Services to ship study drug to an authorized study site, and also contact the site to advise of the shipment and expected date of arrival. Sites will thereafter be able to contact BPCA-CC for a re-supply of study drug. The pharmacist will complete the “Investigational Product (IP) Shipment Request Form” with confirmation of their drug shipment address and fax to BPCA-CC at # 215-282-5528 , Attention: John-Paul Caloiero, Clinical Trial Associate. Study drug will be shipped in the following amounts:

• Initial shipment: 100 vials (estimated supply for approximately 4 infants) • Second shipment: 100 vials (estimated supply for approximately 4 infants) • Third shipment: 50 vials (estimated supply for approximately 2 infants); additional

shipments can be requested by the sites by first contacting BPCA-CC. For more detailed instructions, refer to the Pharmacy Manual NICHD 2005-18 that will be sent to each study site Pharmacist/designee prior to the SIV. 8.2.1. Instructions for Completing the Investigational Drug Accountability Record Investigational products are for investigational use only, and are to be used only within the context of this study. Study drug must be maintained under adequate security. The investigator or his/her designee will verify that study drug supplies are received intact and in the correct amounts. The investigator or his/her designee will document this verification by completing, signing, and dating the appropriate shipment request/ receipt document. An accurate inventory of study drug will be kept by the site. The investigator agrees not to supply study medication to any persons not enrolled in the study. All study drug received and dispensed will be recorded on the “Investigational Drug Accountability Record.” The date and time study drug is received from Fisher Clinical Services will be recorded. When study drug is dispensed, it will be recorded by the subject initials, subject ID number, dose, time and date. The quantity dispensed or received will be recorded with the balance remaining, lot number and recorder’s initials. The clinical monitor will verify study drug accountability at each monitoring visit with the pharmacist or designee. (Refer to the Meropenem Pharmacy Manual). 8.2.2. Study Drug Storage The clinical supplies will be stored at controlled room temperature from 15°- 30°C and protected from light in its carton until used. Investigational products are for investigational use only, and are to be used only within the context of this study. Study drug must be maintained under adequate security. 8.2.3. Study Drug Destruction Study drug (unused meropenem vials) will be returned to Fisher at the conclusion of the trial. Any study forms will be provided for return of drug and your site monitor will work with the pharmacist at study close-out to return drug in the prescribed manner.

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Chapter 9: Study Procedures 9.1. Timing of Study Drug Infusion Before starting the infusion of study drug, the coordinator should carefully map out the time blocks for the infant’s blood samples through the entire four day period. This is to ensure that sampling times will occur at times when it is feasible to collect samples. Once the time of the actual infusion for the study medication is known, the sampling time frames for this infant should be updated. 9.2. Pre-Study Drug Administration Procedures The following procedures will be completed prior to the administration of study drug (Day 0):

1. Obtain signed and dated informed consent/HIPAA consent. 2. Collect demographic data and medical/surgical history. 3. Perform a complete physical examination. 4. Obtain vital sign measurements, length, and head circumference. 5. Determine infant weight in grams (for calculation of appropriate study drug dose). 6. If these labs have been obtained within 72 hours prior to enrollment in accordance with

local standard of care, the results may be used for the baseline values for the study. Use the laboratory values closest to enrollment if there have been multiple tests. Do not collect additional samples for the purposes of this study.

Hematology assays will include: hematocrit, hemoglobin, red blood cell count, white blood cell count with differential, and platelet count. Serum chemistry will include: glucose, creatinine, blood urea nitrogen, aspartate transaminases (AST), alanine transaminase (ALT), alkaline phosphatase, total and direct bilirubin, sodium, potassium, chloride, calcium, magnesium, total protein, and albumin laboratory evaluations.

7. Record results of sterile body fluid cultures (blood, urine, CSF, peritoneal fluid) obtained as standard clinical care in the 1 week prior to study drug administration. Record urine cultures only if obtained by sterile catheterization or suprapubic aspiration.

8. Document antimicrobial agents and concomitant medications in the 72 hours prior to study drug administration.

9. Document prior abdominal surgical procedures in the 1 week prior to study drug administration.

10. Document confirmed serious or suspected intra-abdominal infection. 11. Document clinical signs of intra-abdominal infection. 12. Document the results of abdominal x-ray in prior 72 hours, including A-P and lateral

(either cross-table or left lateral decubitis) plain films. This will serve as the ‘baseline’ film set for the infant.

13. Record the presumptive clinical cure score initial assessment. The 10 elements of the clinical score are as follows: mean blood pressure; temperature; PO2 (mmHg)/FiO2; lowest serum pH (if obtained per standard of care); presence or absence of seizures; urine output; cardiovascular inotrope support (record name and dose of each cardioactive agent); CRP (Obtain 1 CRP in the 72 hours prior to enrollment. If multiple CRPs are collected as part of standard of care during this time, record the value closest to the 1st dose of meropenem); abdominal girth; and findings on abdominal x-ray (if obtained per standard of care). If more than one clinical score element result is obtained on Day 0 prior to study drug administration, record the results of the first study obtained that day. Except for CRP, clinical assessments not obtained as local standard of care will not be recorded.

14. Assess and record AEs between the time informed consent is obtained and the initial dose of study drug that are considered related to a protocol-specified procedure.

9.3. Procedures During Study Drug Administration The following procedures or evaluations will be performed during the treatment phase and the data recorded as indicated. The first dose of drug defines the beginning of study Day 1.

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9.3.1. Study Days 1-27 1. Record study drug timing of infusion before the PK samples are obtained; this includes

start/stop times of infusion, time (24 hour clock) of infusion, concentration (not labeled per the protocol) given and amount given.

2. Assess and record AEs from the time of the first dose of study drug through 72 hours following the last dose study drug.

3. Record daily patient weight during meropenem administration. 4. Record all meropenem drug administration: date, start time, dose (minimum of 3 days

and maximum of 21 days) 5. Dosing adjustments should be made starting on Study Days 7, 14, and 21 based on

change in PNA or new dosing weight to be determined by the infant’s physician. 6. Record all concomitant medications administered. 7. Collect blood for PK analysis (Schedule provided in Chapter 10). PK samples are not to

be drawn from the lumen of the catheter through which meropenem has been administered. Samples may be collected through the lumens of other catheters, venous sampling, arterial sampling, or capillary heel sticks.

8. Record results for clinical laboratory assessments obtained per local standard of care (listed in 9.2.) one time weekly while on study drug (Day 1-7, Day 8-14, Day 15-21, Day 22-28) while on therapy and up until 1 week after therapy completion. These assessments include CBC, AST, ALT, bilirubin (total and direct), creatinine, electrolytes, and BUN. Do not collect additional samples for the purposes of this study.

9. Record the results of cultures from sterile body fluids (blood, urine, CSF, peritoneal fluid or any other sterile body fluid) as obtained per standard of care up to 30 days after last study drug.

10. Record any abdominal surgical procedures up to 30 days after last study drug. 11. Record any abdominal radiological examinations (e.g., x-ray, ultrasound, CT scan, MRI)

up to 30 days after last study drug. 12. If seizures occur while on therapy, obtain 100μL of blood (if possible) to document

meropenem level at time of seizure. These will be sent to the central lab with the other PK samples from the infant. An additional 2 samples, each at least 24 hours apart, during additional infant seizure activity may be obtained. Scavenged samples whenever possible are appropriate during infant seizure activity.

13. Obtain 1 CRP between Study Days 3 and 5. If CRPs are collected as part of standard of care between days 3 and 5, these are to be recorded on the appropriate CRF. If more than one CRP is collected on a calendar day, record the first CRP obtained.

(Refer to Appendix M for substudy procedures.) 9.4. Study Day 28: Documentation of Clinical Response If the infant is nearing discharge, the score may be recorded prior to Study Day 28, provided that the infant has been off meropenem for at least 7 days. Record efficacy assessment variables:

1. Alive 2. Negative bacterial cultures from sterile body fluid 3. Presumptive clinical cure

Record the following and compare to the initial evaluation. I. Mean blood pressure II. Temperature III. PaO2 (mmHg)/FiO2 IV. Lowest serum pH V. Presence or absence of seizures

VI. Urine output VII. Cardiovascular inotrope support: Record number and amount of each cardioactive drug. VIII. C-reactive protein (CRP) IX. Abdominal girth X. Findings on abdominal radiograph

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9.5. Procedures Following Study Drug Administration

1. Record concomitant medications for 72 hours after the last dose of study drug. 2. Record the following information for 30 days following the last dose of study drug.

Assess and record SAEs Record all positive microbiology cultures from sterile body fluids Record any abdominal surgical procedures and surgical finding Record any results from abdominal radiological examinations (e.g., x-ray,

ultrasound, CT scan, MRI) performed Record presence or absence of strictures, peritoneal abscesses

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Chapter 10: Collection of Blood Samples 10.1. Blood Sampling At the time that the study drug is started, infants will be assigned to one of two blood sampling sequence lines based on the infant’s date of birth (Dose 1 PK-odd Group or Dose 1 PK-even Group). The goal of this assignment is to ensure that each time point for pharmacokinetic studies will have enough samples, but that no one infant will donate more than 2mL/kg of blood for study purposes. Infants who were already on meropenem treatment at the time of enrollment will be able to participate in the “safety only” group. All study procedures will remain the same except for the sample times of the PK blood draws. 10.1.1. Sample Times

Dose 1 PK-odd Group (infants with birthday on an odd date, e.g. 1st, 3rd, 5th, etc.):

1. Pre: anytime in the 24 hours prior to the first dose 2. Peak: 30 minutes to 1 hour after completion of first dose 3. 3-4 hours after completion of first dose 4. Trough: 7-8 hours after completion of first dose if Q8 hour dosing, or 10-

12 hours after completion of first dose if Q12 hour dosing

Dose 1 PK-even Group (infants with birthday on an even date, e.g. 2nd, 4th, 6th etc.):

1. Pre: anytime in the 24 hours prior to the first dose 2. Peak: 1-2 hours after completion of first dose 3. 4-6 hours after completion of first dose 4. Trough: 7-8 hours after completion of first dose if Q8 hour dosing, or 10-

12 hours after completion of first dose if Q12 hour dosing Dose 5 PK Steady-state (around 5th dose if possible, but may be done around the 4th, 6th, 7th, 8th, 9th or 10th dose):

1. Pre: anytime in the 3 hours prior to the 5th dose 2. Peak: 15 minutes-2.5 hours after completion of 5th dose 3. 4-12 hours after completion of fifth dose

Safety Steady-state Group:

1. No Dose 1 PK samples should be drawn. 2. Follow Dose 5 PK steady-state instructions above.

10.1.2. Instructions for the Sample Collection Form Record the full date and the exact time that the sample is withdrawn from the infant using a 24- hour clock.

Record the “method” being the source of the blood sample that was withdrawn. Mark the

appropriate box for the form using the following: A = arterial line, V = venous line, HS = heel stick, or P = peripheral venous.

(See laboratory manual located in Appendix B for detailed instructions.) 10.1.3. Sample Collection

Samples may be drawn from an arterial line, a venous line, from a vein, or from a heel stick. However, the samples must not be drawn from the same line used to infuse the study drug.

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10.1.4. Processing Samples Centrifuge and Storage:

1. Collect 100 µl blood in the green top BD Microtainer tube at each designated time point. Hold the tube upright and gently invert up and down by 180°. Repeat this movement 10 times for each sample drawn. Place on ice or at 4oC immediately after sample is mixed.

2. Complete sample PK collection form.

3. Separate the plasma by centrifugation for at least 5 min at 3500 rpm within 4 hours of collection time and record centrifugation time.

4. Transfer plasma to 0.6 mL pre-labeled, clear top micro centrifuge tube.

5. Freeze plasma at -70oC until shipment and record freezing time and accession number

on PK sample collection form. Please contact the lab with any questions you might have at 216-844-6950.

PK samples should be shipped to the Central Lab monthly or more frequently if a site has limited freezer space or if a dosing cohort is near completion.

(Refer to Appendix D for Sample Collection Form and Sample Shipping Log.)

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Chapter 11: Study Sample Shipment Log 11.1. Instructions for Completion of the Study Specimen Shipment Log Record the following information on the log:

• Enter the center number on the top of the form. • Enter the date of shipping on the top of the form. • For each sample being shipped, enter the Sample Identifier,

Center Number, and Sample Number. Blood Samples have Sequence Sampling Numbers.

• Add any comments you would like the assay center to know.

Please refer to Appendix B for sample shipping.

It is critical to ensure that the lab will have an appropriate person prepared to receive each

shipment of samples!

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Chapter 12: Safety, Adverse Events, Serious Adverse Events, and Adverse Events of Special Interest 12.1. Risks/Benefits 12.1.1. Risks Meropenem adverse effects: The most commonly reported side effects related to meropenem in studies in children are diarrhea (3.3 to 4.7%), nausea and vomiting (0.4 to 1%), rash (0.8%), glossitis (1%), oral thrush (1.9%) or diaper rash from yeast (3.1%), and redness and swelling at the injection site (0.5%). Similar results have also been observed in clinical trials of adults receiving meropenem. The potential for CNS effects (particularly seizures) with meropenem has been carefully studied in older subjects. Imipenem, another carbapenem, has been linked to the development of seizures. Because of its chemical structure, meropenem has been found to cause fewer CNS effects than imipenem both in animal studies and during studies in human adults and children. In studies comparing meropenem to cephalosporins, the incidence of seizures was not significantly different between the groups. No seizures have been reported after meropenem use in children treated for non-CNS infections.

Risks of Drawing Blood: Risks associated with blood draws include discomfort and/or bruising at the site of the needle stick. Infection or excess bleeding is also possible, although unlikely. 12.1.2. Benefits Information learned from this study will guide future recommendations on meropenem dosing for infants with and without intra-abdominal infections. Meropenem is a broad spectrum antibiotic that may benefit infants with infections due to susceptible organisms. 12.2. Data Safety Monitoring Plan Safety assessments will include seizure documentation (including correlation of serum meropenem level and seizures), physical examination, clinical laboratory values, LFTs, renal function, and nosocomial infections (tracked by pathogen). The BPCA-CC will establish the Data Safety and Monitoring Plan (DSMP) in compliance with NIH policies for the protection of human subjects in clinical studies. The BPCA-CC DSMP outlines procedures for reporting SAEs and AEs of Special Interest to the BPCA-CC and dissemination of this information from the BPCA-CC to the DSMB and MPODS Clinical Safety Committee. 12.2.1. Safety First Plan The protocol will rely on three mechanisms for safety:

1) The DSMB, whose role is outlined below and in the BPCA-CC DSMB charter; 2) Adverse event and SAE reporting mechanisms in accordance with FDA guidance

outlined below; and 3) The active, daily, real time oversight of the MPODS Clinical Safety Committee.

12.2.2. Data and Safety Monitoring Board An independent DSMB established in accordance with the “NIH Policy for Data and Safety Monitoring” will monitor the conduct of the trial for performance (e.g., recruitment, flow and quality control of data, adherence to the protocol), patient safety, and efficacy. The DSMB may review the data at any time. At any time and for any reason, the DSMB may recommend to the NICHD Project Officer that the trial be interrupted or discontinued. (For DSMB Charter, see Appendix F.) 12.2.3. IRB summary safety reports As required by the NIH “Guidance of Reporting Adverse Events to Institutional Review Boards for NIH-Supported Multicenter Clinical Trials,” the DSMB’s summary safety reports will provide feedback at regular and defined intervals to the Institutional Review Boards (IRBs). After each

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meeting of the DSMB, the executive secretary will send a brief summary safety report to each investigator. The report will document that a review of data and outcomes across all centers took place on a given date and will summarize the Board’s review of the cumulative adverse experiences reported from all participating sites without specific disclosure by treatment arm. It will also inform investigators of the study the Board’s conclusion with respect to progress or need for modification of the protocol. The clinical site investigators are required to transmit the report to their local IRB as soon as they are received.

12.2.4. MPODS Clinical Events and Safety Committee The roles and responsibilities of the MPODS Clinical Events and Safety Committee are outlined in the MPODS Clinical Safety Committee charter. The MPODS Clinical Events and Safety Committee will determine if dose escalation can occur by applying the dose escalation safety rules outlined below. The dose escalation safety rules are to be applied to each GA/PNA group (1-4) separately, thus allowing dosing in each age cohort to progress independently. Rules for Dose Escalation: Escalate dosage if no more than 3 subjects (or 25% of the group if the size of the group is >12) in an age group develop any of the following:

1. Escalation of dosage may occur if no more than 3 subjects (or 25% or the group if the size of the group is > 12) in an age group develop any of the following: • Level 2 AEs (see section 12.3.8., Table 1) judged by the MPODS Clinical Events

and Safety Committee to be related to meropenem • Seizures judged by the MPODS Clinical Events and Safety Committee to be

related to meropenem • SAEs that are judged by the MPODS Clinical Events and Safety Committee to be

related to meropenem 2. DO NOT escalate dosage if > 3 subjects (or > 25% of the group if the size of the group

is > 12) in any age group develop the following: • Level 2 AEs (see section 12.3.8., Table 1) judged by the MPODS Clinical Events

and Safety Committee to be related to meropenem • Seizures judged by the MPODS Clinical Events and Safety Committee to be

related to meropenem • SAEs that are judged by the MPODS Clinical Events and Safety Committee to be

related to meropenem 12.3. Adverse Events 12.3.1. Definition of Adverse Event An adverse event (AE) is defined as any untoward medical occurrence such as a sign(s), symptom(s), and/or laboratory finding(s) concurrent with the use of a drug in humans. AEs include worsening of any baseline symptoms. The event may/may not necessarily have a causal relationship with the administration of the drug. AEs may be reported by the subject, or detected by the investigator, or other competent observer. The investigator will also evaluate any change in laboratory values. If the investigator determines a laboratory abnormality to be clinically significant, it is considered a laboratory AE; however, if the laboratory value abnormality is consistent with a current diagnosis, it may be documented accordingly. 12.3.2. Reporting period AEs will be recorded from the time of informed consent until 72 hours following the last dose of study drug for non-serious AEs and 30 days after the last dose of study drug for SAEs. Any AE that occurs between the time informed consent is obtained and the initial dose of study, that is considered related to a protocol-specified procedure, must also be reported. 12.3.3. Procedures for assessing, recording and reporting AEs Throughout the duration of the study, the investigator will closely monitor each subject for clinical evidence of drug intolerance and monitor all clinically obtained laboratory values for laboratory

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evidence of AEs. AEs not explained by the infant’s underlying illness which occur during the course of the study will be reported in detail on the appropriate CRFs and followed until resolution or until it becomes stable. All SAEs will be reported to BPCA-CC within 24 hours. The description of the AE will include a description of event, start date, stop date, intensity, if it was serious, and relationship to the study drug. The investigator must verify this information. The intensity or severity of AEs will be graded as follows:

• Mild: Awareness of sign or symptom, but easily tolerated. Not expected to have a clinically significant affect on the subject’s overall health and well-being. Not likely to require medical attention.

• Moderate: Discomfort enough to cause interference with usual activity or affects clinical status. May require medical intervention.

• Severe: Incapacitating or significantly affecting clinical status. Likely requires medical intervention and/or close follow-up.

AEs that increase in intensity will be recorded with a stop date on the AE CRF of the milder AE equal to the date that the condition worsened. A new AE with a start date equal to the date of worsening will then be reported. AEs that decrease in severity need not be reported in this way. The start date will be the date entered above and the date of resolution should be reported as the stop date. The investigator is responsible for assessing relationship to study medication using the following definitions:

• Not related: An AE that is due to a pre-existing illness or use of another drug, and is not related to the study drug.

• Possibly related: An AE that has little or no relationship to the study drug and there exists a more likely alternative cause.

• Probably related: An AE that is likely to be related to the administration of the study drug and an alternative cause less likely when compared to the study drug.

• Definitely Related: An AE that has a strong temporal relationship to the study drug. AE will recur with continued or repeated use of the study drug, and another cause is unlikely or less likely.

12.3.4. Follow-up of AEs Adverse events will be followed until resolution or until stability is reached using good clinical practices. 12.3.5. Definition of Serious Adverse Event A SAE is defined (21 Code of Federal Regulations part 312.32) as an AE which meets any of the following serious outcome criteria:

• Is fatal; • Is life-threatening; meaning the subject was, in the view of the investigator, at immediate

risk of death from the reaction as it occurred, i.e., it does not include a reaction that, had it occurred in a more serious form, might have caused death;

• Is a persistent or significant disability/incapacity, i.e., the event causes a substantial disruption of a person’s ability to conduct normal life functions;

• Requires or prolongs inpatient hospitalization; • Is a congenital anomaly/birth defect; • Is an important medical event, based on appropriate medical judgment, that may

jeopardize the subject or that the subject may require medical or surgical intervention to prevent one of the other outcomes above.

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12.3.6. Procedures for assessing, recording and reporting SAEs All SAEs must be reported by facsimile to BPCA-CC within 24 hours after the onset of the SAE (or the awareness of the investigator of the event). Fax all SAEs and follow-up information to: 215-972-0658; Attention BPCA-CC Safety. BPCA-CC will notify the MPODS PI, MPODS Clinical Event and Safety Committee and the DSMB of the SAE within one working day after receiving the report from a clinical site. In addition, a clinical site must report a death or life-threatening event by telephone as soon as possible and within 24 hours to the BPCA-CC. A Serious Adverse Event Form must be completed and signed by the site investigator. All SAEs must also be entered into the AE CRF (select “serious”). Only one event should be reported on each SAE reporting form and the term should be a medical diagnosis, not the signs/symptoms of the event or a procedure. Each symptom in a constellation of symptoms should be listed separately if the investigator has not made a preliminary diagnosis. The FDA requires that all SAEs that are unexpected and potentially related to the study medication must be reported to the FDA in writing within 15 calendar days of notification of BPCA-CC. SAEs that are unexpected and related to study drug that meet the criteria for death or immediately life-threatening also require BPCA-CC to notify the FDA by telephone, facsimile transmission or in writing as soon as possible but no later than seven calendar days, with a follow-up written report within 15 calendar days. BPCA-CC will prepare an expedited report for the FDA and copies will be distributed to all site investigators. Expedited reports will be placed in the Study Binder by the investigator upon receipt. The investigators will also forward a copy of all expedited reports to their Investigational Review Boards in accordance with local guidelines. 12.3.7. Follow-up of SAEs The investigator must complete and submit a follow-up SAE form when important follow-up information (diagnosis, outcome, results of specific investigations, etc.) becomes available after submission of the initial form. Follow-up forms should be submitted according to the same process used for reporting the initial event as described above (i.e., within 24 hours of knowledge). All SAEs and AEs of Special Interest will be followed until resolution, stabilization, or 30 days after the last subject is enrolled, whichever occurs first. The investigator will be responsible for reporting adverse events to the local IRBs in accordance with local guidelines. 12.3.8. AEs of Special Interest The AEs of Special Interest (1and2 below) not otherwise explained by the patient’s underlying illness and all SAEs will be submitted in writing (via fax or electronic communication) to the BPCA-CC medical monitor within 24 hours of occurrence. The BPCA-CC will then notify the MPODS PI, MPODS Clinical Events and Safety Committee, and the DSMB within one working day after receiving the report from a clinical site. Local IRB guidelines will also be followed.

1. Level 2 laboratory AEs (Refer to Table 1) not otherwise explained by the subject’s underlying illness

2. Seizures judged not otherwise explained by the subject’s underlying illnesses including: a. IVH b. Meningitis c. Electrolyte abnormality d. Genetic/metabolic disorder e. Drug withdrawal f. Hypoxia-ischemia g. Cerebral anomalies

3. All SAEs

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Table 1: Laboratory AEs of Special Interest Parameter Level 1 Level 2 Direct bilirubin > 5 mg/dL Indirect bilirubin >15 if 20 if >36 weeks adjusted GA AST Increase 5* (baseline) Increase 10* (baseline) ALT Increase 5* (baseline) Increase 10* (baseline)

Creatinine Doubling of baseline serum creatinine and > 1.5 mg/dL

> 2.5 mg/dL

12.4. Seizures Seizures will be closely monitored throughout the trial. The presentation of a seizure can be subtle such as ocular deviation, sucking and lip smacking movements, swimming or ‘rowing’ or ‘bicycling’ movements of limbs. They can be tonic/clonic, localized, multifocal, or generalized. They may also be diagnosed by EEG. If seizures (or possible seizure like activities) are present, they are to be recorded on the CRF. Assessment of seizure activity prior to enrollment, at enrollment, while on study drug, and up to 30 days post study drug administration are to be recorded on the CRF. If seizures occur while on therapy, obtain 100 µl of blood (if possible) to document meropenem level at time of seizure. When possible, obtain up to 2 additional samples, each at least 24 hours apart, during additional infant seizure activity. Scavenged samples whenever possible are appropriate during infant seizure activity. Time of sample collection will be recorded on the CRF. These samples will be sent to the central lab with the other PK samples from the infant. The CRF will have a seizure documentation page for every infant thought to have a seizure or seizure-like activity by the local site PI not explained by the infant’s underlying illness. When clinical seizures or seizure-like activity occurs, the local PI (or their designee) will record the findings on the CRF. EEGs, if obtained per local standard of care, will be evaluated. The local PI will obtain a copy of the EEG, preferably in digital format, remove all patient identifiers except study ID, and submit as source documentation for the seizure or seizure-like activity. These digital documents and the CRF will be presented to the MPODS Clinical Safety Committee pediatric neurologist. The neurologist will make a final determination of whether or not the infant has had a seizure or seizure like activity. The decision by the MPODS Clinical Events and Safety Committee pediatric neurologist will be used to determine whether dosing level is to be advanced in an age group (Centrally Diagnosed Seizure). Infants with seizures or seizure-like activity will be characterized in four components:

1) Locally Diagnosed Clinical Seizure (yes/no), 2) Locally Diagnosed EEG-confirmed Seizure (yes/no), 3) Centrally Diagnosed Clinical Seizure (yes/no), 4) Centrally Diagnosed EEG-confirmed Seizure (yes/no)

12.5. Blood Volume for PK and Safety Laboratory Tests Blood samples will be minimized by:

1. Hematology and chemistry laboratory measures will be recorded from laboratories drawn as standard of care and will not be drawn strictly for purpose of this study.

2. No more than 2 cc/kg will be obtained for study purposes. First priority for blood acquisition is PK samples (up to 0.7 cc of blood). Second priority is CRP levels.

3. CRP levels will be obtained from the patients on 3 occasions: baseline (72 hours) prior to study drug; between Days 3-5; and on Day 28 of the study. CRP levels can be obtained from residual blood in clinical laboratory if less than 12 hours from the time of sample

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collection. Inability to obtain CRP levels will result in a protocol deviation that will be reported to the MPODS PI but will not disqualify the patient from the study.

4. A limited PK sampling scheme will be employed such that no more than a total of 0.7mL of blood (7 samples) is obtained from each subject for PK analysis.

12.6. SAE Contact Information SAE Reporting to BPCA-CC Safety: SAE Report Form: Fax: 215-972-0658 SAE/Safety Questions: Bernard Brownstein, MD BPCA-CC Medical Monitor Office: 215-282-5558 After Hours Emergency: 215-284-4365 Margaret Wright, RN Premier Research Office: 215-282-5544 Refer to Appendix I for Event Reporting.

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Chapter 13: Data Collection and Data Management 13.1. Case Report Form Completion Refer to the finalized Case Report Form (CRF) and CRF completion guidelines when completing the CRF. (Refer to Appendix J for procedures for documentation and Celcius/Farenheit conversion table. Refer to Appendix K for the list of allowable concomitant medications.) Your Site Monitor will perform 100% verification of all CRFs against source documentation at each study visit. All completed and verified CRF forms will be retrieved by your monitor, and a copy left on site in your subject binder. 13.2. Query Process If a CRF discrepancy is discovered as a result of a programmable edit check or a manual review that cannot be resolved at Premier Data Management via a self-evident correction, a Data Query Form (DQF) will be sent to the site for resolution. All queries are electronically generated and assigned a unique individual tracking number. Queries are faxed directly to the sites and contain a description of the discrepancy, the action required, and a response section to be filled out by the site. Queries must be signed by the Principal Investigator or other authorized site personnel prior to being faxed back to Premier Data Management. The sites will retain the original signed copy of the query. Outstanding Query Reports will be distributed to monitors and other study team members who can assist with the query return process on a regular basis. Certain CRF inconsistencies will be corrected in-house at Premier Data Management via the application of self-evident correction conventions (SECCs). These conventions are sponsor-approved, and the application of these conventions is documented and forwarded to the sites at the conclusion of the study. Site-generated data clarifications are given a unique tracking number and are applied to the database following receipt at Premier.

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Chapter 14: Study Conduct 14.1. Principles of Good Clinical Practice The integrity and ultimate credibility of the study depends on factors such as ensuring adherence to the protocol, obtaining complete follow-up information on all participants enrolled, and using quality control measures to establish and maintain high standards for data quality. The following clinical monitoring is implemented to ensure patient safety and rights, protocol adherence, and complete, accurate, verifiable data:

1. Study initiation-investigator meeting and site initiation visit 2. Interim on-site monitoring visits 3. Final close-out visit

14.2. Standard Operating Procedures (SOPs) Site-specific operating procedures will be used when available for study related processes and procedures. 14.3. Monitoring Monitoring visits to the sites will be made periodically during the study to ensure that all aspects of the protocol are followed. Source documents will be reviewed for verification of data collected on the CRFs. Participating sites and investigators will guarantee access to source documents and CRFs to the CRAs. The principal investigator and relevant site personnel will be available during the monitoring visits and will set aside sufficient time for the process. 14.3.1 Site Initiation Visit

• An on-site initiation visit will occur for each selected PODS site. Site staff participation in the Investigator Meeting is also mandatory, as it provides essential protocol training. There may be additional training sessions offered to sites (i.e., central lab, protocol refresher, and sub study presentations). These can be in the format of a teleconference or web cast.

• The BPCA-CC/Premier (PRG) Project Manager (PM), Clinical Manager (CMgr) and/or Clinical Monitor (CM) will conduct a complete initiation visit. The Site Initiation Visit Team will consist of the PODS PI (or designee), the PRG PM or CM, and the sites’ PRG assigned CM.

• The Premier Research CM will send a confirmation letter one week prior to the scheduled visit with an attached agenda to the investigative site.

Areas of focus include:

• Inclusion/Exclusion Criteria • Study design • Study Procedure Schedule • Reporting and documenting primary and secondary efficacy and safety

assessments • Prohibited concomitant medications • Study drug dispensation and accountability • Informed consent process and documentation • Proper Unexpected AE/AE and SAE documentation and reporting. Detailed

review of CRF pages and SAE Report Form. • Detailed review of Regulatory Binder, with emphasis on maintaining current

regulatory documents. • Instructions to site regarding complete and accurate source documentation as

well as direct access to original source. Source documentation worksheets will be discussed in detail with the study coordinator.

• Review of IVRS system for subject enrollment

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• Review of PK Central Laboratory Manual and instructions for collection, processing and shipment of samples. Review of the PK sample collection sheet.

• Frequency of Monitoring Visits • Premier Research and Study Key Persons Contact List • Define personnel responsibilities and delegation of tasks (review Delegation of

Authority list) • Discuss subject enrollment plan • Assess understanding of GCPs and PI responsibilities • Review all pages of the Case Report Forms (CRFs) and Completion Guidelines

with all applicable study staff personnel. 14.3.2. Interim On-Site Visit BPCA-CC will conduct the first visit within 2-3 weeks of the start of the first subject enrolled at each study site. • Subsequent monitoring visits will occur approximately every 4-6 weeks, depending upon

the number of subjects enrolled. Visits may be approximately (2) days in length, dependent upon CRF and source review, and number of subjects enrolled.

• The CM will send a confirmation letter of each IMV to the investigative site approximately one week before the visit.

Areas of focus include:

• Verify the Site Signature Log and Screening Log are both current and complete. • Confirm principal investigator involvement and determine acceptability of study

staff and facilities. • Verify GCP guidelines are being followed. • Verify protocol compliance. • Verify consent process is documented • Review the Regulatory Binder to ensure it is complete and current. • Review CRFs, ICFs and other related source documentation for compliance with

protocol and regulatory requirements • Assess adequacy and availability of source documentation • Confirm accurate and complete reporting of all adverse events and serious

adverse events. Compare the AE and Concomitant Medication listings to AE and Concomitant Medications CRF pages at site to verify that Premier is in receipt of all AEs and concomitant medications

• Assist site with resolving outstanding queries and ensure their return to Premier/BPCA-CC Data Management

• Conduct study drug accountability • Assess site’s clinical (study drug, lab supplies) and non-clinical supply (case

report forms, study forms) needs • Verify proper use of IVRS system for subject enrollment • Verify site is following procedures as per PK Central Laboratory Manual and

following instructions for collection, processing and shipment of samples • Verify the site is completing the PK sample collection sheet and that sample

collection is being conducted as per protocol. This includes a review of the PK sample collection sheet against the source documents.

• Meet with principal investigator and/or sub-investigators to review any issues found in the above (set pre-arranged appointment when possible).

• Monitor will complete 100% SDV and CRF review of all consented subjects by the final Interim Monitoring Visit

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14.3.3. Final Close-Out Visit The CM will conduct a Close-Out Visit at a pre-determined time point when all subjects have completed the trial and all CRF data has been recorded/ completed. The CM will send a confirmation letter to the investigative site approximately one week before the visit.

Areas of focus include:

• Reconcile any outstanding queries • Review the regulatory binder for completeness

o Reconcile all site regulatory documents o Verify/retrieve IRB Closeout Report o Retrieve original study logs and forms

• Perform 100% reconciliation of drug accountability using listings and compare with CRF binders and source documents at site.

• Assist with drug return and/or destruction procedures as instructed • Inform sites they may retain (or destroy) unused laboratory supplies. The site will

provide a note to file to describe the process for destruction and/or utilization process.

• Review proper retention of study documents. • CM will send a follow-up letter to the investigator, with a copy forwarded to the study

coordinator. The letter will summarize the visit and indicate any outstanding issues requiring resolution.

14.3.4. QA Audit: Per the study protocol, page 31, the study sites may also be subject to quality assurance audits by the NICHD or its designees and appropriate regulatory agencies. 14.3.5. Visit Schedule: This will be according to schedule as determined by NICHD/designee and sites will be duly notified in advance of an audit visit. 14.3.6. PODS Center Visits In addition to the monitoring visits described above, the PODS center may also conduct a site visit to assist with study-related training, clinical safety committee follow-up, or for problem resolution if applicable. 14.3.7. Preparation for a Visit The site will provide an area where subject data can be monitored. This will include access to phone, fax and copy machines (as well as computers in the case of electronic medical records). The SC will be available at intervals throughout the day and provide contact information in their absence in the event the CRA needs to communicate outside of these parameters. Assistance will be provided to the CRA as needed, but it is expected that the CRA will work independently to perform the review of subject records. Where it is mandated, the SC may be in attendance at all times while the CRA accesses these documents. At least 2 weeks prior to the visit, the SC and PI should receive a confirmation letter and/or agenda of the upcoming visit that documents all subject data expected to be monitored at that visit. This will allow for adequate time to obtain the necessary documentation. Sites will ensure that all regulatory documents are current inclusive of updates to any 'expired' certificates, the addition of any investigators to FDA 1572 (with applicable original regulatory

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documents obtained), and verification of ongoing completion/additions to the Site Signature/Delegation of Authority Log. This review may take place in the general monitoring area or may occur in the regulatory department, depending on the location of these documents and the personnel responsible for their upkeep. For sites that have electronic records, the CRA should have appropriate pre-clearance to access these files in order to expedite the monitoring process at the time of the visit. A brief initial 'run-through' of one medical record should occur at the first visit to familiarize the CRA with site records (electronic and hard copy). All source documentation for each subject enrolled will be provided for the CRA to monitor. Appropriate CRF pages should be completed prior to the monitoring visit. It is understood that 'gaps' may occur if there are questions regarding the correct response to particular items. These items should be completed with guidance from the CRA at the time of the visit. Any corrections necessary should be completed at the time of the visit, or a detailed correction plan should be provided to the SC for performing this task if there is insufficient time to accommodate corrections at the time of the visit (due to time constraints on either party's part). The site will have comprehensive lists of all subjects consented and enrolled for the study (ongoing completion of appropriate logs) to provide to the CRA. The SC and CRA will negotiate available time for the CRA to perform drug accountability with the Research Pharmacist or th