Perioperative Tissue Penetration of Antimicrobials in Infants
Conditions: Bowel Dysfunction
Sponsor: Duke University

NCT04299867 
Perioperative Tissue Penetration of Antimicrobials in Infants 
Protocol Date: 
27 February 2020 
Protocol Version: 
0.6 
Latest Consent Date:  
08 March 2022 
Document Date: 
23 June 2023 
Principal Investigator Sponsor: 
 
Christoph P. Hornik, MD, PhD, MPH 
Duke University Medical Center 
Department of Pediatrics 
Duke Clinical Research Institute 
Durham, NC 
Phone: (919) 668-8935 
Fax: (919) 668-7032 
Email: christoph.hornik@duke.edu 
 
 

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Perioperative Tissue Penetration of Antimicrobials in Infants 
 
Phase 1/2 Trial 
 
 
 
Protocol Date: 
27 February 2020 
Protocol Version: 
0.6 
Principal Investigator Sponsor: 
 
Christoph P. Hornik, MD, PhD, MPH 
Duke University Medical Center 
Department of Pediatrics 
Duke Clinical Research Institute 
Durham, NC 
Phone: (919) 668-8935 
Fax: (919) 668-7032 
Email: christoph.hornik@duke.edu 
 
 

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Statement of Compliance 
 
This trial will be conducted in compliance with the protocol, International Conference on Harmonization 
(ICH) guideline E6: Good Clinical Practice (GCP): Consolidated Guideline, and the applicable regulatory 
requirements from the United States Code of Federal Regulations (CFR), including but not limited to 45 
CFR 46 (human participants protection, incorporating Subpart D Additional Protections for Children 
involved as Subjects in Research), 21 CFR part 50 (informed consent, incorporating Subpart D Additional 
Safeguards for Children in Clinical Investigations), and 21 CFR part 56 (institutional review board 
[IRB]). 
 
All individuals responsible for the design and/or conduct of this study have completed Human 
Participants Protection Training and are qualified to be conducting this research. 

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Statement of Compliance ............................................................................................................................... i 
List of Abbreviations ................................................................................................................................... iv 
Protocol Synopsis ..................................................................................................................................... …vi 
Table 1. Schedule of Study Procedures .................................................................................................. …vii 
 
1 
Key Roles .............................................................................................................................. 1 
2 
Background Information and Rationale ..................................................................................... 2 
2.1 
Background Information .............................................................................................. 2 
2.1.1 
Complicated Intra-Abdominal Infections ........................................................... 2 
2.1.2 
Current Antibiotic Practice ............................................................................... 2 
2.1.3 
Antibiotic Penetration of the Intestine ............................................................... 2 
2.1.4 
Metronidazole Metabolism ............................................................................... 2 
2.2 
Study Rationale .......................................................................................................... 2 
2.3 
Potential Risks and Benefits ......................................................................................... 3 
2.3.1 
Risk Assessment ............................................................................................. 3 
2.3.2 
Benefit Assessment ......................................................................................... 3 
2.3.3 
Overall Benefit: Risk Conclusion ...................................................................... 3 
3 
Objectives .............................................................................................................................. 4 
3.1 
Study Outcome Measures ............................................................................................ 4 
3.1.1 
Primary Outcome Measures ............................................................................. 4 
3.1.2 
Secondary Outcome Measures .......................................................................... 4 
4 
Study Design .......................................................................................................................... 5 
4.2 
Study Schema ............................................................................................................. 5 
5 
Study Population .................................................................................................................... 6 
5.1 
Inclusion Criteria ........................................................................................................ 6 
5.2 
Exclusion Criteria ....................................................................................................... 6 
5.3 
Duration of Study Participation .................................................................................... 6 
5.3.1 
Replacement Participants ................................................................................. 6 
5.3.2 
Reasons for Participant Withdrawal .................................................................. 6 
5.3.3 
Termination of Study ....................................................................................... 7 
6 
Study procedures .................................................................................................................... 8 
6.1 
Screening ................................................................................................................... 8 
6.2 
Enrollment/Baseline .................................................................................................... 8 
6.3 
Treatment Procedures .................................................................................................. 8 
6.4 
Postoperative Period .................................................................................................... 9 
6.5 
End of Therapy OR Early Withdrawal/Discontinuation .................................................. 9 
6.6 
Laboratory Evaluations .............................................................................................. 10 
6.6.1 
Clinical Laboratory Evaluations ..................................................................... 10 
6.6.2 
Special Assays or Procedures ......................................................................... 10 
6.6.3 
Example PK Sample Schedule ........................................................................ 11 
6.7 
Concomitant medications ........................................................................................... 11 
7 
Study Product Description ..................................................................................................... 13 
7.1 
Dosage and Study Drug Information ........................................................................... 13 
7.1.1 
Rationale for Dose Selection .......................................................................... 13 
7.1.2 
Dose Frequency ............................................................................................ 13 

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7.1.3 
Study Drug ................................................................................................... 13 
7.1.4 
Preparation and Administration of Study Intervention/ Investigational Product ... 13 
8 
Assessment of Safety ............................................................................................................ 14 
8.1 
Events of Special Interest ........................................................................................... 14 
8.2 
Intraoperative Complications ..................................................................................... 14 
8.3 
Postoperative Complications ...................................................................................... 14 
8.4 
Adverse Events Related to Study Procedures ............................................................... 15 
8.5 
Follow Up of Events of Special Interest, Complications, and SAEs ............................... 15 
8.6 
Reporting of Events of Special Interest, Complications, and AEs ................................... 16 
9 
Clinical Monitoring .............................................................................................................. 17 
10 
Statistical Considerations....................................................................................................... 18 
10.1 
Sample Size Considerations ....................................................................................... 18 
10.2 
Analysis Plan ............................................................................................................ 18 
11 
Participant Confidentiality ..................................................................................................... 20 
12 
Informed Consent Process ..................................................................................................... 21 
13 
Source Documents and Access to Source Data/Documents ....................................................... 22 
14 
Quality Control and Quality Assurance ................................................................................... 23 
15 
Ethics/Protection of Human Participants ................................................................................. 24 
15.1 
Ethical Standard ........................................................................................................ 24 
15.2 
Institutional Review Board ........................................................................................ 24 
15.3 
Informed Consent ..................................................................................................... 24 
15.4 
Study Discontinuation ............................................................................................... 24 
16 
Data Handling and Record Keeping ........................................................................................ 25 
16.1 
Data Management Responsibilities ............................................................................. 25 
16.2 
Types of Data ........................................................................................................... 25 
16.3 
Study Records Retention ........................................................................................... 25 
16.4 
Protocol Deviations ................................................................................................... 25 
16.5 
Participant Privacy/Authorization ............................................................................... 26 
17 
Literature References ............................................................................................................ 27 
         

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PI 
Principle investigator 
cIAI 
Complicated intraabdominal infection 
CI 
Confidence interval 
Cr 
Serum creatinine  
CRF 
Case report form 
DCRI 
Duke Clinical Research Institute 
EKG 
Electrocardiogram 
GCP 
Good clinical practice 
GI 
Gastrointestinal 
ICF 
Informed consent form 
IEC 
Institutional ethics committee 
IRB 
Institutional review board 
ITT 
Intent to treat 
IV 
Intravenous 
PK 
Pharmacokinetic 
PD 
Pharmacodynamic 
REB 
Research ethics board 
SAP 
Statistical analysis plan 
SAE 
Serious adverse event 
SoA 
Schedule of activities 
WBC 
White blood cell count 
Hg 
Hemoglobin 
HCT 
Hematocrit 
ALT 
Alanine aminotransferase  
AST  
Aspartate aminotransferase  
ESR 
Erythrocyte sedimentation rate 
CRP 
C-Reactive Protein  
PK 
Pharmacokinetics 
PD 
Pharmacodynamics 

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Protocol Synopsis 
Protocol Title: 
Perioperative Tissue Penetration of Antimicrobials in Infants 
Phase: 
1/2 
Product: 
Metronidazole 
Objectives: 
Primary:  
1) Characterize the PK of metronidazole and its metabolite 2-
hydroxymetronidazole in the plasma and intestinal wall of healthy infants 
undergoing intestinal surgeries  
Secondary: 
1) Characterize the contribution of intestinal CYP2A6 metabolism on 
metronidazole  
Study Design: 
Prospective, single center, open-label, PK study 
Study Population: 
Children < 2 years of age undergoing intestinal surgery 
Number of 
Participants: 
Up to 20 
Number of Sites: 
1 
Duration of 
Participant 
Participation: 
Day of surgery. Remote monitoring of patient record for 30 days postoperatively  
Dose Schedule: 
Per routine medical care 
Estimated Start: 
May 2020  
Estimated Time to 
Complete 
Enrollment: 
18 months 
Inclusion Criteria 
1) Age 0 to ≤ 2 years at enrollment 
2) Written informed consent provided by a parent or legal guardian 
3) Scheduled to undergo elective intestinal operation for the removal of non-
infected bowel 
4) Sufficient intravascular access to complete the study procedures 
Exclusion 
Criteria: 
1) Prior treatment with metronidazole for any dose during the 72 hours prior to study 
drug administration.  
2) Patients with active inflammatory or infectious conditions of the bowel such as 
inflammatory bowel disease, Hirschprung’s disease in the portion of bowel to be 
excised, diverticular disease, cancerous or pre-cancerous lesions, colitis, enteritis, 
ulcerative disease, Meckel’s diverticulum, celiac disease, and irritable bowel 
syndrome. 
3) Renal dysfunction defined as serum creatinine >2 mg/dL at enrollment 

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4) Receiving any extracorporeal life support including extracorporeal membrane 
oxygenation, ventricular assist devices, and renal replacement therapy at 
enrollment 
5) Any condition or circumstance that, in the opinion of the investigator, would 
compromise the safety of the participant or the quality of the data. 

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Table 1. Schedule of Study Procedures 
 
 
Assessments 
Screening Period 
Treatment Period 
Postoperative Period 
 
Day -30 to 0 
Operative Day, 
Day 1 
Day 2 to Day 31 
Informed consent/assent 
X 
 
 
Demographicsa 
X 
 
 
Clinical datab 
 
 
 
Medical history 
X 
 
 
Physical examination 
X 
X 
 
Height/length and body weight 
X 
X 
 
Vital signsc 
X 
X 
 
Clinical laboratory parametersd 
X 
X 
 
Serum creatinine 
X 
X 
 
    Study drug administration 
 
X 
 
    Events of Special Intereste 
 
X 
X 
    Adverse Eventsf 
X 
X 
X 
    Intraoperative Complicationsg 
 
X 
 
    Postoperative Complicationsg 
 
X 
X 
Prior and Concomitant therapy 
X 
X 
 
Pharmacokinetic data 
 
 
 
PK sample collection 
 
 
 
Plasma sample collection 
 
X 
 
Intestine sample collection 
 
X 
 
a: Demographics to be included: gender, date of birth, age, race, comorbidities, gestational age at birth and birth weight  
b: May be obtained through review of electronic medical record. All assessment or laboratory collections performed as standard of care only. No 
assessments or blood draws other than PK data are performed solely for the purposes of this study 
c: Vital signs to be included: weight, height, heart rate, respiratory rate, oxygen saturation, and blood pressure 
d: Clinical laboratory parameters to be included: WBC, Hg, HCT, Plt, PT, PTT, BUN, serum creatinine, potassium, sodium, AST, ALT, total 
bilirubin, albumin, prealbumin, ESR, CRP, any blood, tissue, urine cultures as obtained per standard of care 
e: Events of Special Interest include: gastrointestinal surgeries, sepsis, wound infection, urinary tract infection, feeding intolerance, transfusion 
requirements, phlebotomy complications 
f: Adverse events related to study procedures (ie phlebotomy) 
g: Complications will be assessed through the electronic medical record including excessive blood loss, transfusion requirements, injury to any 
organ system, infection in any organ system including wound bed, unanticipated return to the operating room, and any unexpected intra- or 
postoperative occurrence that requires medical or surgical attention 

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1 
KEY ROLES 
 
A) Study Principal Investigator:  
 
Christoph P. Hornik, MD, PhD, MPH 
Duke University Medical Center 
Department of Pediatrics 
Duke Clinical Research Institute 
Durham, NC 
Phone: (919) 668-8935 
Fax: (919) 668-7032 
Email: christoph.hornik@duke.edu 
 
 
 
B) Surgical Co-Investigator: 
 
Elisabeth Tracy, MD 
Duke University Medical Center 
Department of Surgery 
Division of Pediatric Surgery 
Durham, NC 
Email: Elisabeth.tracy@duke.edu 
 
 
C) Protocol Chair:  
 
Sarah Jane Commander, MD 
Duke University Medical Center 
Department of Surgery 
Duke Clinical Research Institute 
Durham, NC 
Email: Sarah.commander@duke.edu  

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2 
BACKGROUND INFORMATION AND RATIONALE 
2.1 
Background Information  
 
2.1.1 Complicated Intra-Abdominal Infections 
Complicated intra-abdominal infections (cIAI) are a leading of cause of infant morbidity and mortality. 
Up to 14% of high-risk infants develop cIAI1, and up to 30% of those affected die2. Common infantile 
cIAIs involve bowel necrosis or perforation from necrotizing enterocolitis, Hirschsprung disease, 
gastroschisis, or omphalocele. Bacterial translocation from intestinal lumen into the intestinal wall is a 
key pathophysiologic component of cIAI3.  
2.1.2 Current Antibiotic Practice 
Current antibiotic regimens for cIAI are derived to achieve bactericidal plasma concentrations, but 
whether these dosing regimens result in appropriate antibiotic concentrations in the intestinal wall of 
infants is unknown4-6. cIAI treatment regimens vary, but multi-agent therapy and coverage against 
anaerobes including Bacteroides and Clostridium species is recommended and commonly achieved in 
infants with metronidazole7. 
2.1.3 Antibiotic Penetration of the Intestine 
Intestinal wall concentrations of antibiotics are essential to treat local bacterial infection and improve 
outcomes. Failure to reach optimal antibiotic concentrations in the intestinal wall may result in abscess 
formation, intestinal necrosis, and secondary bacteremia, thus worsening clinical outcomes3. Optimizing 
intestinal wall concentrations of antibiotics in infants with cIAI is therefore an urgent and unmet public 
health need. Antibiotic uptake from the blood stream into the intestinal wall and local metabolism 
determine tissue concentrations, and are complex and understudied processes dependent on perfusion, 
endothelial integrity, and expression and function of transporters and metabolizing enzymes8. These 
processes are affected by both pathophysiologic alterations of cIAI and by infant growth and maturation9. 
Prior studies attempting to understand this relationship sampled enteric flora or peritoneal fluid, but none 
directly studied human intestinal tissue10. These alternate approaches precluded characterization of both 
intestinal wall absorption and intestinal wall metabolism of metronidazole, the latter occurring primarily 
via cytochrome P450 (CYP) 2A6.  
2.1.4 Metronidazole Metabolism 
The primary metabolizing enzyme of metronidazole is CYP2A6 and metronidazole’s primary metabolite 
is 2-hydroxymetronidazole, which can exhibit up to 65% of metronidazole’s antimicrobial activity. 
CYP2A6 exhibits significant ontogeny in liver and oral mucosal tissues, and adult intestinal wall 
expression is highly variable (CV%>50%). However, ontogeny and interindividual variability of 
CYP2A6 expression and activity in the intestinal wall of infants are unknown11,12.  
 
 
2.2 
Study Rationale 
Our overarching hypothesis is that intestinal wall penetration of metronidazole in infants will vary with 
age and require optimization of current dosing regimens designed to target plasma exposure only. To test 
this hypothesis, we will perform an opportunistic PK study of infants receiving perioperative 

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metronidazole per standard of care at the time of scheduled intestinal resection surgery. Plasma and 
intestinal wall samples will be collected intra-operatively following administration of metronidazole for 
measurement of metronidazole and its primary metabolite concentrations in the plasma and the intestinal 
wall. These data will be used to characterize the pharmacokinetics of metronidazole in plasma and 
intestinal wall of infants.  
 
 
2.3 
Potential Risks and Benefits 
2.3.1 Risk Assessment 
Risks of Intestinal Sampling 
There are risks to removing the intestine of a patient, however patients enrolled in this study are already 
undergoing bowel excision for clinical indications described in section 5 in the study design section. A 
small piece (goal 500mg) of bowel will be taken from the excised portion of bowel, but no additional 
bowel will be excised for the purpose of this study. Therefore, no additional risk of surgery will be 
introduced through participation in this study. There will be no discomfort associated with intestinal 
excision as the patient will be under general anesthesia as per standard of care.  
 
Risks of Blood Drawing 
There are risks to blood sampling, usually some pain/discomfort with the blood draw/stick however the 
patient will be under anesthesia during the time of IV insertion per standard of care for surgery. Every 
effort will be made to use an already established intravenous line, rather than a new access site. Less than 
5mL of blood will be sampled in total, therefore this will not contribute to a clinically significant amount 
of blood loss.  
 
Risk of Loss of Confidentiality 
There is a potential risk of loss of confidentiality. Every effort will be made to protect participants’ 
confidential information, but this cannot be guaranteed. All patients will be assigned a study number and 
de-identified information will be housed on a Duke RedCAP database with access only granted to study 
personnel who have had the appropriate training regarding HIPPA compliance and confidentiality.  
 
Unforeseen Risks 
There may be other risks to the participant from this research that are not known or foreseeable at this 
time.  
2.3.2 Benefit Assessment 
This study will provide pediatric population-specific safety, PK, and preliminary efficacy data for 
metronidazole administered per standard-of-care in children with cIAI.  
 
2.3.3 Overall Benefit: Risk Conclusion 
Considering the measures taken to minimize risk to participants in this study, the potential risks identified 
are justified by the anticipated benefits that may be afforded to patients with cIAI. 

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3 
OBJECTIVES 
 
Table 1 
Study Objectives and Endpoints 
Objectives 
Endpoints 
Primary  
 
Characterize the PK of metronidazole and its 
metabolite 2-hydroxymetronidazole in the plasma 
and intestinal wall of healthy infants undergoing 
intestinal surgeries  
 
Primary and secondary PK parameters including 
clearance, half-life, volume of distribution, and 
AUC 
Secondary  
 
Characterize the contribution of intestinal 
CYP2A6 to the metabolism of metronidazole 
 
CYP2A6 quantification, ratios of metronidazole to 
2-hydroxymetronidazole concentrations, ratios of 
metronidazole in plasma/intestine, ratios of 2-
hydroxymetronidazole concentration in 
plasma/intestine 
 
3.1 
Study Outcome Measures 
3.1.1 Primary Outcome Measures 
1) PK parameters after administration of metronidazole and its metabolite 2-
hydroxymetronidazole in the plasma and intestinal wall which may include: 
• 
Clearance (CL)  
• 
Half-life (t1/2) 
• 
Volume of distribution (V) 
• 
Area under the curve (AUC) 
3.1.2 Secondary Outcome Measures 
1) CYP2A6 quantification and other metabolizing and transporter enzymes  
2) Ratios of metronidazole to 2-hydroxymetronidazole concentrations 
3) Ratios of metronidazole in plasma/intestine 
4) Ratios of 2-hydroxymetronidazole concentration in plasma/intestine 
 
 

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4 
Study Design 
Single center, open-label, non-randomized study to assess the intestinal pharmacokinetic profile of 
metronidazole in healthy children ≤ 2 years of age undergoing elective intestinal operations for non-
infectious conditions.  
4.1 
Number of Desired Participants: 
A 20 infant sample size is derived to meet the primary objective of characterizing the PK of 
metronidazole in plasma and the intestinal wall of infants. Two desired gestational age ranges will be 
included in this study:  
• 
< 34 weeks gestational age 
• 
≥ 34 weeks gestational age 
All efforts will be made to approximately stratify enrollment as outlined in table 2.  
 
Table 2 
Age Stratification 
Age 
N = 20 
< 34 weeks gestational age at birth 
10 
≥34 weeks gestational age at birth 
10 
Note: "Enrolled" means a participant's, or their legally acceptable representative’s, agreement to 
participate in a clinical study after completion of the informed consent process. Potential participants who 
are screened for the purpose of determining eligibility for the study, but do not participate in the study, are 
not considered enrolled, unless otherwise specified by the protocol. 
4.2 
Study Schema 
 
 

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5 
Study Population 
5.1 
Inclusion Criteria 
1. Age 0 to ≤ 2 years 
2. Written informed consent provided by a parent or legal guardian 
3. Scheduled to undergo elective intestinal operation for the removal of non-infected, otherwise 
healthy bowel  
4. Sufficient intravascular access to complete the study procedures 
5.2 
Exclusion Criteria 
1) Prior treatment with metronidazole for any dose during the 72 hours prior to study drug 
administration.  
2) Patients with active inflammatory or infectious conditions of the bowel such as inflammatory 
bowel disease, Hirschprung’s disease in the portion of bowel to be excised, diverticular disease, 
cancerous or pre-cancerous lesions, colitis, enteritis, ulcerative disease, Meckel’s diverticulum, 
celiac disease, and irritable bowel syndrome. 
3) Renal dysfunction defined as serum creatinine >2 mg/d at any time during the preoperative 
period. 
4) Receiving any extracorporeal life support including extracorporeal membrane oxygenation, 
ventricular assist devices, and renal replacement therapy. 
5) Any condition or circumstance that, in the opinion of the investigator, would compromise the 
safety of the participant or the quality of the data. 
5.3 
Duration of Study Participation 
 
The maximum duration of participation is approximately 60 days: Screening Period of approximately 30 
days, a 1-day Treatment Period on the day of the operation, and a 30-day Follow-Up Period. 
 
5.3.1 Replacement Participants  
Because accurate characterization of PK in a small sample size of patients is dependent upon adequate 
sampling, participants in this study who are unable to provide at least 1 timed PK sample may be 
replaced. The replaced patient will be considered an early withdrawal from the study and will be 
monitored for AEs related to study procedures, complications, and events of special interest as per 
protocol. The data collected from the replaced patient will be retained and included in the study results.   
5.3.2 Reasons for Participant Withdrawal 
A participant’s parent/guardian may voluntarily discontinue their child’s participation in this study at any 
time. The investigator may also, at his/her discretion; withdraw the participant from this study at any 
time. Participants may be prematurely discontinued from the study for any of the following reasons: 
•    Participant or investigator noncompliance with the study protocol 
•    At the request of the participant’s parent/guardian, investigator, or sponsor 
•    Safety concerns 
 

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Participants are not obligated to state the reason for withdrawal. The reasons for withdrawal, or failure to 
provide a reason, must be documented by the investigator on the completion/ withdrawal section of the 
CRF. Any participant who withdraws early or is withdrawn early will be requested to complete end-of-
study safety evaluations and will be provided appropriate care under medical supervision until the 
symptoms of any events of special interest resolve or the participant’s condition becomes stable.  
Participants withdrawn from the study due to an event of special interest must be followed per protocol 
(See Section 8) 
5.3.3 Termination of Study  
 
The study will be terminated upon study completion. The study is considered closed when all required 
documents and study supplies have been collected and a study-site closure meeting has occurred. The 
Investigator may initiate study closure at any time, provided there is reasonable cause and sufficient 
notice is given in advance of the intended termination. 
Reasons for the early termination of the study may include but are not limited to: 
• 
Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC or local 
health authorities, the sponsor's procedures, or GCP guidelines 
• 
Inadequate recruitment of participants by the investigator 
• 
Discontinuation of further study intervention development 
If the study is prematurely terminated or suspended, the investigators will notify, the IECs/IRBs, the 
regulatory authorities, and any contract research organization(s) used in the study of the reason for 
termination or suspension, as specified by the applicable regulatory requirements. The investigator shall 
promptly inform the participants and should assure appropriate therapy and/or follow-up as necessary. 
 

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6 
STUDY PROCEDURES 
6.1 
Screening  
 
Study procedures and their timing are summarized in the SoA. Protocol waivers or exemptions are not 
allowed unless approved by the study PI and IRB. Immediate safety concerns should be discussed with 
the PI immediately upon occurrence or awareness to determine if the participant should continue or 
discontinue study intervention. Adherence to the study design requirements, including those specified in 
the SoA, is essential and required for study conduct. 
 
All screening evaluations must be completed and reviewed to confirm that potential participants meet all 
eligibility criteria. The investigator will maintain a screening log of consented patients to record details of 
all participants screened and to confirm eligibility or record reasons for screen failure, as applicable. 
Procedures conducted as part of the participant’s routine preoperative management (eg, blood count, 
creatinine) and obtained before signing of the ICF may be used for screening or baseline purposes 
provided the procedures meet the protocol-specified criteria and are performed within the time frame 
defined in the SoA. If a patient does not have desired laboratory values, they will be obtained through 
standard of care measurements as able, most often occurring during preoperative visits to either surgery or 
anesthesia, in hospital consultations to surgery, or in the standard of care preoperative laboratory 
collection on the day of surgery.   
 
This study will consist of a Screening, Treatment, and Postoperative Period.  
 
6.2 
Enrollment/Baseline 
 
Screening Period (Day -30 to 0) 
After the parent or legal guardian has signed the IRB-approved informed consent form/HIPAA 
authorization documents, and after it has been determined that the participant satisfies all inclusion and no 
exclusion criteria, the following evaluations will be extracted from the electronic medical record: 
1) Participant demographics including gender, date of birth, postnatal age, race, gestational age at 
birth and birth weight 
2) Physical examination and vital signs, including weight, height, heart rate, respiratory rate, oxygen 
saturation, and blood pressure, performed at any preoperative visit  
3) Pertinent medical history, including diagnosis for which subject is undergoing surgery and history 
of genetic syndrome (i.e., trisomy 21) 
4) The most recent laboratory determination in pre-operative visits, including serum creatinine, no 
blood draws will be performed just for the purposes of this study (See Section 6.6)  
5) Adverse events related to study procedures 
 
6.3 
Treatment Procedures 
 
Operative Day (Day 1) 

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The following assessments will be conducted on the day the patient is administered the study drug and 
undergoes surgery.   
1) Date, time, dose, route, and duration of metronidazole administration  
2) Physical examination and vital signs, including weight, height, heart rate, respiratory rate, oxygen 
saturation and blood pressure, can be performed prior to intubation on the day of surgery  
3) Laboratory determinations, if available, no blood draws will be performed just for the purposes of 
this study (See Section 6.6)  
4) Concomitant medications of interest  
5) Collection of PK plasma and intestine samples (including date/time; See Section 6.6.2) 
6) Results for laboratory tests of interests (See Section 6.6.1) 
7) Events of special interest (See Section 8.1) 
8) Adverse events related to study procedures (See Section 8.4) 
9) Information regarding the surgery performed including: type of surgery, laparoscopic vs. open 
procedure; times of incision, intestinal excision, closure; intubation, extubation; estimated blood 
loss, blood transfusions given, amount and type of intravenous fluids given  
10) Intraoperative complications including: unexpected alteration in operative plan, excessive blood 
loss, need for transfusion, damage to any structure, conversion from laparoscopic to open 
procedure, death (See Section 8.2) 
 
6.4 
Postoperative Period 
The postoperative period of 30 days will be followed remotely through review of the electronic medical 
record. If no clinical contact has been made by the end of the postoperative period, study personnel will 
phone the parent/guardian to examine for any adverse events or hospitalizations to the participant.  
1) Information regarding any adverse events related to metronidazole administration and/or study 
procedures (see section 8.4) 
2) Information regarding events of special interest (See Section 8.1) 
3) Information regarding postoperative complications including: any unexpected medical or surgical 
intervention, readmission for any reason, postoperative blood loss, transfusion requirements, 
infectious complications of any organ system or the wound, death (See section 8.3) 
 
 
6.5 
End of Therapy OR Early Withdrawal/Discontinuation  
 
As the active participation in the study is only on the day of surgery, it is unlikely that many participants 
would receive the study drug and not have any samples taken as that time period is usually less than a few 
hours. Postoperative monitoring will be done remotely, however if any parent/ guardian wishes to be 
removed from the study and their child’s data no longer monitored through the electronic health record, 
data collection will stop on that patient. 
 

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6.6 
Laboratory Evaluations 
6.6.1 Clinical Laboratory Evaluations 
For all time points, the following labs may be recorded while the patient is on study if collected per 
standard of care.  
1. Any serum chemistry values obtained during perioperative visits prior to or on the day of 
surgery and during duration any postoperative stay. These include: WBC, Hg, HCT, Plt, PT, 
PTT, BUN, serum creatinine, potassium, sodium, AST, ALT, total bilirubin, albumin, 
prealbumin, ESR, CRP. If multiple values for a laboratory are obtained in the pre- or post-
operative period, the values recorded will be the value closest to the day of surgery. 
      
6.6.2 Special Assays or Procedures 
 
 
Intraoperative plasma samples will be obtained from pre-existing vascular access catheters at end of 
bolus, 30, 60, 90 minutes, at time of intestinal excision(s), and at the end of the case in 
ethylenediaminetetraacetic acid microcontainers, exceeding no more than approximately 5 mL total 
(Figure 2). Additional plasma can be collected if the child remains in the hospital either in the recovery 
room or on the surgical ward at times 3-4 hours, 4-6 hours, and 6-12 hours from infusion of 
metronidazole, however these samples are not necessary for a participant to be included in the study 
analysis. At the time of intestinal excision, the surgeon will cut at least 500 mg of intestine from the 
specimen, ensuring all layers of bowel are included. If more than one intestinal sample is taken during the 
surgery, such as in the case of multiple strictures removed, each sample will be obtained and labeled 
appropriately. The sample(s) will be placed in a sterile, dry container.  
 
All samples will be frozen in liquid nitrogen and stored in a -80°C freezer within 1 hour of acquisition. 
Samples will be batched and shipped to a central laboratory for concentration measurement of 
metronidazole and its primary metabolite 2-hydroxymetronidazole using a HPLC/MS/MS plasma assay 
previously developed and validated per FDA guidance13. The plasma and intestine samples will also be 
assayed for CYP2A6, transporters, and metabolizing enzymes though protein quantification assays at a 
proteomics laboratory. 
 
Every effort should be made to collect all PK samples, and the timing of PK sampling with standard-of-
care blood draws when possible. Collection of PK samples outside the windows provided in the sampling 
will not be considered protocol deviations.  
 
If a procedure is shorter than the 90 minutes, this PK sample will not be taken. Similarly, if the procedure 
is less than an hour the 60- and 90-minute samples will not be obtained. Finally, in the unlikely event that 

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a procedure is less than 30 minutes, only the end of bolus, intestinal excision, and end of case samples 
will be taken.  
 
6.6.3 Example PK Sample Schedule 
Sample Number 
Time after end infusion of metronidazole 
(min)* 
Type of Sample 
#1 
0 – At end infusion 
Plasma 
#2 
30 
Plasma 
#3 
60 
Plasma 
#4 
90 
Plasma 
#5 
Time of intestinal excision 
Plasma 
#6 
Time of intestinal excision 
Intestine 
#7 
Time of skin closure 
Plasma 
 *Plasma samples will be accepted +/- 10 minutes from ideal blood draw time 
6.7 
Concomitant medications 
The name, daily dose, and date of administration of each concomitant medication of interest will be 
recorded for all doses given from day of surgery until the end of the study. Medications of interest 
include:  
• 
Other systemic antimicrobials 
• 
Oral anticoagulants 
• 
Inducers of CYP 2A6: 
• 
Rifampicin 
• 
Barbiturates such as amobarbital, pentobarbital, phenobarbital and secobarbital  
• 
Inhibitors of CYP 2A6 such as: 
• 
Amiodarone 
• 
Amlodipine 
• 
Buprenorphine 
• 
Clofibrate 
• 
Clotrimazole 
• 
Desipramine 
• 
Disulfiram 
• 
Entacapone 
• 
Fenofibrate 
• 
Gabapentin, 
• 
Isoniazid 
• 
Ketoconazole 
• 
Letrozole 
• 
Methimazole 
• 
Methoxsalen 

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• 
Metyrapone 
• 
Miconazole 
• 
Modafinil 
• 
Orphenadrine 
• 
Pilocarpine 
• 
Selegiline 
• 
Sulconazole 
• 
Tioconazole 
• 
Tranylcypromine 

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7 
STUDY PRODUCT DESCRIPTION 
7.1 
Dosage and Study Drug Information  
7.1.1 Rationale for Dose Selection  
Dosing will not be prescribed by this protocol. Dosing will be per standard of care and at the discretion of 
the treating physician. 
7.1.2 Dose Frequency  
Frequency of metronidazole dosing will be at the discretion of the treating physician.  
 
7.1.3 Study Drug 
This protocol does not specify the brand of product nor dosing amount or interval.  Product will  
 be “off the shelf” metronidazole as determined by the site.  
7.1.4 Preparation and Administration of Study Intervention/ Investigational Product 
The local pharmacy will prepare the metronidazole per standard of care. 
 
 

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8 
ASSESSMENT OF SAFETY 
8.1 
Events of Special Interest 
Events of special interest to be collected include:  
1. 
Gastrointestinal surgeries subsequent to index surgery 
2. 
Intestinal strictures as defined by the primary clinical team 
 
3. 
Sepsis as defined by the clinical team or positive blood cultures with an organism not 
typically considered a contaminant 
4. 
Wound infection as defined by clinical team or positive wound cultures with an organism 
not typically considered a contaminant 
5. 
Urinary tract infection defined as a positive urine culture with an organism not typically 
considered a contaminant 
6. 
Feeding intolerance as defined by the clinical team or the insertion of any type of 
decompression or feeding tube 
7. 
Transfusion requirements with any blood product 
8. 
Phlebotomy related issues such as thrombophlebitis, hemorrhage, and thrombus 
8.2 
Intraoperative Complications 
An intraoperative complication will be limited to any issue arising from the time the patient enters the 
operating room until the time that the patient leaves the operating room. Intraoperative complications are 
defined as instances where the anesthesia or surgical team alter treatment or surgical management to 
address an issue. All intraoperative complications documented by the anesthesia or surgical teams in the 
electronic medical record will be collected and their severity classified using the CLASSIC scale below14.   
 
CLASSIC 
Grade 
Definition 
Grade 0 
No deviation from the ideal intraoperative course 
Grade 1 
Any deviation from the ideal intraoperative course without the need of any additional 
treatment or intervention 
Grade 2 
Any deviation from the ideal intraoperative course with the need of any additional 
treatment or intervention not life-threatening and not leading to permanent disability 
Grade 3 
Any deviation from the ideal intraoperative course with the need of any additional 
treatment or intervention life-threatening and/or leading to permanent disability 
Grade 4 
Any deviation from the ideal intraoperative course with death of the patient 
 
8.3 
Postoperative Complications 
A postoperative complication will be limited to any issue arising after the patient leaves the operating 
room to 30 days after the operation. Postoperative complications are defined as any issue arising that 

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leads to alteration in the standard recovery pathway. All postoperative complications documented by the 
anesthesia or surgical teams in the electronic medical record will be collected and their severity will be 
classified using the Clavien-Dindo scale below15. 
 
Clavien-Dindo 
Grade 
Definition 
Grade 0 
Standard postoperative care without deviations from protocols 
Grade 1 
Any deviation from postoperative care without the need for pharmacologic, surgical, 
radiologic, or endoscopic interventions. (Allowed interventions – antiemetics, 
antipyretics, analgesics, diuretics, electrolytes, local wound care, and physiotherapy) 
Grade 2 
Requires pharmacologic treatment with drugs other than listed in grade 1, blood 
transfusions, or total parenteral nutrition 
Grade 3 
Requires surgical, endoscopic, or radiological intervention 
Grade 4 
Life-threatening complication with/ without intensive care unit management 
Grade 5 
Death 
 
8.4 
Adverse Events Related to Study Procedures  
 
AEs and SAEs caused by the study specimen collections (e.g. bruising, bleeding) will be reported each 
time blood is collected for the study. No intestine will be removed for the purposes of the study and no 
surgery will be altered by participation in the study. AE information will be obtained by direct monitoring 
of the study subject by clinician observation by the care team, and self-reporting by the study subject or 
his/her guardian(s).  
  
AEs related to study procedures will be followed until resolution or until 48 hours after study initiation or 
until discharge from the hospital, whichever comes first. Resolution of an AE is defined as the return to 
pretreatment status or stabilization of the condition with the expectation that it will remain chronic. 
 
8.5 
Follow Up of Events of Special Interest, Complications, and SAEs 
All events of special interest, complications and AEs related to study procedures will be monitored 
through the electronic health record. 
• 
The investigator is obligated to perform or arrange for the conduct of supplemental measurements 
and/or evaluations as medically indicated or as requested to elucidate the nature and/or causality 
of the event as fully as possible. This may include additional laboratory tests or investigations, 
histopathological examinations, or consultation with other health care professionals. 
• 
New or updated information will be recorded in the originally completed CRF. 
• 
The investigator will submit any updated event data within 24 hours of receipt of the information. 
 

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8.6 
Reporting of Events of Special Interest, Complications, and AEs 
Reporting will be completed via an Electronic Data Collection Tool 
• 
The primary mechanism for reporting a complication, events of special interest, or AEs related to 
study procedures will be the electronic data collection tool in the protocol specific Duke RedCAP 
database. 
• 
If the Duke RedCAP is unavailable, then the investigator will enter the complications, events of 
special interest, or AEs related to study procedures into the electronic system as soon as it 
becomes available. 
 
 

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9 
CLINICAL MONITORING 
This study does not provide intervention to the patient that has the potential to cause harm. Enrolled 
patients are receiving metronidazole as part of their treatment plan. However, the study will collect 
information regarding the presence of harmful clinical events that occur as a result of metronidazole 
infusion. 
 
The electronic medical record will be searched for blood, urine, and tissue cultures in the postoperative 
period to monitor for infectious complications and noted in the CRF.  
 

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10 
STATISTICAL CONSIDERATIONS 
10.1 Sample Size Considerations 
 
Sample size is derived to meet the primary objective of characterizing the PK of metronidazole in plasma 
and the intestinal wall of infants. As per FDA guidance, 20 infants will provide > 80% power to target a 
95% confidence interval within 60% and 140% of the geometric mean estimates of metronidazole 
clearance and volume of distribution, assuming a coefficient of variation of up to 40%16. This will also 
provide >80% power to identify a 20% difference in plasma and intestinal wall concentrations of 
metronidazole and its primary metabolite 2-hydroxymetronidazole using a paired t-test at an alpha of 
0.05. Because the study requires participation from the subject only during time of surgery, dropout rates 
should be low, and operative cancellations will be replaced.  
 
10.2 Analysis Plan 
 
Population for Analysis 
All enrolled participants with at least 1 evaluable PK sample will be included in the PK analysis and all 
participants who receive at least 1 dose of study metronidazole will be included in the safety analysis 
population.   
 
Statistical Methodology 
Descriptive statistics, such as number of observations, mean, median, 95% CI, standard deviation, 
standard error, minimum, and maximum, will be presented by age cohort for continuous variables (such 
as height, weight, and BMI percentile). Other descriptive statistics, such as counts, proportions, and/or 
percentages, will be presented by age cohort group to summarize discrete variables (such as race and sex). 
 
Demographics, Baseline Characteristics, and Clinical Course 
The number of participants completed and discontinued early from study, and the reasons for 
discontinuation, will be summarized. Demographic and baseline characteristics will also be summarized. 
Variables include race, age, sex, ethnicity, and other selected clinical variables will be recorded prior to 
initiation of study drug. Variables including drug dosing and other selected clinical variables during study 
drug administration will be recorded.  
 
Safety and Clinical Laboratory Analyses  
Laboratory data (serum BUN, serum creatinine, potassium, sodium, AST, ALT, total bilirubin, albumin, 
prealbumin, ESR, CRP, serum WBC count, Hg, Hct, platelet, PT, PTT) will be tabulated by age cohort.  
Continuous laboratory measurements will be described using univariable descriptive statistics (mean, 
median, etc.); observed values and changes from baseline will be summarized. Lab tests reflective of 
electrolyte abnormalities (e.g., hyponatremia, hypokalemia) will be further summarized in terms of the 
most extreme values and largest changes from baseline (in the appropriate direction) observed from start 
of study drug through the end of therapy.  
 
Adverse events and events of special interest will be summarized by age cohort and relationship to drug 
exposure will be explored.  Prior and concomitant medications will be summarized by World Health 
Organization (WHO) drug class.  
 

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PK Analysis 
Population PK analysis using non-linear mixed effects modeling (NONMEM VII software) will be used 
to estimate population PK parameters and their variance for both plasma and intestinal PK. The influence 
of covariates (i.e. postnatal age, gestational age, etc.) on PK parameters will be explored. Post-hoc 
Bayesian individual PK parameters will then be estimated for each subject. The plasma and intestinal 
concentrations-time profiles of metronidazole will be presented in figure form by subject and cohort as 
well as plasma to intestine concentration. Descriptive statistics will be presented for continuous and 
categorical variables. A detailed description of population PK analyses can be found in the PK analysis 
plan.  
 
 

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PARTICIPANT CONFIDENTIALITY  
The principal investigator will ensure that the use and disclosure of protected health information obtained 
during this research study complies with the Health Insurance Portability and Accountability Act 
(HIPAA) Privacy Rule. The rule provides U.S. federal protection for the privacy of protected health 
information by implementing standards to protect and guard against the misuse of individually 
identifiable health information of participants participating in clinical trials. “Authorization” is required 
from each research participant (i.e., specific permission granted by an individual to a covered entity for 
the use or disclosure of an individual’s protected health information). A valid authorization must meet the 
implementation specifications under the HIPAA Privacy Rule. Authorization will be combined in the 
informed consent document (approved by the IRB). 
 
Participants will have code numbers and will not be identified by name. Participant confidentiality is held 
strictly in trust by the participating investigators, their staff, and the sponsor(s), and their agents. This 
confidentiality is extended to cover testing of biological samples and genetic tests, in addition to the 
clinical information relating to participating participants. 
 
The study protocol, documentation, data, and all other information generated will be held in strict 
confidence. No information concerning the study, or the data will be released to any unauthorized third 
party without prior written approval of the sponsor. 
 
The study monitors or other authorized representatives of the sponsor may inspect all documents and 
records required to be maintained by the investigator. This documentation includes, but is not limited to, 
medical records (office, clinic, or hospital) and pharmacy records for the participants in this study. 
Clinical study sites will permit access to such records. 
 

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INFORMED CONSENT PROCESS 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in the study 
and continues throughout the individual’s study participation. Extensive discussion of risks and possible 
benefits of participation in this study will be provided to the participants’ families. Consent forms 
describing in detail the study procedures and risks are given to the participant’s legal guardian, and 
written documentation of informed consent is required prior to enrolling in the study. Consent forms will 
be IRB-approved, and the participant’s legal guardian will be asked to read and review the document. 
Upon reviewing the document, the investigator will explain the research study to the participant’s legal 
guardian and answer any questions that may arise. The participant’s legal guardian will sign the informed 
consent document prior to the participant being enrolled in the study. The participant’s legal guardian 
may withdraw consent at any time throughout the course of the study. A copy of the informed consent 
document will be given to the participants’ legal guardian for their records. The rights and welfare of the 
participants will be protected by emphasizing to their legal guardians that the quality of their medical care 
will not be adversely affected if they decline to participate in this study. 
 
Site staff may employ IRB-approved recruitment efforts prior to the participant consenting. However, 
before any protocol-specific procedures are performed to determine protocol eligibility, an informed 
consent form must be signed.  By signing the informed consent form, the participant’s legal guardian 
agrees that the participant will complete all evaluations required by the trial, unless the participant is 
withdrawn voluntarily or is terminated from the trial for any reason. 

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13 
SOURCE DOCUMENTS AND ACCESS TO SOURCE 
DATA/DOCUMENTS  
A CRF will be used to record all participant data. The CRF will be used for the recording of all historical 
participant information and study data as specified by this protocol. The CRF must be completed by 
designated and trained study personnel. The CRF will be signed by the principal investigator. 
 
According to ICH E6 source data is defined as all information in original records and certified copies of 
original records of clinical findings, observations, or other activities in a clinical trial necessary for the 
reconstruction and evaluation of the trial. Source data are contained in source 
documents (original records or certified copies). Source documents are defined as original documents, 
data, and records (e.g., hospital records, clinical and office charts, laboratory notes, memoranda, 
participants' diaries or evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies or transcriptions certified after verification as being accurate and complete, 
microfiches, photographic negatives, microfilm or magnetic media, x-rays, participant files, and records 
kept at the pharmacy, at the laboratories, and at medico-technical departments involved in the clinical 
trial).  
 
It will be the responsibility of the investigator(s) to ensure that the study file at the site is maintained. The 
study file will contain, but will not be limited to: 
• 
Current investigator’s brochure and all previous versions 
• 
Study protocol 
• 
Protocol amendments (if applicable) 
• 
Manual of operations (if applicable) 
• 
Informed consent form (blank) 
• 
Signed informed consent forms 
• 
Revised informed consent forms and/or all addenda (blank) 
• 
DHHS number for IRB or other documentation of IRB compliance with FDA regulations (if 
applicable) 
• 
Documentation of IRB approval of protocol, consent form, any protocol amendments, and any 
consent form revisions. 
• 
Annual IRB updates and approvals 
• 
All correspondence between the investigator and IRB 
 
The site will maintain appropriate medical and research records for this trial, in compliance with ICH E6, 
Section 4.9, and regulatory and institutional requirements for the protection of confidentiality of 
participants. The site will permit authorized representatives of the sponsor, its designees, and appropriate 
regulatory agencies to examine (and, when required by applicable law, to copy) clinical records for the 
purposes of quality assurance reviews, audits, and evaluation of the study safety and progress. These 
representatives will be permitted access to all source data, which include, but are not limited to, hospital 
records, clinical and office charts, laboratory notes, memoranda, participants’ memory aid or evaluation 
checklists, pharmacy dispensing records, recorded data from automated instruments, copies or 
transcriptions certified after verification as being accurate and complete, microfiches,  
photographic negatives, microfilm or magnetic media, x-rays, and participant files and records kept at the 
pharmacy, at the laboratories, and medico-technical departments involved in the clinical trial. Data 
collection forms will be derived from the CRFs.  

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QUALITY CONTROL AND QUALITY ASSURANCE  
The principal investigator will provide direct access to all trial-related sites, source data/documents, data 
collection forms, and reports for the purpose of monitoring and auditing by the safety monitor, and 
inspection by local and regulatory authorities. The principal investigator will ensure that all study 
personnel are appropriately trained, and applicable documentations are maintained on site. 
 

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15 
ETHICS/PROTECTION OF HUMAN PARTICIPANTS  
15.1 Ethical Standard 
 
The investigator will ensure that the study will be conducted in accordance with U.S. federal regulation 
21 CFR Part 50, 45 CFR Part 46 and 21 CFR Part 312.60-69, as specified on the signed form FDA 1572, 
applicable state laws, and the International Conference on Harmonization: Good Clinical Practice: 
Consolidation Guideline. The investigator is responsible for informing the IRB of any safety issues 
related to the study and the study drug, including reports of SAEs, if required. The institution must also 
have a Federal Wide Assurance to perform the trial.   
15.2 Institutional Review Board 
Prior to enrollment of participants into this trial, the protocol, the informed consent form, and any 
materials or advertisements presented to participants will be reviewed and approved by the appropriate 
IRB constituted according to FDA regulations and be registered with OHRP. Should amendments to the 
protocol be required, the amendments will be written by the sponsor and provided to the investigator for 
submission to the IRB. Participants will not be compensated by the sponsor for their participation in this 
study. 
15.3 Informed Consent  
 
The investigator will choose participants in accordance with the eligibility criteria detailed previously. 
The investigator will not exercise selectivity so that bias is prevented. In this study, participants’ legal 
guardian will sign one IRB-approved informed consent form for study enrollment. All participants’ 
guardian must sign an informed consent form that complies with the requirements of both 21 CFR Part 50 
and Health Insurance Portability and Accountability Act (HIPAA) before entering the trial. A consent 
form that complies with the requirements of 21 CFR Part 50 and a separate HIPAA-compliant 
authorization form for the use and disclosure of the participant’s protected health information may be 
used instead, per institutional standard operating procedures. For details regarding the informed consent 
process, see Section 12. 
15.4 Study Discontinuation 
 
If the study is discontinued by the safety monitor or principal investigator, enrolled participants will 
continue to be followed for safety assessments for 48 hours (See Section 8). 

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DATA HANDLING AND RECORD KEEPING 
The investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness of the 
data reported. Data collection forms will be derived from paper or electronic CRFs. All source documents 
should be completed in a neat, legible manner to ensure accurate interpretation of data. Data reported in 
the CRF should be consistent with the data collection form/source documents, or the discrepancies should 
be documented.  
16.1 Data Management Responsibilities 
 
All data collection forms, and laboratory reports must be reviewed by the clinical team and data entry 
staff, who will ensure that they are accurate and complete. AEs related to study procedures and 
complications must be graded, assessed for severity and causality, and reviewed by the site principal 
investigator or designee. During the study, the investigator must maintain complete and accurate 
documentation for the study. 
 
16.2 Types of Data 
 
Data for this study will include safety, laboratory [e.g., PK data], and surgical outcome measures. 
16.3 Study Records Retention 
 
Records and source documents pertaining to the conduct of the studies (i.e. including CRFs, data 
collection forms when used as source, electronic medical records, consent forms, laboratory test results 
and study product accountability records), must be retained by the investigator for 5 years after the end of 
the study. Study information in a subject’s medical records will be retained forever.   
16.4 Protocol Deviations 
 
A protocol deviation is any noncompliance with the clinical trial protocol, GCP, or requirements of the 
manual of procedures. The noncompliance may be on the part of the participant, the investigator, or the 
study site staff. As a result of deviations, corrective actions are to be developed by the site and 
implemented promptly.  
 
These practices are consistent with the following sections of the ICH guidance for Good Clinical Practice: 
4.5. Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3 
5.1. Quality Assurance and Quality Control, section 5.1.1 
5.2. Noncompliance, sections 5.20.1, and 5.20.2 
 
It is the responsibility of the site to use continuous vigilance to identify and report deviations within 5 
working days of identification of the protocol deviation or within 5 working days of the scheduled 
protocol-required activity. All deviations must be promptly reported to the sponsor. 
 

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All deviations from the protocol must be addressed in study data collection forms. A completed copy of 
the protocol deviation form must be maintained in the regulatory file. Protocol deviations must be 
submitted to the local IRB/IEC per their guidelines.  
16.5 Participant Privacy/Authorization 
 
The principal investigator will ensure that the use and disclosure of protected health information obtained 
during a research study complies with the HIPAA Privacy Rule. The rule provides U.S. federal protection 
for the privacy of protected health information by implementing standards to protect and guard against the 
misuse of individually identifiable health information of participants participating in clinical trials. 
Authorization is required from each research participant (i.e., specific permission granted by an individual 
to a covered entity for the use or disclosure of an individual’s protected health information). A valid 
authorization must meet the implementation specifications under the HIPAA Privacy Rule. Authorization 
will be combined in the informed consent document (approved by the IRB). 
 
 
 

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LITERATURE REFERENCES 
1. 
Lemons JA, Bauer CR, Oh W, et al. Very low birth weight outcomes of the National Institute of Child 
health and human development neonatal research network, January 1995 through December 1996. NICHD 
Neonatal Research Network. Pediatrics. 2001;107(1):E1. 
2. 
Blackwood BP, Hunter CJ, Grabowski J. Variability in Antibiotic Regimens for Surgical Necrotizing 
Enterocolitis Highlights the Need for New Guidelines. Surg Infect (Larchmt). 2017;18(2):215-220. 
3. 
Blot S, De Waele JJ. Critical issues in the clinical management of complicated intra-abdominal infections. 
Drugs. 2005;65(12):1611-1620. 
4. 
Perez Gaudio DS, Martinez G, Fernandez Paggi MB, et al. Ex vivo penetration of fosfomycin into healthy 
and Lawsonia intracellularis-colonized swine intestinal mucosa. J Vet Pharmacol Ther. 2018;41(6):878-
886. 
5. 
Rubino CM, Ma L, Bhavnani SM, et al. Evaluation of tigecycline penetration into colon wall tissue and 
epithelial lining fluid using a population pharmacokinetic model and Monte Carlo simulation. Antimicrob 
Agents Chemother. 2007;51(11):4085-4089. 
6. 
Gascon AR, Gutierrez-Aragon G, Hernandez RM, Errasti J, Pedraz JL. Pharmacokinetics and tissue 
penetration of pefloxacin plus metronidazole after administration as surgical prophylaxis in colorectal 
surgery. Int J Clin Pharmacol Ther. 2003;41(6):267-274. 
7. 
Autmizguine J, Hornik CP, Benjamin DK, Jr., et al. Anaerobic antimicrobial therapy after necrotizing 
enterocolitis in VLBW infants. Pediatrics. 2015;135(1):e117-125. 
8. 
Wang LA, Gonzalez D, Leeder JS, et al. Metronidazole Metabolism in Neonates and the Interplay Between 
Ontogeny and Genetic Variation. J Clin Pharmacol. 2017;57(2):230-234. 
9. 
Kuno T, Hirayama-Kurogi M, Ito S, Ohtsuki S. Proteomic analysis of small intestinal epithelial cells in 
antibiotic-treated mice: Changes in drug transporters and metabolizing enzymes. Drug Metab 
Pharmacokinet. 2019;34(2):159-162. 
10. 
Murao N, Ohge H, Ikawa K, et al. Pharmacokinetics of piperacillin-tazobactam in plasma, peritoneal fluid 
and peritoneum of surgery patients, and dosing considerations based on site-specific pharmacodynamic 
target attainment. Int J Antimicrob Agents. 2017;50(3):393-398. 
11. 
Pearce RE, Cohen-Wolkowiez M, Sampson MR, Kearns GL. The role of human cytochrome P450 
enzymes in the formation of 2-hydroxymetronidazole: CYP2A6 is the high affinity (low Km) catalyst. 
Drug Metab Dispos. 2013;41(9):1686-1694. 
12. 
Lindell M, Karlsson MO, Lennernas H, Pahlman L, Lang MA. Variable expression of CYP and Pgp genes 
in the human small intestine. Eur J Clin Invest. 2003;33(6):493-499. 
13. 
Cohen-Wolkowiez M, Ouellet D, Smith PB, et al. Population pharmacokinetics of metronidazole evaluated 
using scavenged samples from preterm infants. Antimicrob Agents Chemother. 2012;56(4):1828-1837. 
14. 
Rosenthal R, Hoffmann H, Clavien PA, Bucher HC, Dell-Kuster S. Definition and Classification of 
Intraoperative Complications (CLASSIC): Delphi Study and Pilot Evaluation. World J Surg. 
2015;39(7):1663-1671. 
15. 
Clavien PA, Barkun J, de Oliveira ML, et al. The Clavien-Dindo classification of surgical complications: 
five-year experience. Ann Surg. 2009;250(2):187-196. 
16. 
Wang Y, Jadhav PR, Lala M, Gobburu JV. Clarification on precision criteria to derive sample size when 
designing pediatric pharmacokinetic studies. J Clin Pharmacol. 2012;52(10):1601-1606. 
 

 
 
 
Form 
M0345 
DUKE UNIVERSITY HEALTH SYSTEM 
 
Consent To Participate In A Research Study 
Minor Consent 
Perioperative Tissue Penetration of Antimicrobials in Infants 
 
 
 
Concise Summary 
 
The purpose of this study is to see how an antibiotic used during surgery, called metronidazole, is 
processed in the blood and tissue of infants having intestinal surgery and whether the dose given is 
enough to help prevent infections after surgery. 
 
If you agree for your child to participate, blood samples will be obtained from intravenous lines 
placed for the surgery. Blood will be collected at the end of antibiotic infusion, and then at 30, 60 
and 90 minutes after infusion. Additional blood will be collected at the time of surgery and at the 
end of the surgery. The amount of blood collected will be about 5 mL (1 teaspoon) total. No 
additional needle sticks or intravenous lines will be required for your child to be involved in this 
study. In addition, a small piece of tissue will be taken from the intestine after it’s removed. 
 
The samples will be analyzed to see how much metronidazole is found in the blood at each 
timepoint, and in the tissue post-surgery. 
 
To minimize risk to your child, we have limited the volume of blood that we will draw to 
approximately 5 mL in total. 
 
Please let the study doctor or study team know if you are interested in learning more about this study 
as explained in the remainder of this consent form. 
 
You are being asked to allow your child to participate in this research study because he/she is 
undergoing intestinal surgery. Research studies are voluntary and include only people who choose to 
take part. Please read this consent form carefully and take your time in making your decision. Your 
child’s study doctor or study staff will discuss this consent form with you. Please ask about any words or 
information that you do not clearly understand. 
 
This consent form describes the nature of the study, risks, inconveniences, discomforts, and other 
important information about the study. It is important that you ask questions about what is required for 
participation in this research study. We encourage you to talk with your family and friends before you 
decide to allow your child to take part in this research study. 
 
Please tell the study doctor or study staff if your child is taking part in another research study. 
 
WHO WILL BE MY CHILD’S DOCTOR ON THIS STUDY? 
If you decide to allow your child to participate, Dr. Elisabeth Tracy or Dr. Sarah Commander will be 
your child’s doctor for the study and will be in contact with your child’s regular health care provider 
throughout the time that your child is in the study and afterwards, if needed. 
 
 
DUHS /RB 
/RB NUMBER: Pro00103890 
/RB REFERENCE DATE: 03/08/2022 
/RB EXP/RAT/ON DATE: 01/01/2100 
 
Page 1 of 6 
Parent/Guardian Initials: 

 
 
 
Form 
M0345 
DUKE UNIVERSITY HEALTH SYSTEM 
 
Consent To Participate In A Research Study 
Minor Consent 
Perioperative Tissue Penetration of Antimicrobials in Infants 
 
 
WHY IS THIS STUDY BEING DONE? 
The purpose of this study is to see how an antibiotic used during surgery, called metronidazole, is 
processed in the blood and tissue of infants having intestinal surgery and whether the dose given is 
enough to help prevent infections after surgery. 
 
HOW MANY CHILDREN WILL TAKE PART IN THIS STUDY? 
Up to 20 children at Duke University Medical Center will participate in this study. 
 
WHAT IS INVOLVED IN THIS STUDY? 
If you agree to allow your child to participate, you will be asked to sign and date this consent form. 
The surgeon will perform surgery as part of your child’s standard of care. Enrolling your child in this 
study will not affect his or her hospital care in any way. 
 
As part of your child’s routine care, a needle will be placed into a vein (called an “intravenous line”) in 
your child’s arm or leg in order to collect blood during the hospital stay. This means that the intravenous 
lines will need to be placed even if your child is not involved in this study. 
 
Your child will also be given an antibiotic called metronidazole as part of the routine care prior to 
surgery. 
 
While your child is undergoing surgery, blood samples will be obtained from these intravenous lines. No 
additional needle sticks or intravenous lines will be required for your child to be involved in this study. 
 
If you agree for your child to participate, blood samples will be obtained from intravenous lines placed 
for the surgery. Blood will be collected at the following timepoints: 
 End of antibiotic infusion 
 30 minutes post-infusion 
 60 minutes post-infusion 
 90 minutes post-infusion. 
 At the time of surgery 
 At the end of the surgery 
 
The amount of blood collected will be about 5 mL (1 teaspoon) total. No additional needle sticks or 
intravenous lines will be required for your child to be involved in this study. 
 
In addition, a small piece of tissue will be taken from the intestine after it’s removed. 
 
The samples will be analyzed to see how much metronidazole is found in the blood at each timepoint, 
and in the tissue post-surgery. 
 
 
 
DUHS /RB 
/RB NUMBER: Pro00103890 
/RB REFERENCE DATE: 03/08/2022 
/RB EXP/RAT/ON DATE: 01/01/2100 
 
Page 2 of 6 
Parent/Guardian Initials: 

 
 
 
Form 
M0345 
DUKE UNIVERSITY HEALTH SYSTEM 
 
Consent To Participate In A Research Study 
Minor Consent 
Perioperative Tissue Penetration of Antimicrobials in Infants 
 
 
HOW LONG WILL MY CHILD BE IN THIS STUDY? 
Your child’s direct participation in the study will last for the duration of his or her surgery at Duke 
University Health System (DUHS), however their medical records may be reviewed by the research 
staff for at least one month afterwards. 
 
You can choose to stop your child’s participation at any time without penalty or loss of any benefits to 
which your child is entitled. However, if you decide to stop your child’s participation in the study, we 
encourage you to talk to your child’s doctor first. 
 
WHAT ARE THE RISKS OF THE STUDY? 
As a result of your child’s participation in this study, he/she has the following risks. You should discuss 
these with the study doctor and your child’s regular health care provider if you choose. 
 
Loss of confidentiality: 
We will be collecting information from your child’s medical record for this study. We will only collect 
information that is directly related to the study and every effort will be made to keep your child’s 
information confidential; however, there is the potential risk of loss of confidentiality. 
 
Risks of Blood Drawing: 
No additional needle sticks will be performed to draw blood for research. To minimize risk to your 
child, we have limited the volume of blood that we will draw to approximately 5 mL (about 1 teaspoon) 
in total. 
 
There may be risks that are not yet known. 
 
ARE THERE BENEFITS TO TAKING PART IN THE STUDY? 
There is no direct benefit to your child from participating in this research study. This study will provide 
valuable information that may eventually help us to better prevent infections in infants undergoing 
intestinal surgery in the future. 
 
WILL MY CHILD’S INFORMATION BE KEPT CONFIDENTIAL? 
Participation in research involves some loss of privacy. We will do our best to make sure that 
information about your child is kept confidential, but we cannot guarantee total confidentiality. Your 
child’s personal information may be viewed by individuals involved in this research and may be seen by 
people including those collaborating, funding, and regulating the study. These may include 
representatives from the Duke Cancer Research Institute and representatives of the Thrasher Research 
Fund – Medical Research for Children. We will share only the minimum necessary information in order 
to conduct the research. Your child’s personal information may also be given out if required by law. 
 
As part of the study, your child’s records may be reviewed in order to meet federal or state regulations. 
Reviewers may include representatives of the Duke University Health System Institutional Review 
 
DUHS /RB 
/RB NUMBER: Pro00103890 
/RB REFERENCE DATE: 03/08/2022 
/RB EXP/RAT/ON DATE: 01/01/2100 
 
Page 3 of 6 
Parent/Guardian Initials: 

 
 
 
Form 
M0345 
DUKE UNIVERSITY HEALTH SYSTEM 
 
Consent To Participate In A Research Study 
Minor Consent 
Perioperative Tissue Penetration of Antimicrobials in Infants 
 
 
Board, and Office for Human Research Protections. If they review your child’s research record, they 
may also need to review your child’s entire medical record. 
 
The doctors taking care of your child will document in the medical record that your child is participating 
in this study. Results of tests and studies done solely for this research study and not as part of your 
child’s regular care will not be included in your child’s medical record. Any research information in 
your child’s medical record will be kept indefinitely. 
 
The study results will be retained in your child’s research record forever. Any research information in 
your child’s medical record will also be kept indefinitely. 
 
While the information and data resulting from this study may be presented at scientific meetings or 
published in a scientific journal, your child’s identity will not be revealed. 
 
Some people or groups who receive your child’s health information might not have to follow the same 
privacy rules. Once your child’s information is shared outside of DUHS, we cannot guarantee that it will 
remain private. If you decide to share private information with anyone not involved in the study, the 
federal law designed to protect your child’s health information privacy may no longer apply to the 
information you have shared. Other laws may or may not protect sharing of private health information. 
 
WHAT ARE THE COSTS? 
There are no costs to you for participating in this study. You or your insurance provider will be 
responsible and billed for all costs related to your child’s routine medical care, including copayments 
and deductibles. Routine medical care services are those that your child would have received for their 
condition if your child were not participating in this research study. 
 
WHAT ABOUT COMPENSATION? 
You or your child will not receive compensation for your child’s participation in this study. 
 
WHAT ABOUT RESEARCH RELATED INJURIES? 
Immediate necessary medical care is available at Duke University Medical Center in the event that your 
child is injured as a result of participation in this research study. However, there is no commitment by 
Duke University Medical Center, Duke University Health System, Inc., or your child’s Duke University 
Medical Center physicians, to provide monetary compensation or free medical care to your child in the 
event of a study-related injury. 
 
For questions about the study or a research-related injury, contact Dr. Tracy at 919-681-5077 during 
regular business hours and at pager number 919-970-9649 after hours and on weekends and holidays. 
 
 
 
 
 
DUHS /RB 
/RB NUMBER: Pro00103890 
/RB REFERENCE DATE: 03/08/2022 
/RB EXP/RAT/ON DATE: 01/01/2100 
 
Page 4 of 6 
Parent/Guardian Initials: 

 
 
 
Form 
M0345 
DUKE UNIVERSITY HEALTH SYSTEM 
 
Consent To Participate In A Research Study 
Minor Consent 
Perioperative Tissue Penetration of Antimicrobials in Infants 
 
 
 
WHAT ABOUT MY RIGHTS TO DECLINE PARTICIPATION OR WITHDRAW MY CHILD 
FROM THE STUDY? 
You may choose to not allow your child to be in the study, or, if you agree to the study, you may 
withdraw your child from the study at any time. If you withdraw your child from the study, no new data 
about your child will be collected for study purposes. Data and samples already collected for the study 
cannot be withdrawn. 
 
Your decision not to allow your child to participate, or to withdraw from the study will not involve any 
penalty or loss of benefits to which your child is entitled, and will not affect your child’s access to health 
care at Duke University Medical Center. If you do decide to withdraw your child, we ask that you 
contact Dr. Tracy in writing and let her know that you are withdrawing from the study. Dr. Tracy’s 
mailing address is DUMC, Box 3815, Durham, NC 27710. 
 
We will tell you and your child about new information that may affect your child’s health, welfare, or 
willingness to stay in this study. 
 
Your child’s doctor may decide to take your child off this study if your child’s condition gets worse, if 
your child has serious side effects, or if your child’s study doctor determines that it is no longer in your 
child’s best interest to continue. If this occurs, you will be notified and your child’s study doctor will 
discuss other options with you and your child. 
 
Your child’s samples and/or data may be stored and shared for future research without additional 
informed consent if identifiable private information, such as your child’s name and medical record 
number, are removed. If your child’s identifying information is removed from their samples or data, we 
will no longer be able to identify and destroy them. 
 
The use of your child’s samples may result in commercial profit. You and your child will not be 
compensated for the use of the samples other than what is described in this consent form. 
 
WHOM DO I CALL IF I HAVE QUESTIONS OR PROBLEMS? 
For questions about the study or a research-related injury, or if you or your child have problems, 
concerns, questions or suggestions about the research, contact Dr. Tracy at 919-681-5077 during regular 
business hours and at pager number 919-970-9649 after hours and on weekends and holidays. 
 
For questions about your child’s rights as a research participant, or to discuss problems, concerns or 
suggestions related to the research, or to obtain information or offer input about the research, Duke 
University Health System Institutional Review Board (IRB) Office at (919) 668-5111. 
 
 
 
 
DUHS /RB 
/RB NUMBER: Pro00103890 
/RB REFERENCE DATE: 03/08/2022 
/RB EXP/RAT/ON DATE: 01/01/2100 
 
Page 5 of 6 
Parent/Guardian Initials: 

 
 
 
Form 
M0345 
DUKE UNIVERSITY HEALTH SYSTEM 
 
Consent To Participate In A Research Study 
Minor Consent 
Perioperative Tissue Penetration of Antimicrobials in Infants 
 
 
 
 
STATEMENT OF CONSENT 
The purpose of this study, procedures to be followed, risks and benefits have been explained to my child 
and me. I have been allowed to ask questions, and my questions have been answered to my satisfaction. 
I have been told whom to contact if I have questions, to discuss problems, concerns, or suggestions 
related to the research, or to obtain information or offer input about the research. I have read this consent 
form and agree for my child to be in this study, with the understanding that I may withdraw my child at 
any time. We have discussed the study with my child (if over age 6), who agrees to be in the study. I have been 
told that I will be given a signed and dated copy of this consent form. 
 
 
 
 
 
Signature of Parent or Legal Guardian 
Date 
Time 
 
 
 
 
Signature of Person Obtaining Consent 
Date 
Time 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DUHS /RB 
/RB NUMBER: Pro00103890 
/RB REFERENCE DATE: 03/08/2022 
/RB EXP/RAT/ON DATE: 01/01/2100 
 
Page 6 of 6 
Parent/Guardian Initials: