A Phase 1b, Open-label, Single-dose Study to Evaluate the Pharmacokinetics, Safety, and Tolerability of MK-7655A in Pediatric Subjects From Birth to Less Than 18 Years of Age With Confirmed or Suspected Gram-negative Infections
Phase: PHASE1
Conditions: Suspected or Documented Gram-negative Bacterial Infection
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title: 
NCT number: 
NCT03230916  
Document Date: 
22-AUG-2019
A Phase 1b, Open-label, Single-dose Study to Evaluate the 
Pharmacokinetics, Safety, and Tolerability of MK-7655A in Pediatric 
Subjects From Birth to Less Than 18 Years of Age With Confirmed 
or Suspected Gram-negative Infections

Product:  MK-7655A 
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THIS PROTOCOL AMENDMENT AND ALL OF THE INFORMATION RELATING 
TO IT ARE CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK 
SHARP & DOHME CORP., A SUBSIDIARY OF MERCK & CO., INC., 
WHITEHOUSE STATION, NJ, U.S.A.
SPONSOR:
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. 
(hereafter referred to as the Sponsor or Merck)
One Merck Drive
P.O. Box 100
Whitehouse Station, New Jersey, 08889-0100, U.S.A.
Protocol-specific Sponsor Contact information can be found in the Investigator Trial File 
Binder (or equivalent).
TITLE:
A Phase 1b, Open-label, Single-dose Study to Evaluate the Pharmacokinetics, Safety, and 
Tolerability of MK-7655A in Pediatric Subjects From Birth to Less Than 18 Years of Age 
With Confirmed or Suspected Gram-negative Infections
IND NUMBER: 108,754
EudraCT NUMBER:  2016-004328-43
 
 
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TABLE OF CONTENTS
DOCUMENT HISTORY ....................................................................................................... 9
SUMMARY OF CHANGES................................................................................................ 10
1.0
TRIAL SUMMARY.................................................................................................. 11
2.0
TRIAL DESIGN........................................................................................................ 11
Trial Design ........................................................................................................... 11
Trial Diagram........................................................................................................ 13
3.0
OBJECTIVE(S) & HYPOTHESIS(ES).................................................................. 15
Primary Objective(s) & Hypothesis(es).............................................................. 15
Secondary Objective(s) & Hypothesis(es)........................................................... 15
4.0
BACKGROUND & RATIONALE.......................................................................... 15
Background ........................................................................................................... 15
Pharmaceutical and Therapeutic Background .................................................... 15
Preclinical and Clinical Trials............................................................................. 16
Preclinical Trials .......................................................................................... 16
Preclinical Juvenile Toxicity Studies.................................................... 16
Phase 1 Clinical Trials ................................................................................. 16
Phase 2 Clinical Trials ................................................................................. 17
Phase 3 Clinical Trials ................................................................................. 18
Ongoing Clinical Trials....................................................................................... 19
Imipenem/Cilastatin Clinical Experience in Pediatric Populations.................... 19
Rationale................................................................................................................ 19
Rationale for the Trial and Selected Subject Population .................................... 19
Rationale for Dose Selection/Regimen/Modification......................................... 21
Starting Dose for This Trial......................................................................... 21
Maximum Dose/Exposure for This Trial..................................................... 21
Rationale for Dose Interval and Trial Design.............................................. 21
Rationale for Endpoints ...................................................................................... 21
Pharmacokinetic/Pharmacodynamic Endpoints........................................... 21
 
 
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Safety Endpoints.......................................................................................... 22
Benefit/Risk ........................................................................................................... 23
5.0
METHODOLOGY ................................................................................................... 23
Entry Criteria........................................................................................................ 23
Diagnosis/Condition for Entry into the Trial ...................................................... 23
Subject Inclusion Criteria.................................................................................... 24
Subject Exclusion Criteria .................................................................................. 25
Trial Treatment(s) ................................................................................................ 27
Dose Selection/Modification .............................................................................. 27
Dose Selection (Preparation) ....................................................................... 27
Dose Modification ....................................................................................... 28
Dose Modifications and Decisions After Interim Reviews .................. 29
Timing of Dose Administration.......................................................................... 31
Trial Blinding...................................................................................................... 31
Randomization or Treatment Allocation............................................................ 31
Stratification.......................................................................................................... 31
Concomitant Medications/Vaccinations (Allowed & Prohibited).................... 31
Rescue Medications & Supportive Care............................................................. 32
Diet/Activity/Other Considerations..................................................................... 32
Subject Withdrawal/Discontinuation Criteria................................................... 32
Discontinuation of Treatment ............................................................................. 32
Withdrawal from the Trial .................................................................................. 33
Subject Replacement Strategy............................................................................. 33
Beginning and End of the Trial ........................................................................... 33
Clinical Criteria for Early Trial Termination ................................................... 34
6.0
TRIAL FLOW CHART ........................................................................................... 35
7.0
TRIAL PROCEDURES ........................................................................................... 37
Trial Procedures ................................................................................................... 37
Administrative Procedures.................................................................................. 37
Informed Consent/Assent............................................................................. 37
General Informed Consent/Assent........................................................ 37
 
 
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Inclusion/Exclusion Criteria ........................................................................ 38
Subject Identification Card .......................................................................... 38
Medical History ........................................................................................... 38
Prior and Concomitant Medications Review............................................... 38
Prior Medications.................................................................................. 38
Concomitant Medications..................................................................... 38
Assignment of Screening Number............................................................... 38
Assignment of Treatment/Randomization Number..................................... 39
Trial Compliance ......................................................................................... 39
Clinical Procedures/Assessments........................................................................ 39
Full and Directed Physical Examinations.................................................... 39
Height and Weight ....................................................................................... 39
Vital Sign Measurements............................................................................. 40
Adverse Event Monitoring........................................................................... 40
Local Tolerability Monitoring ..................................................................... 40
Laboratory Procedures/Assessments .................................................................. 40
Laboratory 
Safety 
Evaluations 
(Hematology, 
Chemistry, 
and 
Urinalysis).................................................................................................... 40
Pharmacokinetic/Pharmacodynamic Evaluations........................................ 41
Blood Collection for Plasma MK-7655A ............................................. 42
Other Procedures................................................................................................. 43
Withdrawal/Discontinuation........................................................................ 43
Subject Blinding/Unblinding ....................................................................... 43
Domiciling ................................................................................................... 43
Calibration of Equipment............................................................................. 43
Visit Requirements.............................................................................................. 43
Screening...................................................................................................... 43
Treatment Period.......................................................................................... 44
Discontinued Subjects Continuing to be Monitored in the Trial................. 44
Post-Trial...................................................................................................... 44
Assessing and Recording Adverse Events .......................................................... 44
Definition of an Overdose for This Protocol and Reporting of Overdose to 
the Sponsor.......................................................................................................... 45
 
 
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Reporting of Pregnancy and Lactation to the Sponsor ....................................... 45
Immediate Reporting of Adverse Events to the Sponsor.................................... 46
Serious Adverse Events ............................................................................... 46
Events of Clinical Interest............................................................................ 47
Evaluating Adverse Events................................................................................. 47
Sponsor Responsibility for Reporting Adverse Events ...................................... 50
8.0
STATISTICAL ANALYSIS PLAN ........................................................................ 50
Statistical Analysis Plan Summary ..................................................................... 50
Responsibility for Analyses/In-House Blinding ................................................. 51
Hypotheses/Estimation ......................................................................................... 52
Analysis Endpoints ............................................................................................... 52
Pharmacokinetic/Pharmacodynamic Endpoints.................................................. 52
Safety Endpoints ................................................................................................. 52
Analysis Populations............................................................................................. 52
Pharmacokinetics Population.............................................................................. 52
Safety Analysis Populations ............................................................................... 53
Statistical Methods................................................................................................ 53
Modeling & Simulation Methods for Pharmacokinetic Analyses ...................... 53
Statistical Methods for Safety Analyses ............................................................. 53
Interim Reviews for Potential Dose Adjustment ............................................... 54
Multiplicity ............................................................................................................ 54
Sample Size and Power Calculations .................................................................. 54
9.0
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES ................................................................................................................. 55
Investigational Product ........................................................................................ 55
Packaging and Labeling Information ................................................................. 55
Clinical Supplies Disclosure................................................................................. 55
Storage and Handling Requirements.................................................................. 55
Discard/Destruction/Returns and Reconciliation .............................................. 56
Standard Policies................................................................................................... 56
10.0
ADMINISTRATIVE AND REGULATORY DETAILS....................................... 56
Confidentiality....................................................................................................... 56
 
 
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Confidentiality of Data ....................................................................................... 56
Confidentiality of Subject Records..................................................................... 56
Confidentiality of Investigator Information........................................................ 57
Confidentiality of IRB/IEC Information............................................................. 57
Compliance with Financial Disclosure Requirements....................................... 57
Compliance with Law, Audit and Debarment ................................................... 58
Compliance with Trial Registration and Results Posting Requirements ........ 59
Quality Management System............................................................................... 60
Data Management................................................................................................. 60
Publications ........................................................................................................... 60
11.0
LIST OF REFERENCES......................................................................................... 61
12.0
APPENDICES........................................................................................................... 64
Merck Code of Conduct for Clinical Trials........................................................ 64
Approximate Blood/Tissue Volumes Drawn/Collected by Trial Visit and 
by Sample Types ................................................................................................... 66
Acceptable Creatinine Clearance Ranges by Age Range for Study 
Inclusion................................................................................................................. 67
List of Abbreviations ............................................................................................ 68
13.0
SIGNATURES........................................................................................................... 70
Sponsor's Representative ..................................................................................... 70
Investigator............................................................................................................ 70
 
 
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LIST OF TABLES
    
Table 1
Trial Treatment ....................................................................................................... 27
Table 2
Imipenem/Cilastatin/Relebactam (IMI/REL) Doses by Age Cohort...................... 28
Table 3
Laboratory Tests ..................................................................................................... 41
Table 4
Evaluating Adverse Events..................................................................................... 48
Table 5
Product Descriptions............................................................................................... 55
 
 
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LIST OF FIGURES
          
Figure 1
Schematic of Study Design for Study MK-7655A-020...................................... 14
Figure 2
Dose Modifications for Cohorts 1, 2, 3, and 4 After Interim Reviews............... 30
 
 
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DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
MK-7655A-020-00
15-NOV-2016
Original Protocol
MK-7655A-020-01
11-JAN-2019
Amendment 1 (Global)
Primary reasons for the amendment:

Allow enrollment of subjects who may have neonatal 
hyperbilirubinemia within 24 hours of birth that is part of a 
normal physiologic process.

Remove weight-based exclusion criterion for Cohorts 4 and 5.
MK-7655A-020-02
22-AUG-2019
Amendment 2 (Global)
Primary reason for the amendment:

Allow enrollment into Cohort 5 of subjects who are at least 
37 weeks postmenstrual age at the time of screening, regardless 
of their actual gestational age at birth.
 
 
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SUMMARY OF CHANGES
PRIMARY REASON(S) FOR THIS AMENDMENT:
Section Number (s)
Section Title(s)
Description of Change (s)
Rationale
5.1.2
Subject Inclusion Criteria
Inclusion Criterion #4: Revised 
to 
allow 
enrollment 
into 
Cohort 5 of subjects who are at 
least 37 weeks postmenstrual 
age at the time of screening.
Eligible subjects will not be 
excluded from Cohort 5 based 
on gestational age at birth, as 
long as their postmenstrual age 
at the time of screening is at 
least 37 weeks.
ADDITIONAL CHANGE(S) FOR THIS AMENDMENT:
Section Number (s)
Section Title (s)
Description of Change (s)
Rationale
2.1
2.2
4.2.2.1
5.2.1.1
5.2.1.2.1
5.2.2
8.7
Trial Design
Trial Diagram
Starting Dose for This Trial
Dose Selection (Preparation)
Dose 
Modifications 
and 
Decisions 
After 
Interim 
Reviews
Timing of Dose Administration
Interim Reviews for Potential 
Dose Adjustment
Updated 
text 
to 
reflect
a) completion 
of 
Cohort 
4 
interim review and resulting 
dose 
modifications, 
as 
previously communicated via 
Protocol Clarification Letter, 
and 
b) completion 
of 
enrollment into Cohort 4.
Revised 
to 
incorporate 
summary 
of 
dose 
modifications implemented 
after the interim review after 
50% enrollment in Cohort 4.
 
 
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1.0 TRIAL SUMMARY
Abbreviated Title
A Single-dose Pharmacokinetics Study of MK-7655A in Pediatric 
Subjects
Sponsor Product Identifiers
MK-7655A (imipenem/cilastatin/relebactam [IMI/REL])
Generic Name: N/A
Trial Phase
Phase 1b
Clinical Indication
Treatment of bacterial infections in pediatric populations
Trial Type
Interventional
Type of control
No treatment control
Route of administration
Intravenous
Trial Blinding
Unblinded Open-label
Treatment Groups
MK-7655A (IMI/REL)
Number of trial subjects
Approximately 44 subjects will be enrolled.
Estimated duration of trial
The Sponsor estimates that the trial will require approximately 3 years
from the time the first subject signs the informed consent/assent until 
the last subject’s last study-related phone call or visit.
Duration of Participation
Each subject will participate in the trial for up to 18 days from the 
time the subject’s parent or legally acceptable representative signs the 
informed consent/assent form through the final contact. After a 
screening phase of up to 2 days, each subject will receive 1 dose of 
IMI/REL. After the single dose, each subject will be followed for 
14 (+2) days for adverse events.
A list of abbreviations used in this document can be found in Section 12.4 – List of 
Abbreviations.
2.0 TRIAL DESIGN
Trial Design
This is an open-label, noncomparative study of a single intravenous (IV) dose of MK-7655A
(a fixed-dose combination of imipenem/cilastatin/relebactam, hereafter referred to as 
IMI/REL) in male and female pediatric subjects from birth to less than 18 years of age 
receiving standard-of-care antibacterial therapy for treatment of a confirmed or suspected 
Gram-negative bacterial infection.
A minimum of 44 subjects will be enrolled, each into 1 of the following 5 pediatric age 
cohorts:

Cohort 1: Adolescents (age 12 to <18 years); at least 6 subjects

Cohort 2: Older children (6 to <12 years); at least 6 subjects

Cohort 3: Younger children (2 to <6 years); at least 6 subjects

Cohort 4: Infants and toddlers (3 months to <2 years); at least 8 subjects, at least 4 of 
whom are <1 year of age
 
 
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
Cohort 5: Neonates and young infants (birth to <3 months); at least 18 subjects, who 
will be further divided into the following age subcohorts:
o
4 weeks to <3 months of age; at least 6 subjects
o
1 to <4 weeks of age; at least 6 subjects
o
<1 week of age; at least 6 subjects
All subjects will receive a single dose of IMI/REL administered via IV infusion at the doses
specified in Table 2 of Section 5.2 – Trial Treatments. The initial dose for Cohorts 1, 2, and 3 
was IMI/REL 15/7.5 mg/kg, and single IV doses for all cohorts did not exceed the adult 
maximum dose of 500 mg IMI and 250 mg REL. The study design is depicted as a trial 
diagram in Section 2.2 – Trial Diagram.
For Cohorts 1, 2, and 3, enrollment was initiated in parallel, and an interim review was 
conducted in each age cohort after the first 3 (50%) subjects were enrolled, at which point, 
enrollment in that cohort was paused.
Enrollment in each cohort would continue past the third subject without dose modification 
until all 6 subjects were enrolled in Cohorts 1, 2, and 3 if the following occurred:
1. The interim review demonstrated that the selected initial dose was suitable based on 
pharmacokinetic (PK) target attainment that was similar to that in adults for a given
age cohort (details in Section 5.2.1.2 – Dose Modification), and
2. The dose demonstrated an acceptable safety profile in the exposed cohort, as 
described in Section 5.2.1.2 – Dose Modification.
Alternatively, enrollment in each cohort would continue with a dose modification based on 
Section 5.2.1.2 if the following occurred:
1. The interim review revealed a suboptimal (ie, too high or too low) initial dose based
on inadequate (ie, too high or too low) PK target attainment relative to adults for a 
given age cohort (details in Section 5.2.1.2 – Dose Modification), or
2. The safety profile was not acceptable.
Dose modifications following the interim reviews in Cohorts 1 through 3 are described in 
Section 5.2.1.2.1.
When enrollment of all 6 subjects each in Cohorts 1, 2, and 3 was completed, a second
interim review was performed in which aggregated data from Cohorts 1, 2, and 3 was used to 
(1) develop and refine a pediatric population PK model and conduct simulations to evaluate 
PK target attainment, and (2) assess whether the safety profile was acceptable for each age 
cohort. The findings from the second interim review were used to inform the proposed initial 
doses for Cohorts 4 and 5, which is 10/5 mg/kg IMI/REL. Subject enrollment of Cohorts 4 
and 5 was initiated in parallel.
For Cohorts 4 and 5, an interim review will be conducted in each age cohort after the first 
4 (50%) subjects are enrolled in Cohort 4 and the first 9 (50%) subjects are enrolled in 
Cohort 5 (regardless of subcohort), at which point, enrollment in that cohort will pause.
Enrollment will continue past the fourth subject in Cohort 4 and the ninth subject in Cohort 5 
without dose modification if the following occurs:
 
 
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1. The interim review demonstrates that the selected initial dose is suitable based on PK
target attainment that is similar to that in adults for a given age cohort (details in 
Section 5.2.1.2 – Dose Modification), and
2. The dose demonstrates an acceptable safety profile in the exposed cohort, as 
described in Section 5.2.1.2 – Dose Modification.
Alternatively, enrollment in each cohort will continue with a dose modification based on 
Section 5.2.1.2 – Dose Modification if the following occurs:
1. The interim review reveals a suboptimal (too high or too low) initial dose based on 
inadequate (too high or too low) PK target attainment relative to adults for a given 
age cohort (details in Section 5.2.1.2 – Dose Modification), or
2. The safety profile is not acceptable.
When enrollment into Cohorts 4 and 5 has been completed, a final analysis of PK and safety 
data will be performed with aggregated data from Cohorts 1 through 5 to refine the optimal 
dosing for pediatric subjects based on PK target attainment and an acceptable safety profile.
At the time of this protocol amendment (-02), enrollment into Cohort 4 has been completed. 
Dose modifications following the interim review (ie, after achieving 50% enrollment) in 
Cohort 4 are described in Section 5.2.1.2.1.
Any dose modifications for Cohort 5 will be selected and communicated as described in 
Section 5.2.1.2 – Dose Modification and will not exceed the single IV dosage of IMI/REL 
500/250 mg.
For each subject, PK parameters will be assessed for up to 6 hours and safety parameters will 
be assessed for up to 24 hours following the single IV dose of IMI/REL. Subjects will have a 
safety follow-up visit or telephone contact 14 (+2) days after the infusion.
Each subject will participate in the trial for up to 18 days from the time the subject’s parent 
or legally acceptable representative (LAR) signs the informed consent form through the final 
contact. This includes a screening phase of up to 2 days before receiving a single dose of 
IMI/REL, and then a follow-up period of 14 (+2) days.
Specific procedures to be performed during the trial, as well as their prescribed times and 
associated visit windows, are outlined in the Trial Flow Chart - Section 6.0. Details of each 
procedure are provided in Section 7.0 – Trial Procedures.
Trial Diagram
The trial design is depicted in Figure 1.
 
 
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Figure 1
Schematic of Study Design for Study MK-7655A-020
Abbreviations: IMI/REL: imipenem/cilastatin/relebactam; mos: months; PK: pharmacokinetic; TBD: to be 
determined; yrs: years
a.
Will not exceed a single IV dose of IMI/REL 500/250 mg.
b.
The criteria for PK and safety target achievement are described in Section 5.2.1.2 – Dose Modification. 
c.
New doses of IMI/REL will be selected and communicated as described in Section 5.2.1.2 – Dose 
Modification and will not exceed the single IV dosage of IMI/REL 500/250 mg. Dose modifications and 
decisions following the interim reviews in Cohorts 1 through 4 are described in Section 5.2.1.2.1.
 
 
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3.0 OBJECTIVE(S) & HYPOTHESIS(ES)
Primary Objective(s) & Hypothesis(es)
Objective:
To obtain plasma PK data and characterize the PK profile of imipenem, 
cilastatin, and relebactam (REL) following administration of a single IV dose of IMI/REL in 
pediatric subjects from birth to less than 18 years of age receiving standard-of-care 
antibacterial therapy for a confirmed or suspected Gram-negative bacterial infection.
Hypothesis: No formal hypothesis testing will be performed for this objective.
Secondary Objective(s) & Hypothesis(es)
Objective:  To evaluate the safety and tolerability profile of a single IV dose of IMI/REL in 
pediatric subjects from birth to less than 18 years of age receiving standard-of-care 
antibacterial therapy for a confirmed or suspected Gram-negative bacterial infection.
4.0 BACKGROUND & RATIONALE
Background
Refer to the Investigator’s Brochure (IB) for detailed background information on MK-
7655A.
Pharmaceutical and Therapeutic Background
MK-7655 (relebactam, referred to as REL) is a parenteral (IV), small-molecule β-lactamase 
inhibitor (BLI), which is being developed as a fixed-dose combination in a single vial with 
imipenem/cilastatin (referred to as IMI) for the treatment of infections caused by 
Gram-negative bacteria. Throughout this document,
the fixed-dose combination of 
imipenem/cilastatin/relebactam (MK-7655A) is referred to as IMI/REL.
β-lactam antibiotics (penicillins, cephalosporins, carbapenems, and monobactams) are among 
the most frequently used antimicrobial agents in clinical practice. The unrelenting 
development of resistance to these β-lactam antibiotics by the production of β-lactamases is 
the most important resistance mechanism among Gram-negative bacteria and poses an 
ongoing threat to the clinical utility of all β-lactams. Therefore, there is an urgent need for 
new BLIs that can be combined with existing β-lactam antibiotics to protect against 
hydrolysis by 1 or more of the 4 classes (A, B, C and D) of β-lactamase enzymes.
Relebactam represents a new generation of BLIs to combat evolving clinical resistance and 
to maintain the usefulness of the β-lactam class of antibiotics. Relebactam is an inhibitor of 
Ambler class A and class C BLIs. This BLI has sub-micromolar potency for AmpC, a class C 
β-lactamase responsible for resistance in a majority of imipenem-resistant Pseudomonas 
aeruginosa. In addition, REL is active against the class A KPC β-lactamase present in some 
Enterobacteriaceae, including Klebsiella strains, as well as against many other class A and C 
β-lactamases. Relebactam has no activity against the class B metallo-β-lactamases (including 
 
 
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NDM-1, IMP, or VIM-containing strains) or class D β-lactamases (including 
OXA-producing strains).
Preclinical and Clinical Trials
Preclinical Trials
Preclinical data, including in vitro microbiological studies with imipenem-resistant clinical 
isolates of P. aeruginosa and KPC-producing organisms, as well as in vivo infection models 
with imipenem-resistant P. aeruginosa and K. pneumoniae, suggest that REL, in combination 
with IMI, has the potential to fulfill a significant and growing medical need by providing a 
next-generation BLI to combat severe Gram-negative bacterial infections. Preclinical toxicity 
studies in rats and monkeys have demonstrated that REL is generally well tolerated. There 
was no evidence of adverse effects of REL as a single agent on cardiovascular, central 
nervous system, and respiratory function in well-characterized preclinical safety 
pharmacology models. In monkeys, reversible renal tubular degeneration was seen in 
monkeys at 7-fold the therapeutic exposure at 250 mg every 6 hours; however, no evidence 
of renal tubular epithelial degeneration or any other form of renal injury was detected up to 
3X the clinical exposure after 3 months of repeated dosing. Combination studies conducted 
in monkeys demonstrate that dosing with REL and IMI at 1X the projected therapeutic 
exposure was well tolerated, and antemortem and postmortem findings were similar to 
monkeys treated with IMI alone, demonstrating that toxicity is not exacerbated by the 
combination. In addition, no evidence of renal toxicity has been observed in clinical studies.
Preclinical Juvenile Toxicity Studies
Results from preclinical juvenile toxicity studies in rats have demonstrated that the 
no-observed-effect level for REL in juvenile rats was ≥450 mg/kg/day. Relebactam was 
administered to rats subcutaneously (postnatal day 14 to 34) or intravenously (postnatal 
day 35 to 56/57) once daily at doses of 0, 65, 200, or 450 mg/kg/day from postnatal week 3 
through postnatal week 9. There were no REL-related findings up to the maximum feasible 
dose of 450 mg/kg/day. Histomorphologic findings related to repeated IV administration 
were present at comparable incidences between control and REL-treated animals.
Phase 1 Clinical Trials
To date, REL has been evaluated in approximately 232 individuals who have received at 
least 1 dose of REL across 7 completed Phase 1 studies (PN001, PN002, PN005, PN007, 
PN009, PN012, and PN019). Healthy young and elderly adults of both sexes and adults of
varying degrees of renal insufficiency have been studied, including patients with end-stage 
renal disease on hemodialysis.
Unblinded safety data from the Phase 1 studies have demonstrated that single and multiple 
IV doses of REL have been generally safe and well tolerated throughout the dose ranges 
tested and across the various subject populations. In PN009 (a standard thorough QTc study 
evaluating the effect of REL on the QTc interval), a supratherapeutic dose of REL did not 
prolong the QTc interval to a clinically meaningful extent and no risk of cardiac 
repolarization prolongation was identified.
 
 
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In PN001, cases of mild elevations in hepatic transaminases above the upper limit of normal 
range (ULN) were observed in the multiple-dose treatment arms in which REL was 
coadministered with IMI. Elevations were also seen at similar frequencies in subjects 
receiving IMI alone. None of the liver transaminase elevations in these subjects were 
associated with clinical manifestations. The elevations were not dose-related and were 
reversible after discontinuation of dosing. Generally mild elevations in hepatic transaminases 
were also observed in Japanese subjects receiving multiple doses of REL in PN012. Similar 
to observations in PN001, the increases in alanine aminotransferase (ALT)/aspartate 
aminotransferase (AST) resolved after completion of dosing. Elevations have not been 
observed in subjects administered single or multiple doses in PN002, PN005, PN007, or 
single doses in PN009.
Pharmacokinetic data from Phase 1 studies demonstrate the following:

REL exposures increase proportionally with dose; doses at 125 mg and above 
adequately achieved and exceeded the identified REL PK target of area under the 
concentration time curve (AUC0-∞) ≥37.5 μM-hr.

For all age and gender comparisons, the 90% confidence intervals for the geometric 
mean ratios of AUC0-∞for REL, imipenem, and cilastatin fell completely within the 
(0.50 to 2.00) target interval. Therefore, no dose adjustments are recommended based 
on age or gender.

PK profiles of REL, imipenem, and cilastatin in healthy Japanese subjects were 
similar to historical data obtained from non-Japanese subjects.

PK data from a study of renal-impaired subjects (PN005) were consistent with 
expectations given that REL, imipenem, and cilastatin are cleared almost entirely 
renally in healthy subjects. Plasma clearance, terminal half-life (t1/2), and AUC0-∞
were significantly and similarly altered for each of these 3 analytes when comparing 
subjects with renal impairment to their healthy matched control subjects.

REL and imipenem penetrate to a similar extent into the extracellular (epithelial 
lining fluid) of the lung.

Supratherapeutic levels of REL had no impact on population-specific QTc.

REL has low potential for any clinically meaningful drug-drug interactions.
Phase 2 Clinical Trials
To date, coadministration of IMI and REL has been evaluated in 2 Phase 2 randomized, 
double-blind, multicenter, comparative studies evaluating the safety, tolerability, and efficacy 
of IMI + REL versus IMI alone in adults with complicated intra-abdominal infection (cIAI) 
(PN004; 351 subjects total) and in adults with complicated urinary tract infection (cUTI) 
including pyelonephritis (PN003; 302 subjects total). In each study, subjects were 
randomized in a 1:1:1 ratio to 1 of 3 treatment groups: (1) IMI + REL (250 mg), 
(2) IMI + REL (125 mg), or (3) IMI + placebo (to REL).
The primary efficacy analysis for each study indicates that treatment with either 250 mg or 
125 mg of IMI + REL is at least as effective as IMI alone as measured by the proportion of 
 
 
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subjects with favorable clinical (PN004) or microbiological (PN003) response at 
discontinuation of IV study therapy. Specifically, in PN004, the proportion of subjects in the 
primary analysis population with a favorable clinical response was 96.3% (78/81) in subjects 
who received IMI + REL (250 mg), 98.8% (85/86) in subjects who received IMI + REL 
(125 mg), and 95.2% (79/83) in subjects who received IMI + placebo. In PN003, the 
proportion of subjects in the primary analysis population with a favorable microbiological 
response was 95.5% (64/67) in subjects who received IMI + REL (250 mg), 98.6% (70/71) in 
subjects who received IMI + REL (125 mg), and 98.7% (74/75) in subjects who received 
IMI + placebo.
The incidence rate of adverse experiences observed in subjects in studies PN004 and PN003 
who received either dose of IMI + REL (either the 125 mg or the 250 mg dose of REL) was 
generally comparable to that observed in subjects who received IMI + placebo. No evidence 
of significant renal toxicity or hepatotoxicity was observed. Given the mild elevations in 
hepatic transaminases
observed in
PN001
(Section 4.1.2.2), close monitoring for 
transaminase elevations was included in PN004 and PN003. As part of this monitoring, the 
following 2 prespecified events of clinical interest (ECIs) triggered staged evaluation and 
monitoring of subjects with these elevations: (1) confirmed AST or ALT ≥5 × ULN, and (2) 
ALT or AST ≥3 × ULN and total bilirubin ≥2 × ULN and, at the same time, alkaline 
phosphatase <2 × ULN. These ECIs were experienced by a small number of subjects in each 
study (no more than 2 subjects in a given treatment group per study), and in both studies, 
there were no statistically significant differences in the percentage of subjects meeting the 
definition of either ECI between either of the 2 IMI + REL groups versus the IMI + placebo 
group.
Phase 3 Clinical Trials
One completed pivotal Phase 3 study (PN013) evaluated the safety and efficacy of the fixed-
dose combination IMI/REL versus comparator (colistin [in the form of colistimethate 
sodium, CMS] + IMI) in 50 subjects with hospital-acquired or ventilator-associated bacterial 
pneumonia (HABP/VABP), cIAI, or cUTI caused by imipenem-nonsusceptible Gram-
negative bacterial infections.  
In PN013, IMI/REL was at least as efficacious as CMS + IMI, as supported by the results of 
the primary and secondary efficacy endpoints as follows:

The primary efficacy endpoint of favorable overall response was achieved by a 
comparable percentage of subjects who received IMI/REL and CMS + IMI.

Favorable clinical response was achieved by a higher percentage of subjects who 
received IMI/REL than subjects who received CMS + IMI at all time points assessed.

All-cause mortality was experienced by a lower percentage of subjects who received 
IMI/REL than subjects who received CMS + IMI.
In addition, results from PN013 demonstrated that treatment with IMI/REL was well 
tolerated in critically ill subjects and had a more favorable safety profile than treatment with 
CMS + IMI. In addition, treatment with IMI/REL exhibited a more favorable renal safety 
profile than treatment with CMS + IMI, as demonstrated by a lower incidence of 
 
 
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treatment-emergent nephrotoxicity (a reported side effect of colistin) in subjects who 
received IMI/REL.
Ongoing Clinical Trials
The following studies in adults are currently ongoing:

Two Phase 3 studies to evaluate the safety and efficacy of IMI/REL compared with 
that of piperacillin/tazobactam in adult subjects with HABP/VABP (Protocol 014 
[PN014], which was initiated in early 2016 [first subject enrolled 28-JAN-2016], and 
Protocol 016 [PN016], which was initiated in 2018 [first subject enrolled 18-SEP-
2018]. PN016 is being conducted to support IMI/REL registration in China).

A Phase 3 study to evaluate the safety and efficacy of IMI/REL in Japanese adult 
subjects with cIAI or cUTI (Protocol 017 [PN017], which was initiated in late 2017 
[first subject enrolled 04-OCT-2017]). As of January 2019, enrollment was complete, 
but the final Clinical Study Report was not available.
Imipenem/Cilastatin Clinical Experience in Pediatric Populations
There has been considerable experience with the use of IMI in both adults and pediatric 
patients since its initial approval over 30 years ago. Imipenem/cilastatin is currently 
registered and approved in 106 countries. As of 27-JUN-2018, an estimated 35,853,953 
patients have been treated with IMI. To date, approximately 2,332 patients (including 
223 pediatric subjects) have been exposed to IMI alone or as part of an active comparator 
regimen in clinical trials conducted by the Sponsor. The 2 pediatric clinical trials conducted 
by the Sponsor were open-label studies to evaluate the efficacy, safety, tolerability, and PK 
of IMI in hospitalized pediatric subjects with serious bacterial infections, including intra-
abdominal, urinary tract, and respiratory tract infections. Imipenem/cilastatin was efficacious 
and generally well tolerated in both studies.
Rationale
Rationale for the Trial and Selected Subject Population
This is the first study in support of the pediatric development of IMI/REL for the treatment of 
bacterial infections caused by Gram-negative bacteria, including HABP, VABP, cUTI, and 
cIAI. Overall, the pathogenesis, microbiology, and treatment of these diseases are similar in 
pediatric patients and in adults.
Increasingly, multidrug resistant (MDR) Gram-negative bacteria, especially extended 
spectrum β-lactamase-producing organisms and carbapenem-resistant organisms, are 
becoming a worldwide problem in both adult as well as pediatric patients. Multidrug 
resistance severely limits the utility of currently available antibacterials. Although new and 
effective antibacterials have been introduced to combat MDR Gram-positive organisms, 
clinicians have been forced to utilize older drugs with known limitations in the treatment of 
resistant Gram-negative pathogens, most notably those with carbapenem resistance. Due to 
the 
absence 
of 
effective 
and 
tolerable 
antibacterials, 
infections 
caused 
by 
carbapenem-resistant Gram-negative organisms have a high mortality rate. Even with 
 
 
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treatment using last-resort therapies such as colistin, mortality rates in critically ill patients 
with MDR pathogens, including carbapenem-resistant pathogens, range from 16% up to as 
high as 60% [1, 2, 3, 4, 5].
As with adults, infections caused by extended spectrum β-lactamase-producing organisms in 
pediatric patients are associated with longer hospital stays, frequent complications, and 
increased mortality, at higher than adult rates in certain regions [6, 7, 8]. Pediatric patients 
are particularly vulnerable to MDR Gram-negative pathogens due to lack of broad-spectrum 
antibiotics approved for use in pediatric patients. For treatment of carbapenem-resistant 
Enterobacteriaceae infections in pediatric patients, there are few treatment alternatives, such 
as 
aminoglycoside 
monotherapy, 
fluoroquinolones, 
trimethoprim-sulfamethoxazole,
fosfomycin, and nitrofurantoin (mostly for treatment of uncomplicated urinary tract 
infection). Many of these antibiotics have limitations, such as the rapid emergence of 
resistance when aminoglycosides are used as single agents for bacteremia and the caution 
that needs to be exercised when prescribing fluoroquinolones to pediatric patients owing to 
osteoarticular side-effects observed in animal models [9].
As treatment options are limited for MDR infections, and given that there are fewer 
antibiotics approved for use in pediatric patients as well as the dearth of clinical trials 
conducted in pediatric patients, the problem is even more critically important to address [9]. 
Carbapenems are the mainstay of treatment of MDR Gram-negative infections; therefore, the 
emergence of carbapenem-resistant organisms in recent years is particularly worrisome [10].
The addition of REL to IMI to restore IMI susceptibility for pathogens that produce class A 
and C β-lactamases therefore addresses an area of growing unmet medical need. 
Furthermore, IMI/REL is unique among β-lactam/BLI combinations in development due to 
the long history of pediatric safety and efficacy (Section 4.1.4 – Imipenem/Cilastatin Clinical 
Experience in Pediatric Populations) and the broad spectrum of activity of the β-lactam 
compound.
The current United States (US) Food and Drug Administration guidance document for 
pediatric PK studies focuses on appropriate dosing in the pediatric population based on PK 
data [11]. The PK of a drug in the pediatric population usually cannot be precisely predicted 
from PK or clinical studies of adult subjects; rather, specific PK studies in pediatric subjects 
are needed to determine appropriate pediatric dosing. Thus, the current study will be 
conducted to investigate the PK and safety of a single IV dose of IMI/REL in pediatric 
subjects from birth to <18 years of age receiving standard-of-care antibacterials for treatment 
of confirmed or suspected Gram-negative bacterial infection. The current study will be 
conducted using 5 age cohorts, with the predominance of subjects in the youngest age cohort, 
in accordance with guidance from the Food and Drug Administration and the European 
Medicines Agency (EMA). The information from this study will be used to determine 
appropriate dosing regimens for a subsequent efficacy study of IMI/REL in a pediatric 
population.
 
 
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Rationale for Dose Selection/Regimen/Modification
Starting Dose for This Trial
The initial dose of IMI for pediatric subjects in Cohorts 1 through 3 in this study was 
15 mg/kg, as designated in the current IMI label (PRIMAXIN® and TIENAM®). The dosing 
ratio of 2:1 for IMI:REL that is used in adult Phase 2 and 3 trials is used in the current trial. 
Thus, the initial dose of REL for pediatric subjects in Cohorts 1 through 3 was 7.5 mg/kg. 
The initial doses were modified (maintaining the 2:1 IMI:REL dosing ratio) based on interim 
reviews in each age cohort, per the criteria described in Section 5.2.1.2 – Dose Modification.
The dose modifications for Cohorts 1 through 3 are described in Section 5.2.1.2.1.
The initial dose of IMI/REL for pediatric subjects in Cohorts 4 and 5 was selected based on 
updated PK modeling and simulation analyses, after incorporating observed PK data from 
Cohorts 1 through 3 during the second interim review (Section 5.2.1.2.1). For Cohort 4, the 
initial dose of 10/5 mg/kg was modified based on the interim review as described in 
Section 5.2.1.2.1. For Cohort 5, the initial dose of 10/5 mg/kg may later be modified 
(maintaining the 2:1 IMI:REL dosing ratio) based on subsequent interim reviews in that age 
cohort.
Maximum Dose/Exposure for This Trial
As described in Section 5.2.1.2 – Dose Modification, the doses for each age cohort in this 
study may be modified based on results of observed PK data from interim reviews. The final 
pediatric doses will not exceed the dosage currently under study for adult subjects in 
2 separate Phase 3 trials (ie, maximum single IV dose of IMI/REL 500/250 mg).
Rationale for Dose Interval and Trial Design
A single IV dose of IMI/REL will be administered to each subject in this study. A 
single-dose rather than a multiple-dose study design was selected from the observed PK 
properties of IMI/REL in adults. A short half-life (approximately 30 to 60 minutes) of both 
imipenem and REL and lack of accumulation of any drug components was observed in adult 
studies; these properties are expected to be the same in pediatric subjects.
Rationale for Endpoints
Pharmacokinetic/Pharmacodynamic Endpoints
Based on established literature in the field and data from the adult development program, 
efficacy of IMI/REL is driven by the time spent above the minimum inhibitory concentration 
(TMIC) within the dosing interval for imipenem and by drug exposure (as measured by 
AUC) for REL. Because the pathogenesis and microbiology of the infections for which 
IMI/REL is being developed are similar in adult and pediatric populations, the PK targets 
selected in this trial are the same as those for adults. For REL, exposure is the metric of 
interest, with a target of AUC0- ∞≥37.5 μM-hr (and ≤200 μM-hr) after single-dose IV 
administration of IMI/REL. For imipenem, the target is for subjects to have TMIC of ≥30%
for relevant minimum inhibitory concentrations of interest (and AUC0-∞≤250 μM-hr). Doses 
 
 
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of IMI/REL associated with this exposure and TMIC have been established as being safe and 
efficacious in adults.
Plasma concentrations of REL, imipenem, and cilastatin will be determined. The REL and 
imipenem data will be used to develop a pediatric population PK model, using the adult 
model as a starting point; the model will then be used in simulations to determine suitable 
dosing regimens for subsequent and separate pediatric clinical efficacy trials. The PK 
properties of cilastatin based on data from this trial will also be described.
Rationale for PK Sampling Scheme
Pharmacokinetic sampling will be conducted in each age cohort, taking into consideration the
likely minimum body weight of each age cohort and recommended limits on pediatric blood 
sampling.
Four PK samples per subject will be collected in each of the age cohorts as follows:
1. First PK sample: predose sample taken within 30 minutes before the start of study 
drug infusion.
2. Second PK sample: collected within 10 minutes after the end of study drug infusion.
3. Third PK sample:

Cohorts 1 through 4: obtained 1.5 to 2.5 hours after the start of study drug
infusion.

Cohort 5: obtained 2 to 5 hours after the start of study drug infusion.
4. Fourth PK sample:

Cohorts 1 through 4: obtained 4.5 to 6 hours after the start of study drug 
infusion.

Cohort 5: obtained 6 to 12 hours after the start of study drug infusion.
All PK samples must be drawn within the specified time windows, and the actual sampling 
times must be documented. The first PK sample establishes a baseline and will allow for 
evaluation of bioanalytical interference (ie, to ensure there is no analyte of interest detected 
before dosing). The second PK sample will be used to determine the maximum observed 
plasma concentration (Cmax). The third and fourth PK samples will provide data during the 
elimination phase of the study drug and thus, will allow characterization of the selected PK
parameters, AUC0-∞and TMIC. For Cohort 5, a full PK profile is anticipated by the end of 
6 hours; however, sampling out to 12 hours will provide additional information regarding the 
elimination tail. The above sampling scheme allows for a balance between the maximum 
coverage of the concentration profile across time required to adequately characterize the PK, 
while minimizing the number of blood samples per subject.
Safety Endpoints
Safety will be assessed through descriptive statistics within the safety analysis population for 
each age cohort. Safety assessments will include AEs, local tolerability assessments, clinical 
laboratory evaluations, vital sign measurements, and physical examinations.
 
 
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Benefit/Risk
In this trial, subjects will receive a single IV infusion of IMI/REL in addition to 
standard-of-care treatment. No direct or immediate clinical benefit is anticipated from 
participation in this single-dose PK study. While no direct clinical benefit to participants is 
anticipated, the risks of administration of a single dose of IMI/REL are considered to be 
minimal. Imipenem/cilastatin has a well-established safety and tolerability profile among 
pediatric patients, both from the pediatric development program and from decades of clinical 
use for serious bacterial infections (see more in Section 4.1.4 – Imipenem/Cilastatin Clinical 
Experience in Pediatric Populations). Furthermore, there are no significant or excessive 
adverse effects observed among other clinical studies involving IMI/REL to date (see more 
in Section 4.1.2 – Preclinical and Clinical Trials and Section 4.1.3 – Ongoing Clinical 
Trials).
Obtaining blood samples for PK analysis does pose a small risk, which is minimized by 
imposing blood sampling volume limits and reducing the frequency of sampling. Although 
more frequent, the proposed study procedures described in Section 6.0 – Trial Flow Chart are 
generally standard procedures performed for the target patient population (eg, chemistry and 
hematology measurements). One study visit is scheduled 14 days after study drug infusion 
and therefore will occur generally when the subject is no longer expected to be hospitalized; 
this visit can be conducted in person at the study site or by telephone, and only a concomitant 
medication review and AE monitoring will be conducted.
The procedures required for this protocol are necessary to support thorough evaluation of the 
PK and safety profile of the study drug. A thorough assessment of PK and safety in this study 
will support determination of adequate and safe dosing for evaluation of efficacy of treatment 
in subsequent confirmatory trial(s), thus ensuring an ethically sound treatment regimen that 
will minimize potential for treatment failure in this vulnerable population. As such, data from 
this study present a future opportunity to support availability of IMI/REL to pediatric patients
with unmet medical need.
Notably, subjects are required to be concomitantly receiving or to have recently completed 
(within 48 hours prior to study drug administration) standard-of-care antibacterial treatment 
for their confirmed or suspected underlying infection. No reliance is placed on the single 
dose of IMI/REL to provide efficacious treatment.
Additional details regarding specific benefits and risks for subjects participating in this 
clinical trial may be found in the accompanying IB and informed consent documents.
5.0 METHODOLOGY
Entry Criteria
Diagnosis/Condition for Entry into the Trial
Male and female subjects from birth to <18 years of age with confirmed or suspected 
Gram-negative bacterial infection will be enrolled in this trial.
 
 
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Subject Inclusion Criteria
In order to be eligible for participation in this trial, the subject must:
1. Have a parent or LAR who provides written informed consent for the trial on the 
subject’s behalf after understanding the study procedures, alternative treatments 
available, and risks involved with the study, and voluntarily agrees to allow the 
subject to participate. Assent is to be obtained from minors as applicable according to 
institutional practices.
2. Be able to comply with the protocol for the duration of the study.
3. Be male or female from birth to <18 years of age at screening.
4. For Cohorts 4 and 5, is at least 37 weeks postmenstrual age at the time of screening. 
Postmenstrual age is calculated by adding the gestational age at the time of birth to 
the chronological age at the time of screening.
5. Be hospitalized, currently receiving antibacterial treatment for confirmed or suspected 
Gram-negative bacterial infection, and expected to require hospitalization until at 
least 24 hours after completion of study drug administration. Subjects who are not 
receiving antibacterial treatment for the qualifying infection at the time of screening 
are eligible for this trial if either (1) they will be initiating antibacterial treatment for 
the qualifying infection prior to study drug administration, or (2) they have recently 
(within 48 hours prior to study drug administration) completed antibacterial treatment 
for the qualifying infection.
6. Meet 1 of the following categories:
a) The subject is a male who is not of reproductive potential, defined as a male who 
has azoospermia (whether due to having had a vasectomy or due to an underlying 
medical condition).
b) The subject is a female who is not of reproductive potential, defined as a female 
who either: (1) who has not undergone menarche, (2) has had a hysterectomy and/or 
bilateral oophorectomy, bilateral salpingectomy, or bilateral tubal ligation/occlusion 
at least 6 weeks prior to screening, OR (3) has a congenital or acquired condition that 
prevents childbearing.
c) The subject is a female or a male who is of reproductive potential and agrees to 
avoid becoming pregnant or impregnating a partner from the time of consent through 
24 hours after completion of study drug administration by complying with 1 of the 
following:  (1) practice abstinence from heterosexual activity OR (2) use (or have 
their partner use) acceptable contraception during heterosexual activity. Acceptable 
methods of contraception are:
Single method (1 of the following is acceptable):

Intrauterine device

Vasectomy of a female subject’s male partner

Contraceptive rod implanted into the skin
 
 
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Combination method (requires use of 2 of the following):

Diaphragm with spermicide (cannot be used in conjunction with cervical 
cap/spermicide)

Cervical cap with spermicide (nulliparous women only)

Contraceptive sponge (nulliparous women only)

Male condom or female condom (cannot be used together)

Hormonal contraceptive: oral contraceptive pill (estrogen/progestin pill or 
progestin-only pill), contraceptive skin patch, vaginal contraceptive ring, 
or subcutaneous contraceptive injection
Abstinence (relative to heterosexual activity) can be used as the sole method of 
contraception if it is consistently employed as the subject’s preferred and usual 
lifestyle and if considered acceptable by local regulatory agencies and Ethical Review 
Committee (ERCs)/Institutional Review Boards (IRBs). Periodic abstinence (eg, 
calendar, ovulation, sympto-thermal, post-ovulation methods, etc.) and withdrawal 
are not acceptable methods of contraception.
If a contraceptive method listed above is restricted by local regulations/guidelines, 
then it does not qualify as an acceptable method of contraception for subjects 
participating at sites in this country/region.
7. Have clinically stable renal function at the time of screening that is judged to be 
within acceptable ranges for age, as measured by creatinine clearance and as defined 
in Section 12.3.
8. Have sufficient intravascular access to receive study drug through an existing 
peripheral or central line.
Subject Exclusion Criteria
The subject must be excluded from participating in the trial if the subject:
1. Has a personal history of hypersensitivity to IMI or to any of the following:

Any carbapenem, cephalosporin, penicillin, or other β-lactam agent

Other BLIs (eg, tazobactam, sulbactam, clavulanic acid, avibactam)
2. If female, is currently pregnant or breast feeding or has a positive serum β-human 
chorionic gonadotropin (β-hCG) pregnancy test prior to administration of the study 
drug.
3. Has a history of a seizure disorder (requiring ongoing treatment with anti-convulsive 
therapy or prior treatment with anti-convulsive therapy within the last 3 years).
4. Has used or plans to use valproic acid or divalproex sodium within 2 weeks prior to 
screening or at any point between screening and 24 hours after the completion of 
study drug infusion.
 
 
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5. Has received treatment or plans to receive treatment with any carbapenem antibiotic
within 48 hours prior to initiation of study drug infusion or at any point between 
administration of study drug and the last PK sample collection.
6. Has used or plans to use any of the following medications, which are organic anion 
transporter (OAT) 1 or OAT3 inhibitors, within 1 week prior to screening or at any 
point between screening and the last PK sample collection: cimetidine, probenecid, 
indomethacin, mefenamic acid, furosemide or other loop diuretics (eg, bumetanide, 
torsemide, ethacrynic acid), angiotensin receptor blockers (eg, valsartan), and 
ketorolac.
7. Is currently participating in or has participated in an interventional clinical trial with 
an investigational compound or device within 30 days prior to screening.
8. Has enrolled previously in the current trial and been discontinued, or has received 
REL for any other reason.
9. Has a current diagnosis of cystic fibrosis, meningitis, or severe sepsis.
10. Has a history or current evidence of any condition, therapy, laboratory abnormality, 
or other circumstance that might expose the subject to risk by participating in the 
trial, confound the results of the trial, or interfere with the subject’s participation for 
the full duration of the trial.
11. Is expected to survive less than 72 hours after completion of study drug 
administration.
12. Has any of the following laboratory abnormalities at the time of screening (with the 
exception of values, as determined by the investigator, that would be part of normal 
physiologic process for a particular age group [eg, physiologic hyperbilirubinemia in 
a newborn]):

ALT or AST ≥3 × ULN,

ALT or AST ≥2 × ULN accompanied by total bilirubin >ULN,

Total bilirubin ≥2 × ULN, or

Any other clinically significant abnormal laboratory test results not related to 
the underlying infection, as determined by the investigator.
13. Has a history of clinically significant renal, hepatic, or hemodynamic instability 
(defined as a requirement for pharmacological intervention to manage blood pressure 
in the 24-hour window prior to enrollment).
14. Has planned use of cardiopulmonary bypass, extracorporeal membrane oxygenation, 
hemodialysis, or peritoneal dialysis during the study.
15. For Cohorts 1 through 3 only: Has weight outside of the 5th to 95th percentile based 
on age.
16. Is, at the time of signing informed consent, a user of recreational or illicit drugs or has 
had a recent history (within the last year) of drug or alcohol abuse or dependence.
 
 
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17. Has a planned blood transfusion within 24 hours of study drug administration or 
expected before the end of the PK sampling.
18. Has had significant blood loss (≥5% of total blood volume) within 4 weeks before the 
screening visit. Total blood volume can be estimated as 80 mL/kg of body weight.
19. Is or has an immediate family member (e.g., spouse, parent/legal guardian, sibling or 
child) who is investigational site or sponsor staff directly involved with this trial.
Trial Treatment(s)
The treatment to be used in this trial is outlined below in Table 1.
Table 1
Trial Treatment
Drug
Dose/Potency
Dose 
Frequency
Route of 
Administration
Regimen
Use
IMI/RELa
Varies based on age 
cohort (Table 2)
Maximum dosage: 
Single IV infusion 
of 
500 mg IMI/ 
250 mg REL
Single 
dose
IVb
Visit 2 
(Study 
Day 1)
Experimental
Abbreviation: IMI/REL: imipenem/cilastatin/relebactam
a IMI/REL will be provided as a fixed-dose combination in a single vial.
b Infused over 30 (±5) minutes (initial infusion duration for Cohorts 1 through 3; see Section 5.2.1.2.1 for modifications for 
these age cohorts) or 60 (±5) minutes (initial infusion duration for Cohorts 4 and 5).
A single IV dose of IMI/REL will be administered to subjects any time after initiating 
standard-of-care treatment for a confirmed or suspected Gram-negative bacterial infection.
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of trial 
treatments in accordance with the protocol and any applicable laws and regulations.
Dose Selection/Modification
Dose Selection (Preparation)
Table 2 displays the proposed initial doses of the study drug for each age cohort. The 
proposed initial doses may be modified as described in Section 5.2.1.2 – Dose Modification.
The dose modifications for Cohorts 1 through 4 that occurred as a result of the first interim 
review in these cohorts (ie, after 50% enrollment; see Section 8.7) are described in 
Section 5.2.1.2.1, along with the results of the second interim review (ie, following 
completion of enrollment in Cohorts 1 through 3) that led to the initial doses for Cohorts 4 
and 5.
 
 
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Table 2
Imipenem/Cilastatin/Relebactam (IMI/REL) Doses by Age Cohort
Age Cohort
Age Range
IMI/REL 
Proposed Initial Dosea
1 (n=6)
12 to <18 years
15/7.5 mg/kg over 30 min
2 (n=6)
6 to <12 years
15/7.5 mg/kg over 30 min
3 (n=6)
2 to <6 years
15/7.5 mg/kg over 30 min
4 (n=8)
3 months to <2 yearsb
10/5 mg/kg over 60 min c
5 (n=18)
Birth to <3 monthsd
10/5 mg/kg over 60 min c
Abbreviations: IMI/REL: imipenem/cilastatin/relebactam; TBD: to be determined
a The proposed initial doses may be modified based on interim data as described in Section 5.2.1.2 – Dose 
Modification. The dose modifications for Cohorts 1 through 4 that occurred as a result of the first interim 
review in these cohorts are described in Section 5.2.1.2.1. Single IV doses for all cohorts will not exceed the 
adult maximum dose of 500 mg IMI and 250 mg REL.
b At least 4 subjects in Cohort 4 will be <1 year of age.
c Initial doses of IMI/REL for subjects in Cohorts 4 and 5 were selected based on PK modeling and simulation 
analyses, after incorporating observed PK data from Cohorts 1 through 3 (Section 5.2.1.2.1). Initial doses for 
Cohorts 4 and 5 were communicated to sites via a Protocol Clarification Letter.
d Cohort 5 will be further subdivided into the following 3 age subcohorts:

4 weeks to <3 months of age; at least 6 subjects

1 to <4 weeks of age; at least 6 subjects

<1 week of age; at least 6 subjects
The rationale for selection of doses to be used in this trial is provided in Section 4.0 –
Background & Rationale. Additional details for preparation and administration of study drug 
are provided in a separate Pharmacy Manual.
Dose Modification
The goal of this trial is to determine doses of IMI/REL for each pediatric age cohort that 
achieve similar therapeutic exposure parameters as seen in clinical trials in adults and have 
an acceptable safety profile. As such, all observed PK data will be entered into a rolling 
population PK model-based simulation. For each age cohort, the Sponsor will assess dose 
suitability during the planned interim reviews based on the observed PK and safety data from 
the first half of subjects enrolled into the cohort. The following parameters will be considered 
in determination of pediatric doses:

Simulated population PK parameters for each age cohort approach the following 
values, as expected in adults:
o
Single-dose REL exposure of AUC0-∞≥37.5 μM-hr (and ≤200 μM-hr). Doses 
associated with this exposure have been established as being well tolerated in 
adults.
o
≥30% TMIC (within proposed dosing interval) for single-dose imipenem (and 
AUC0-∞≤250 μM-hr). Doses achieving these targets have been established as 
safe and efficacious in adults.
 
 
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
Observed safety data demonstrates an acceptable safety profile, as defined by no 
life-threatening toxicities considered by the investigator to be related to study 
treatment. Life-threatening toxicities are defined as follows:
o
For laboratory AEs, a grade of 4 on the Division of Microbiology and 
Infectious Diseases pediatric toxicity scale [12].
o
For clinical AEs, events that are considered serious due to being 
life-threatening, as defined in Section 7.2.4 – Evaluating Adverse Events and 
as documented on the electronic case report form (eCRF).
Modified doses will not exceed the adult maximum of 500 mg IMI and 250 mg REL for a 
single IV dose, and dose modifications, if required, will be communicated to sites via 
Protocol Clarification Letters.
Dose Modifications and Decisions After Interim Reviews
At the time of this protocol amendment (-02), enrollment into Cohorts 1 through 4 has been 
completed. As planned, protocol-defined interim reviews of safety and PK data were 
completed for the first 50% of subjects in each age cohort. The dose modifications that were 
made as a result of the interim reviews are shown in Figure 2. These dose modifications were 
communicated to sites via Protocol Clarification Letters and are based on the following
considerations:

At time of enrolling Cohorts 1 through 3, no pediatric-specific population PK model 
for imipenem and REL was available; therefore, PK endpoints from these cohorts 
were estimated based on an allometrically-scaled adult population PK model. The 
interim reviews in each cohort showed that the scaled adult model appropriately 
described the observed imipenem and REL concentrations from pediatric subjects in 
Cohorts 1 through 3.

Cohort 1: At the initial dosing guidance of 15/7.5 mg/kg IMI/REL as a 30-minute IV 
infusion, all subjects received the full adult dose of 500/250 mg IMI/REL based on 
their weight. Based on modeling, likely weights of subjects in the age cohort would 
almost always necessitate the full 500/250 mg dose of IMI/REL; therefore, the dosing 
regimen was simplified to a flat single dose of 500/250 mg IMI/REL administered as 
a 30-minute IV infusion for the remaining subjects of Cohort 1.

Cohort 2: Simulations showed that by increasing the study drug infusion duration 
from 30 minutes to 60 minutes at the proposed initial dose of 15/7.5 mg/kg IMI/REL, 
>90% of subjects in this age cohort would meet the protocol-defined safety targets, 
and ~ 75% of subjects in this age cohort would meet PK targets for both imipenem 
and REL. Therefore, the dosing regimen was changed to 15/7.5 mg/kg IMI/REL as a 
60-minute intravenous infusion for the remaining Cohort 2 subjects in order to ensure 
the majority of patients met the safety and PK targets.

Cohort 3: Simulations showed that by infusing IMI/REL at 15/7.5 mg/kg over 
60 minutes (rather than over 30 minutes), ~98% of subjects in this age cohort would 
meet the protocol-defined safety targets for both imipenem and REL. Furthermore, a 
change in the infusion period from 30 minutes to 60 minutes was consistent with the 
 
 
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updated regimen for the remaining subjects in Cohort 2. Therefore, the dosing 
regimen was changed to 15/7.5 mg/kg IMI/REL as a 60-minute intravenous infusion 
for the remaining Cohort 3 subjects.
After completion of enrollment of Cohorts 1 through 3 (2 to <18 years of age), the protocol-
defined interim review of aggregate safety and PK data from these 3 cohorts was conducted.
The observed safety data for all 19 subjects who received IMI/REL demonstrated an 
acceptable safety profile. PK data from the 18 PK evaluable subjects were used to develop a
pediatric-specific population PK model for imipenem and relebactam. In order to extrapolate 
the developed pediatric population PK model for the older cohorts (2 to <18 years of age) to 
Cohorts 4 and 5 (<2 years of age), an adjustment function was included to account for a lack 
of full renal maturation for the subjects in this age range. Simulations were conducted to 
project the initial doses for Cohorts 4 and 5. The dosing regimen specified in Table 2 for 
Cohorts 4 and 5 was selected based on drug exposures that were projected to provide optimal 
probability of safety and efficacy.
For Cohort 4, simulations from the interim review showed that infusing IMI/REL at 
15/7.5 mg/kg (rather than 10/5 mg/kg) over 60 minutes would result in projected efficacy and 
safety targets similar to the evaluated initial Cohort 4 dose of 10/5 mg/kg. Furthermore, 
choosing a 15/7.5 mg/kg dose for the remaining 4 subjects enabled data collection over an 
expanded dosing range, and therefore supports population PK model optimization and future 
clinical use. Additionally, the 15/7.5 mg/kg dosing regimen of IMI/REL is consistent with 
the current PRIMAXIN®/TIENAM® (imipenem/cilastatin) dosing recommendations for 
pediatric patients, for which there is a long history of safe and efficacious use.
Figure 2
Dose Modifications for Cohorts 1, 2, 3, and 4 After Interim Reviews
 
 
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Timing of Dose Administration
A single dose of IMI/REL will be administered as an IV infusion. The infusion durations for 
each age cohort are as follows:

Cohorts 1 through 3: subjects enrolled prior to the 50% interim review for each of 
these cohorts received a 30 (±5)-minute infusion. Following the interim review (see 
Section 5.2.1.2.1), subjects in these cohorts received a 60 (±5)-minute infusion.

Cohort 4:
subjects enrolled prior to the 50% interim review received a 
60 (±5)-minute infusion. Following the interim review (see Section 5.2.1.2.1), 
remaining subjects in this cohort also received a 60 (±5)-minute infusion.

Cohort 5: 60 (±5) minutes. Any modification to this infusion duration following the 
planned interim reviews will be communicated via a Protocol Clarification Letter.
The dose can be administered any time after initiating standard-of-care treatment for a 
confirmed or suspected Gram-negative bacterial infection, but no more than 48 hours
following the screening visit for this study and no more than 48 hours after completing 
antibacterial treatment for the qualifying infection. The study drug must not be administered 
simultaneously through the same infusion line/lumen with any other drugs (including IV 
nonstudy drugs). If another IV drug is required either prior to or after study drug and only 1 
line/lumen is available, an appropriate volume of saline flush must be used between IV 
infusions.
Trial Blinding 
This is an open-label trial; therefore, the Sponsor, investigator and subject will know the 
treatment administered.
Randomization or Treatment Allocation
During the course of the study, subjects will be allocated to age cohorts by nonrandom 
assignment. After the informed consent form is signed by the parent or LAR and study 
eligibility is confirmed, designated site study staff will obtain the subject’s 
treatment/randomization number from a computer-generated code via interactive voice or 
web response system (IVRS or IWRS).
Stratification
Treatment allocation/randomization will be stratified according to the following factors:
1. Age:  subjects will be allocated to age cohorts as described in Section 2.1 – Trial 
Design.
Concomitant Medications/Vaccinations (Allowed & Prohibited)
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial.  If there is a clinical indication for any medication or vaccination 
specifically prohibited during the trial, discontinuation from trial therapy or vaccination may 
 
 
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be required.  The investigator should discuss any questions regarding this with the Sponsor 
Clinical Director.  The final decision on any supportive therapy or vaccination rests with the 
investigator and/or the subject's primary physician.  However, the decision to continue the 
subject on trial therapy or vaccination schedule requires the mutual agreement of the 
investigator, the Sponsor and the subject’s legally acceptable representative.
Listed below are specific restrictions for concomitant therapy during the course of the trial:
1. Valproic acid or divalproex sodium within 2 weeks prior to screening or at any point 
between screening and 24 hours after the completion of study drug infusion.
2. Any carbapenem antibiotic within 48 hours prior to initiation of study drug infusion 
or at any point between administration of study drug and the last PK sample 
collection.
3. Has used or plans to use any of the following medications, which are OAT1 or OAT3 
inhibitors, within 1 week prior to screening or at any point between screening and the 
last PK sample collection: cimetidine, probenecid, indomethacin, mefenamic acid, 
furosemide or other loop diuretics (eg, bumetanide, torsemide, ethacrynic acid), 
angiotensin receptor blockers (eg, valsartan), and ketorolac.
Rescue Medications & Supportive Care
No rescue or supportive medications are specified to be used in this trial.
Diet/Activity/Other Considerations
Subjects will refrain from consumption of alcohol from screening through 24 hours after the 
completion of study drug infusion.
Subjects will avoid strenuous physical activity (eg, weight lifting, running, bicycling) from 
screening through 24 hours after the completion of study drug infusion.
Subject Withdrawal/Discontinuation Criteria
Discontinuation of Treatment
Discontinuation of treatment (for this single-dose study, this would be discontinuation of 
study drug partway through the infusion) does not represent withdrawal from the trial.
As certain data on clinical events beyond treatment discontinuation may be important to the 
study, they must be collected through the subject’s last scheduled follow-up, even if the 
subject has discontinued treatment.  Therefore, all subjects who discontinue trial treatment 
prior to completion of the treatment will still continue to participate in the trial as specified in 
Section 6.0 – Trial Flow Chart and Section 7.1.5.3 – Discontinued Subjects Continuing to be 
Monitored in the Trial.
Subjects may discontinue treatment at any time for any reason or be dropped from treatment 
at the discretion of the investigator should any untoward effect occur.  In addition, a subject 
may be discontinued from treatment by the investigator or the Sponsor if treatment is 
inappropriate, the trial plan is violated, or for administrative and/or other safety reasons.  
 
 
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Specific details regarding procedures to be performed at treatment discontinuation are 
provided in Section 7.1.4 – Other Procedures.
A subject must be discontinued from treatment but continue to be monitored in the trial for 
any of the following reasons:
o
The subject or subject’s legally acceptable representative requests to discontinue 
treatment.
o
The subject has a medical condition or personal circumstance that, in the opinion of 
the investigator and/or Sponsor, places the subject at unnecessary risk from continued 
administration of study drug.
For subjects who are discontinued from treatment but continue to be monitored in the trial, 
see Section 6.0 – Trial Flow Chart, and Section 7.1.5.3 – Discontinued Subjects Continuing 
to be Monitored in the Trial for those procedures to be completed at each specified visit.
Discontinuation from treatment is “permanent.” Once a subject is discontinued, he/she shall 
not be allowed to restart treatment.
Withdrawal from the Trial
Subjects may withdraw from the trial at any time for any reason.  If a subject withdraws from 
the trial, they will no longer receive treatment or be followed at scheduled protocol visits.
A subject must be withdrawn from the trial if:
○
The subject or subject’s legally acceptable representative withdraws consent from the 
trial.
○
The subject is lost to follow-up.
Specific details regarding procedures to be performed at the time of withdrawal from the trial 
are outlined in Section 7.1.4 – Other Procedures.
Subject Replacement Strategy
If a subject discontinues from trial treatment, withdraws from the trial, or is missing PK 
samples, a replacement subject may be enrolled if deemed appropriate by the Sponsor in 
order to ensure that a sufficient number of evaluable PK samples are collected in each age 
cohort.
The replacement subject will be assigned a unique treatment/randomization number by the 
IVRS or IWRS. The subject being replaced will still be included in the safety analysis if they 
received any study treatment.
Beginning and End of the Trial
The overall trial begins when the first subject signs the informed consent/assent form.  The 
overall trial ends when the last subject completes the last study-related phone-call or visit,
withdraws from the trial or is lost to follow-up (i.e. the subject is unable to be contacted by 
the investigator).
 
 
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Clinical Criteria for Early Trial Termination
The clinical trial may be terminated early if the extent (incidence and/or severity) of 
emerging effects/clinical endpoints is such that the risk/benefit ratio to the trial population as 
a whole is unacceptable.  In addition, further recruitment in the trial or at (a) particular trial 
site(s) may be stopped due to insufficient compliance with the protocol, GCP and/or other 
applicable regulatory requirements, procedure-related problems or the number of 
discontinuations for administrative reasons is too high.
 
 
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6.0 TRIAL FLOW CHART
Trial Period:
Screening
Treatment
Post-treatment
Early 
Discontinuation1
Visit Title:
1
Screening
2
3
4
Unscheduled
Scheduled Day:
–2 to 12
1
2
15
(In Person or by Telephone)
Unscheduled
Scheduling Window:
24 (±8) hours after 
completion of 
study drug infusion 
+2 days
Discontinuation
Administrative Procedures
Informed Consent/Assent3
X
Inclusion/Exclusion Criteria
X
Subject Identification Card
X
Medical History
X
Prior and Concomitant Medication Review4
X
X
X
X
X
IMI/REL (Study Drug) Administration
X
Clinical Procedures/Assessments
Full Physical Examination
X
Directed Physical Examination
X5
X
X
Height
X
Weight
X
Vital Sign Measurements (heart rate, blood pressure, 
respiratory rate, temperature)
X
X6
X
X
Adverse Events Monitoring
X
X
X
X
X
Local Tolerability Monitoring
X
X
X7
Laboratory Procedures/Assessments
Serum Pregnancy Test (if applicable)8
X
Hematology Sampling9
X
X
X
Blood Chemistry Sampling9
X
X
X
Urinalysis Sampling10
X
X
X
Plasma Pharmacokinetic Sampling11
X12
 
 
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1.
To be performed for all subjects who discontinue from treatment (ie, discontinue study drug partway through the infusion) or withdraw from the trial at any 
point after the start of study drug infusion.
2.
Screening procedures must be completed within 48 hours prior to the start of study drug infusion.
3.
Written informed consent from parent or legally acceptable representative and age-appropriate assent.
4.
Includes medications of mothers of breast-fed subjects.
5.
To be performed before the start of study drug infusion.
6.
To be performed (1) within 2 hours before the start of study drug infusion, (2) 15 to 30 minutes after completion of study drug infusion, and (3) 4.5 to 
6 hours after the start of study drug infusion.
7.
Only for subjects who discontinue from treatment or withdraw from the trial at any point between the start of study drug infusion and the Day 2 visit.
8.
Female subjects of child-bearing potential only.
9.
If blood tests (chemistry and hematology) have been conducted at the local laboratory within 48 hours of dosing, they may be used (ie, they do not need to 
be repeated at screening for the purpose of the study).
10. Urine will be collected from subjects who are either toilet trained and able to provide a specimen, catheterized, or fitted with a urine collection bag.
11. The method of collection for pharmacokinetic samples is at the discretion of the investigator (eg, peripherally inserted central catheter line, indwelling 
catheter access, individual peripheral phlebotomies, peri-operatively placed arterial line). A separate IV line for PK sample collection is highly 
recommended; if a separate IV line is not clinically feasible, refer to the operations/laboratory manual for further details of allowable alternative collection 
methods.
12. Blood samples for plasma pharmacokinetic assessments will be collected at the following time points: (1) within 30 minutes before the start of study drug 
infusion, (2) within 10 minutes after the end of study drug infusion, (3) 1.5 to 2.5 hours (for Cohorts 1 through 4) or 2 to 5 hours (for Cohort 5) after the start 
of study drug infusion, and (4) 4.5 to 6 hours (for Cohorts 1 through 4) or 6 to 12 hours (for Cohort 5) after the start of study drug infusion.
 
 
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7.0 TRIAL PROCEDURES
Trial Procedures
The Trial Flow Chart - Section 6.0 summarizes the trial procedures to be performed at each 
visit.  Individual trial procedures are described in detail below.  It may be necessary to 
perform these procedures at unscheduled time points if deemed clinically necessary by the 
investigator.
Furthermore, additional evaluations/testing may be deemed necessary by the investigator and 
or the Sponsor for reasons related to subject safety. In some cases, such evaluation/testing 
may be potentially sensitive in nature (e.g., HIV, Hepatitis C, etc.), and thus local regulations 
may require that additional informed consent, and assent if applicable, be obtained from the 
subject.  In these cases, such evaluations/testing will be performed in accordance with those 
regulations.
Administrative Procedures
Informed Consent/Assent
The investigator or medically qualified designee (consistent with local requirements) must 
obtain documented consent, and assent if applicable, from each potential subject or each 
subject’s legally acceptable representative prior to participating in a clinical trial. If there are 
changes to the subject’s status during the trial (e.g., health or age of majority requirements), 
the investigator or medically qualified designee must ensure the appropriate consent/assent is 
in place. 
General Informed Consent/Assent
Consent/assent must be documented by the subject’s dated signature or by the subject’s 
legally acceptable representative’s dated signature on a consent/assent form along with the 
dated signature of the person conducting the consent discussion. 
A copy of the signed and dated consent/assent form should be given to the subject before 
participation in the trial.
The initial informed consent/assent form, any subsequent revised written informed 
consent/assent form and any written information provided to the subject must receive the 
IRB/ERC’s approval/favorable opinion in advance of use.  The subject or his/her legally 
acceptable representative should be informed in a timely manner if new information becomes 
available that may be relevant to the subject’s willingness to continue participation in the 
trial.  The communication of this information will be provided and documented via a revised 
consent/assent form or addendum to the original consent/assent form that captures the 
subject’s dated signature or by the subject’s legally acceptable representative’s dated 
signature.
Specifics about a trial and the trial population will be added to the consent/assent form 
template at the protocol level. The assent, as applicable, will adhere to IRB/ERC 
requirements, applicable laws and regulations and Sponsor requirements.  
 
 
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The informed consent will adhere to IRB/ERC requirements, applicable laws and regulations 
and Sponsor requirements.
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator who is a qualified 
physician to ensure that the subject qualifies for the trial.
Subject Identification Card
All subjects and/or subjects’ parents or legally acceptable representative (as appropriate) will 
be given a Subject Identification Card identifying them as participants in a research trial. The 
card will contain trial site contact information (including direct telephone numbers) to be 
utilized in the event of an emergency. The investigator or qualified designee will provide the 
subject with a Subject Identification Card immediately after the subject provides written 
informed consent/assent. At the time of treatment allocation/randomization, site personnel 
will add the treatment/randomization number to the Subject Identification Card.
The subject identification card also contains contact information for the emergency 
unblinding call center so that a health care provider can obtain information about trial 
medication/vaccination in emergency situations where the investigator is not available.
Medical History
Relevant medical history will be obtained by the investigator or qualified designee. Details of 
the qualifying infection will be recorded.
Prior and Concomitant Medications Review
Prior Medications
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the subject 
within 7 days before screening. For breast-fed subjects, medications taken by the mother 
during the same timeframe will also be recorded.
Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the subject 
during the trial. For breast-fed subjects, medications taken by the mother during the trial will 
also be recorded.
Assignment of Screening Number
All consented subjects will be given a unique screening number that will be used to identify 
the subject for all procedures that occur prior to randomization or treatment allocation.  Each 
subject will be assigned only one screening number.  Screening numbers must not be re-used 
for different subjects.
 
 
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Any subject who is screened multiple times will retain the original screening number 
assigned at the initial screening visit.
Specific details on the screening visit requirements (screening/rescreening) are provided in 
Section 7.1.5.1 – Screening.
Assignment of Treatment/Randomization Number
All eligible subjects will be allocated, by non-random assignment, and will receive a 
treatment/randomization number.  The treatment/randomization number identifies the subject 
for all procedures occurring after treatment allocation/randomization.   Once a 
treatment/randomization number is assigned to a subject, it can never be re-assigned to 
another subject.
A single subject cannot be assigned more than 1 treatment/randomization number.
Trial Compliance
Interruptions from the protocol specified treatment require consultation between the 
investigator and the Sponsor and written documentation of the collaborative decision on 
subject management.
Administration of the single dose of trial medication will be witnessed by the investigator 
and/or trial staff, and the time and date will be recorded in the subject’s eCRF.
Clinical Procedures/Assessments
Full and Directed Physical Examinations
All physical examinations must be performed by an investigator or medically qualified 
designee (consistent with local requirements).
A complete physical examination performed at the screening visit includes the following 
assessments: general appearance, head, eyes, ears/nose/throat, neck, lymph nodes, skin, 
lungs, heart, abdomen, musculoskeletal, and neurologic evaluations. Rectal
and 
genitourinary/pelvic exams should be performed when clinically indicated. If a physical 
examination was performed within 72 hours prior to screening, those results can be recorded 
and a repeat physical examination is not required.
After the initial full physical examination, a directed physical examination targeted to the 
subject’s illness and complaints will be performed at subsequent visits as specified in 
Section 6.0 – Trial Flow Chart.
Any abnormal or clinically significant findings from the physical examinations must be 
recorded on the appropriate eCRF.
Height and Weight
The subject’s height and weight should be measured at screening.
 
 
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Vital Sign Measurements
Vital sign measurements should include heart rate, blood pressure, respiratory rate, and oral 
temperature. Subjects should be in a seated or semirecumbent position prior to having vital 
sign measurements obtained. For those subjects who cannot sit up for any reason (eg, 
neonates, infants, intubated subjects), vital sign measurements will be taken in a supine or 
semirecumbent position. Oral temperatures should be taken, but if oral is not possible, 
tympanic, rectal, or axillary methods are acceptable.
Any abnormal or clinically significant findings from the vital sign measurements must be 
recorded on the appropriate eCRF.
Adverse Event Monitoring
Please refer to Section 7.2 – Assessing and Recording Adverse Events for details regarding 
assessment and documentation of AEs. Laboratory AEs will be based on safety laboratory 
test results, including hematology and chemistry tests from blood and urinalysis from urine. 
All AEs should be documented on the appropriate eCRF. Refer to Section 7.1.3 – Laboratory 
Procedures/Assessments and Section 6.0 – Trial Flow Chart for more details on types of tests 
and timing of collection.
Local Tolerability Monitoring
Local infusion site tolerability will be evaluated at the time points specified in Section 6.0 –
Trial Flow Chart. The tolerability of all study therapy at the local IV infusion site will be 
based on investigator inspection and, when applicable, subject comments regarding signs and 
symptoms of intolerance. The IV infusion site should be observed to determine the 
presence/absence of erythema, induration, pain, tenderness, warmth, swelling, ulceration, 
local phlebitis, rash, or other reactions.
Laboratory Procedures/Assessments
Details regarding specific laboratory procedures/assessments to be performed in this trial are 
provided below. The total amount of blood to be drawn over the course of the trial (from 
pre-trial to post-trial visits), including approximate blood volumes drawn by visit and by 
sample type per subject, can be found in Appendix 12.2 – Approximate Blood/Tissue 
Volumes Drawn/Collected by Trial Visit and by Sample Types.
Laboratory Safety Evaluations (Hematology, Chemistry, and Urinalysis)
Laboratory tests for hematology, chemistry and urinalysis are specified in Table 3.
Clinically stable renal function, as measured by creatinine clearance (see Appendix 12.3), is 
an inclusion criterion for this trial. In addition to values obtained from scheduled chemistry 
blood draws during the study, the serum creatinine values used to calculate creatinine 
clearance for eligibility determination will also be recorded on the appropriate eCRF.
Urine will be collected from subjects who are either toilet trained and able to provide a 
specimen, catheterized, or fitted with a urine collection bag.
 
 
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Table 3
Laboratory Tests
Hematology
Chemistry
Urinalysis
Other
Hematocrit
Albumin
Blood
Serum β-hCGa
Hemoglobin
Alkaline phosphatase
Glucose
Platelet count
ALT
Protein
WBC count (total 
and differential)
AST
Specific gravity 
Neutrophils 
(%, absolute)
Bicarbonate
Microscopic 
exam, 
if 
abnormal results are noted
Band 
neutrophils 
(%, absolute)
Calcium
pH
Lymphocytes 
(%, absolute)
Carbon dioxide
Eosinophils 
(%, absolute)
Chloride
Basophils 
(%)
Creatinine
Glucose
Phosphorus
Potassium
Sodium
Total bilirubin
Direct and indirect bilirubin, 
if total bilirubin is elevated 
above the ULN
Total protein
Blood urea nitrogen
Abbreviations: ALT: alanine aminotransferase; AST: aspartate aminotransferase; β-hCG: β-human chorionic 
gonadotropin; ULN: upper limit of normal; WBC: white blood cell.
a.
Female subjects of child-bearing potential only.
Pharmacokinetic/Pharmacodynamic Evaluations
Four PK samples per subject will be collected in each of the age cohorts as follows:
1. First PK sample: predose sample taken within 30 minutes before the start of study 
drug infusion.
2. Second PK sample: collected within 10 minutes after the end of study drug infusion.
3. Third PK sample:

Cohorts 1 through 4: obtained 1.5 to 2.5 hours after the start of study drug 
infusion.

Cohort 5: obtained 2 to 5 hours after the start of study drug infusion.
 
 
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4. Fourth PK sample:

Cohorts 1 through 4: obtained 4.5 to 6 hours after the start of study drug 
infusion.

Cohort 5: obtained 6 to 12 hours after the start of study drug infusion.
All PK samples must be drawn within the specified time windows, and the actual sampling 
times must be documented. This sampling scheme allows for a balance between the 
maximum coverage of the concentration profile across time required to adequately 
characterize the PK profile, while maintaining a minimal number of samples per subject.
The following model-based and derived PK parameters will be calculated for REL and/or
imipenem, as appropriate:

AUC0-∞

Cmax

%TMIC (imipenem only)

Systemic clearance (CL)

Central volume of distribution (Vc)
The following noncompartmental analysis (NCA)-based PK parameters will be calculated for 
cilastatin:

AUC0-∞

Time to maximum observed plasma drug concentration

Concentration at end of infusion (CEOI)

t1/2

CL

Volume of distribution (Vss)
Blood Collection for Plasma MK-7655A
Sample collection, storage, and shipment instructions for plasma samples will be provided in 
the operations/laboratory manual.
The method of collection for PK samples is at the discretion of the investigator (eg, 
peripherally inserted central catheter line, indwelling catheter access, individual peripheral 
phlebotomies, peri-operatively placed arterial line). A separate IV line for PK sample 
collection is highly recommended; if a separate IV line is not clinically feasible, refer to the 
operations/laboratory manual for further details of allowable alternative collection methods.
 
 
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Other Procedures
Withdrawal/Discontinuation
Subjects who discontinue treatment prior to completion of the treatment regimen (ie, 
discontinuation of study drug partway through the infusion) should be encouraged to 
continue to be followed for all remaining study visits.
When a subject discontinues/withdraws from participation in the trial, all applicable activities 
scheduled for the early withdrawal trial visit, as specified in Section 6.0 – Trial Flow Chart,
should be performed at the time of discontinuation.  Any adverse events which are present at 
the time of discontinuation/withdrawal should be followed in accordance with the safety 
requirements outlined in Section 7.2 - Assessing and Recording Adverse Events.
Subject Blinding/Unblinding
This is an open label trial; there is no blinding for this trial.
Domiciling
In order to participate in this study, subjects must be hospitalized and expected to remain 
hospitalized until at least 24 hours after completion of study drug administration.
Calibration of Equipment
The investigator or qualified designee has the responsibility to ensure that any device or 
instrument used for a clinical evaluation/test during a clinical study that provides information 
about inclusion/exclusion criteria and/or safety or efficacy parameters shall be suitably 
calibrated and/or maintained to ensure that the data obtained is reliable and/or reproducible. 
Documentation of equipment calibration must be retained as source documentation at the 
study site.
Visit Requirements
Visit requirements are outlined in Section 6.0 - Trial Flow Chart. Specific procedure-related 
details are provided above in Section 7.1 - Trial Procedures.
Screening
Within 48 hours prior to the start of study drug infusion, potential subjects will be evaluated 
to determine that they fulfill the entry requirements as set forth in Section 5.1 – Entry 
Criteria. Screening procedures may be repeated after consultation with the Sponsor. If the 
subject is rescreened, screening procedures should be repeated, unless they fall within the 
window specified.
 
 
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Treatment Period
Details regarding procedures, assessments, and scheduling windows for the single treatment 
visit (ie, Visit 2) are presented in Section 6.0 – Trial Flow Chart. Notably, blood samples for 
plasma PK assessments and vital sign measurements will be collected several times at Visit 2 
(see Section 6.0 – Trial Flow Chart for further details).
Discontinued Subjects Continuing to be Monitored in the Trial
Subjects that discontinue treatment (ie, subjects that discontinue from study drug partway 
through the infusion) or who withdraw from the trial at any point after the start of study drug 
infusion should have all safety assessments, including clinical safety laboratory assessments, 
vital sign measurements, directed physical examination, collection of AEs and concomitant 
medications, and local tolerability monitoring (for subjects who discontinue from treatment 
or withdraw from the trial between the start of study drug infusion and the Day 2 visit)
completed as per Section 6.0 – Trial Flow Chart, but do not need to have PK sampling 
performed.
Subjects that withdraw from the trial prior to receiving a dose of study drug (eg, due to 
removal of consent by the parent or LAR, or due to an emergent condition or circumstance 
which, in the opinion of the investigator or Sponsor, places the subject at unnecessary risk 
through continued participation, or does not allow adherence to the protocol) do not need to 
undergo further visits or assessments.
Post-Trial
Subjects will be required to either return to the study site or have a telephone contact 
approximately 14 days after the single dose of study drug for a concomitant medication 
review and AE monitoring.
Assessing and Recording Adverse Events
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily 
have to have a causal relationship with this treatment. An adverse event can therefore be any 
unfavourable and unintended sign (including an abnormal laboratory finding, for example), 
symptom, or disease temporally associated with the use of a medicinal product or protocol-
specified procedure, whether or not considered related to the medicinal product or protocol-
specified procedure.  Any worsening (i.e., any clinically significant adverse change in 
frequency and/or intensity) of a preexisting condition that is temporally associated with the 
use of the Sponsor’s product, is also an adverse event.
Changes resulting from normal growth and development that do not vary significantly in 
frequency or severity from expected levels are not to be considered adverse events.  
Examples of this may include, but are not limited to, teething, typical crying in infants and 
children and onset of menses or menopause occurring at a physiologically appropriate time.
Sponsor's product includes any pharmaceutical product, biological product, device, 
diagnostic agent or protocol-specified procedure, whether investigational (including placebo 
 
 
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or active comparator medication) or marketed, manufactured by, licensed by, provided by or 
distributed by the Sponsor for human use.
Adverse events may occur during clinical trials, or as prescribed in clinical practice, from 
overdose (whether accidental or intentional), from abuse and from withdrawal.
All adverse events that occur after the consent form is signed but before treatment 
allocation/randomization must be reported by the investigator if they cause the subject to be 
excluded from the trial, or are the result of a protocol-specified intervention, including but 
not limited to washout or discontinuation of usual therapy, diet, placebo treatment or a 
procedure. From the time of treatment allocation/randomization through 14 days following 
cessation of treatment, all adverse events must be reported by the investigator. Such events 
will be recorded at each examination on the Adverse Event case report forms/worksheets.  
The reporting timeframe for adverse events meeting any serious criteria is described in 
section 7.2.3.1. The investigator will make every attempt to follow all subjects with non-
serious adverse events for outcome.
Electronic reporting procedures can be found in the Electronic Data Capture (EDC) data 
entry guidelines. Paper reporting procedures can be found in the Investigator Trial File 
Binder (or equivalent).
Definition of an Overdose for This Protocol and Reporting of Overdose to the 
Sponsor
In this trial, an overdose is any dose higher than 10% of the calculated age-appropriate dose
specified in Section 5.2.1.1 – Dose Selection (Preparation) or in subsequent Protocol 
Clarification Letters.
If an adverse event(s) is associated with (“results from”) the overdose of Sponsor's product or 
vaccine, the adverse event(s) is reported as a non-serious adverse event, unless other serious
criteria are met.
If a dose of Sponsor's product or vaccine meeting the protocol definition of overdose is taken 
without any associated clinical symptoms or abnormal laboratory results, the overdose is 
reported as a non-serious adverse event, using the terminology “accidental or intentional 
overdose without adverse effect.”
All reports of overdose with and without an adverse event must be reported by the 
investigator within 24 hours to the Sponsor either by electronic media or paper. Electronic 
reporting procedures can be found in the EDC data entry guidelines. Paper reporting 
procedures can be found in the Investigator Trial File Binder (or equivalent).
Reporting of Pregnancy and Lactation to the Sponsor
Although pregnancy and lactation are not considered adverse events, it is the responsibility of 
investigators or their designees to report any pregnancy or lactation in a subject 
(spontaneously reported to them) that occurs during the trial.
Pregnancies and lactations that occur after the consent form is signed but before treatment 
allocation/randomization must be reported by the investigator if they cause the subject to be 
 
 
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excluded from the trial, or are the result of a protocol-specified intervention, including but 
not limited to washout or discontinuation of usual therapy, diet, placebo treatment or a 
procedure.  Pregnancies and lactations that occur from the time of treatment 
allocation/randomization through 14 days following cessation of Sponsor’s product must be 
reported by the investigator.  All reported pregnancies must be followed to the 
completion/termination of the pregnancy. Pregnancy outcomes of spontaneous abortion, 
missed abortion, benign hydatidiform mole, blighted ovum, fetal death, intrauterine death, 
miscarriage and stillbirth must be reported as serious events (Important Medical Events). If 
the pregnancy continues to term, the outcome (health of infant) must also be reported.
Such events must be reported within 24 hours to the Sponsor either by electronic media or 
paper. Electronic reporting procedures can be found in the EDC data entry guidelines. Paper 
reporting procedures can be found in the Investigator Trial File Binder (or equivalent).
Immediate Reporting of Adverse Events to the Sponsor
Serious Adverse Events
A serious adverse event is any adverse event occurring at any dose or during any use of 
Sponsor's product that:
●
Results in death;
●
Is life threatening;
●
Results in persistent or significant disability/incapacity;
●
Results in or prolongs an existing inpatient hospitalization;
●
Is a congenital anomaly/birth defect;
●
Is an other important medical event.
Note: In addition to the above criteria, adverse events meeting either of the below criteria, 
although not serious per ICH definition, are reportable to the Sponsor in the same timeframe 
as SAEs to meet certain local requirements. 
●
Is a cancer;
●
Is associated with an overdose.
Refer to Table 4 for additional details regarding each of the above criteria.
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any serious adverse event, or follow up to a serious adverse event, 
including death due to any cause, that occurs to any subject must be reported within 24 hours 
to the Sponsor if it causes the subject to be excluded from the trial, or is the result of a 
protocol-specified intervention, including but not limited to washout or discontinuation of 
usual therapy, diet, placebo treatment or a procedure.
For the time period beginning at treatment allocation/randomization through 14 days 
following cessation of treatment, any serious adverse event, or follow up to a serious adverse 
event, including death due to any cause, whether or not related to the Sponsor's product, must 
be reported within 24 hours to the Sponsor either by electronic media or paper. Electronic 
reporting procedures can be found in the EDC data entry guidelines. Paper reporting 
procedures can be found in the Investigator Trial File Binder (or equivalent).
 
 
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Additionally, any serious adverse event, considered by an investigator who is a qualified 
physician to be related to the Sponsor's product that is brought to the attention of the 
investigator at any time outside of the time period specified in the previous paragraph also 
must be reported immediately to the Sponsor.
All subjects with serious adverse events must be followed up for outcome.
Events of Clinical Interest
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI) and must be reported to the Sponsor.
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any ECI, or follow up to an ECI, that occurs to any subject must be 
reported within 24 hours to the Sponsor if it causes the subject to be excluded from the trial, 
or is the result of a protocol-specified intervention, including but not limited to washout or 
discontinuation of usual therapy, diet, placebo treatment or a procedure.
For the time period beginning at treatment allocation/randomization through 14 days 
following cessation of treatment, any ECI, or follow up to an ECI, whether or not related to 
the Sponsor’s product, must be reported within 24 hours to the Sponsor, either by electronic 
media or paper.  Electronic reporting procedures can be found in the EDC data entry 
guidelines.  Paper reporting procedures can be found in the Investigator Trial File Binder (or 
equivalent).
Events of clinical interest for this trial include:
1. an elevated AST or ALT lab value that is greater than or equal to 3X the upper limit 
of normal and an elevated total bilirubin lab value that is greater than or equal to 2X 
the upper limit of normal and, at the same time, an alkaline phosphatase lab value that 
is less than 2X the upper limit of normal, as determined by way of protocol-specified 
laboratory testing or unscheduled laboratory testing.*
*Note:  These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may require 
an additional evaluation for an underlying etiology. The trial site guidance for assessment 
and follow up of these criteria can be found in the Investigator Trial File Binder (or 
equivalent).
2. a confirmed (ie, verified by repeat testing) elevated AST or ALT laboratory value that 
is greater than or equal to 5 × ULN as a result of within-protocol-specific testing or 
unscheduled testing.
Evaluating Adverse Events
An investigator who is a qualified physician will evaluate all adverse events with respect to 
the elements outlined in Table 4. The investigator’s assessment of causality is required for 
each adverse event.  Refer to Table 4 for instructions in evaluating adverse events.
 
 
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Table 4
Evaluating Adverse Events
Maximum
Mild
awareness of sign or symptom, but easily tolerated  (for pediatric trials, awareness of symptom, but easily tolerated)
Intensity
Moderate
discomfort enough to cause interference with usual activity (for pediatric trials, definitely acting like something is wrong)
Severe
incapacitating with inability to work or do usual activity (for pediatric trials, extremely distressed or unable to do usual activities)
Seriousness
A serious adverse event (AE) is any adverse event occurring at any dose or during any use of Sponsor's product that:
†Results in death; or
†Is life threatening; or places the subject, in the view of the investigator, at immediate risk of death from the event as it occurred [Note: This does not include an 
adverse event  that, had it occurred in a more severe form, might have caused death.]; or
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct normal life functions); or
†Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient admission, regardless of length of stay, even if the 
hospitalization is a precautionary measure for continued observation.  (Note: Hospitalization for an elective procedure to treat a pre-existing condition that has not 
worsened is not a serious adverse event.  A pre-existing condition is a clinical condition that is diagnosed prior to the use of a Merck product and is documented in the 
patient’s medical history.); or
†Is a congenital anomaly/birth defect  (in offspring of subject taking the product regardless of time to diagnosis); or
Is a cancer (although not serious per ICH definition, is reportable to the Sponsor within 24 hours to meet certain local requirements); or
Overdose, although not serious per ICH definition, whether accidental or intentional, with or without an accompanying adverse event/serious adverse event, is
reportable to the Sponsor within 24 hours to meet certain local requirements.
Other important medical events that may not result in death, not be life threatening, or not require hospitalization may be considered a serious adverse event when, 
based upon appropriate medical judgment, the event may jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes listed 
previously (designated above by a †).
Duration
Record the start and stop dates of the adverse event.  If less than 1 day, indicate the appropriate length of time and units
Action taken 
Did the adverse event cause the Sponsor's product to be discontinued?
Relationship to 
Sponsor's 
Product
Did the Sponsor's product cause the adverse event? The determination of the likelihood that the Sponsor's product caused the adverse event will be provided by an 
investigator who is a qualified physician.  The investigator’s signed/dated initials on the source document or worksheet that supports the causality noted on the AE 
form, ensures that a medically qualified assessment of causality was done.  This initialed document must be retained for the required regulatory time frame.  The 
criteria below are intended as reference guidelines to assist the investigator in assessing the likelihood of a relationship between the test drug and the adverse event 
based upon the available information
The following components are to be used to assess the relationship between the Sponsor's product and the AE; the greater the correlation with the components 
and their respective elements (in number and/or intensity), the more likely the Sponsor's product caused the adverse event:
Exposure
Is there evidence that the subject was actually exposed to the Sponsor's product such as:  reliable history, acceptable compliance assessment (pill 
count, diary, etc.), expected pharmacologic effect, or measurement of drug/metabolite in bodily specimen?
Time Course
Did 
the 
AE 
follow 
in 
a 
reasonable 
temporal 
sequence 
from 
administration 
of 
the 
Sponsor's 
product? 
Is the time of onset of the AE compatible with a drug-induced effect (applies to trials with investigational medicinal product)?
Likely Cause
Is the AE not reasonably explained by another etiology such as underlying disease, other drug(s)/vaccine(s), or other host or environmental
factors
 
 
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Relationship
The following components are to be used to assess the relationship between the Sponsor's product and the AE:  (continued)
to Sponsor's 
Product
(continued) 
Dechallenge
Was the Sponsor's product discontinued or dose/exposure/frequency reduced?
      If yes, did the AE resolve or improve?
           If yes, this is a positive dechallenge.    If no, this is a negative dechallenge.
(Note:  This criterion is not applicable if:  (1) the AE resulted in death or permanent disability; (2) the AE resolved/improved despite 
continuation of the Sponsor's product; (3) the trial is a single-dose drug trial); or (4) Sponsor's product(s) is/are only used one time.)
Rechallenge
Was the subject re-exposed to the Sponsor's product in this trial?
      If yes, did the AE recur or worsen?
          If yes, this is a positive rechallenge.    If no, this is a negative rechallenge.
(Note:  This criterion is not applicable if:  (1) the initial AE resulted in death or permanent disability, or (2) the trial is a single-dose drug trial); 
or (3) Sponsor's product(s) is/are used only one time.)
NOTE:  IF A RECHALLENGE IS PLANNED FOR AN ADVERSE EVENT WHICH WAS SERIOUS AND WHICH MAY HAVE BEEN 
CAUSED BY THE SPONSOR'S PRODUCT, OR IF RE-EXPOSURE TO THE SPONSOR'S PRODUCT POSES ADDITIONAL POTENTIAL 
SIGNIFICANT RISK TO THE SUBJECT THEN THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE SPONSOR
CLINICAL DIRECTOR AND THE INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE.
Consistency 
with Trial 
Treatment 
Profile
Is the clinical/pathological presentation of the AE consistent with previous knowledge regarding the Sponsor's product or drug class 
pharmacology or toxicology?
The assessment of relationship will be reported on the case report forms /worksheets by an investigator who is a qualified physician according to his/her best clinical judgment, including 
consideration of the above elements.
Record one of the following:
Use the following scale of criteria as guidance (not all criteria must be present to be indicative of a Sponsor's product relationship).
Yes, there is a reasonable 
possibility of Sponsor's product 
relationship.
There is evidence of exposure to the Sponsor's product.  The temporal sequence of the AE onset relative to the administration of the Sponsor's 
product is reasonable.  The AE is more likely explained by the Sponsor's product than by another cause. 
No, there is not a reasonable 
possibility of Sponsor's product 
relationship
Subject did not receive the Sponsor's product OR temporal sequence of the AE onset relative to administration of the Sponsor's product is not 
reasonable OR the AE is more likely explained by another cause than the Sponsor’s product.  (Also entered for a subject with overdose without 
an associated AE.)
 
 
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Sponsor Responsibility for Reporting Adverse Events
All Adverse Events will be reported to regulatory authorities, IRB/IECs and investigators in 
accordance with all applicable global laws and regulations, i.e., per ICH Topic E6 (R1) 
Guidelines for Good Clinical Practice.
8.0 STATISTICAL ANALYSIS PLAN
This section outlines the statistical analysis strategy and procedures for the study. If, after the 
study has begun, but prior to any final database lock, changes are made to primary and/or key 
secondary objectives, or the related statistical methods, then the protocol will be amended 
(consistent with ICH Guideline E9). Changes to exploratory or other nonconfirmatory 
analyses made after the protocol has been finalized, but prior to final database lock, will be 
documented in a supplemental Statistical Analysis Plan and referenced in the Clinical Study 
Report (CSR) for the study. Post hoc exploratory analyses will be clearly identified in the 
CSR. No separate Statistical Analysis Plan will be issued for this study.
Statistical Analysis Plan Summary
Key elements of the Statistical Analysis Plan are summarized below; the comprehensive plan 
is provided in Section 8.2 – Responsibility for Analyses/In-House Blinding through 
Section 8.9 – Sample Size and Power Calculations.
Study Design Overview
A Phase 1b, Open-label, Single-dose Study to Evaluate the 
Pharmacokinetics, Safety, and Tolerability of MK-7655A in Pediatric 
Subjects From Birth to Less Than 18 Years of Age With Confirmed or 
Suspected Gram-negative Infections
Treatment Assignment
Single IV dose of MK-7655A (IMI/REL)
Analysis Populations
Pharmacokinetics: Per Protocol: all subjects who comply with the 
protocol sufficiently to ensure that their data will be likely to exhibit 
the primary endpoints, according to the underlying scientific model, 
and who have at least 1 postdose PK data point.
Safety: All Subjects as Treated (ASaT): All subjects who received 
infusion (including partial doses) of study medication.
Primary Endpoint(s)
Pharmacokinetic: Plasma PK concentration data; 4 PK samples per 
subject will be collected. Primary model-based endpoints for REL and 
imipenem and non-model-based endpoints for cilastatin are listed in 
Section 8.4.1 – Pharmacokinetic/Pharmacodynamic Endpoints.
Secondary Endpoints
Safety: Safety evaluation will be based on the following endpoints: 
AEs (including ECIs), local tolerability assessments, clinical 
laboratory data, vital sign measurements, and physical examinations
findings.
 
 
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Modeling and Simulation
(M&S) Methods for Key 
Pharmacokinetic Analyses
Pediatric REL and imipenem data will be used to determine pediatric 
PK parameters by using the previous adult PK model as a starting 
point. The PK parameters will be continuously updated as pediatric 
PK data become available from each age cohort. A nonlinear mixed 
effects modeling approach will be applied for model building.
The target is AUC0-∞≥37.5 μM-hr (and ≤200 μM-hr) for REL and
TMIC ≥30% (and AUC0-∞≤250 μM-hr) for imipenem. The goal of 
model-based simulations will be to derive a dosing regimen where 
these predefined targets are jointly achieved in a proportion of
pediatric subjects similarly covered in adults (~90% probability of 
target attainment) for each age cohort.
For cilastatin, descriptive statistics will be provided for PK parameters 
by age cohort, based on NCA.
Details on modeling and simulation (M&S) methods are provided in 
Section 8.6.1 – Modeling & Simulation Methods for Pharmacokinetic 
Analyses.
Statistical Methods for 
Safety Analyses
Descriptive statistics will be provided for all safety assessments
described above.
Interim Reviews
Interim reviews of PK and safety data are planned at 3 stages in the 
study. Dose modification may be suggested based on interim review 
results. The planned interim reviews are summarized in Section 8.7 –
Interim Review for Potential Dose Adjustment.
Multiplicity
No multiplicity adjustment is planned.
Sample Size and Power 
Based on PK Precision
Proposed number of study participants by pediatric subset:
Cohort 1 (age 12 to <18 years); at least 6 subjects
Cohort 2 (6 to <12 years); at least 6 subjects
Cohort 3 (2 to <6 years); at least 6 subjects
Cohort 4 (3 months to <2 years); at least 8 subjects, at least 4 of 
whom are <1 year of age
Cohort 5 (birth to <3 months); at least 18 subjects with at least 
6 younger neonates (<1 week age), at least 6 older neonates (1 to 
<4 weeks age), and at least 6 infants (4 weeks to <3 months)
Details on sample size calculation are provided in Section 8.9 –
Sample Size and Power Calculations.
Responsibility for Analyses/In-House Blinding
The statistical analysis of the data obtained from this study will be the responsibility of the 
Clinical Biostatistics department of the Sponsor. The analyses and summaries described in 
Section 8.6.1 – Modeling & Simulation Methods for Pharmacokinetic Analyses are the 
responsibility of the Quantitative Pharmacology and Pharmacometrics group and the Early 
Clinical Development Statistics group of the Sponsor.
This trial is being conducted as a nonrandomized, open-label study (ie, subjects, 
investigators, and Sponsor personnel will be aware of subject treatment assignments after 
each subject is enrolled and treatment is assigned).
 
 
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Subjects participating in this trail will be allocated to age cohorts as described in 
Section 2.1 – Trial Design. The Clinical Biostatistics department will generate the allocation 
schedule, and allocation/non-random assignment will be implemented in an IVRS or IWRS.
There are no plans to conduct formal interim analyses in this study. Planned interim reviews
of PK and safety data for each age cohort are described in Section 8.7 – Interim Review for 
Potential Dose Adjustment. An internal M&S team will be appointed to review the PK 
profile and safety and tolerability data for each age cohort when PK data from 50% of 
subjects in each cohort is available. Dose modification may be suggested based on the results 
of interim reviews as described in Section 5.2.1.2 – Dose Modification.
Hypotheses/Estimation
Objectives of the study are stated in Section 3.0 – Objective(s) and Hypothesis(es). No 
hypothesis testing will be performed for this study.
Analysis Endpoints
Pharmacokinetic/Pharmacodynamic Endpoints
Plasma concentrations of REL, imipenem, and cilastatin will be determined. The REL and 
imipenem data will be used to develop a pediatric population PK model, which will be used 
to perform simulations to derive suitable pediatric doses. Cilastatin data will be used to 
summarize its PK profile based on NCA.
For REL, plasma exposure (AUC0-∞) and Cmax will be the primary endpoints. For imipenem, 
%TMIC, plasma exposure (AUC0-∞), and Cmax will be the primary endpoints. In addition, the 
following model-based population mean PK parameters for both REL and imipenem will be 
determined: CL and Vc.
For cilastatin, the following PK parameters will be determined: AUC0-∞, CEOI, t1/2, CL, and 
Vss.
Safety Endpoints
A description of safety measures is contained in Section 7.0 – Trial Procedures. Safety 
assessments will include AEs, local tolerability assessments, clinical laboratory evaluations, 
vital sign measurements, and physical examinations.
Analysis Populations
Pharmacokinetics Population
The Per Protocol population will be used for the PK analysis. This population is the set of 
data generated by the subset of subjects who comply with the protocol sufficiently to ensure 
that these data will be likely to exhibit the primary endpoints, according to the underlying 
scientific model. Compliance covers such considerations as exposure to treatment, 
availability of measurements, and absence of major protocol violations. Subjects with major 
protocol violations will be identified to the extent possible by individuals responsible for data 
 
 
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collection/compliance and its analysis and interpretation. Any subjects or data values 
excluded from analysis will be identified, along with their reasons for exclusion, in the CSR. 
At the end of the trial, all subjects who are compliant with the trial procedure as described 
and have at least 1 postdose PK data point available will be included in the primary PK 
analysis dataset.
Safety Analysis Populations
The All Subjects as Treated (ASaT) population will be used for the analysis of safety data in 
this study. The ASaT population consists of all allocated subjects who received infusion
(including partial doses) of study medication.
Statistical Methods
Modeling & Simulation Methods for Pharmacokinetic Analyses
Relebactam and imipenem data will be used to develop a pediatric population PK model by 
using previous adult data in the form of the adult population PK model, which will be
continuously updated as pediatric PK data become available from each age cohort. Any 
missing postdose plasma concentrations will be treated as missing. Values below the limit of 
quantification will be assigned a value of zero. A nonlinear mixed effects modeling approach 
will be used for model building. A Modeling and Simulation Analysis Plan with further 
details on the methodology will be prepared and finalized before database lock and analysis 
of the data.
There will be no formal hypothesis testing. The target is AUC0-∞≥37.5 µM-hr (and 
≤200 µM-hr) for REL and TMIC ≥30% (and AUC0-∞≤250 µM-hr) for imipenem. The goal 
of model-based simulations will be to derive a dosing regimen where these targets are jointly 
achieved in a proportion of pediatric subjects similarly covered in adults (~ 90% probability 
of target attainment) for each age cohort; hence, achieving these targets implies similar 
efficacy as that obtained in adults. An absolute (mg) or weight-based (mg/kg) dose, 
whichever is found most suitable for each age cohort, will be selected based on the 
simulation results.
For cilastatin, an NCA will be conducted to determine its PK parameters. Descriptive 
statistics will be provided for cilastatin PK parameters by age cohort.
Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
the incidence, severity, and type of AEs, changes in clinical laboratory tests, and changes 
from baseline in vital sign measurements at the interim reviews and the end of study.
The type and incidence of all AEs and serious adverse events (SAEs) will be tabulated for 
each age cohort and dose level. The broad clinical and laboratory AE categories consisting of 
the percentage of subjects with any AE, a drug-related AE, an SAE, a drug-related SAE, and 
who discontinued due to an AE, as well as the most frequently occurring individual AEs will 
be summarized in the same manner. Special attention will be given to local tolerability events 
occurring at time of study drug administration and to those subjects who discontinue due to 
 
 
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an AE or an SAE. Descriptive and/or summary statistics for the raw laboratory safety tests, 
vital sign measurements, and/or changes from baseline may also be computed, as deemed 
clinically appropriate.
Interim Reviews for Potential Dose Adjustment
Interim reviews of PK and safety data will occur at 3 stages in the study. First, interim 
reviews were performed for each of Cohorts 1 through 3 in this study when data from 50% 
(3 subjects) of subjects were available from a specific cohort. Second, an interim review of 
complete aggregated PK data from Cohorts 1 through 3 was performed prior to enrollment of 
Cohorts 4 and 5. Third, interim reviews for each of Cohorts 4 and 5 will be performed when
data from 50% of subjects are available from a specific cohort. Results will be reviewed by 
an internal team. During the first and third interim reviews, the suitability of the initial dose
for each age cohort will be assessed and a dose modification may be suggested for the
remaining 50% of subjects in that cohort, as described in Section 5.2.1.2 – Dose 
Modification. The dose modifications that occurred as a result of the completed interim 
reviews are described in Section 5.2.1.2.1.
Multiplicity
Because there are no pre-specified hypotheses, no adjustments for multiplicity will be made.
Sample Size and Power Calculations
The proposed number of study participants by pediatric subset includes the following:

Cohort 1 (age 12 to <18 years); at least 6 subjects

Cohort 2 (6 to <12 years); at least 6 subjects

Cohort 3 (2 to <6 years); at least 6 subjects

Cohort 4 (3 months to <2 years); at least 8 subjects, at least 4 of whom are <1 year of 
age

Cohort 5 (birth to <3 months); at least 18 subjects with at least 6 younger neonates 
(<1 week age), at least 6 older neonates (1 to <4 weeks age), and at least 6 infants 
(4 weeks to <3 months)
A simulation-based methodology was implemented in order to determine the appropriate 
sample size for each pediatric age cohort that would have at least 80% probability to achieve 
reasonable precision, defined as the 95% confidence interval within 60% to 140% of the 
population mean (approximately ≤20% RSE [relative standard error]), in the model-based 
estimation of primary PK parameters for both REL and imipenem in each pediatric age 
cohort. Variability in primary PK parameters was assumed to be the same as that estimated in 
adults based on the adult population PK model (coefficient of variation (%CV) for 
imipenem: 50% for CL, 75% for Vc; %CV for REL: 40% for CL, 50% for Vc).
The proposed trial design, in terms of sample sizes combined with the PK sampling scheme, 
was found to be sufficient to have >80% probability (based on replicate simulations) to 
 
 
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achieve the defined target precision in model-based primary PK parameter estimates (CL, 
Vc) for both REL and imipenem, and thus, is expected to adequately capture the PK 
characterization for both drugs in the pediatric population.
9.0 LABELING, PACKAGING,
STORAGE AND RETURN OF CLINICAL
SUPPLIES
Investigational Product
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of 
investigational product in accordance with the protocol and any applicable laws and 
regulations.
Clinical Supplies will be provided by the Sponsor as summarized in Table 5.
Clinical supplies will be packaged to support enrollment and replacement subjects as 
required.  When a replacement subject is required, the Sponsor or designee needs to be 
contacted prior to dosing the replacement supplies.
Table 5
Product Descriptions
Product Name & 
Potency
Dosage Form
Source/Additional Information
MK-7655A, 
MK-7655 250 mg/
Imipenem 500 mg/
Cilastatin 500 mg
Powder for Constitution
Provided centrally by the Sponsor
Packaging and Labeling Information
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements.
Subjects will receive open-label, single-dose vials. No kitting is required.
Clinical Supplies Disclosure
This trial is open-label; therefore, the subject, the trial site personnel, the Sponsor and/or 
designee are not blinded. Treatment MK-7655A, MK-7655 250 mg, IMIPENEM 500 mg and 
CILASTATIN EQUIVALENT 500 mg (name, strength or potency) is included in the label 
text; random code/disclosure envelopes or lists are not provided.
Storage and Handling Requirements
Clinical supplies must be stored in a secure, limited-access location under the storage 
conditions specified on the label.  
 
 
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Receipt and dispensing of trial medication must be recorded by an authorized person at the 
trial site.
Clinical supplies may not be used for any purpose other than that stated in the protocol.
Discard/Destruction/Returns and Reconciliation
The investigator is responsible for keeping accurate records of the clinical supplies received 
from the Sponsor or designee, the amount dispensed to and returned by the subjects and the 
amount remaining at the conclusion of the trial. For all trial sites, the local country Sponsor 
personnel or designee will provide appropriate documentation that must be completed for 
drug accountability and return, or local discard and destruction if appropriate.  Where local 
discard and destruction is appropriate, the investigator is responsible for ensuring that a local
discard/destruction procedure is documented.
Standard Policies
Trial 
site 
personnel 
will 
have 
access 
to 
a 
central 
electronic 
treatment 
allocation/randomization system (IVRS/IWRS system) to allocate subjects, to assign 
treatment to subjects and to manage the distribution of clinical supplies. Each person 
accessing the IVRS system must be assigned an individual unique PIN.  They must use only 
their assigned PIN to access the system, and they must not share their assigned PIN with 
anyone.
10.0 ADMINISTRATIVE AND REGULATORY DETAILS
Confidentiality
Confidentiality of Data
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will 
be divulged to the institutional review board, ethics review committee (IRB/ERC) or similar 
or expert committee; affiliated institution and employees, only under an appropriate 
understanding of confidentiality with such board or committee, affiliated institution and 
employees.  Data generated by this trial will be considered confidential by the investigator, 
except to the extent that it is included in a publication as provided in the Publications section 
of this protocol.
Confidentiality of Subject Records
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/ERC, or regulatory authority representatives may consult and/or copy trial documents in 
order to verify worksheet/case report form data.  By signing the consent form, the subject 
agrees to this process.  If trial documents will be photocopied during the process of verifying 
worksheet/case report form information, the subject will be identified by unique code only; 
full names/initials will be masked prior to transmission to the Sponsor.
 
 
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By signing this protocol, the investigator agrees to treat all subject data used and disclosed in 
connection with this trial in accordance with all applicable privacy laws, rules and 
regulations.
Confidentiality of Investigator Information
By signing this protocol, the investigator recognizes that certain personal identifying 
information with respect to the investigator, and all subinvestigators and trial site personnel, 
may be used and disclosed for trial management purposes, as part of a regulatory 
submissions, and as required by law.  This information may include:
1. name, address, telephone number and e-mail address;
2. hospital or clinic address and telephone number;
3. curriculum vitae or other summary of qualifications and credentials; and
4. other professional documentation.
Consistent with the purposes described above, this information may be transmitted to the 
Sponsor, and subsidiaries, affiliates and agents of the Sponsor, in your country and other 
countries, including countries that do not have laws protecting such information.  
Additionally, the investigator’s name and business contact information may be included 
when reporting certain serious adverse events to regulatory authorities or to other 
investigators.  By signing this protocol, the investigator expressly consents to these uses and 
disclosures.
If this is a multicenter trial, in order to facilitate contact between investigators, the Sponsor 
may share an investigator’s name and contact information with other participating 
investigators upon request.
Confidentiality of IRB/IEC Information
The Sponsor is required to record the name and address of each IRB/IEC that reviews and 
approves this trial.  The Sponsor is also required to document that each IRB/IEC meets 
regulatory and ICH GCP requirements by requesting and maintaining records of the names 
and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
Compliance with Financial Disclosure Requirements
Financial Disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54).  It is the 
Sponsor's responsibility to determine, based on these regulations, whether a request for 
Financial Disclosure information is required.  It is the investigator's/subinvestigator's 
responsibility to comply with any such request.  
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements.  
The investigator/subinvestigator(s) further agree to provide this information on a 
 
 
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Certification/Disclosure Form, commonly known as a financial disclosure form, provided by 
the Sponsor. The investigator/subinvestigator(s) also consent to the transmission of this 
information to the Sponsor in the United States for these purposes.  This may involve the 
transmission of information to countries that do not have laws protecting personal data.
Compliance with Law, Audit and Debarment
By signing this protocol, the investigator agrees to conduct the trial in an efficient and 
diligent manner and in conformance with this protocol; generally accepted standards of Good 
Clinical Practice (e.g., International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use Good Clinical Practice: 
Consolidated Guideline and other generally accepted standards of good clinical practice); and 
all applicable federal, state and local laws, rules and regulations relating to the conduct of the 
clinical trial.
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by Merck, is provided in Section 12.1 -
Merck Code of Conduct for Clinical Trials.
The investigator also agrees to allow monitoring, audits, IRB/ERC review and regulatory 
authority inspection of trial-related documents and procedures and provide for direct access 
to all trial-related source data and documents.
The investigator agrees not to seek reimbursement from subjects, their insurance providers or 
from government programs for procedures included as part of the trial reimbursed to the 
investigator by the Sponsor.
The investigator shall prepare and maintain complete and accurate trial documentation in 
compliance with Good Clinical Practice standards and applicable federal, state and local 
laws, rules and regulations; and, for each subject participating in the trial, provide all data, 
and, upon completion or termination of the clinical trial, submit any other reports to the 
Sponsor as required by this protocol or as otherwise required pursuant to any agreement with 
the Sponsor.
Trial documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the trial site upon request for inspection, 
copying, review and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities.  The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor as a result of an audit to cure deficiencies in the trial documentation 
and worksheets/case report forms.
The investigator must maintain copies of all documentation and records relating to the 
conduct of the trial in compliance with all applicable legal and regulatory requirements.  This 
documentation includes, but is not limited to, the protocol, worksheets/case report forms, 
advertising for subject participation, adverse event reports, subject source data, 
correspondence with regulatory authorities and IRBs/ERCs, consent forms, investigator’s 
curricula vitae, monitor visit logs, laboratory reference ranges, laboratory certification or 
quality control procedures and laboratory director curriculum vitae.  By signing this protocol, 
the investigator agrees that documentation shall be retained until at least 2 years after the last 
approval of a marketing application in an ICH region or until there are no pending or 
 
 
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contemplated marketing applications in an ICH region or until at least 2 years have elapsed 
since the formal discontinuation of clinical development of the investigational product.  
Because the clinical development and marketing application process is variable, it is 
anticipated that the retention period can be up to 15 years or longer after protocol database 
lock. The Sponsor will determine the minimum retention period and notify the investigator 
when documents may be destroyed.  The Sponsor will determine the minimum retention 
period and upon request, will provide guidance to the investigator when documents no longer 
need to be retained.  The sponsor also recognizes that documents may need to be retained for 
a longer period if required by local regulatory requirements. All trial documents shall be 
made available if required by relevant regulatory authorities. The investigator must consult 
with and obtain written approval by the Sponsor prior to destroying trial and/or subject files.  
ICH Good Clinical Practice guidelines recommend that the investigator inform the subject’s 
primary physician about the subject’s participation in the trial if the subject has a primary 
physician and if the subject agrees to the primary physician being informed.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this trial.
Persons debarred from conducting or working on clinical trials by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s trials.  The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the trial is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
In the event the Sponsor prematurely terminates a particular trial site, the Sponsor will 
promptly notify that trial site’s IRB/IEC.
According to European legislation, a Sponsor must designate an overall coordinating 
investigator for a multi-center trial (including multinational).  When more than one trial site 
is open in an EU country, Merck, as the Sponsor, will designate, per country, a national 
principal coordinator (Protocol CI), responsible for coordinating the work of the principal 
investigators at the different trial sites in that Member State, according to national 
regulations.  For a single-center trial, the Protocol CI is the principal investigator.  In 
addition, the Sponsor must designate a principal or coordinating investigator to review the 
trial report that summarizes the trial results and confirm that, to the best of his/her 
knowledge, the report accurately describes the conduct and results of the trial [Clinical Study 
Report (CSR) CI].  The Sponsor may consider one or more factors in the selection of the 
individual to serve as the Protocol CI and or CSR CI (e.g., availability of the Protocol/CSR 
CI during the anticipated review process, thorough understanding of clinical trial methods, 
appropriate enrollment of subject cohort, timely achievement of trial milestones).  The 
Protocol CI must be a participating trial investigator.
Compliance with Trial Registration and Results Posting Requirements
Under the terms of the Food and Drug Administration Amendments Act (FDAAA) of 2007 
and the European Medicines Agency (EMA) clinical trial Directive 2001/20/EC, the Sponsor 
of the trial is solely responsible for determining whether the trial and its results are subject to 
the 
requirements 
for 
submission 
to 
http://www.clinicaltrials.gov, 
 
 
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www.clinicaltrialsregister.eu or other local registries.  Merck, as Sponsor of this trial, will 
review this protocol and submit the information necessary to fulfill these requirements. 
Merck entries are not limited to FDAAA or the EMA clinical trial directive mandated trials.  
Information posted will allow subjects to identify potentially appropriate trials for their 
disease conditions and pursue participation by calling a central contact number for further 
information on appropriate trial locations and trial site contact information.  
By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAAA, the EMA clinical trials directive or other locally mandated registries are that of the 
Sponsor and agrees not to submit any information about this trial or its results to those 
registries.
Quality Management System
By signing this protocol, the Sponsor agrees to be responsible for implementing and 
maintaining a quality management system with written development procedures and 
functional area standard operating procedures (SOPs) to ensure that trials are conducted and 
data are generated, documented, and reported in compliance with the protocol, accepted 
standards of Good Clinical Practice, and all applicable federal, state, and local laws, rules and 
regulations relating to the conduct of the clinical trial.
Data Management
The investigator or qualified designee is responsible for recording and verifying the accuracy 
of subject data.  By signing this protocol, the investigator acknowledges that his/her 
electronic signature is the legally binding equivalent of a written signature.  By entering 
his/her electronic signature, the investigator confirms that all recorded data have been 
verified as accurate.
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
Publications
This trial is intended for publication, even if terminated prematurely. Publication may include 
any or all of the following: posting of a synopsis online, abstract and/or presentation at a 
scientific conference, or publication of a full manuscript.  The Sponsor will work with the 
authors to submit a manuscript describing trial results within 12 months after the last data 
become available, which may take up to several months after the last subject visit in some 
cases such as vaccine trials.  However, manuscript submission timelines may be extended on 
OTC trials.  For trials intended for pediatric-related regulatory filings, the investigator agrees 
to delay publication of the trial results until the Sponsor notifies the investigator that all 
relevant regulatory authority decisions on the trial drug have been made with regard to 
pediatric-related regulatory filings. Merck will post a synopsis of trial results for approved 
products on www.clinicaltrials.gov by 12 months after the last subject's last visit for the 
primary outcome, 12 months after the decision to discontinue development, or product 
marketing (dispensed, administered, delivered or promoted), whichever is later.
 
 
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These timelines may be extended for products that are not yet marketed, if additional time is 
needed for analysis, to protect intellectual property, or to comply with confidentiality 
agreements with other parties.  Authors of the primary results manuscript will be provided 
the complete results from the Clinical Study Report, subject to the confidentiality agreement. 
When a manuscript is submitted to a biomedical journal, the Sponsor's policy is to also 
include the protocol and statistical analysis plan to facilitate the peer and editorial review of 
the manuscript.  If the manuscript is subsequently accepted for publication, the Sponsor will 
allow the journal, if it so desires, to post on its website the key sections of the protocol that 
are relevant to evaluating the trial, specifically those sections describing the trial objectives 
and hypotheses, the subject inclusion and exclusion criteria, the trial design and procedures, 
the efficacy and safety measures, the statistical analysis plan, and any amendments relating to 
those sections.  The Sponsor reserves the right to redact proprietary information.
For multicenter trials, subsequent to the multicenter publication (or after public disclosure of 
the results online at www.clinicaltrials.gov if a multicenter manuscript is not planned), an 
investigator and his/her colleagues may publish their data independently.  In most cases, 
publication of individual trial site data does not add value to complete multicenter results, 
due to statistical concerns.  In rare cases, publication of single trial site data prior to the main 
paper may be of value.  Limitations of single trial site observations in a multicenter trial 
should always be described in such a manuscript.
Authorship credit should be based on 1) substantial contributions to conception and design, 
or acquisition of data, or analysis and interpretation of data; 2) drafting the article or revising 
it critically for important intellectual content; and 3) final approval of the version to be 
published. Authors must meet conditions 1, 2 and 3.  Significant contributions to trial 
execution may also be taken into account to determine authorship, provided that 
contributions have also been made to all three of the preceding authorship criteria.  Although 
publication planning may begin before conducting the trial, final decisions on authorship and 
the order of authors’ names will be made based on participation and actual contributions to 
the trial and writing, as discussed above. The first author is responsible for defending the 
integrity of the data, method(s) of data analysis and the scientific content of the manuscript.
The Sponsor must have the opportunity to review all proposed abstracts, manuscripts or 
presentations regarding this trial 45 days prior to submission for publication/presentation. 
Any information identified by the Sponsor as confidential must be deleted prior to 
submission; this confidentiality does not include efficacy and safety results. Sponsor review 
can be expedited to meet publication timelines.
11.0 LIST OF REFERENCES
1. Markou N, Apostolakos H, Koumoudiou C, Athanasiou M, Koutsoukou A, Alamanos I, 
et al. Intravenous colistin in the treatment of sepsis from multiresistant Gram-negative 
bacilli in critically ill patients. Critical Care 2003;7(5):R78-R83.
2. Reina R, Estenssoro E, Saenz G, Canales HS, Gonzalvo R, Vidal G, et al. Safety and 
efficacy of colistin in Acinetobacter and Pseudomonas infections:  a prospective cohort 
study. Intensive Care Med 2005;31:1058-65.
 
 
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3. Pintado V, García San Miguel L, Grill F, Mejía B, Cobo J, Fortún J, et al. Intravenous 
colistin sulphomethate sodium for therapy of infections due to multidrug-resistant gram-
negative bacteria. Journal of Infection 2008;56:185-90.
4. Chopra I, Schofield C, Everett M, O'Neill A, Miller K, Wilcox M, et al. Treatment of 
health-care-associated infections caused by Gram-negative bacteria: a consensus 
statement. Lancet Infect Dis 2008;8:133-9.
5. Boucher HW, Talbot GH, Bradley JS, Edwards JE Jr, Gilbert D, Rice LB, et al. Bad 
bugs, no drugs: no ESKAPE! An update from the Infectious Diseases Society of 
America. Clin Infect Dis 2009;48(1):1-12.
6. Blomberg B, Jureen R, Manji KP, Tamim BS, Mwakagile DS, Urassa WK, et al. High 
rate of fatal cases of pediatric septicemia caused by gram-negative bacteria with 
extended-spectrum beta-lactamases in Dar es Salaam, Tanzania. J Clin Microbiol. 2005 
Feb;43(2):745-9.
7. Zaoutis TE, Goyal M, Chu JH, Coffin SE, Bell LM, Nachamkin I, et al. Risk factors for 
and outcomes of bloodstream infection caused by extended-spectrum beta-lactamase-
producing Escherichia coli and Klebsiella species in children. Pediatrics. 2005 
Apr;115(4):942-9.
8. Stone PW, Gupta A, Loughrey M, Della-Latta P, Cimiotti J, Larson E, et al. Attributable 
costs and length of stay of an extended-spectrum beta-lactamase-producing Klebsiella 
pneumoniae outbreak in a neonatal intensive care unit. Infect Control Hosp Epidemiol. 
2003 Aug;24(8):601-6.
9. Hsu AJ, Tamma PD. Treatment of multidrug-resistant Gram-negative infections in 
children. Clin Infect Dis. 2014 May;58(10):1439-48.
10. Paterson DL, Bonomo RA. Extended-spectrum beta-lactamases: a clinical update. Clin 
Microbiol Rev. 2005 Oct;18(4):657-86.
11. Food and Drug Administration (CDER). General clinical pharmacology considerations 
for pediatric studies for drugs and biological products [Internet]. Silver Spring, MD: U.S. 
Department 
of 
Health 
and 
Human 
Services; 
2014. 
Available 
from: 
http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidanc
es/ucm425885.pdf.
12. National Institute of Allergy and Infectious Diseases. Division of microbiology and 
infectious diseases (DMID) pediatric toxicity tables [internet]. Bethesda, MD: NIAID; 
2007.
Available 
from: 
https://www.niaid.nih.gov/sites/default/files/documents/dmidpedtox.pdf.
13. Brion LP, Fleischman AR, McCarton C, Schwartz GJ. A simple estimate of glomerular 
filtration rate in low birth weight infants during the first year of life: noninvasive 
assessment of body composition and growth. J Pediatr. 1986 Oct;109(4):698-707.
 
 
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14. Schwartz GJ, Work DF. Measurement and estimation of GFR in children and 
adolescents.  Clin J Am Soc Nephrol 2009;4:1832-43.
15. Sakellaris G, editor. Essentials in Pediatric Urology. Trivandrum: Research Signpost; 
c2012. Chapter 2. The development of renal function; p. 9-20.
 
 
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12.0 APPENDICES
Merck Code of Conduct for Clinical Trials
Merck*
Code of Conduct for Clinical Trials
I.
Introduction
A. Purpose
Merck, through its subsidiaries, conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, implementing, conducting, analyzing and reporting these trials in 
compliance with the highest ethical and scientific standards. Protection of subject safety is the overriding concern in 
the design of clinical trials. In all cases, Merck clinical trials will be conducted in compliance with local and/or 
national regulations and in accordance with the ethical principles that have their origin in the Declaration of Helsinki. 
B. Scope
Such standards shall be endorsed for all clinical interventional investigations sponsored by Merck irrespective of the 
party (parties) employed for their execution (e.g., contract research organizations, collaborative research efforts). This 
Code is not intended to apply to trials which are observational in nature, or which are retrospective. Further, this Code 
does not apply to investigator-initiated trials which are not under the control of Merck.
II. Scientific Issues
A. Trial Conduct
1. Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-driven to assess safety, efficacy 
and/or pharmacokinetic or pharmacodynamic indices of Merck or comparator products.  Alternatively, Merck may 
conduct outcomes research trials, trials to assess or validate various endpoint measures, or trials to determine 
subject preferences, etc.  
The design (i.e., subject population, duration, statistical power) must be adequate to address the specific purpose 
of the trial.  Research subjects must meet protocol entry criteria to be enrolled in the trial. 
2. Site Selection
Merck selects investigative sites based on medical expertise, access to appropriate subjects, adequacy of facilities 
and staff, previous performance in Merck trials, as well as budgetary considerations.  Prior to trial initiation, sites 
are evaluated by Merck personnel to assess the ability to successfully conduct the trial.
3. Site Monitoring/Scientific Integrity
Trial sites are monitored to assess compliance with the trial protocol and general principles of Good Clinical 
Practice.  Merck reviews clinical data for accuracy, completeness and consistency. Data are verified versus source 
documentation according to standard operating procedures.  Per Merck policies and procedures, if fraud, 
misconduct or serious GCP-non-Compliance are suspected, the issues are promptly investigated. When necessary, 
the clinical site will be closed, the responsible regulatory authorities and ethics review committees notified and 
data disclosed accordingly. 
B. Publication and Authorship
To the extent scientifically appropriate, Merck seeks to publish the results of trials it conducts.  Some early phase or 
pilot trials are intended to be hypothesis-generating rather than hypothesis testing.  In such cases, publication of 
results may not be appropriate since the trial may be underpowered and the analyses complicated by statistical issues 
of multiplicity.
Merck’s policy on authorship is consistent with the requirements outlined in the ICH-Good Clinical Practice 
guidelines. In summary, authorship should reflect significant contribution to the design and conduct of the trial, 
performance or interpretation of the analysis, and/or writing of the manuscript.  All named authors must be able to 
defend the trial results and conclusions.  Merck funding of a trial will be acknowledged in publications. 
 
 
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III. Subject Protection
A. IRB/ERC review
All clinical trials will be reviewed and approved by an independent IRB/ERC before being initiated at each site.  
Significant changes or revisions to the protocol will be approved by the IRB/ERC prior to implementation, except that 
changes required urgently to protect subject safety and well-being may be enacted in anticipation of IRB/ERC 
approval. For each site, the IRB/ERC and Merck will approve the subject informed consent form. 
B. Safety
The guiding principle in decision-making in clinical trials is that subject welfare is of primary importance.  Potential 
subjects will be informed of the risks and benefits of, as well as alternatives to, trial participation. At a minimum, trial 
designs will take into account the local standard of care.  Subjects are never denied access to appropriate medical care 
based on participation in a Merck clinical trial. 
All participation in Merck clinical trials is voluntary.  Subjects are enrolled only after providing informed consent for 
participation.  Subjects may withdraw from a Merck trial at any time, without any influence on their access to, or 
receipt of, medical care that may otherwise be available to them.
C. Confidentiality
Merck is committed to safeguarding subject confidentiality, to the greatest extent possible. Unless required by law, 
only the investigator, sponsor (or representative) and/or regulatory authorities will have access to confidential medical 
records that might identify the research subject by name.  
D. Genomic Research
Genomic Research will only be conducted in accordance with informed consent and/or as specifically authorized by 
an Ethics Committee.
IV. Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive.  It is Merck’s policy to compensate investigators (or the sponsoring 
institution) in a fair manner for the work performed in support of Merck trials.  Merck does not pay incentives to 
enroll subjects in its trials.  However, when enrollment is particularly challenging, additional payments may be made 
to compensate for the time spent in extra recruiting efforts.
Merck does not pay for subject referrals.  However, Merck may compensate referring physicians for time spent on 
chart review to identify potentially eligible subjects.
B. Clinical Research Funding 
Informed consent forms will disclose that the trial is sponsored by Merck, and that the investigator or sponsoring 
institution is being paid or provided a grant for performing the trial.  However, the local IRB/ERC may wish to alter 
the wording of the disclosure statement to be consistent with financial practices at that institution.  As noted above, 
publications resulting from Merck trials will indicate Merck as a source of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (e.g., to scientific meetings, investigator meetings, etc.) will be 
consistent with local guidelines and practices including, in the U.S., those established by the American Medical 
Association (AMA). 
V. Investigator Commitment
Investigators will be expected to review Merck’s Code of Conduct as an appendix to the trial protocol, and in signing 
the protocol, agree to support these ethical and scientific standards.
* In this document, "Merck" refers to Merck Sharp & Dohme Corp. and Schering Corporation, each of which is a 
subsidiary of Merck & Co., Inc.  Merck is known as MSD outside of the United States and Canada.  As warranted by 
context, Merck also includes affiliates and subsidiaries of Merck & Co., Inc."
 
 
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Approximate Blood/Tissue Volumes Drawn/Collected by Trial Visit and by 
Sample Types
It is recognized that pediatric centers reduce required blood volumes for standard clinical 
testing based on the size of the child, with many centers suggesting a 0.5 mL blood draw for
most standard clinical tests in neonates (blood culture, hematology with differential, and 
clinical chemistry panels). With this recognition in mind, expected blood volumes for the 
youngest age group (neonates) are calculated below:
Trial Visit/Cycle/etc:
Screening
Visits 1
Treatment 
Visit 2
Post-
Treatment
Visit 3
Post-
Treatment
Visit 4
Blood Parameter 
Approximate Blood Volume
Serum β-Human Chorionic 
Gonadotropin (β-hCG)a
0.5 mL
Hematology
0.5 mL
0.5 mL
0.5 mL
Blood Chemistry
0.5 mL
0.5 mL
0.5 mL
Plasma Pharmacokinetics
1 mL
(4 × 250 µL)
Expected Total (mL)
1.5 mL
1 mL
1 mL
1 mL
a.
For female subjects of child-bearing potential only.
The approximate total blood volume to be drawn is within 3% of total blood volume (2.4 mL 
blood per kg of body weight) even for the lowest approximate weight for eligible subjects in 
this study (ie, female neonates in the first percentile of growth according to World Health 
Organization growth charts). Maximum volume for an individual subject should be based on 
weight and should generally not exceed 3% of total blood volume (2.4 mL blood per kg of 
body weight) unless appropriate justification is documented by the investigator.
 
 
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Acceptable Creatinine Clearance Ranges by Age Range for Study Inclusion
Age Range
Creatinine Clearance Acceptable 
Range for Inclusiona
Formula for Estimating 
Creatinine Clearanceb
12 to <18 years
≥80 mL/min
Cockcroft-Gaultc
2 to <12 years
≥80 mL/min/1.73m2
Modified Schwartzd
18 months to <2 years
≥76 mL/min/1.73m2
Modified Schwartzd
12 to <18 months
≥73 mL/min/1.73m2
Modified Schwartzd
8 to <12 months
≥65 mL/min/1.73m2
Modified Schwartzd
14 weeks to <8 months
≥57 mL/min/1.73m2
Modified Schwartzd
6 to <14 weeks
≥47 mL/min/1.73m2
Modified Schwartzd
2 to <6 weeks
≥41 mL/min/1.73m2
Modified Schwartzd
1 to <2 weeks
≥25 mL/min/1.73m2
Modified Schwartzd
Birth to <1 week
≥20 mL/min/1.73m2
Modified Schwartzd
a.
Normal creatinine clearance ranges taken from published lower-bound standard deviation of age-appropriate means
[13, 14, 15].
b.
Food and Drug Administration guidance recommends Cockcroft-Gault formula in adolescents ≥12 years of age and the 
modified Schwartz formula for infants and children <12 years of age [11].
c.
Cockcroft-Gault formula (subjects ≥12 years of age):
Creatinine clearance (males) = (weight in kg) × (140 minus age)    
(72) × (creatinine in mg/dL)
Creatinine clearance (females) = 0.85 × the value obtained using the formula above
d.
Modified Schwartz formula (subjects <12 years of age):
Creatinine clearance =     K × (height in cm)___  
(creatinine in mg/dL)
K (proportionality constant):
Infant (term <1 year): K=0.45
Female child (≥1 year and <12 years): K=0.55
Male child (≥1 year and <12 years): K=0.70
 
 
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List of Abbreviations
Abbreviation
Definition
AE
adverse event
ALT
alanine aminotransferase
ASaT
all subjects as treated
AST
aspartate aminotransferase
AUC0-∞
area under the concentration time curve 
β-hCG
β-human chorionic gonadotropin
BLI
β-lactamase inhibitor 
CEOI
concentration at end of infusion
CI
coordinating investigator
cIAI
complicated intra-abdominal infection
CL
systemic clearance
Cmax
maximum observed plasma concentration
CMS
colistimethate sodium
CSR
clinical study report
cUTI
complicated urinary tract infection
%CV
coefficient of variation
ECI
event of clinical interest
eCRF
electronic case report form
EDC
electronic data capture
EMA
European Medicines Agency
ERC
Ethical Review Committee
FDAAA
Food and Drug Administration Amendments Act
GCP
Good Clinical Practice
HABP
hospital-acquired bacterial pneumonia
IB
Investigator’s Brochure
ICH
International Council for Harmonisation
IEC
Independent Ethics Committee
IMI
imipenem/cilastatin
IMI/REL
fixed-dose combination of imipenem/cilastatin/relebactam 
(MK-7655A)
IMP
Imipenemase metallo-β-lactamase
IRB
Institutional Review Board
IV
intravenous (parental)
IVRS
interactive voice response system
IWRS
interactive web response system
KPC
Klebsiella pneumoniae carbapenemase 
LAR
legally acceptable representative
M&S
modeling and simulation
MDR
multi-drug resistant
NCA
noncompartmental analysis
NDM-1
New Delhi metallo-β-lactamase 1
OAT
organic anion transporter
OXA
oxacillinase
PIN
personal identification number
PK
pharmacokinetic
 
 
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Abbreviation
Definition
QTc
corrected measure of the time between the start of the Q 
wave and the end of the T wave in the heart’s electrical 
cycle
REL
relebactam
SAE
serious adverse event
t1/2
terminal half-life 
TMIC
time spent above the minimum inhibitory concentration
ULN
upper limit of normal
US
United States
VABP
ventilator-associated bacterial pneumonia
Vc
central volume of distribution
VIM
Verona integron-encoded metallo-β-lactamase
Vss
volume of distribution
 
 
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13.0 SIGNATURES
Sponsor's Representative
TYPED NAME
TITLE
SIGNATURE
DATE SIGNED
Investigator
I agree to conduct this clinical trial in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol (including other manuals and documents 
referenced from this protocol).  I agree to conduct the trial in accordance with generally 
accepted standards of Good Clinical Practice.  I also agree to report all information or data in 
accordance with the protocol and, in particular, I agree to report any serious adverse events 
as defined in Section 7.0 – TRIAL PROCEDURES (Assessing and Recording Adverse 
Events).  I also agree to handle all clinical supplies provided by the Sponsor and collect and 
handle all clinical specimens in accordance with the protocol.  I understand that information 
that identifies me will be used and disclosed as described in the protocol, and that such 
information may be transferred to countries that do not have laws protecting such 
information.  Since the information in this protocol and the referenced Investigator’s 
Brochure is confidential, I understand that its disclosure to any third parties, other than those 
involved in approval, supervision, or conduct of the trial is prohibited.  I will ensure that the 
necessary precautions are taken to protect such information from loss, inadvertent disclosure 
or access by third parties.
TYPED NAME
TITLE
SIGNATURE
DATE SIGNED
 
 
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