Clinical trial NCT04147221
Conditions: Sepsis
Keywords: beta-lactam pharmacokinetics
Sponsor: Hartford Hospital
Start date: 2020-02-10; Completion date: 2021-09-19
Enrollment: 9 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Critically ill patients with sepsis undergo several physiological alterations that can alter the distribution, metabolism, and elimination of drugs. Some patients with sepsis may realize enhanced cardiac output leading to increases in glomerular filtration that result in increasing drug clearance. This clinical state is referred as Augmented Renal Clearance (ARC). Importantly, many beta-lactam antibiotics can be adversely affected by ARC, and some of these agents required increasing dosage to compensate for enhanced clearance. Imipenem-relebactam is a new broad spectrum antibiotic. This study is designed to assess the pharmacokinetics of both components, imipenem and relebactam, in critically ill patients with ARC.

Detailed description:
This is a single center, open-label study to determine imipenem-relebactam pharmacokinetics in critically ill patients with Augmented Renal Clearance (ARC). Twelve patients with suspected ARC will be enrolled to ensure complete pharmacokinetic data in at least eight patients with confirmed ARC. Confirmation of ARC will be established by eight hour urine creatine determination. Each participant will receive a single dose of imipenem-relebactam (500mg/250mg) followed by six blood samples over a 6 hour interval to determine concentrations. Non-compartmental and population pharmacokinetic analyses will be determined to assess the effects of ARC on imipenem and relebactam pharmacokinetic parameters.

Arms: arm 1: Participants will receive a single dose of intravenous imipenem-relebactam (500mg-250mg) as a 30 minute infusion.
Interventions: intervention 1: Imipenem-relebactam
Intervention descriptions: intervention 1: After receipt of imipenem-relebactam, participants will have six blood samples collected over 6 hours for determination of imipenem and relebactam concentrations.

Protocol documents:
Prot_SAP_000.pdf: 
      MISP Template: Protocol
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Investigator Studies Program (MISP)
Protocol Template
Requirements for Submitting a Full Proposal
Section #1 - MISP Protocol Identification
Study Title:
An Open-label Pharmacokinetic Study of Imipenem-Cilastatin-Relebactam in 
Critically-Ill Patients with Augmented Renal Clearance
Request Date:
Original Submission: February 7, 2019
Amendment 1 Version: May 14, 2020
Amendment 2 Version: July 31, 2020
Amendment 3 Version: December 22, 2020
Institution Name
Hartford Hospital
Investigator 
Contact 
Information:
­Full address 
­Phone No.
­Fax  No.
­e-mail address
Joseph L. Kuti, PharmD, FIDP
Center for Anti-Infective Research and Development
Hartford Hospital
80 Seymour Street
Hartford, CT 06102
Tel: 860-972-3612
Fax: 860-545-3992
Email: joseph.kuti@hhchealth.org
HHC-IRB
IRB NUMBER: HHC-2019-0237
IRB APPROVAL DATE: 12/22/2020


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Section #2- Core Protocol
2.1 Objectives & 
Hypotheses 
1.0 Amendment 1 – Dated May 14, 2020
1.
Imipenem-relebactam changed to imipenem-cilastatin-relebactam 
throughout the protocol to document inclusion of cilastatin.  This maintains 
consistency with the package insert for the drug and also clarifies the 
dosage.
2.
The dosage has been changed to 1.25 grams throughout the protocol.  This 
total dose is consistent with the package insert and contains 500mg of 
imipenem, 500mg of cilastatin, and 250mg of relebactam.  Note, the total 
amount of imipenem and relebactam administered to the patient is not 
different from the original protocol.
3.
Section 2.1: correct misspelling
4.
Section 2.2: Background updated to indicate approval of imipenem-
cilastatin-relebactam for complicated urinary tract and intra-abdominal 
infections.
5.
Section 2.5 modified to indicate collection of blood in K2EDTA lavender 
tubes instead of sodium heparin tubes.  The assay to be used requires 
K2EDTA tubes for collection.  As a result, the maximum blood volume per 
sample has been reduced from 7 mL to 4 mL, since the latter is the 
maximum volume of a lavender top tube.  Additional details provided on 
processing of plasma with MES stabilizer.
6.
Section 2.5 modified to add free drug assessments of imipenem and 
relebactam.
7.
Section 2.7 modified to provide details of analytical service by Q2 Solutions, 
Ithaca NY.
8.
Section 2.7 modified to incorporate fraction unbound estimates into Monte 
Carlo simulations.
1.1 Amendment 2 – Dated July 31, 2020
1.
Section 2.5 modified to indicate collection of additional pre-dose blood 
sample within 30 minutes of infusion start time.
1.2 Amendment 3 – Dated December 22, 2020
1.
Section 2.5 inclusion criteria #3 modified to lower creatinine clearance 
(CrCL) from 150 mL/min to 130 mL/min. This has been changed throughout 
protocol accordingly. This will increase the target population while still 
limiting patients to those with augmented renal clearance.
2.
Section 2.5 inclusion criteria #4 modified to include only antibiotic use as a 
method for determining whether or not a patient has a documented or 
presumed infection, and removing other criteria related to infection 
(temperature, elevated WBC). 
3.
Section 2.5 inclusion criteria #10 modified to reduce minimum APACHE II 
score from >12 to ≥10.  The threshold of 12 was arbitrary, while the intent is 
to include relatively sick patients in the study, which will still be the case.
4.
Section 2.5 exclusion criteria #9 modified to remove valproic acid.
5.
Section 2.5 addition of criteria #10 excluding patients currently receiving or 
anticipated to receive valproic acid. The change in criteria 9 and 10 will allow 
for patients to receive imipenem-cilastatin-relebactam despite a prior recent 
history of valproic acid use.
HHC-IRB
IRB NUMBER: HHC-2019-0237
IRB APPROVAL DATE: 12/22/2020


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2.1 Objectives 
1.
Determine the single-dose pharmacokinetics of intravenous imipenem (when 
administered as imipenem-cilastatin-relebactam 1.25 grams as a 30 minute 
infusion) in adult critically ill patients with known or suspected sepsis and 
ARC 
2.
Determine the single-dose pharmacokinetics of intravenous relebactam 
(when administered as imipenem-cilastatin-relebactam 1.25 grams as a 30 
minute infusion) in adult critically ill patients with known or suspected sepsis 
and ARC
3.
Determine a dose of imipenem-cilastatin-relebactam that achieves greater 
than 90% probability of pharmacodynamic target attainment using the 
imipenem P. aeruginosa susceptibility breakpoint of 2 µg/mL and the MIC 
distribution of a contemporary P. aeruginosa and KPC producing K. 
pneumoniae population
4.
Assess the safety and tolerability of single-dose imipenem-cilastatin-
relebactam in adult critically ill patients with known or suspected sepsis and 
ARC
2.1.1 Null Hypotheses
The pharmacokinetics of imipenem and relebactam will not be affected by the 
presence of augmented renal clearance in adult critically ill patients.
2.2 Background & 
Rationale, 
Significance of 
Selected Topic & 
Preliminary Data 
The continuous rise of bacterial resistance to antibiotics is among the most 
challenging concerns in contemporary clinical medicine. Imipenem-relebactam 
(Merck&Co, Inc., Kenilworth, NJ) is an investigational broad-spectrum antibiotic that 
combines the known carbapenem, imipenem, with the novel beta-lactamase 
inhibitor, relebactam (1).  The addition of relebactam provides imipenem protection 
against serine based carbapenemases, including the Klebsiella pneumoniae 
carbapenemase (KPC), as well as improved activity against imipenem non-
susceptible Pseudomonas aeruginosa (2).  Imipenem-cilastatin-relebactam is 
approved in the United States for complicated urinary tract infections and 
complicated intra-abdominal infections; it is under investigation for hospital-acquired 
and ventilator-associated pneumonia, and specifically for multidrug resistant Gram-
negative infections when it retains activity (1).  
Given its potent activity against KPC producing Enterobacteriaceae and 
imipenem non-susceptible P. aeruginosa, it is reasonable to consider that imipenem-
cilastatin-relebactam will be used in patients who are critically ill in the intensive care 
unit (ICU).  Critically ill patients may have varied kidney dysfunction as a result of 
acute infection.  Most clinicians are familiar with acute and chronic kidney 
impairment, which results in decreased elimination of drugs that are cleared by 
glomerular filtration.  Both imipenem and relebactam are predominantly excreted via 
the kidneys (3); therefore, dosage adjustments will be required based on calculated 
creatinine clearance.  Sepsis in ICU patients, however, may also produce a 
syndrome called Augmented Renal Clearance (ARC), whereby increased blood flow 
to the kidneys results in enhanced renal elimination and solute clearance (4).  This 
enhanced clearance is typically defined by an 8 hour urine creatinine clearance ≥ 
130 ml/min/1.73 m2 and has been observed in as many as 65% of ICU patients on at 
least one day during their ICU admission (4,5).  ARC has been directly linked to sub-
therapeutic concentrations of β-lactam antibiotics, including imipenem (6,7,8,9).   
Furthermore, simulation of another carbapenem, meropenem, based on 
pharmacokinetics observed in patients with ARC resulted in regrowth of a 
susceptible Pseudomonas aeruginosa in hollow-fiber experiments (10).  
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To our knowledge, the pharmacokinetics of relebactam, with or without 
imipenem, have not been studied in critically ill patients with ARC.  If ARC affects 
relebactam clearance to a similar degree as imipenem and other renally eliminated 
β-lactams, larger doses or prolonged infusion may be required to maintain optimized 
pharmacodynamic exposure.  Importantly, the effect of ARC on beta-lactam 
exposure is highly dependent on the MIC of the causative organism.  Therefore, it is 
also possible that the lower MICs observed with imipenem when combined with 
relebactam may mean that ARC has little effect on achievable time above the MIC 
exposure.
2.3 Study Design
This will be a single center, observational, pharmacokinetic study. Eligible 
patients will be evaluated for inclusion/exclusion criteria.  Following consent by the 
patient, legal authorized representative (LAR), or next of kin, participants will receive 
a single dose of imipenem-cilastatin-relebactam 1.25 grams administered as a 30 
minute infusion.  Blood samples will be collected over the following 6 hours 
(consistent with proposed dosing interval) for characterization of imipenem and 
relebactam concentrations.  Pharmacokinetic analyses will be conducted to describe 
parameter estimates in patients with ARC.  We aim to enroll up to 12 patients so that 
complete data for 8 patients with ARC can be collected.
2.4 Study Flowchart
N/A
2.5 Study 
Procedures
Study Locations
The Center for Anti-Infective Research and Development (CAIRD), Hartford 
Hospital, CT will coordinate the study.  The study will conducted in the medical, 
surgical, and neurosurgical ICUs at Hartford Hospital, an 890 bed tertiary care 
hospital in Hartford, CT.  Institutional Review Board approval will be required based 
on local regulations.  If LAR or next of kin are consented, local regulations will be 
followed to collect written informed consent from the patient once able to provide 
consent.
Study Population
Inclusion Criteria
Patients eligible to participate in the study must meet all of the following criteria 
prior to any study-related procedure:
1.
Male or female aged 18-54 years;
2.
APACHE II score ≥ 10 and ≤ 35;
3.
Creatinine clearance (CrCL) ≥130 mL/min (as calculated by the Cockcroft-
Gault equation using ideal or adjusted body weight) within 24 hours of 
dosing (Note: using a higher CrCL threshold for Cockcroft-Gault CrCL will 
increase likelihood that enrolled participants have a urine CrCL ≥ 130 
ml/min/1.73 m2 and thus qualify as ARC);
4.
Documented infection or presumed infection by receiving another antibiotic.
Exclusion Criteria
Patients will be considered ineligible if they meet any of the following criteria:
1.
If female, currently pregnant or breast feeding;
2.
History of any moderate or severe hypersensitivity or allergic reaction to any 
β-lactam antibiotic (Note: mild rash or erythema to penicillin or cephalosporin 
antibiotics would not disqualify a patient if they have received a carbapenem 
without problem);
3.
History of chronic kidney disease, hemodialysis, or peritoneal dialysis; or 
history of acute renal replacement therapy (e.g., hemodialysis, 
HHC-IRB
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hemofiltration, hemodiafiltration) or extracorporeal membrane oxygenation 
(ECMO) associated with current illness;
4.
Suspected rhabdomyolysis or creatine kinase > 10,000 U/L;
5.
Any serum creatinine (SCr) before dosing that is increased ≥ 0.3 mg/dL from 
the baseline SCr used qualifying for enrollment;
6.
Urinary output <20 ml/hour for at least 2 hours (oliguria) within 24 hours 
before enrollment;
7.
Sustained (at least 1 hour) hypotension (systolic pressure < 90 mmHG or 
mean arterial pressure < 55 mmHg) refractory to vasopressors or IV fluid 
resuscitation for at least 24 hours before enrollment;
8.
Significant anemia defined as a hemoglobin < 8 g/dL at baseline;
9.
Use of probenecid or imipenem within 3 days before study drug infusion;
10. Current use of valproic acid or anticipated use during study enrollment.
11. Acute liver injury, defined as aspartate aminotransferase (AST) or alanine 
aminotransferase (ALT) > 5 times the upper limit of normal, or AST or ALT > 
3 times the upper limit of normal with an associated total bilirubin > 2 times 
upper limit of normal;
12. Any rapidly-progressing disease or immediately life-threatening illness 
(defined as imminent death within 48 hours in the opinion of the 
investigator);
13. Any condition or circumstance that, in the opinion of the investigator, would 
compromise the safety of the patient or the quality of study data;
14. Planned or prior participation in any other interventional drug study within 30 
days.
Study Procedures
Screening/Baseline
Screening/Baseline assessments and procedures must be completed within 
24 hours before the start of the study drug infusion. Potential subjects who do 
not meet enrollment criteria may, as appropriate, repeat the screening 
assessments once at a later time for possible enrollment into the study.  Local 
laboratory results will be used to determine subject eligibility for study 
enrollment. Any protocol-required eligibility laboratory evaluations already done 
as part of the patient’s regular medical care within 24 hours before the start of 
the study drug infusion on Study Day 1 do not have to be repeated for purposes 
of determining eligibility for this study.
•
Obtain informed consent in writing from patient, legal authorized 
representative, or next of kin, according to local regulations.
•
Clinical Assessments:
•
Obtain a complete medical and surgical history, including: a) all active 
conditions and all conditions diagnosed within the previous 1 year
•
Perform a complete physical examination (general/appearance; head, 
eyes, ears, nose, and throat [HEENT]; neurological; pulmonary; 
cardiovascular; gastrointestinal; musculoskeletal; and skin)
•
Record height and weight
•
Record resting pulse, blood pressure, and respiratory rate; oxygen 
saturation (by pulse oximeter), including rate of supplemental oxygen 
(i.e., FiO2); ventilator support; and highest (or lowest if hypothermia) 
daily temperature (oral, rectal, tympanic, or core) measured
•
Record total fluid balance including total fluid intake and total fluid output 
for the period encompassing the signing of the ICF to the start of the 
study drug infusion
•
Record each component of the Acute Physiology and Chronic Health 
Evaluation II (APACHE II) assessment at Screening/Baseline
HHC-IRB
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•
Record all prior medications taken or received within 3 days before study 
drug infusion
•
Identify, assess, and record any new adverse events or Serious Adverse 
Events (SAE) after signing of informed consent
•
Laboratory Assessments:
•
Collect the following labs within 24 hours of study dose administration: 
serum creatinine, blood urea nitrogen, glucose, sodium, potassium, 
chloride, bicarbonate, albumin, total protein, complete blood count 
(CBC) with differential, total bilirubin, direct bilirubin, alkaline phosphate, 
alanine aminotransferase, aspartame aminotransferase, and urine 
analysis with microscopy.  A serum hCG test will be collected for 
females of child-bearing potential.
•
Calculation of CrCL using Cockcroft-Gault based on screening/baseline 
serum creatinine:
Calculated CrCL =  (140 - age in years) × ideal body weight (kg)a,b,c
    72 × SCr (mg/dL)
Multiply by 0.85 for female patients
a Ideal body weight (IBW, kg): Males = 50 + [2.3 × (Height (in) - 60)]; 
Females = 45.5 + [2.3 × (Height (in) - 60)]
b For patients with total body weight (TBW) that is greater than 20% 
over IBW, use adjusted body weight (ABW, kg): IBW + 0.4*(TBW-
IBW)
c If TBW is less than IBW, use TBW in equation
Study Medication Administration
All participants will receive a single dose of imipenem-cilastatin-relebactam 
1.25 grams as a 30 minute (+/- 5 minutes) infusion.  Imipenem-cilastatin-
relebactam vials will be supplied by the study sponsor.  The dose will be 
prepared according to manufacturer recommendations in precisely 100 ml of 
0.9% sodium chloride.  Imipenem-cilastatin-relebactam must be administered 
through a peripheral intravenous catheter, peripherally inserted central catheter 
(PICC), central line, or port-a-catheter, whichever is determined to be most 
appropriate by the local investigator and care provider for each participant.  
Participants will also receive standard intravenous antibiotic therapy (excluding 
generic or branded intravenous imipenem) to treat their suspected infection, as 
determined by the responsible provider.  No other intravenous medications will 
be co-administered with imipenem-cilastatin-relebactam.
Study Day 1 
•
Within 8 hours of beginning study medication infusion, a pre-dose SCr will be 
collected to confirm calculated CrCL remains ≥130 mL/min and that no 
change in SCr was observed to be ≥ 0.3 mg/dL from the baseline SCr used 
qualifying for enrollment.
•
An 8 hour (± 1 hour) urine creatinine collection will be initiated within 4 hours 
prior to study medication infusion.  The results of the measured urine CrCL 
will be used to confirm ARC in the patient over the time period that blood 
samples for imipenem-cilastatin-relebactam are collected. 
HHC-IRB
IRB NUMBER: HHC-2019-0237
IRB APPROVAL DATE: 12/22/2020


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Measured CrCL (ml/min) = UCr (mg/dL) x  urine volume (mL)
       Predose-SCr  x  timea
Abbreviations: CrCl = creatinine clearance; SCr = serum creatinine; UCr 
= urine creatinine.
a Time = The 8-hour urine collection has a ± 1 hour window (i.e., 480 
min ± 60 min); use the exact number of minutes of the urine collection 
in the equation
•
Vital signs (temperature, heart rate, blood pressure, respiratory rate) will be 
recorded within 15 minutes prior to starting the study drug infusion.
•
Participants will receive the single dose of imipenem-relebactam as 
described above. Exact start and stop times will be recorded in military time.  
•
Identify, assess, and record any new adverse events or Serious Adverse 
Events (SAE)
•
Concomitant medications will be recorded.
•
Blood Sample Collection: Seven blood samples (4 ml per sample) will be 
collected in K2EDTA vacutainers at the following time points to determine 
the concentrations of imipenem and relebactam in plasma: 0 hour (within 30 
minutes prior to the start of infusion), 0.5 hours (end of infusion), 0.75, 1, 2, 
4, and 6 hours after the start of the infusion.  The timing of all blood samples 
should be +/- 5 minutes of protocol defined time, except for the 0.5 hour 
(peak concentration), which can be + 5 minutes and should be collected as 
close to the end of the infusion as possible.  All blood samples will be 
collected via a peripheral intravenous catheter inserted into the contralateral 
arm to drug administration for collection of blood samples. Alternatively, 
venipuncture may be used to collect the seven blood samples.  
•
Blood samples will be immediately stored on ice and centrifuged within 30 
minutes of collection at 1000-1300 x g (rcf) for 10 minutes at 4°C to separate 
the plasma.
•
Immediately after centrifugation of whole blood, use a 1.0 mL pipette to 
transfer exactly 1.0 mL of plasma to labeled, cryovials containing 1.0 mL of 
plasma stabilizer (2-(N-morpholino) ethanesulfonic acid (MES)).  Add a 
second 1.0 mL of plasma to a second cryovial to serve as a back-up sample.
•
Cap the cryovials and mix the plasma with the preservative stabilizer by 
inverting at least six times.  Freeze and store at -80 °C.  No more than 60 
minutes should elapse between the blood draw and freezing of plasma 
sample.
•
An additional 8ml blood sample will be collected for imipenem and 
relebactam protein binding determination at 0.5 hours (end of infusion). 
Plasma will be separated by centrifugation as previously explained. 
Approximately 0.9 mL of plasma will be loaded in an ultrafiltration device 
(Centrifree®, Merck Millipore Ltd., Ireland) and centrifuged for 45 minutes at 
10º C at 2,000 x g to obtain an ultrafiltrate containing only free-drug 
concentrations. Protein binding will be conducted in triplicate.  The protein-
free ultrafiltrate volume will be measured, transferred to a cryovial and then, 
an equal volume of the stabilizer will be added (confirmation of processing 
instructions for protein-free imipenem and relebactam will be provided by Q2 
Solutions, Ithaca, NY). The cryovials will be stored at -80º C until 
concentration determination. The final protein percentage will be calculated 
by dividing the free concentration by the total plasma concentration and 
subtracting from 100 (%). 
Study Day 2
•
Clinical Assessments:
•
Perform a complete physical examination
HHC-IRB
IRB NUMBER: HHC-2019-0237
IRB APPROVAL DATE: 12/22/2020


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•
Record resting pulse, blood pressure, and respiratory rate; oxygen 
saturation (by pulse oximeter), including rate of supplemental oxygen 
(i.e., FiO2); ventilator support; and highest (or lowest if hypothermia) 
daily temperature (oral, rectal, tympanic, or core) measured
•
Identify, assess, and record any new adverse events or Serious Adverse 
Events (SAE) 
•
Laboratory Assessments:
•
Collect the following labs within 24 hours after completion of last blood 
sample collection: serum creatinine, blood urea nitrogen, glucose, 
sodium, potassium, chloride, bicarbonate, albumin, total protein, 
complete blood count (CBC) with differential, total bilirubin, direct 
bilirubin, alkaline phosphate, alanine aminotransferase, aspartame 
aminotransferase, and urine analysis with microscopy.  
2.6 Study Duration
Final Protocol 
2 months
IRB Approval
2 months
Enrollment and Sampling
10 months
Imipenem-relebactam Analytical (by Sponsor)
TBD
Pharmacokinetic Analyses
1 months
Final Report
1 months
2.7 Statistical 
Analysis and 
Sample Size 
Justification 
Data Analyses
Data Collection
Patient demographics, medical/surgical history, concomitant medications, 
and adverse event data will be collected throughout the study on a provided 
case report form.  Protected Health Information (PHI) will be maintained at 
CAIRD.  
Analysis Populations
All patients enrolled will be included in the safety population.  However, only 
the 8 patients who meet the definition of ARC will served as the primary 
pharmacokinetic population.  Any additional patients enrolled who do not meet 
the definition of ARC will have imipenem and relebactam concentrations 
determined for informational purposes.  These patients will not be included in the 
summary pharmacokinetic analyses.  
Analytical
Cryovials containing plasma and protein free filtrate will be overnight shipped 
on dry ice to Q2 Solutions (Ithaca, NY) for imipenem and relebactam 
concentration determination.  The back-up vial will be shipped separately.  
Imipenem and relebactam concentrations will be determined by a liquid 
chromatography mass spectrometry assay.  
Pharmacokinetic Analyses
Non-compartmental
Non-compartmental modeling will be conducted using WinNonlin (Pharsight 
Corporation, Cary, NC) using the latest version licensed for the laboratory.  All 
concentration time curves will be plotted for visual inspection.  The following 
pharmacokinetic parameters will be estimated for imipenem and relebactam in 
each of the 8 participants.  The maximum concentration (Cmax) will be the highest 
concentration observed for the concentration time profile of each participant.  
The time to maximum concentration (Tmax) will be the observed sampling time of 
the Cmax.  The minimum concentration (Cmin) will be the lowest concentration 
observed for the concentration time profile of each participant that occurs after 
the observed Cmax.  Lambda (z) will be the resulting slope of the regression line 
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of best fit.  Half-life (T1/2) will be calculated as ln(2)/z.  Area under the curve for 
the dosing interval (AUC0-) will be calculated by the linear/log trapezoidal rule 
(linear during increasing concentrations, log during decreasing concentrations), 
where  is the dosing interval for the drug studied. The AUC to infinity (AUCINF) 
will be calculated as the AUC extrapolated to infinity by the equation: AUC + 
Clast/z. Clearance (CL) will be estimated by Dose/AUC0-.  The volume of 
distribution based on the terminal elimination phase (Vz) will be estimated by 
Dose/(z*AUC0-).  
Population Pharmacokinetic Analyses
Imipenem and relebactam concentrations will be modeled using the non-
parametric adaptive grid program (NPAG) with adaptive gamma in the Pmetrics 
package for R (Laboratory of Applied Pharmacokinetics and Bioinformatics, Los 
Angeles, CA) using either a one or two compartment model.  Appropriate model 
selection will be based on visual inspection, observed versus predicted plots, 
and Akaike Information Criterion (AIC). The effect of specific body size 
descriptors (actual body weight, ideal body weight, body mass index, body 
surface area) and both calculated and measured CrCL will be analyzed for 
correlation with pharmacokinetic parameters (i.e., CL and volume of distribution).
Monte Carlo Simulation
Using the population pharmacokinetic model, a 5000 patient Monte Carlo 
simulation will be conducted for the standard imipenem and relebactam dosing 
regimen to determine probability of achieving pharmacodynamic thresholds, as 
defined by Sponsor, at the imipenem susceptibility breakpoint of 2 µg/mL. 
Observed fraction unbound estimates from the protein-free ultrafiltrate studies in 
these patients will be incorporated into simulations.  In the scenario that the 
probability of target attainment (PTA) is less than 90%, a higher dose and longer 
infusion time (e.g., 2-3 hours) will be simulated to determine a dose that 
achieves at least 90% PTA.  Analyses will also be conducted using 
contemporary MIC distributions of P. aeruginosa and KPC producing K. 
pneumoniae.  
Power/Sample Size:
Based upon relebactam single dose pharmacokinetic data from healthy 
volunteers receiving the drug with or without imipenem (3), clearance across all 
doses was 8.6 L/h with a standard deviation of 1.2 L/h.  Eight in the ARC group 
would provide 80% power at an alpha of 0.05 to detect a 40% difference in total 
body clearance from the historical healthy volunteer data; this also assumes an 
increase in coefficient of variability (CV) to 25%, which is expected in critically ill 
patients.  Since some patients with calculated CrCL via Cockcroft-Gault will not 
have 8 hour urine CrCL of at least 130 ml/min/1.73 m2, this study will enroll up to 
12 patients to have complete data for 8 patients with ARC.  Enrollment will stop 
once complete data for 8 patients who meet the definition of ARC is confirmed or 
a maximum of 12 patients complete the study, whichever occurs first.
2.8 Specific Drug 
Supply 
Requirements 
Imipenem-Cilastatin-Relebactam 1.25 gram vials (n=15 vials)
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2.9 Adverse 
Experience 
Reporting
Participants will be monitored for any sign or symptom of adverse events 
throughout the course of the study. Unanticipated, life-threatening or fatal adverse 
events will be reported to the IRB, the manufacturer, and the Food and Drug 
Administration according to federal guidelines. All adverse events requiring medical 
attention will be treated by the study physician and will be recorded by the 
investigator.
For the purpose of this study, an adverse event will be defined as any pathologic 
or unintended change in the structure (signs), function (symptoms), or chemistry 
(laboratory values) of the body associated with the use of the study drug, whether or 
not considered drug related, and will be categorized as one of the following:  

MILD – present, but easily tolerated

MODERATE – discomfort that interferes with usual activities

SEVERE – incapacitating, inability to work or do usual activities
Relationship of the AE to the study medication (i.e., causality) will be evaluated 
according to the investigator’s opinion, as one of the following:

Concurrent condition – unrelated to study drug

REMOTE adverse drug event – little or no temporal relationship to study 
drug

POSSIBLE adverse drug event – temporal relationship to study drug

PROBABLE adverse drug event – commonly associated with study drug

DEFINTE adverse drug event – reappeared on re-challenge of study drug
All SAEs will be reported to the Institutional Review Board, sponsor, and the Food 
and Drug Administration according to Federal and local guidelines. A serious 
adverse event will be defined as any adverse event that results in death, is 
immediately life-threatening, requires or prolongs hospitalization, or is an important 
medical event that may jeopardize the participant or may require medical 
intervention to prevent one of the previously mentioned outcomes.
2.10 Itemized Study 
Budget 
See Proposed Budget 
2.11 References
1.
Zhanel GC, Lawrence CK, Adam H, Schweizer F, Zelenitsky S, Zhanel M, 
Lagace-wiens PRS, Walkty A, Denisuik A, Golden A, Gin AS, Hoban DJ, 
Lynch JP, Karlowsky JA. Imipenem-relebactam and meropenem-
vaborbactam: two novel carbapenem-beta-lactamase inhibitor combinations. 
Drugs 2018;78:65-98.
2.
Lob SH, Hackel MA, Kazmierczak KM, Young K, Motyl MR, Karlowsky JA, 
Sahm DF. In vitro activity of imipenem-relebactam against gram-negative 
ESKAPE pathogens isolated by clinical laboratories in the United states in 
2015 (results from the SMART global surveillance program). Antimicrob 
Agents Chemother 2017;61:e02209-16.
3.
Rhee EG, Rizk ML, Calder N, Nefliu M, Warrington SJ, Schwartz MS, 
Mangin E, Boundy K, Bhagunde P, Colon-Gonzalez F, Jumes P, Liu Y, 
Butterton JR. Pharmacokinetcs, safety, and tolerability of single and multiple 
doses of relebactam, a beta-lactamase inhibitor, in combination with 
imipenem and cilastatin in healthy participants. Antimicrob Agents 
Chemother 2018;62:e00280.
4.
Udy AA, Roberts JA, Shorr AF, Boots RJ, Lipman J. Augmented renal 
clearance in septic and traumatized patients with normal plasma creatinine 
HHC-IRB
IRB NUMBER: HHC-2019-0237
IRB APPROVAL DATE: 12/22/2020


      MISP Template: Protocol
11
Final Version: 8/13/2010
concentrations: identifying at-risk patients. Crit Care 2013;17:R35.
5.
Udy AA, Baptista JP, Lim NL, Joynt GM, Jarrett P, Wockner L, Boots RJ, 
Lipman J. Augmented renal clearance in the ICU: results of a multicenter 
observational study of renal function in critically ill patients with normal 
plasma creatinine concentrations. Crit Care Med 2014;42:520-7.
6.
Troger U, Drust A, Martens-Lobenhoffer J, Tanev I, Braun-Dullaeus RC, 
Bode-Boger SM. Decreased meropenem levels in intensive care unit 
patients with augmented renal clearance: benefit of therapeutic drug 
monitoring. Int J Antimicrob Agents 2012;40:370-2.
7.
Carler M, Carrette S, Roberts JA, Stove V, Verstraete A, Hoste E, Depuydt 
P, Decruyenaere J, Lipman J, Wallis SC, De Waele JJ. Meropenem and 
piperacillin/tazobactam prescribing in critically ill patients: does augmented 
renal clearance affect pharmacokinetic/pharmacodynamic target attainment 
when extended infusions are used? Crit Care 2013;17:R84.
8.
De Waele JJ, Lipman J, Akova M, Bassetti M, Dimopoulos G, Kaukonen M, 
Koulenti D, Martin C, Montravers P, Rello J, Rhodes A, Udy AA, Starr T, 
Wallis SC, Roberts JA. Risk factors for target non-attainment during 
empirical treatment with β-lactam antibiotics in critically ill patients. Intensive 
Care Med 2014;40:1340-51.
9.
Huttner A, Von Dach E, Renzoni A, Huttner BD, Affaticati M, Pagani L, Daali 
Y, Pugin J, Karmime A, Fathi M, Lew D, Harbarth S. Augmented renal 
clearance, low β-lactam concentrations and clinical outcomes in the critically 
ill: an observational prospective cohort study. Int J Antimicrob Agents 
2015;45:385-92.
10. Bergen PJ, Bulitta JB, Kirkpatrick CMJ, Rogers KE, McGregor MJ, Wallis 
SC, Paterson DL, Nation RL, Lipman J, Roberts JA, Landersdorfer CB. 
Substantial impact of altered pharmacokinetics in critically ill patients on the 
antibacterial effects of meropenem evaluated via the dynamic hollow-fiber 
infection model. Antimicrob Agents Chemother 2017;61:e02642-16.
2.12 Publication 
Plan
The results of this study would be presented at an international congress such as the 
ASM Microbe Meeting, IDWeek, ECCMID, or SCCM.  A final publication would be 
submitted to a peer reviewed journal such as Antimicrobial Agents and 
Chemotherapy or Journal of Antimicrobial Chemotherapy.
2.13 Curriculum 
Vitae
Investigator should provide curriculum vitae in English and a listing of references to MSD.
2.13 Protocol 
Submission for 
Investigator-
Initiated Studies 
U.S. protocols should be submitted by US investigators directly or through the Global 
Research Specialist at  www.merckiisp.com  
Non U.S. protocols should be submitted to the MSD office by the investigators.
HHC-IRB
IRB NUMBER: HHC-2019-0237
IRB APPROVAL DATE: 12/22/2020