Final Full Clinical Study Report
Protocol C3591036

CLINICAL STUDY REPORT SYNOPSISSYNOPSIS
Study Title: A Phase 3, Multicenter, Open-Label, Single-Arm Study to Assess the Efficacy
and Safety of Ceftazidime-Avibactam (PF-06947386) Plus Metronidazole in Japanese Adult
Patients With Complicated Intra-Abdominal Infection Requiring Hospitalization
Study Number: C3591036
Regulatory Agency or Public Disclosure Identifier Number: NCT04927312
Study Phase: 3
Name of Study Intervention: PF-06947386 (Ceftazidime-Avibactam)
Name of Sponsor/Company: Pfizer Inc.
CSR Version and Report Date: 1.0, 27 March 2023
Number of Study Center(s) and Investigator(s):A total of 60 participants were enrolled at 27 sites in Japan.
A list of study centers and investigators involved in this study is provided inAppendix 16.1.4.1.
Publications:
Not Applicable
Study Period:
The study initiation date was 01 October 2021 and the study completion date was
15 September 2022.
This study was neither discontinued nor interrupted.
Rationale:
PF-06947386 is a combination drug that contains ceftazidime, the third-generation
cephalosporin antibiotic (-lactam) and avibactam, a novel non--lactam -lactamase
inhibitor. PF-06947386 has received regulatory approval in 78 countries/regions as ofAugust 2020 including approval in the Unites States (US) in February 2015 and in theEuropean Union (EU) in June 2016. PF-06947386 is indicated in the US and Europe for thetreatment of adults with complicated intra-abdominal infection (cIAI), complicated urinary
tract infection (cUTI) and hospital-acquired pneumonia (HAP)/ventilator-associatedpneumonia (VAP). In Europe, it is also indicated for the treatment of infections due toaerobic Gram-negative organisms in adult patients with limited treatment options and, inPFIZER CONFIDENTIAL
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2020, it was approved for the treatment of bacteremia associated with, or suspected to beassociated with, any of the above infections.
The pharmacokinetics (PK) of ceftazidime and avibactam is sufficiently similar acrossindications, and in Japanese, non-Japanese and non-Asian patient populations. Population PK
modeling/simulation analysis has demonstrated sufficient exposure and high probability oftarget attainment in Japanese patients at the adult doses currently approved outside of Japan.
There are no notable differences in diagnostics and treatment for cIAI between Japan andother countries. These infections require operative intervention or percutaneous drainage inconjunction with broad spectrum antibacterial therapy. Almost all intra-abdominal infections
are polymicrobial and are caused by organisms from the gastrointestinal tract, including
aerobes and facultative and obligate anaerobes. Gram-negative Enterobacterales are mostcommonly isolated. Currently, extended-spectrum -lactamases producing pathogens are
increasing among the Enterobacterales, such as Escherichia coli (E.coli).
Hence, for the treatment of cIAI, broad-spectrum single agent (-lactam/-lactamase
inhibitor combination drugs, carbapenems) or combination therapy regimens (concomitant
use of cephem antibiotics) are recommended.

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CLINICAL STUDY REPORT SYNOPSIS
Objectives, Endpoints, and Statistical Methods:
Table 1.

Objectives and Endpoints

Type and Objective
PrimaryEfficacy
To assess the efficacy of PF-06947386 plus
metronidazole
Secondary
Efficacy
To determine the efficacy of PF-06947386 plus
metronidazole

Endpoints

To determine the per-patient microbiologicalresponse of PF-06947386 plus metronidazole

Per-patient microbiological response at EOT, TOC, andLFU visits

To determine the per-pathogen microbiologicalresponse of PF-06947386 plus metronidazole

Per-pathogen microbiological response at EOT, TOC,and LFU visits
Per-pathogen microbiological response at EOT, TOC,and LFU visits by MIC categories

SafetyTo evaluate the safety and tolerability profile ofPF-06947386 plus metronidazole in the treatmentof participants with cIAIs

Clinical response at the TOC visit

Clinical response at EOT and LFU visits

AEs and SAEs, all cause mortality, reasons fordiscontinuations of IV study intervention and study,
vital sign measurements, and potentially clinicallysignificant changes in laboratory parameters during theentire study

PKTo evaluate the pharmacokinetics of theCeftazidime and avibactam plasma concentrations by
individual components of PF-06947386 in
nominal sampling windowparticipants with cIAIs
Efficacy and safety
To investigate safety and efficacy for participants Selected efficacy and safety endpoints as describedwith sepsis (if available)
above
AE = adverse event, cIAI = complicated intra-abdominal infection, CRP = C-reactive protein, EOT = end oftreatment, IV = intravenous, LFU = late follow-up, MIC = minimum inhibitory concentration, SAE = serious
adverse event, TOC = test of cure, WBC = white blood cell

Statistical Methods
No formal hypothesis testing was conducted. As an efficacy evaluation criterion, it wasconfirmed that the point estimate of proportion of patients with clinical cure at TOC visit in
the clinically evaluable (CE) analysis set (the primary analysis) was ≥78.0%.
Main analysis of the primary endpoint included number of participants, frequency, andproportion and the 95% CI was calculated for the CE at TOC analysis set. The assessment by
the adjudication committee was used.
Descriptive summaries were provided where appropriate for each of the primary andsecondary endpoints. In general, summaries were presented for the modified intent-to-treatPFIZER CONFIDENTIAL
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CLINICAL STUDY REPORT SYNOPSIS(MITT) and microbiologically modified intent-to-treat (mMITT) analysis sets, and themicrobiologically evaluable (ME), extended microbiologically evaluable (eME), and CE
analysis sets at the appropriate visit.
Methodology:
Study C3591036 assessed the efficacy and safety of PF-06947386 in Japanese patients withcIAI requiring hospitalization. This was a multicenter, open-label, single-arm study. Thestudy had a maximum duration of approximately 6 weeks for each participant. This included
5 to 14 days of IV study period, TOC visit at Day 28, and LFU visit at Day 42.
Number of Participants (planned and analyzed):
Approximately 60 participants were planned to be enrolled to study intervention, which
could contribute to have approximately 50 evaluable participants in the CE analysis set and3 to 5 enrolled participants to meet the definition of the sepsis patients subset.
A total of 60 participants were enrolled to study intervention including 40 participants in theCE at TOC analysis set and 2 participants in the sepsis patients subset.
Diagnosis and Main Criteria for Inclusion and Exclusion:
Participants ≥20 years at the time of the Screening visit with clinical evidence of cIAI,
willing and able to give signed informed consent and meet all inclusion criteria and noexclusion criteria were enrolled in the study.
Clinical evidence of cIAI for pre-operative participants included requirement for surgicalintervention, evidence of systemic inflammatory response, physical and/or imaging findings
consistent with cIAI.
Criteria for intra-operative/post-operative participants included diagnosis of at least one of
the following during surgical intervention:
a. Cholecystitis with gangrenous rupture or perforation or progression of the infection
beyond the gallbladder wall.
b. Diverticular disease with perforation or abscess.
c. Appendiceal perforation or peri-appendiceal abscess.
d. Acute gastric or duodenal perforations, only if operated on 24 hours after
perforation occurs.
e. Traumatic perforation of the intestines, only if operated on 12 hours after
perforation occurs.

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f. Secondary peritonitis (but not spontaneous bacterial peritonitis associated withcirrhosis and chronic ascites).
g. Intra-abdominal abscess (including of liver or spleen provided that there wasextension beyond the organ with evidence of intraperitoneal involvement).
Study Interventions, Dose, Mode of Administration, and Batch Number(s):Intervention NameType
Dose Formulation
Unit Dose Strength(s)Route of AdministrationUse
IMP or NIMP
Manufacturing Lot Number
Sourcing
Packaging and Labeling

PF-06947386(ceftazidime-avibactam)
Drug
Powder for concentrate for solution
for infusion
2.0 g ceftazidime and 0.5 g avibactam
Intravenous
Experimental
IMP21-AE-00133
Provided centrally by the sponsor
Study intervention was provided invials. Each vial was labeled as
required per country requirement.

Metronidazole
Drug
Solution for injection
0.5 g
Intravenous
ConcomitantIMP
21-AE-00151
Provided centrally by the sponsor
Study intervention was provided invials. Each vial was labeled as
required per country requirement.

IMP = investigational medicinal product; NIMP = noninvestigational medicinal productDuration of Study Intervention:
Eligible participants with creatinine clearance (CLcr) 50 mL/min were given an IV dose of
2.5 g PF-06947386 (ceftazidime 2.0 g/avibactam 0.5 g) q8h with infusion time of 2 hours for
5 to 14 days. For participants enrolled into the study whose CLcr dropped to ≤50 mL/min
while on IV investigational drug therapy, dosage adjustment was required depending on thedegree of renal impairment based on the CLcr value. All eligible participants received
metronidazole (0.5 g) intravenously with an infusion duration of 60 minutes. When both PF06947386 and metronidazole were administered at the same time, metronidazole wasadministered immediately after administration of PF-06947386.
Summary of Results:
Demographic and Other Baseline Characteristics:
In the MITT analysis set, all participants enrolled in the study were Asian. A slightly higher
proportion of male participants (57.6%) versus female participants (42.4%) was included.
The mean age was 57 years (range: 20 to 90 years). Distribution of participants was balanced
across age categories and included 18.6% of participants over ≥75 years of age.
In the MITT analysis set, all participants had a primary diagnosis of cIAI. The most common
secondary diagnoses were secondary peritonitis (100%), intra-abdominal abscess (72.9%),
and perforated appendicitis (44.1%). Majority of the participants had polymicrobial
infections (61.0%) versus monomicrobial infection (10.2%).

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CLINICAL STUDY REPORT SYNOPSIS
Exposure:
Overall, the mean (SD) duration of treatment was 7.2 (2.19) days. Majority of theparticipants (54 [90.0%]) received treatment between 5 and 10 days.
Efficacy Results:Primary Efficacy Endpoint: Clinical Response at the TOC VisitThe proportion of participants in the CE analysis set with clinical cure at the TOC
visit was 90.0% (95% CI: 76.3, 97.2), which was greater than the pre-specified point
estimate threshold value of 78.0%.

The proportion of participants with clinical cure at the TOC visit was 90.0%, 88.1%,85.7%, 94.3%, and 94.4% for the CE, MITT, mMITT, ME, and eME analysis sets,respectively.

Secondary Efficacy Endpoint: Clinical Response at EOT and LFU VisitsThe proportion of participants with clinical cure at the EOT visit was 90.5%, 91.5%,90.5%, 94.4% and 94.6% for the CE, MITT, mMITT, ME, and eME analysis sets,respectively.

The proportion of participants with clinical cure at the LFU visit was 90.0%, 88.1%,85.7%, 94.3% and 94.4% for the CE, MITT, mMITT, ME, and eME analysis sets,respectively.

Two (2) participants were included in the sepsis patients subset and achieved clinicalcure at the TOC, EOT and LFU visits. Out of 2 participants, one (1) participant wasincluded in the sepsis evaluable patients subset and achieved clinical cure at the TOC,EOT, and LFU visits. No clinical failures were observed in these subsets.

Secondary Efficacy Endpoint: Per-patient Microbiological Response at EOT, TOC, andLFU VisitsIn the mMITT analysis set, the proportion of participants with a favorable per-patient
microbiological response was high (≥90.0%) and was similar at the TOC, EOT, andLFU visits. In the ME and eME analysis sets, the proportions of participants with afavorable per-patient microbiological response at each scheduled assessment weresimilar to those observed in the mMITT analysis set at the TOC, EOT, and LFUvisits.

Both participants included in the sepsis patients subset (100.0%) and the single
participant included in the sepsis evaluable patients subset (100.0%) had a favorable
per-patient microbiological response at the TOC, EOT, and LFU visits.
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Secondary Efficacy Endpoint: Per-pathogen Microbiological Response at EOT, TOC,and LFU VisitsThe favorable per-pathogen microbiological response rate for Gram-negative
pathogens (other than R. planticola), including E. coli, K. pneumoniae, P. aeruginosa
were over 90% at all visits in the mMITT analysis set.

Per-pathogen microbiological response for eME and ME were similar to thoseobserved for the mMITT analysis set at EOT, TOC, and LFU visits.

Secondary Efficacy Endpoint: Per-pathogen Microbiological Response at EOT, TOC,and LFU Visits by MIC Categories
All Enterobacterales including E. coli, K. pneumoniae, and P. aeruginosa weresusceptible. The favorable response rates for these pathogens other than R. planticola
were over 90% at EOT, TOC, and LFU visits in the mMITT, eME, and ME analysis
sets.

Safety Results:
A total of 112 AEs were reported for 42 (70.0%) participants overall. Number of participants
who discontinued from the study due to adverse events (AEs) were 2 (3.3%). Participants
with dose reduced or temporary discontinuation due to AEs were 3 (5.0%).
Most of the AEs were mild or moderate in severity and only 1 AE was severe(pneumonia aspiration) with outcome of death, which was considered unrelated to thestudy drug.

A total of 6 serious adverse events (SAEs) were reported for 3 participants overall. Of the6 SAEs, 4 were reported in a single participant (pneumonia aspiration, contusion, ileus,and femur fracture). Another 2 participants had 1 SAE reported each, pyelonephritis andgout, respectively.

Overall, 2 (3.3%) participants discontinued from the study (1 due to pneumonia
aspiration and 1 due to pyelonephritis). Both of these events were not considered related
to the study drug.

The most common laboratory test abnormalities were C-reactive protein (1.1x ULN) in 60(100.0%), albumin (0.8x LLN) in 53 (88.3%) participants and lymphocytes/leukocytes(<0.8x LLN) in 48 (80.0%) participants. Three (3) (5.0%) and 5 (8.3%) participants reported
abnormal ALT levels (3.0x ULN) and AST levels (3.0x ULN), respectively. Though
1 participant met the Hy’s Law criteria, the investigator considered that this was not a Hy’s
Law case.

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CLINICAL STUDY REPORT SYNOPSIS
No meaningful findings in the vital sign measurements or other observations related to safety
were observed in this study.
Pharmacokinetic Results:All the participants in the PK Analysis Set obtained 3 PK samples on Day 3 or Day 4 ofthe study as planned. Plasma concentration of ceftazidime and avibactam were thehighest around the end of infusion (anytime from 15 minutes prior to stopping until
15 minutes after stopping PF-06947386 infusion).

Plasma concentration of ceftazidime and avibactam gradually decreased at time windows
between 30 and 90 minutes and between 300 minutes and 360 minutes after stopping
PF-06947386 infusion but before the next dose.

Conclusions:
The proportion of participants in the CE analysis set with clinical cure at the TOC visit
was 90.0%; (95% CI: 76.3 to 97.2), which was greater than the pre-specified point
estimate threshold value of 78%.

The clinical cure rates at the EOT and LFU visits were similar to the results at the TOC inthe CE analysis set.

The favorable per-patient microbiological response at all visits were similar to the resultof clinical responses.

All Enterobacterales including E. coli and K. pneumoniae, and P. aeruginosa weresusceptible. The favorable response rates for these pathogens other than R. planticola
were over 90% at EOT, TOC, and LFU visits in the mMITT, eME, and ME analysis sets.

PF-06947386 was well tolerated, with no new safety signals identified in this Japanesestudy.

For both sepsis patients subset (2 participants) and sepsis evaluable patients(1 participant), the clinical responses and microbiological responses observed for allparticipants were cure and favorable at EOT, TOC, and LFU visits, and no additionalsafety concerns were observed.

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