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Japanese

July. 21, 2021

Dec. 12, 2023

jRCT2061210026

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 to Assess Efficacy and Safety of PF-06947386 in Japanese Adult Patients With Complicated Intra-abdominal Infection

Feb. 24, 2023

60

In the modified intent-to-treat (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.

A total of 60 participants were enrolled, all of whom received at least one dose of study treatment, and 59 (98.3%) of whom completed treatment. Overall, 57 participants completed test of cure (TOC) visit and 56 participants completed the study [late follow-up (LFU) visit]. 4 participants were discontinued study, one each due to adverse events (AEs), death, withdrawal of participant's consent, and other (participant's request for early start of chemotherapy).

A total of 112 AEs were reported for 42 (70.0%) participants overall. Number of participants who discontinued from the study due to 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 the study drug. * A total of 6 serious adverse events (SAEs) were reported for 3 participants overall. Of the 6 SAEs, 4 were reported in a single participant (pneumonia aspiration, contusion, ileus, and femur fracture). Another 2 participants had 1 SAE reported each, pyelonephritis and gout, 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.

Primary Efficacy Endpoint: Clinical Response at the TOC Visit * The proportion of participants in the clinically evaluable (CE) analysis set with clinical cure at the TOC visit was 90.0% [95% confidence interval: 76.3, 97.2], which was greater than the pre-specified point estimate threshold value of 78.0%. * The proportion of participants in the other analysis sets with clinical cure at the TOC visit was 88.1%, 85.7%, 94.3%, and 94.4% for the MITT, microbiologically modified intent-to-treat (mMITT), microbiologically evaluable (ME), and extended microbiologically evaluable (eME) analysis sets, respectively. Secondary Efficacy Endpoint: Clinical Response at End of Treatment (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. * 2 participants were included in the sepsis patients subset and achieved clinical cure at the TOC, EOT and LFU visits. Out of 2 participants, 1 participant was included in the sepsis evaluable patients subset. Secondary Efficacy Endpoint: Per-patient Microbiological Response at EOT, TOC, and LFU 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, and LFU visits. In the ME and eME analysis sets, the proportions of participants with a favorable per-patient microbiological response at each scheduled assessment were similar to those observed in the mMITT analysis set at the TOC, EOT, and LFU visits. * Both 2 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. 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 those observed 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 Minimum Inhibitory Concentration Categories * All Enterobacterales including E. coli, K. pneumoniae, and P. aeruginosa were susceptible. 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.

The proportion of participants in the CE analysis set with clinical cure at the TOC visit was greater than the pre-specified point estimate threshold value of 78.0%. The favorable per-patient microbiological response at all visits were similar to the clinical responses. PF-06947386 was well tolerated, with no new safety signals. For sepsis and sepsis evaluable patients, the clinical responses and microbiological responses for all participants were cure and favorable, with no additional safety concerns.

Dec. 07, 2023

Yes

Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests.

https://jrct.niph.go.jp/latest-detail/jRCT2061210026

Kawai Norisuke

Pfizer R&D Japan G.K.

Shinjuku Bunka Quint Bldg., 3-22-7 Yoyogi, Shibuya-ku, Tokyo

+81-3-5309-7000

clinical-trials@pfizer.com

Clinical Trials Information Desk

Pfizer R&D Japan G.K.

Shinjuku Bunka Quint Bldg., 3-22-7 Yoyogi, Shibuya-ku, Tokyo

+81-3-5309-7000

clinical-trials@pfizer.com

Complete

Oct. 01, 2021

Oct. 01, 2021
60

Interventional

single arm study

open(masking not used)

uncontrolled control

single assignment

treatment purpose

*Participant who is capable of giving signed, dated and timed informed consent (or by their legally acceptable representative)
*Participant aged 20 years or older
*Participant who is willing and able to comply with all scheduled visits, treatment plan, laboratory tests, and other study procedures
*Confirmation of infection by surgical intervention within 24 hours of entry: evidence of systemic inflammatory response; physical findings consistent with intra-abdominal infection; supportive radiologic imaging findings of intra-abdominal infections
*Intraoperative/postoperative enrollment with visual confirmation (presence of pus within the abdominal cavity) of an intra-abdominal infection associated with peritonitis

*Participant will undergo surgery for traumatic bowel perforation within 12 hours or perforation of gastroduodenal ulcers within 24 hours. Other intra-abdominal processes that are not infectious.
*Participant has abdominal wall abscess or bowel obstruction without perforation or ischemic bowel without perforation
*Participant whose surgery will include staged abdominal repair, or "open abdomen" technique, or marsupialization.
*Participant has evidence of sepsis with shock not responding to IV fluid challenge or anticipated to require the administration of vasopressors for >24 hours
*Participant has suspected intra-abdominal infections due to fungus, parasites (eg, amebic liver abscess), virus, or tuberculosis
*Participant is considered unlikely to survive the 6- to 8-week study period or has a rapidly progressive or terminal illness
*Participant is pregnant or breastfeeding.
*Participant has received systemic antibacterial agents within the 72-hour period prior to study entry except for cases specified in the protocol such that participant is considered to have failed the previous treatment regimen, or participant has received systemic antibiotic agents no more than 24 hours (no more than one daily dose) within the 72-hour period prior to study entry, etc.
*Estimated CrCL <=50 mL/min calculated by Cockcroft-Gault method.

20age old over
No limit

Both

Complicated Intra-abdominal Infection

Drug: PF-06947386
Ceftazidime-Avibactam powder for concentrate for solution for infusion 2.0 g/ 0.5 g. Dosage will be adjusted based on renal function after enrollment.

Drug: Metronidazole
Metronidazole 0.5 g solution for injection.

Primary Outcomes:
The percentage of participants having clinical cure.
* Time Frame:
Test of Cure (TOC) on study Day 28-35.
* Analysis set:
Clinically Evaluable (CE) (Primary), Modified Intent-to-Treat (MITT), Microbiological Modified Intent-to-Treat (mMITT), Microbiologically Evaluable (ME), and extended-Microbiologically Evaluable (eME) analysis sets.

Secondary Outcomes:
1. The percentage of participants having clinical cure.
* Time Frame: End of Treatment (EOT, within 24 hours after completion of last IV infusion) and LFU (Late Follow-Up) on study Day 42-49.
* Analysis set: CE, MITT, mMITT, ME, and eME analysis sets.

2. The percentage of participants having favorable per-patient microbiological response.
* Time Frame: EOT (within 24 hours after completion of last IV infusion), TOC on study Day 28-35, and LFU on study Day 42-49.
* Analysis set: mMITT, ME, and eME analysis sets.

3. The percentage of participants having favorable per-pathogen microbiological response.
* Time Frame: EOT (within 24 hours after completion of last IV infusion), TOC on study Day 28-35, and LFU on study Day 42-49.
* Analysis set: mMITT, ME, and eME analysis sets.

4. The percentage of participants having favorable per-pathogen microbiological response by MIC categories.
* Time Frame: EOT (within 24 hours after completion of last IV infusion), TOC on study Day 28-35, and LFU on study Day 42-49.
* Analysis set: mMITT, ME, and eME analysis sets.

5. Percentage of participants experiencing adverse events/serious adverse events.
* Time Frame: Up to a minimum of approximately 28 days after the last administration of study drug.
* Analysis set: Safety analysis set.

6. Ceftazidime/avibactam plasma concentrations by nominal sampling window.
* Time Frame: Day 3, Day 4.
* Analysis set: PK analysis set.

7. Percentage of sepsis patients having clinical cure.
* Time Frame: EOT (within 24 hours after completion of last IV infusion), TOC on study Day 28-35, and LFU on study Day 42-49.
* Analysis set: Sepsis patients subset, sepsis evaluable patients subset.

8. Percentage of sepsis patients having per-patient favorable microbiological response.
* Time Frame: EOT (within 24 hours after completion of last IV infusion), TOC on study Day 28-35, and LFU on study Day 42-49.
* Analysis set: Sepsis patients subset, sepsis evaluable patients subset.

9. Percentage of sepsis patients having favorable per-pathogen microbiological response.
* Time Frame: Time Frame: EOT (within 24 hours after completion of last IV infusion), TOC on study Day 28-35, and LFU on study Day 42-49.
* Analysis set: Sepsis patients subset, sepsis evaluable patients subset.

10. Percentage of sepsis patients having favorable per-pathogen microbiological response by MIC category.
* Time Frame: EOT (within 24 hours after completion of last IV infusion), TOC on study Day 28-35, and LFU on study Day 42-49.
* Analysis set: Sepsis patients subset, sepsis evaluable patients subset.

11. Percentage of participants experiencing adverse events/serious adverse events in sepsis patients.
* Time Frame: Up to a minimum of approximately 28 days after the last administration of the study drug.
* Analysis set: Sepsis patients subset, sepsis evaluable patients subset.

Pfizer Japan Inc.
Okayama City General Medical Center Okayama City Hospital Institutional Review Board
3-20-1 Kitanagaseomotemachi, Kita-ku, Okayama, Okayama

+81-86-737-3000

Approval

May. 28, 2021

NCT04927312
ClinicalTrials.gov

none

History of Changes

No Publication date
3 Dec. 12, 2023 (this page) Changes
2 Mar. 31, 2023 Detail Changes
1 July. 21, 2021 Detail