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

Phase 3

Completed

• Conditions: Complicated Intra-abdominal Infection
• Interventions: Drug: PF-06947386; Drug: Metronidazole

• Registration Number: NCT04927312
• Lead Sponsor: Pfizer

Brief Summary

Study C3591036 is a Phase 3 study to assess the efficacy and safety of PF-06947386 in Japanese adult patients with complicated intra-abdominal infection requiring hospitalization. This is a multicenter, open-label, single-arm study. All eligible participants will receive intravenous infusion of PF-06947386 followed by intravenous infusion of metronidazole.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2021-06-04
• Study First Submitted QC: 2021-06-14
• Study First Posted: 2021-06-15
• Study Start: 2021-10-01
• Primary Completion: 2022-09-15
• Study Completion: 2022-09-15
• Results First Submitted: 2023-09-11
• Results First Submitted QC: 2023-09-11
• Status Verified: 2024-03
• Results First Posted: 2024-03-08
• Last Update Submitted: 2024-03-08
• Last Update Posted: 2024-03-13

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 60

Inclusion Criteria

• 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

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Exclusion Criteria

• 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.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
PF-06947386 + Metronidazole	PF-06947386	Multiple intravenous infusion of ceftazidime-avibactam followed by intravenous infusion of metronidazole, repeated every 8 hours for 5-14 days.
PF-06947386 + Metronidazole	Metronidazole	Multiple intravenous infusion of ceftazidime-avibactam followed by intravenous infusion of metronidazole, repeated every 8 hours for 5-14 days.

Primary Outcome Measures

Name	Time	Method
Number of Participants With Clinical Response at Test of Cure (TOC) Visit: Clinically Evaluable (CE) Analysis Set	TOC: Any day from Day 28 to Day 35	Clinical response: Clinical response of cure was defined as complete resolution or significant improvement of signs and symptoms of the index infection such that no further antimicrobial therapy, drainage, or surgical intervention was necessary. TOC was after 28 calendar days from the day of the first IV infusion, allowed visit window was 28 to 35 calendar days after the day of the first IV infusion; clinical failure: Death related to intra-abdominal infection, Persisting or recurrent infection within the abdomen, Postsurgical wound infections, participant who received treatment with additional antibiotics for ongoing symptoms of intra-abdominal infection; Indeterminate: Study data was not available for evaluation of efficacy for any reason. TOC was after 28 calendar days from the day of the first IV infusion, allowed visit window was 28 to 35 calendar days after the day of the first IV infusion.

Secondary Outcome Measures

Name	Time	Method
Number of Participants With Clinical Response at EOT and LFU Visits: Modified Intent-to-Treat (MITT) Analysis Set	EOT: 24 hours after last IV infusion; LFU: Any day from Day 42 to Day 49	Clinical response: Clinical response of cure was defined as complete resolution or significant improvement of signs and symptoms of the index infection such that no further antimicrobial therapy, drainage, or surgical intervention was necessary. TOC was after 28 calendar days from the day of the first IV infusion, allowed visit window was 28 to 35 calendar days after the day of the first IV infusion; clinical failure: Death related to intra-abdominal infection, Persisting or recurrent infection within the abdomen, Postsurgical wound infections, participant who received treatment with additional antibiotics for ongoing symptoms of intra-abdominal infection; Indeterminate: Study data was not available for evaluation of efficacy for any reason. EOT: within 24 hours after completion of last IV infusion. LFU: after 42 calendar days from the day of the first IV infusion, the allowed visit window was 42 to 49 calendar days from the day of the first IV infusion.
Percentage of Participants With Clinical Response at End of Treatment (EOT) and Late Follow-up (LFU) Visits: CE Analysis Set	EOT: 24 hours after last IV infusion; LFU: Any day from Day 42 to Day 49	Clinical response: Clinical response of cure was defined as complete resolution or significant improvement of signs and symptoms of the index infection such that no further antimicrobial therapy, drainage, or surgical intervention was necessary. TOC was after 28 calendar days from the day of the first IV infusion, allowed visit window was 28 to 35 calendar days after the day of the first IV infusion; clinical failure: Death related to intra-abdominal infection, Persisting or recurrent infection within the abdomen, Postsurgical wound infections, participant who received treatment with additional antibiotics for ongoing symptoms of intra-abdominal infection; Indeterminate: Study data was not available for evaluation of efficacy for any reason. EOT: within 24 hours after completion of last IV infusion. LFU: after 42 calendar days from the day of the first IV infusion, the allowed visit window was 42 to 49 calendar days from the day of the first IV infusion.
Number of Participants With Clinical Response at EOT and LFU Visits: Microbiological Modified Intent-to-Treat (mMITT) Analysis Set	EOT: 24 hours after last IV infusion; LFU: Any day from Day 42 to Day 49	Clinical response: Clinical response of cure was defined as complete resolution or significant improvement of signs and symptoms of the index infection such that no further antimicrobial therapy, drainage, or surgical intervention was necessary. TOC was after 28 calendar days from the day of the first IV infusion, allowed visit window was 28 to 35 calendar days after the day of the first IV infusion; clinical failure: Death related to intra-abdominal infection, Persisting or recurrent infection within the abdomen, Postsurgical wound infections, participant who received treatment with additional antibiotics for ongoing symptoms of intra-abdominal infection; Indeterminate: Study data was not available for evaluation of efficacy for any reason. EOT: within 24 hours after completion of last IV infusion. LFU: after 42 calendar days from the day of the first IV infusion, the allowed visit window was 42 to 49 calendar days from the day of the first IV infusion.
Percentage of Participants With Clinical Response at EOT and LFU Visits: Microbiologically Evaluable (ME) Analysis Set	EOT: 24 hours after last IV infusion; LFU: Any day from Day 42 to Day 49	Clinical response: Clinical response of cure was defined as complete resolution or significant improvement of signs and symptoms of the index infection such that no further antimicrobial therapy, drainage, or surgical intervention was necessary. TOC was after 28 calendar days from the day of the first IV infusion, allowed visit window was 28 to 35 calendar days after the day of the first IV infusion; clinical failure: Death related to intra-abdominal infection, Persisting or recurrent infection within the abdomen, Postsurgical wound infections, participant who received treatment with additional antibiotics for ongoing symptoms of intra-abdominal infection; Indeterminate: Study data was not available for evaluation of efficacy for any reason. LFU: after 42 calendar days from the day of the first IV infusion, the allowed visit window was 42 to 49 calendar days from the day of the first IV infusion.
Percentage of Participants With Clinical Response EOT and LFU Visits: Extended Microbiologically Evaluable (eME) Analysis Set	EOT: 24 hours after last IV infusion; LFU: Any day from Day 42 to Day 49	Clinical response: Clinical response of cure was defined as complete resolution or significant improvement of signs and symptoms of the index infection such that no further antimicrobial therapy, drainage, or surgical intervention was necessary. TOC was after 28 calendar days from the day of the first IV infusion, allowed visit window was 28 to 35 calendar days after the day of the first IV infusion; clinical failure: Death related to intra-abdominal infection, Persisting or recurrent infection within the abdomen, Postsurgical wound infections, participant who received treatment with additional antibiotics for ongoing symptoms of intra-abdominal infection; Indeterminate: Study data was not available for evaluation of efficacy for any reason. EOT: within 24 hours after completion of last IV infusion. LFU: after 42 calendar days from the day of the first IV infusion, the allowed visit window was 42 to 49 calendar days from the day of the first IV infusion.
Number of Participants With Microbiological Response EOT, TOC and LFU Visits: mMITT Analysis Set	EOT: 24 hours after last IV infusion; TOC: Any day from Day 28 to 35; LFU: Any day from Day 42 to Day 49	Microbiological response: Favorable microbiological response assessments include "eradication", "presumed eradication" and "colonization". Unfavorable microbiological response assessments include "persistence", "persistence with increasing MIC", and "presumed persistence. Indeterminate: Study data are not available for evaluation of efficacy. "Indeterminate" were not included in the denominator. EOT: within 24 hours after completion of last IV infusion. LFU: after 42 calendar days from the day of the first IV infusion, the allowed visit window was 42 to 49 calendar days from the day of the first IV infusion. TOC: after 28 calendar days from the day of the first IV infusion, allowed visit window was 28 to 35 calendar days after the day of the first IV infusion.
Percentage of Participants With Microbiological Response EOT, TOC and LFU Visits: ME Analysis Set	EOT: 24 hours after last IV infusion; TOC: Any day from Day 28 to 35; LFU: Any day from Day 42 to Day 49	Microbiological response: Favorable microbiological response assessments include "eradication", "presumed eradication" and "colonization". Unfavorable microbiological response assessments include "persistence", "persistence with increasing MIC", and "presumed persistence. Indeterminate: Study data was not available for evaluation of efficacy. "Indeterminate" were not included in the denominator. EOT: within 24 hours after completion of last IV infusion. LFU: after 42 calendar days from the day of the first IV infusion, the allowed visit window was 42 to 49 calendar days from the day of the first IV infusion. TOC: after 28 calendar days from the day of the first IV infusion, allowed visit window was 28 to 35 calendar days after the day of the first IV infusion.
Percentage of Participants With Microbiological Response EOT, TOC and LFU Visits: eME Analysis Set	EOT: 24 hours after last IV infusion; TOC: Any day from Day 28 to 35; LFU: Any day from Day 42 to Day 49	Microbiological response: Favorable microbiological response assessments include "eradication", "presumed eradication" and "colonization". Unfavorable microbiological response assessments include "persistence", "persistence with increasing MIC", and "presumed persistence. Indeterminate: Study data was not available for evaluation of efficacy. "Indeterminate" were not included in the denominator. EOT: within 24 hours after completion of last IV infusion. LFU: after 42 calendar days from the day of the first IV infusion, the allowed visit window was 42 to 49 calendar days from the day of the first IV infusion. TOC: after 28 calendar days from the day of the first IV infusion, allowed visit window was 28 to 35 calendar days after the day of the first IV infusion.
Percentage of Participants With Favorable Per-Pathogen Microbiological Response at EOT, TOC and LFU Visits: mMITT Analysis Set	EOT: 24 hours after last IV infusion; TOC: Any day from Day 28 to 35; LFU: Any day from Day 42 to Day 49	Microbiological response: Favorable microbiological response assessments include "eradication", "presumed eradication" and "colonization". Unfavorable microbiological response assessments include "persistence", "persistence with increasing MIC", and "presumed persistence. Indeterminate: Study data was not available for evaluation of efficacy. "Indeterminate" were not included in the denominator. EOT: within 24 hours after completion of last IV infusion. Response of baseline pathogens cultured from intra-abdominal site or blood. A participant can have more than 1 pathogen. LFU: after 42 calendar days from the day of the first IV infusion, the allowed visit window was 42 to 49 calendar days from the day of the first IV infusion. TOC: after 28 calendar days from the day of the first IV infusion, allowed visit window was 28 to 35 calendar days after the day of the first IV infusion.
Percentage of Participants With Favorable Per-Pathogen Microbiological Response at EOT, TOC and LFU Visits: ME Analysis Set	EOT: 24 hours after last IV infusion; TOC: Any day from Day 28 to 35; LFU: Any day from Day 42 to Day 49	Microbiological response: Favorable microbiological response assessments include "eradication", "presumed eradication" and "colonization". Unfavorable microbiological response assessments include "persistence", "persistence with increasing MIC", and "presumed persistence. Indeterminate: Study data are not available for evaluation of efficacy. "Indeterminate" were not included in the denominator. EOT: within 24 hours after completion of last IV infusion. Response of baseline pathogens cultured from intra-abdominal site or blood. A participant can have more than 1 pathogen. LFU: after 42 calendar days from the day of the first IV infusion, the allowed visit window was 42 to 49 calendar days from the day of the first IV infusion. TOC: after 28 calendar days from the day of the first IV infusion, allowed visit window was 28 to 35 calendar days after the day of the first IV infusion.
Change From Baseline in Vital Sign Parameters at Day 2 to 14, EOT, TOC and, LFU Visits: Temperature	Baseline, Day 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, and EOT: 24 hours after last IV infusion; TOC: Any day from Day 28 to 35; LFU: Any day from Day 42 to Day 49	Temperature was measured in a supine position, after the participant had rest for at least 5 minutes.
Change From Baseline in Vital Sign Parameters at Day 2 to 14, EOT, TOC and, LFU Visits: Respiratory Rate	Baseline, Day 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, and EOT: 24 hours after last IV infusion; TOC: Any day from Day 28 to 35; LFU: Any day from Day 42 to Day 49	Respiratory rate was measured in a supine position, after the participant had rest for at least 5 minutes.
Percentage of Participants With Favorable Per-Pathogen Microbiological Response at EOT, TOC and LFU Visits: eME Analysis Set	EOT: 24 hours after last IV infusion; TOC: Any day from Day 28 to 35; LFU: Any day from Day 42 to Day 49	Microbiological response: Favorable microbiological response assessments include "eradication", "presumed eradication" and "colonization". Unfavorable microbiological response assessments include "persistence", "persistence with increasing MIC", and "presumed persistence. Indeterminate: Study data was not available for evaluation of efficacy. "Indeterminate" were not included in the denominator. EOT: within 24 hours after completion of last IV infusion. Response of baseline pathogens cultured from intra-abdominal site or blood. A participant can have more than 1 pathogen. LFU: after 42 calendar days from the day of the first IV infusion, the allowed visit window was 42 to 49 calendar days from the day of the first IV infusion. TOC: after 28 calendar days from the day of the first IV infusion, allowed visit window was 28 to 35 calendar days after the day of the first IV infusion.
Percentage of Participants With Favorable Per-Pathogen Microbiological Response by Minimum Inhibitory Concentration (MIC) Categories at EOT, TOC and LFU Visits: mMITT Analysis Set	EOT: 24 hours after last IV infusion; TOC: Any day from Day 28 to 35; LFU: Any day from Day 42 to Day 49	Microbiological response: Favorable microbiological response assessments include "eradication", "presumed eradication" and "colonization". Unfavorable microbiological response assessments include "persistence", "persistence with increasing MIC", and "presumed persistence. Indeterminate: Study data was not available for evaluation of efficacy. "Indeterminate" were not included in the denominator. EOT: within 24 hours after completion of last IV infusion. LFU: after 42 calendar days from the day of the first IV infusion, the allowed visit window was 42 to 49 calendar days from the day of the first IV infusion. TOC: after 28 calendar days from the day of the first IV infusion, allowed visit window was 28 to 35 calendar days after the day of the first IV infusion.
Percentage of Participants With Favorable Per-Pathogen Microbiological Response by MIC Categories at EOT, TOC and LFU Visits: ME Analysis Set	EOT: 24 hours after last IV infusion; TOC: Any day from Day 28 to 35; LFU: Any day from Day 42 to Day 49	Microbiological response: Favorable microbiological response assessments include "eradication", "presumed eradication" and "colonization". Unfavorable microbiological response assessments include "persistence", "persistence with increasing MIC", and "presumed persistence. Indeterminate: Study data was not available for evaluation of efficacy. "Indeterminate" were not included in the denominator. EOT: within 24 hours after completion of last IV infusion. LFU: after 42 calendar days from the day of the first IV infusion, the allowed visit window was 42 to 49 calendar days from the day of the first IV infusion. TOC: after 28 calendar days from the day of the first IV infusion, allowed visit window was 28 to 35 calendar days after the day of the first IV infusion.
Percentage of Participants With Favorable Per-Pathogen Microbiological Response by MIC Categories at EOT, TOC and LFU Visits: eME Analysis Set	EOT: 24 hours after last IV infusion; TOC: Any day from Day 28 to 35; LFU: Any day from Day 42 to Day 49	Microbiological response: Favorable microbiological response assessments include "eradication", "presumed eradication" and "colonization". Unfavorable microbiological response assessments include "persistence", "persistence with increasing MIC", and "presumed persistence. Indeterminate: Study data was not available for evaluation of efficacy. "Indeterminate" were not included in the denominator. EOT: within 24 hours after completion of last IV infusion. LFU: after 42 calendar days from the day of the first IV infusion, the allowed visit window was 42 to 49 calendar days from the day of the first IV infusion. TOC: after 28 calendar days from the day of the first IV infusion, allowed visit window was 28 to 35 calendar days after the day of the first IV infusion.
Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious AEs (SAEs)	Up to Day 49	An AE was any untoward medical occurrence in a participant or clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. SAE was defined as any untoward medical occurrence that, at any dose that resulted in death, was life-threatening, inpatient hospitalization or prolongation of existing hospitalization, persistent disability/incapacity, a congenital anomaly/birth defect as per medical or scientific judgment. AEs included both SAEs and non-SAEs. TEAE was defined as an AE that emerges or worsened during the effective duration of treatment. All events that started on or after the first dosing day were flagged as TEAEs.
All-cause Mortality	Up to Day 49	Number of participants with death is presented.
Number of Participants Who Discontinued Treatment and Study Due to Adverse Events	Up to Day 49	Number of participants who discontinued treatment and study due to adverse events is presented.
Change From Baseline in Vital Sign Parameters at Day 2 to 14, EOT, TOC and, LFU Visits: Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)	Baseline, Day 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, and EOT: 24 hours after last IV infusion; TOC: Any day from Day 28 to 35; LFU: Any day from Day 42 to Day 49	A semiautomated recording device was used to measure SBP and DBP with participant in a supine position after at least 5 minutes of rest.
Change From Baseline in Vital Sign Parameters at Day 2 to 14, EOT, TOC and, LFU Visits: Pulse Rate	Baseline, Day 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, and EOT: 24 hours after last IV infusion; TOC: Any day from Day 28 to 35; LFU: Any day from Day 42 to Day 49	Pulse rate was measured for in a supine position preceded by at least 5 minutes of rest for the participant.
Change From Baseline in Vital Sign Parameters at Day 2 to 14, EOT, TOC and, LFU Visits: Weight	Baseline, Day 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, and EOT: 24 hours after last IV infusion; TOC: Any day from Day 28 to 35; LFU: Any day from Day 42 to Day 49	Body weight was measured using a balance scale.
Number of Participants With Laboratory Test Abnormalities	Up to Day 49	Criteria for abnormal laboratory values for chemistry parameters: Bilirubin \>1.5\*upper limit of normal (ULN), direct Bilirubin \>1.5\*ULN, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase \>3.0\*ULN, total protein and albumin \<0.8\*lower limit of normal (LLN), urea nitrogen and creatinine \>1.3\*ULN, sodium \>0.95\*LLN, potassium \>0.9\*LLN and \>1.1\*ULN, calcium \>0.9\*LLN, glucose \> 1.5\*LLN; hematology parameters: Hemoglobin, hematocrit, erythrocytes \<0.8\*LLN, platelets \<0.5\*LLN and \> 1.75\*ULN, leukocytes \<0.6\*LLN and \<0.6\*LLN, lymphocytes \<0.8\* LLN, lymphocytes/leukocytes \<0.8\* LLN and \>1.2\*ULN, neutrophils \>1.2\*ULN, neutrophils/leukocytes \<0.8\*LLN and \>1.2\* ULN, basophils/leukocytes \>1.2\*ULN, eosinophils \>1.2\*ULN, eosinophils/leukocytes \>1.2\*ULN, monocytes and monocytes/leukocytes \>1.2\*ULN; Criteria for abnormal laboratory values for urinalysis parameters: urine glucose, \>=1, urine protein \>=1, urine Hemoglobin\>=1.
Plasma Concentration of Avibactam	Day 3, Day 4, and Combination of Day 3 and 4: 15 minutes before or after infusion, 30-90 minutes after infusion, 300-360 minutes after infusion	Plasma concentrations of avibactam was measured by nominal sampling window.
Plasma Concentration of Ceftazidime	Day 3, Day 4, and Combination of Day 3 and 4: 15 minutes before or after infusion, 30-90 minutes after infusion, 300-360 minutes after infusion	Plasma concentrations of ceftazidime was measured by nominal sampling window.

Trial Locations

Locations (28)

Saiseikai Maebashi Hospital; 🇯🇵 Maebashi, Gunma, Japan

Yamagata City Hospital Saiseikan; 🇯🇵 Yamagata, Japan

National Hospital Organization Osaka Minami Medical Center; 🇯🇵 Kawachinagano, Osaka, Japan

Okayama City General Medical Center Okayama City Hospital; 🇯🇵 Okayama, Japan

National Hospital Organization Nagoya Medical Center; 🇯🇵 Nagoya, Aichi, Japan

St.Mary's Hospital; 🇯🇵 Kurume, Fukuoka, Japan

Gunma Saiseikai Maebashi Hospital; 🇯🇵 Maebashi, Gunma, Japan

Teine Keijinkai Hospital; 🇯🇵 Sapporo, Hokkaido, Japan

Sagamihara Kyodo Hospital; 🇯🇵 Sagamihara, Kanagawa, Japan

Tsuchiura Kyodo General Hospital; 🇯🇵 Tsuchiura, Ibaraki, Japan

National Hospital Organization Kanazawa Medical Center; 🇯🇵 Kanazawa, Ishikawa, Japan

Kawasaki Saiwai Hospital; 🇯🇵 Kawasaki-shi, Kanagawa, Japan

Suwa Red Cross Hospital; 🇯🇵 Suwa, Nagano, Japan

Nagaoka Chuo General Hospital; 🇯🇵 Nagaoka, Niigata, Japan

National Hospital Organization Nagasaki Medical Center; 🇯🇵 Omura, Nagasaki, Japan

Nagoya Ekisaikai Hospital; 🇯🇵 Nagoya, Aichi, Japan

Fukuoka Tokushukai Hospital; 🇯🇵 Kasuga, Fukuoka, Japan

National Hospital Organization Yokohama Medical Center; 🇯🇵 Yokohama, Kanagawa, Japan

Naha City Hospital; 🇯🇵 Naha, Okinawa, Japan

Yamanashi Prefectural Central Hospital; 🇯🇵 Kofu, Yamanashi, Japan

Rinku General Medical Center; 🇯🇵 Izumisano, Osaka, Japan

National Hospital Organization Kumamoto Medical Center; 🇯🇵 Kumamoto, Japan

National Hospital Organization Chiba Medical Center; 🇯🇵 Chiba, Japan

National Hospital Organization Kyoto Medical Center; 🇯🇵 Kyoto, Japan

Toyama University Hospital; 🇯🇵 Toyama, Japan

Fukuoka Wajiro Hospital; 🇯🇵 Fukuoka, Japan

National Hospital Organization Toyohashi Medical Center; 🇯🇵 Toyohashi, Aichi, Japan

Osaka Saiseikai Nakatsu Hospital; 🇯🇵 Osaka, Japan