Ceftolozane/Tazobactam (MK-7625A) Plus Metronidazole Versus Meropenem for Participants With Complicated Intra-abdominal Infection (MK-7625A-015)

Complicated Intra-abdominal Infections Clinical Trial

— 7625ACNPhase3  

Official title:

A Phase 3, Multicenter, Double-blind, Randomized, Active-controlled Clinical Study to Evaluate the Efficacy and Safety of Ceftolozane/Tazobactam (MK-7625A) Plus Metronidazole Versus Meropenem in Chinese Participants With Complicated Intra-abdominal Infection

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03830333
• Other study ID #: 7625A-015
• Secondary ID: MK-7625A-015
• Status: Completed
• Phase: Phase 3
• Start date: March 20, 2019
• Est. completion date: October 14, 2020

Study information

• Verified date: January 2023
• Source: Merck Sharp & Dohme LLC
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This study aims to evaluate the efficacy of ceftolozane/tazobactam (MK-7625A) plus metronidazole versus meropenem in adults diagnosed with complicated intra-abdominal infection (cIAI). The primary hypothesis is ceftolozane/tazobactam plus metronidazole is non-inferior to meropenem, as measured by the clinical response rate at the Test-of Cure (TOC) visit in the Clinically Evaluable (CE) population.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 268
• Est. completion date: October 14, 2020
• Est. primary completion date: October 14, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

Inclusion Criteria:

• Must have one of the following diagnoses in which there is evidence of bacterial intraperitoneal infection: Cholecystitis (including gangrenous cholecystitis) with rupture, perforation, or progression of the infection beyond the gallbladder wall; Acute gastric or small intestine including duodenal perforation, only if operated on > 24 hours after perforation occurs; Traumatic perforation of the intestine (including colon), only if operated on > 12 hours after perforation occurs; Appendiceal perforation or peri-appendiceal abscess; Diverticular disease with perforation or abscess; Peritonitis due to other perforated viscus or following a prior operative procedure; Intra-abdominal abscess (including liver or spleen).

• Evidence of systemic infection

• Requires surgical intervention (e.g., laparotomy, laparoscopic surgery, or percutaneous draining of an abscess) within 24 hours of (before or after) the first dose of study drug

• If participant is to be enrolled preoperatively, the participant should have radiographic evidence of gastric or bowel perforation or intra-abdominal abscess or other radiographic evidence for cIAI

• Participants who failed prior antibacterial treatment for the current cIAI can be enrolled but must: (a) have a positive culture (from an intra-abdominal site or blood sample) and (b) require surgical intervention.

• Is a Chinese participant, defined as a person of Chinese descent. A potential participant who is of ex-China descent (e.g. Western European) descent living in China will be excluded

• Male agrees to use contraception during the treatment period, and for at least 30 days after the last dose of study medication, and refrain from donating sperm during this period

• Female is not pregnant or breastfeeding; is not a woman of childbearing potential (WOCBP); or if WOCBP agrees to use a contraceptive method that is highly effective, or be abstinent from heterosexual intercourse as their preferred and usual lifestyle during the treatment period, and for at least 30 days after the last dose of study medication; or must have a negative highly sensitive pregnancy test (serum) within 48 hours before the first dose of study intervention.

Exclusion Criteria:

• Has any of the following diagnoses: simple appendicitis; abdominal wall abscess; small bowel obstruction or ischemic bowel disease without perforation; spontaneous (primary) bacterial peritonitis associated with cirrhosis and chronic ascites; or pelvic infections

• Has any of the following diseases: acute suppurative cholangitis; infected necrotizing pancreatitis; pancreatic abscess

• Has complicated intra-abdominal infection managed by staged abdominal repair (STAR), open abdomen technique (i.e. fascia not closed) including temporary closure of the abdomen, or any situation where infection source control was not likely to be achieved

• Has abscess that is confirmed on imaging test but has not been or cannot be managed by surgical intervention including drainage

• Is expected to be cured by only surgical intervention (e.g., drainage) without use of systemic antibiotic therapy

• Has the following underlying conditions or the following serious conditions:

considered unlikely to survive during the study period (predicted life expectancy is < 4 weeks after randomization); organic brain or spinal cord disease; any rapidly-progressing disease or immediately life-threatening illness (including respiratory failure and septic shock); an immunocompromising condition

• Has a history of any hypersensitivity or allergic reaction to any beta-lactam, antibacterials, including cephalosporins, carbapenems, penicillins, or tazobactam, or metronidazole, or nitroimidazole derivatives; or if a skin test is required by local clinical regulations, has a positive skin test result if no prior history of allergic reaction to beta-lactam antibacterials

• A WOCBP who has a positive serum pregnancy test within 24 hours before the first dose of study intervention

• Used systemic antibiotic therapy with known coverage of pathogens that cause IAI for more than 24 hours during the previous 72 hours prior to the first dose of study drug, unless there is a documented treatment failure with such therapy

• For participants that are enrolled postoperatively, more than 1 dose of an active non-study antibacterial regimen administered postoperatively. For participants enrolled preoperatively, no postoperative non-study antibacterial therapy is allowed

• Participants who need additional non-study systemic antibacterial therapy with gram-negative activity in addition to study drug therapy; drugs with only gram-positive activity (eg, IV vancomycin, teicoplanin, linezolid and daptomycin) are allowed

• Anticipates treatment with traditional Chinese medicine or herbal medicine during study period

• Has received disulfiram, valproic acid or divalproex sodium within 14 days before the proposed first day of study drug or who are currently receiving probenecid

• Is currently participating in, or has participated in, any other clinical study involving the administration of investigational or experimental medication (not licensed by regulatory agencies) at the time of the presentation or during the previous 90 days prior to screening or is anticipated to participate in such a clinical study during the course of this study

• Has participated in a ceftolozane/tazobactam clinical study at any time in the past

• Has severe impairment of renal function (CrCL <30 mL/min) or requirement for peritoneal dialysis, hemodialysis or hemofiltration, or oliguria

Related Conditions & MeSH terms

• Communicable Diseases
• Complicated Intra-abdominal Infections
• Infections
• Intraabdominal Infections

Intervention

Drug:
• Ceftolozane/Tazobactam
Ceftolozane 1000 mg / tazobactam 500 mg by IV infusion every 8 hours for 4 to 14 days. Participants with CrCL of 30 to = 50 mL/min will receive ceftolozane 500 mg / tazobactam 250 mg.
• Metronidazole
Metronidazole 500 mg by IV infusion every 8 hours for 4 to 14 days.
• Meropenem
Meropenem 1000 mg by IV infusion every 8 hours for 4 to 14 days. Participants with CrCL of 30 to = 50 mL/min will receive IV infusion every 12 hours.
• Placebo
Saline by IV infusion every 8 hours for 4 to 14 days.

Locations

Country	Name	City	State
China	Baotou Central Hospital ( Site 0013)	Baotou	Inner Mongolia
China	Navy General Hospital ( Site 0009)	Beijing	Beijing
China	Peking University Third Hospital ( Site 0002)	Beijing	Beijing
China	The Second Hospital of Jilin University ( Site 0048)	Changchun	Jilin
China	The First People's Hospital of Changzhou ( Site 0054)	Changzhou	Jiangsu
China	Southern Medical University Nanfang Hospital ( Site 0055)	Guangzhou
China	The First Affiliated Hospital of Guangzhou Medical University ( Site 0026)	Guangzhou	Guangdong
China	Hainan General Hospital ( Site 0042)	Haikou	Hainan
China	Anhui Provincial Hospital ( Site 0033)	Hefei	Anhui
China	The First Hospital of Kunming ( Site 0041)	Kunming	Yunnan
China	Liaocheng People s hospital ( Site 0014)	Liaocheng	Shandong
China	The First Affiliated Hospital of Nanchang University ( Site 0029)	Nanchang	Jiangxi
China	The Second Affiliated Hospital of Nanchang University ( Site 0053)	Nanchang	Jiangxi
China	Central Hospital of Minhang District ( Site 0052)	Shanghai	Shanghai
China	Shanghai General Hospital ( Site 0016)	Shanghai	Shanghai
China	Zhongshan Hospital of Fudan University ( Site 0001)	Shanghai	Shanghai
China	Taizhou Hospital of Zhejiang Province ( Site 0035)	Taizhou	Zhejiang
China	Tianjin People's Hospital ( Site 0040)	Tianjin	Tianjin
China	The First Affiliated Hospital of Xinjiang Medical University ( Site 0034)	Urumqi	Xinjiang
China	The 2nd Affiliated Hospital of Wenzhou Medical University ( Site 0051)	Wenzhou	Zhejiang
China	The First Affiliated Hospital of Wenzhou Medical University ( Site 0015)	Wenzhou	Zhejiang
China	Wuxi No.2 People's Hospital ( Site 0050)	Wuxi	Jiangsu
China	Wuxi People's Hospital ( Site 0020)	Wuxi	Jiangsu
China	Subei People's Hospital ( Site 0046)	Yangzhou	Jiangsu
China	Affiliated Hospital of Jiangsu University ( Site 0049)	Zhenjiang	Jiangsu

Sponsors (1)

Lead Sponsor	Collaborator
Merck Sharp & Dohme LLC

Country where clinical trial is conducted

China, 

References & Publications (1)

Sun Y, Fan J, Chen G, Chen X, Du X, Wang Y, Wang H, Sun F, Johnson MG, Bensaci M, Huntington JA, Bruno CJ. A phase III, multicenter, double-blind, randomized clinical trial to evaluate the efficacy and safety of ceftolozane/tazobactam plus metronidazole v — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Percentage of Participants With Clinical Response (Clinical Cure or Clinical Failure) at Test of Cure (TOC) Visit: Clinically Evaluable (CE) Population	Clinical response was classified as "cure" or "failure". Clinical cure (favorable) was defined as complete resolution or significant improvement in signs and symptoms of the index infection, such that no additional antibacterial therapy or surgical or drainage procedure is required for the index infection. Clinical failure (unfavorable) was defined as death related to IAI at any time point; persisting or recurrent infection within the abdomen requiring additional intervention to cure; need for treatment with additional antibiotics for ongoing IAI symptoms; or post-surgical wound infection that requires additional antimicrobial therapy and/or non-routing wound care. The percentage of participants with clinical response of clinical cure or clinical failure at TOC was summarized.	Up to approximately Day 30
Secondary	Percentage of Participants With Clinical Response (Clinical Cure, Clinical Failure, or Indeterminate) at TOC Visit: Intent to Treat (ITT) Population	Clinical response was classified as "cure", "failure", or "indeterminate". Clinical cure (favorable) was defined as complete resolution or significant improvement in signs and symptoms of the index infection, such that no additional antibacterial therapy or surgical or drainage procedure is required for the index infection. Clinical failure (unfavorable) was defined as death related to IAI at any time point; persisting or recurrent infection within the abdomen requiring additional intervention to cure; need for treatment with additional antibiotics for ongoing IAI symptoms; or post-surgical wound infection that requires additional antimicrobial therapy and/or non-routing wound care. Indeterminate (unfavorable) was defined as participants for whom study data were not available for evaluation of efficacy for any reason. The percentage of participants with clinical response of clinical cure, clinical failure, or indeterminate at TOC was summarized.	Up to approximately Day 30
Secondary	Percentage of Participants With Clinical Response (Clinical Cure or Clinical Failure) at End of Therapy (EOT) Visit: CE Population	Clinical response was classified as "cure" or "failure". Clinical cure (favorable) was defined as complete resolution or significant improvement in signs and symptoms of the index infection, such that no additional antibacterial therapy or surgical or drainage procedure is required for the index infection. Clinical failure (unfavorable) was defined as death related to IAI at any time point; persisting or recurrent infection within the abdomen requiring additional intervention to cure; need for treatment with additional antibiotics for ongoing IAI symptoms; or post-surgical wound infection that requires additional antimicrobial therapy and/or non-routing wound care. The percentage of participants with clinical response of clinical cure or clinical failure at EOT was summarized.	Up to approximately Day 15
Secondary	Percentage of Participants With Clinical Response (Clinical Cure, Clinical Failure, or Indeterminate) at EOT Visit: ITT Population	Clinical response was classified as "cure", "failure", or "indeterminate". Clinical cure (favorable) was defined as complete resolution or significant improvement in signs and symptoms of the index infection, such that no additional antibacterial therapy or surgical or drainage procedure is required for the index infection. Clinical failure (unfavorable) was defined as death related to IAI at any time point; persisting or recurrent infection within the abdomen requiring additional intervention to cure; need for treatment with additional antibiotics for ongoing IAI symptoms; or post-surgical wound infection that requires additional antimicrobial therapy and/or non-routing wound care. Indeterminate (unfavorable) was defined as participants for whom study data are not available for evaluation of efficacy for any reason. The percentage of participants with clinical response of clinical cure, clinical failure, or indeterminate at EOT was summarized.	Up to approximately Day 15
Secondary	Percentage of Participants With Favorable Per-Participant Microbiological Response of Eradication or Presumed Eradication at TOC Visit: Expanded Microbiologically Evaluable (EME) Population	An overall microbiological response was determined by the Sponsor for each participant based on individual microbiological responses for each baseline bacterial pathogen. A favorable individual microbiological response was eradication (absence of the baseline bacterial pathogen in a specimen appropriately obtained from the original site of infection) or presumed eradication (absence of material to culture in a participant who is assessed as a clinical cure). In order for the participant to have a favorable overall microbiological response, each individual baseline bacterial pathogen must have had a favorable microbiological outcome. The percentage of participants with a favorable per-participant microbiological response of eradication or presumed eradication was reported for the TOC visit.	Up to approximately Day 30
Secondary	Percentage of Participants With Favorable Microbiological Response of Eradication or Presumed Eradication, by Pathogen, at the TOC Visit: EME Population	A microbiological response was determined for each bacterial pathogen isolated at baseline by the Sponsor. Favorable microbiological responses included eradication (absence of the baseline bacterial pathogen in a specimen appropriately obtained from the original site of infection) or presumed eradication (absence of material to culture in a participant who is assessed as a clinical cure). The percentage of participants with a favorable microbiological response of eradication or presumed eradication was reported per pathogen for the TOC visit.	Up to approximately Day 30
Secondary	Percentage of Participants Who Experienced 1 or More Adverse Events (AEs)	An AE was any untoward medical occurrence in a participant administered a pharmaceutical product that did not necessarily have to have a causal relationship with this treatment. An AE could therefore have been any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not related to the medicinal product. The percentage of participants who experienced 1 or more AEs were summarized.	Up to approximately Day 30
Secondary	Percentage of Participants That Discontinued Study Treatment Due to an AE	An AE was any untoward medical occurrence in a participant administered a pharmaceutical product that did not necessarily have to have a causal relationship with this treatment. An AE could therefore have been any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not related to the medicinal product. The percentage of participants who had study drug discontinued during the study due to an AE was summarized.	Up to Day 14