Clinical trial NCT03830333: Ceftolozane/Tazobactam (MK-7625A) Plus Metronidazole Versus Meropenem for Participants With Complicated Intra-abdominal Infection (MK-7625A-015)
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Complicated Intra-abdominal Infections
Lead sponsor: Merck Sharp & Dohme LLC
Sponsor class: INDUSTRY
First posted: 2019-02-05
Enrollment: 268
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.


Eligibility criteria: 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

Primary outcomes:
measure: Percentage of Participants With Clinical Response (Clinical Cure or Clinical Failure) at Test of Cure (TOC) Visit: Clinically Evaluable (CE) Population
timeFrame: Up to approximately Day 30
Secondary outcomes:
measure: Percentage of Participants With Clinical Response (Clinical Cure, Clinical Failure, or Indeterminate) at TOC Visit: Intent to Treat (ITT) Population
timeFrame: Up to approximately Day 30
measure: Percentage of Participants With Clinical Response (Clinical Cure or Clinical Failure) at End of Therapy (EOT) Visit: CE Population
timeFrame: Up to approximately Day 15
measure: Percentage of Participants With Clinical Response (Clinical Cure, Clinical Failure, or Indeterminate) at EOT Visit: ITT Population
timeFrame: Up to approximately Day 15
measure: Percentage of Participants With Favorable Per-Participant Microbiological Response of Eradication or Presumed Eradication at TOC Visit: Expanded Microbiologically Evaluable (EME) Population
timeFrame: Up to approximately Day 30
measure: Percentage of Participants With Favorable Microbiological Response of Eradication or Presumed Eradication, by Pathogen, at the TOC Visit: EME Population
timeFrame: Up to approximately Day 30
measure: Percentage of Participants Who Experienced 1 or More Adverse Events (AEs)
timeFrame: Up to approximately Day 30
measure: Percentage of Participants That Discontinued Study Treatment Due to an AE
timeFrame: Up to Day 14
Other outcomes:
Locations:
city: Hefei
country: China
facility: Anhui Provincial Hospital ( Site 0033)
state: Anhui
city: Beijing
country: China
facility: Navy General Hospital ( Site 0009)
state: Beijing
city: Beijing
country: China
facility: Peking University Third Hospital ( Site 0002)
state: Beijing
city: Guangzhou
country: China
facility: The First Affiliated Hospital of Guangzhou Medical University ( Site 0026)
state: Guangdong
city: Haikou
country: China
facility: Hainan General Hospital ( Site 0042)
state: Hainan
city: Baotou
country: China
facility: Baotou Central Hospital ( Site 0013)
state: Inner Mongolia
city: Changzhou
country: China
facility: The First People's Hospital of Changzhou ( Site 0054)
state: Jiangsu
city: Wuxi
country: China
facility: Wuxi No.2 People's Hospital ( Site 0050)
state: Jiangsu
city: Wuxi
country: China
facility: Wuxi People's Hospital ( Site 0020)
state: Jiangsu
city: Yangzhou
country: China
facility: Subei People's Hospital ( Site 0046)
state: Jiangsu
city: Zhenjiang
country: China
facility: Affiliated Hospital of Jiangsu University ( Site 0049)
state: Jiangsu
city: Nanchang
country: China
facility: The First Affiliated Hospital of Nanchang University ( Site 0029)
state: Jiangxi
city: Nanchang
country: China
facility: The Second Affiliated Hospital of Nanchang University ( Site 0053)
state: Jiangxi
city: Changchun
country: China
facility: The Second Hospital of Jilin University ( Site 0048)
state: Jilin
city: Liaocheng
country: China
facility: Liaocheng People s hospital ( Site 0014)
state: Shandong
city: Shanghai
country: China
facility: Zhongshan Hospital of Fudan University ( Site 0001)
state: Shanghai
city: Shanghai
country: China
facility: Shanghai General Hospital ( Site 0016)
state: Shanghai
city: Shanghai
country: China
facility: Central Hospital of Minhang District ( Site 0052)
state: Shanghai
city: Tianjin
country: China
facility: Tianjin People's Hospital ( Site 0040)
state: Tianjin
city: Urumqi
country: China
facility: The First Affiliated Hospital of Xinjiang Medical University ( Site 0034)
state: Xinjiang
city: Kunming
country: China
facility: The First Hospital of Kunming ( Site 0041)
state: Yunnan
city: Taizhou
country: China
facility: Taizhou Hospital of Zhejiang Province ( Site 0035)
state: Zhejiang
city: Wenzhou
country: China
facility: The 2nd Affiliated Hospital of Wenzhou Medical University ( Site 0051)
state: Zhejiang
city: Wenzhou
country: China
facility: The First Affiliated Hospital of Wenzhou Medical University ( Site 0015)
state: Zhejiang
city: Guangzhou
country: China
facility: Southern Medical University Nanfang Hospital ( Site 0055)
Study officials:
affiliation: Merck Sharp & Dohme LLC
name: Medical Director
role: STUDY_DIRECTOR
References:
citation: 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 versus meropenem in Chinese participants with complicated intra-abdominal infections. Int J Infect Dis. 2022 Oct;123:157-165. doi: 10.1016/j.ijid.2022.08.003. Epub 2022 Aug 17.