7625ACNPhase3: Ceftolozane/Tazobactam (MK-7625A) Plus Metronidazole Versus Meropenem for Participants With Complicated Intra-abdominal Infection (MK-7625A-015)
Study Details
Study Description
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 3 |
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Ceftolozane/Tazobactam + Metronidazole Participants receive ceftolozane/tazobactam 1500 mg (ceftolozane 1000 mg + tazobactam 500 mg) plus metronidazole 500 mg administered as an intravenous (IV) infusion every 8 hours for 4 to 14 days (per protocol, ceftolozane/tazobactam may be adjusted to 500 mg/250 mg if creatinine clearance [CrCL] is 30 to ≤50 mL/min) |
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.
Other Names:
Drug: Metronidazole
Metronidazole 500 mg by IV infusion every 8 hours for 4 to 14 days.
|
| Active Comparator: Meropenem + Placebo Participants receive meropenem 1000 mg plus saline administered as an IV infusion every 8 hours for 4 to 14 days (per protocol, meropenem may be adjusted to every 12 hours if CrCL was 30 to ≤50 mL/min). |
Drug: 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.
Drug: Placebo
Saline by IV infusion every 8 hours for 4 to 14 days.
|
Outcome Measures
Primary Outcome Measures
- Percentage of Participants With Clinical Response (Clinical Cure or Clinical Failure) at Test of Cure (TOC) Visit: Clinically Evaluable (CE) Population [Up to approximately Day 30]
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.
Secondary Outcome Measures
- Percentage of Participants With Clinical Response (Clinical Cure, Clinical Failure, or Indeterminate) at TOC Visit: Intent to Treat (ITT) Population [Up to approximately Day 30]
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.
- Percentage of Participants With Clinical Response (Clinical Cure or Clinical Failure) at End of Therapy (EOT) Visit: CE Population [Up to approximately Day 15]
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.
- Percentage of Participants With Clinical Response (Clinical Cure, Clinical Failure, or Indeterminate) at EOT Visit: ITT Population [Up to approximately Day 15]
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.
- Percentage of Participants With Favorable Per-Participant Microbiological Response of Eradication or Presumed Eradication at TOC Visit: Expanded Microbiologically Evaluable (EME) Population [Up to approximately Day 30]
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.
- Percentage of Participants With Favorable Microbiological Response of Eradication or Presumed Eradication, by Pathogen, at the TOC Visit: EME Population [Up to approximately Day 30]
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.
- Percentage of Participants Who Experienced 1 or More Adverse Events (AEs) [Up to approximately Day 30]
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.
- Percentage of Participants That Discontinued Study Treatment Due to an AE [Up to Day 14]
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.
Eligibility Criteria
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
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Anhui Provincial Hospital ( Site 0033) | Hefei | Anhui | China | 230001 |
| 2 | Navy General Hospital ( Site 0009) | Beijing | Beijing | China | 100048 |
| 3 | Peking University Third Hospital ( Site 0002) | Beijing | Beijing | China | 100191 |
| 4 | The First Affiliated Hospital of Guangzhou Medical University ( Site 0026) | Guangzhou | Guangdong | China | 510120 |
| 5 | Hainan General Hospital ( Site 0042) | Haikou | Hainan | China | 570311 |
| 6 | Baotou Central Hospital ( Site 0013) | Baotou | Inner Mongolia | China | 014040 |
| 7 | The First People's Hospital of Changzhou ( Site 0054) | Changzhou | Jiangsu | China | 213000 |
| 8 | Wuxi No.2 People's Hospital ( Site 0050) | Wuxi | Jiangsu | China | 214002 |
| 9 | Wuxi People's Hospital ( Site 0020) | Wuxi | Jiangsu | China | 214023 |
| 10 | Subei People's Hospital ( Site 0046) | Yangzhou | Jiangsu | China | 200080 |
| 11 | Affiliated Hospital of Jiangsu University ( Site 0049) | Zhenjiang | Jiangsu | China | 212000 |
| 12 | The First Affiliated Hospital of Nanchang University ( Site 0029) | Nanchang | Jiangxi | China | 330006 |
| 13 | The Second Affiliated Hospital of Nanchang University ( Site 0053) | Nanchang | Jiangxi | China | 330006 |
| 14 | The Second Hospital of Jilin University ( Site 0048) | Changchun | Jilin | China | 130022 |
| 15 | Liaocheng People s hospital ( Site 0014) | Liaocheng | Shandong | China | 252000 |
| 16 | Zhongshan Hospital of Fudan University ( Site 0001) | Shanghai | Shanghai | China | 200032 |
| 17 | Shanghai General Hospital ( Site 0016) | Shanghai | Shanghai | China | 200080 |
| 18 | Central Hospital of Minhang District ( Site 0052) | Shanghai | Shanghai | China | 201100 |
| 19 | Tianjin People's Hospital ( Site 0040) | Tianjin | Tianjin | China | 300121 |
| 20 | The First Affiliated Hospital of Xinjiang Medical University ( Site 0034) | Urumqi | Xinjiang | China | 830054 |
| 21 | The First Hospital of Kunming ( Site 0041) | Kunming | Yunnan | China | 650200 |
| 22 | Taizhou Hospital of Zhejiang Province ( Site 0035) | Taizhou | Zhejiang | China | 317000 |
| 23 | The 2nd Affiliated Hospital of Wenzhou Medical University ( Site 0051) | Wenzhou | Zhejiang | China | 325000 |
| 24 | The First Affiliated Hospital of Wenzhou Medical University ( Site 0015) | Wenzhou | Zhejiang | China | 325000 |
| 25 | Southern Medical University Nanfang Hospital ( Site 0055) | Guangzhou | China | 510515 |
Sponsors and Collaborators
- Merck Sharp & Dohme LLC
Investigators
- Study Director: Medical Director, Merck Sharp & Dohme LLC
Study Documents (Full-Text)
More Information
Publications
None provided.- 7625A-015
- MK-7625A-015
Study Results
Participant Flow
| Recruitment Details | Adult participants with complicated intra-abdominal infection (cIAI) were recruited at 21 study sites in China. Participants with severe impairment of renal function (estimated creatinine clearance [CrCL] <30 mL/min) were excluded. |
|---|---|
| Pre-assignment Detail |
| Arm/Group Title | Ceftolozane/Tazobactam + Metronidazole | Meropenem + Placebo |
|---|---|---|
| Arm/Group Description | Participants received ceftolozane/tazobactam 1500 mg (ceftolozane 1000 mg + tazobactam 500 mg) plus metronidazole 500 mg administered as an intravenous (IV) infusion every 8 hours for 4 to 14 days (per protocol, ceftolozane/tazobactam could be adjusted to 500 mg/250 mg if CrCL was 30 to ≤50 mL/min). | Participants received meropenem 1000 mg plus saline administered as an IV infusion every 8 hours for 4 to 14 days (per protocol, meropenem could be adjusted to every 12 hours if CrCL was 30 to ≤50 mL/min). |
| Period Title: Overall Study | ||
| STARTED | 134 | 134 |
| Clinically Evaluable Population | 105 | 116 |
| COMPLETED | 126 | 130 |
| NOT COMPLETED | 8 | 4 |
Baseline Characteristics
| Arm/Group Title | Ceftolozane/Tazobactam + Metronidazole | Meropenem + Placebo | Total |
|---|---|---|---|
| Arm/Group Description | Participants received ceftolozane/tazobactam 1500 mg (ceftolozane 1000 mg + tazobactam 500 mg) plus metronidazole 500 mg administered as an intravenous (IV) infusion every 8 hours for 4 to 14 days (per protocol, ceftolozane/tazobactam could be adjusted to 500 mg/250 mg if CrCL was 30 to ≤50 mL/min). | Participants received meropenem 1000 mg plus saline administered as an IV infusion every 8 hours for 4 to 14 days (per protocol, meropenem could be adjusted to every 12 hours if CrCL was 30 to ≤50 mL/min). | Total of all reporting groups |
| Overall Participants | 134 | 134 | 268 |
| Age (Years) [Mean (Standard Deviation) ] | |||
| Mean (Standard Deviation) [Years] |
47.5
(16.2)
|
51.1
(15.7)
|
49.3
(16.0)
|
| Sex: Female, Male (Count of Participants) | |||
| Female |
55
41%
|
49
36.6%
|
104
38.8%
|
| Male |
79
59%
|
85
63.4%
|
164
61.2%
|
| Ethnicity (NIH/OMB) (Count of Participants) | |||
| Hispanic or Latino |
0
0%
|
0
0%
|
0
0%
|
| Not Hispanic or Latino |
134
100%
|
134
100%
|
268
100%
|
| Unknown or Not Reported |
0
0%
|
0
0%
|
0
0%
|
| Race (NIH/OMB) (Count of Participants) | |||
| American Indian or Alaska Native |
0
0%
|
0
0%
|
0
0%
|
| Asian |
134
100%
|
134
100%
|
268
100%
|
| Native Hawaiian or Other Pacific Islander |
0
0%
|
0
0%
|
0
0%
|
| Black or African American |
0
0%
|
0
0%
|
0
0%
|
| White |
0
0%
|
0
0%
|
0
0%
|
| More than one race |
0
0%
|
0
0%
|
0
0%
|
| Unknown or Not Reported |
0
0%
|
0
0%
|
0
0%
|
| Primary Site of Infection (Count of Participants) | |||
| Bowel (small or large) |
5
3.7%
|
8
6%
|
13
4.9%
|
| Other site of infection |
129
96.3%
|
126
94%
|
255
95.1%
|
Outcome Measures
| Title | Percentage of Participants With Clinical Response (Clinical Cure or Clinical Failure) at Test of Cure (TOC) Visit: Clinically Evaluable (CE) Population |
|---|---|
| Description | 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. |
| Time Frame | Up to approximately Day 30 |
Outcome Measure Data
| Analysis Population Description |
|---|
| All participants of the CE population who met the protocol definition of cIAI, had no significant protocol deviations, received the minimum duration of randomized IV study therapy, and had an efficacy assessment of cure or failure at the TOC visit were analyzed. |
| Arm/Group Title | Ceftolozane/Tazobactam + Metronidazole | Meropenem + Placebo |
|---|---|---|
| Arm/Group Description | Participants received ceftolozane/tazobactam 1500 mg (ceftolozane 1000 mg + tazobactam 500 mg) plus metronidazole 500 mg administered as an intravenous (IV) infusion every 8 hours for 4 to 14 days (per protocol, ceftolozane/tazobactam could be adjusted to 500 mg/250 mg if CrCL was 30 to ≤50 mL/min). | Participants received meropenem 1000 mg plus saline administered as an IV infusion every 8 hours for 4 to 14 days (per protocol, meropenem could be adjusted to every 12 hours if CrCL was 30 to ≤50 mL/min). |
| Measure Participants | 105 | 116 |
| Clinical Cure (favorable) |
95.2
71%
|
93.1
69.5%
|
| Clinical Failure (unfavorable) |
4.8
3.6%
|
6.9
5.1%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Ceftolozane/Tazobactam + Metronidazole, Meropenem + Placebo |
|---|---|---|
| Comments | Difference in percentage was based on Miettinen and Nurminen method with the Cochran-Mantel-Haenszel (CMH) weighting stratified by anatomic site of infection (bowel [small or large] versus other site of cIAI). | |
| Type of Statistical Test | Non-Inferiority | |
| Comments | Ceftolozane/tazobactam + metronidazole is concluded to be non-inferior to meropenem + placebo if the lower bound of the 95% CI for the treatment difference in percent response is above -12.5 percentage points. | |
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Difference in percentages |
| Estimated Value | 2.1 | |
| Confidence Interval |
(2-Sided) 95% -4.7 to 8.8 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Percentage of Participants With Clinical Response (Clinical Cure, Clinical Failure, or Indeterminate) at TOC Visit: Intent to Treat (ITT) Population |
|---|---|
| Description | 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. |
| Time Frame | Up to approximately Day 30 |
Outcome Measure Data
| Analysis Population Description |
|---|
| The ITT population consisted of all randomized participants. Participants in the ITT population were analyzed based on the treatment they were randomized to, irrespective of what they actually received. |
| Arm/Group Title | Ceftolozane/Tazobactam + Metronidazole | Meropenem + Placebo |
|---|---|---|
| Arm/Group Description | Participants received ceftolozane/tazobactam 1500 mg (ceftolozane 1000 mg + tazobactam 500 mg) plus metronidazole 500 mg administered as an intravenous (IV) infusion every 8 hours for 4 to 14 days (per protocol, ceftolozane/tazobactam could be adjusted to 500 mg/250 mg if CrCL was 30 to ≤50 mL/min). | Participants received meropenem 1000 mg plus saline administered as an IV infusion every 8 hours for 4 to 14 days (per protocol, meropenem could be adjusted to every 12 hours if CrCL was 30 to ≤50 mL/min). |
| Measure Participants | 134 | 134 |
| Clinical Cure (favorable) |
85.1
63.5%
|
89.6
66.9%
|
| Clinical Failure (unfavorable) |
14.2
10.6%
|
9.7
7.2%
|
| Indeterminate (unfavorable) |
0.7
0.5%
|
0.7
0.5%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Ceftolozane/Tazobactam + Metronidazole, Meropenem + Placebo |
|---|---|---|
| Comments | Difference in percentage was based on Miettinen and Nurminen method with the CMH weighting stratified by anatomic site of infection (bowel [small or large] versus other site of cIAI). | |
| Type of Statistical Test | Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Difference in percentages |
| Estimated Value | -4.4 | |
| Confidence Interval |
(2-Sided) 95% -12.6 to 3.7 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Percentage of Participants With Clinical Response (Clinical Cure or Clinical Failure) at End of Therapy (EOT) Visit: CE Population |
|---|---|
| Description | 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. |
| Time Frame | Up to approximately Day 15 |
Outcome Measure Data
| Analysis Population Description |
|---|
| All participants of the CE population who met the protocol definition of cIAI, had no significant protocol deviations, received the minimum duration of randomized IV study therapy, and had an efficacy assessment of cure or failure at the EOT visit were analyzed. |
| Arm/Group Title | Ceftolozane/Tazobactam + Metronidazole | Meropenem + Placebo |
|---|---|---|
| Arm/Group Description | Participants received ceftolozane/tazobactam 1500 mg (ceftolozane 1000 mg + tazobactam 500 mg) plus metronidazole 500 mg administered as an intravenous (IV) infusion every 8 hours for 4 to 14 days (per protocol, ceftolozane/tazobactam could be adjusted to 500 mg/250 mg if CrCL was 30 to ≤50 mL/min). | Participants received meropenem 1000 mg plus saline administered as an IV infusion every 8 hours for 4 to 14 days (per protocol, meropenem could be adjusted to every 12 hours if CrCL was 30 to ≤50 mL/min). |
| Measure Participants | 105 | 116 |
| Clinical Cure (favorable) |
98.1
73.2%
|
96.6
72.1%
|
| Clinical Failure (unfavorable) |
1.9
1.4%
|
3.4
2.5%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Ceftolozane/Tazobactam + Metronidazole, Meropenem + Placebo |
|---|---|---|
| Comments | Difference in percentage was based on Miettinen and Nurminen method with the CMH weighting stratified by anatomic site of infection (bowel [small or large] versus other site of cIAI). | |
| Type of Statistical Test | Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Difference in percentages |
| Estimated Value | 1.4 | |
| Confidence Interval |
(2-Sided) 95% -3.8 to 6.7 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Percentage of Participants With Clinical Response (Clinical Cure, Clinical Failure, or Indeterminate) at EOT Visit: ITT Population |
|---|---|
| Description | 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. |
| Time Frame | Up to approximately Day 15 |
Outcome Measure Data
| Analysis Population Description |
|---|
| The ITT population consisted of all randomized participants. Participants in the ITT population were analyzed based on the treatment they were randomized to, irrespective of what they actually received. |
| Arm/Group Title | Ceftolozane/Tazobactam + Metronidazole | Meropenem + Placebo |
|---|---|---|
| Arm/Group Description | Participants received ceftolozane/tazobactam 1500 mg (ceftolozane 1000 mg + tazobactam 500 mg) plus metronidazole 500 mg administered as an intravenous (IV) infusion every 8 hours for 4 to 14 days (per protocol, ceftolozane/tazobactam could be adjusted to 500 mg/250 mg if CrCL was 30 to ≤50 mL/min). | Participants received meropenem 1000 mg plus saline administered as an IV infusion every 8 hours for 4 to 14 days (per protocol, meropenem could be adjusted to every 12 hours if CrCL was 30 to ≤50 mL/min). |
| Measure Participants | 134 | 134 |
| Clinical Cure (favorable) |
92.5
69%
|
94.0
70.1%
|
| Clinical Failure (unfavorable) |
7.5
5.6%
|
4.5
3.4%
|
| Indeterminate (unfavorable) |
0.0
0%
|
1.5
1.1%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Ceftolozane/Tazobactam + Metronidazole, Meropenem + Placebo |
|---|---|---|
| Comments | Difference in percentage was based on Miettinen and Nurminen method with the CMH weighting stratified by anatomic site of infection (bowel [small or large] versus other site of cIAI). | |
| Type of Statistical Test | Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Difference in percentages |
| Estimated Value | -1.5 | |
| Confidence Interval |
(2-Sided) 95% -8.0 to 4.8 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Percentage of Participants With Favorable Per-Participant Microbiological Response of Eradication or Presumed Eradication at TOC Visit: Expanded Microbiologically Evaluable (EME) Population |
|---|---|
| Description | 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. |
| Time Frame | Up to approximately Day 30 |
Outcome Measure Data
| Analysis Population Description |
|---|
| The EME population consisted of all randomized participants who had cIAI as evidenced by identification of at least 1 baseline intra-abdominal pathogen, regardless of susceptibility to study drug and met all CE population criteria. |
| Arm/Group Title | Ceftolozane/Tazobactam + Metronidazole | Meropenem + Placebo |
|---|---|---|
| Arm/Group Description | Participants received ceftolozane/tazobactam 1500 mg (ceftolozane 1000 mg + tazobactam 500 mg) plus metronidazole 500 mg administered as an intravenous (IV) infusion every 8 hours for 4 to 14 days (per protocol, ceftolozane/tazobactam could be adjusted to 500 mg/250 mg if CrCL was 30 to ≤50 mL/min). | Participants received meropenem 1000 mg plus saline administered as an IV infusion every 8 hours for 4 to 14 days (per protocol, meropenem could be adjusted to every 12 hours if CrCL was 30 to ≤50 mL/min). |
| Measure Participants | 54 | 73 |
| Number [Percentage of Participants] |
94.4
70.4%
|
93.2
69.6%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Ceftolozane/Tazobactam + Metronidazole, Meropenem + Placebo |
|---|---|---|
| Comments | Difference in percentage based on Miettinen and Nurminen method with the CMH weighting stratified by anatomic site of infection (bowel [small or large] versus other site of cIAI). | |
| Type of Statistical Test | Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Difference in percentages |
| Estimated Value | 1.2 | |
| Confidence Interval |
(2-Sided) 95% -9.2 to 10.4 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Percentage of Participants With Favorable Microbiological Response of Eradication or Presumed Eradication, by Pathogen, at the TOC Visit: EME Population |
|---|---|
| Description | 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. |
| Time Frame | Up to approximately Day 30 |
Outcome Measure Data
| Analysis Population Description |
|---|
| The EME population consisted of all randomized participants with data available who had cIAI as evidenced by identification of at least 1 baseline intra-abdominal pathogen, regardless of susceptibility to study drug and met all CE population criteria. |
| Arm/Group Title | Ceftolozane/Tazobactam + Metronidazole | Meropenem + Placebo |
|---|---|---|
| Arm/Group Description | Participants received ceftolozane/tazobactam 1500 mg (ceftolozane 1000 mg + tazobactam 500 mg) plus metronidazole 500 mg administered as an intravenous (IV) infusion every 8 hours for 4 to 14 days (per protocol, ceftolozane/tazobactam could be adjusted to 500 mg/250 mg if CrCL was 30 to ≤50 mL/min). | Participants received meropenem 1000 mg plus saline administered as an IV infusion every 8 hours for 4 to 14 days (per protocol, meropenem could be adjusted to every 12 hours if CrCL was 30 to ≤50 mL/min). |
| Measure Participants | 54 | 73 |
| Gram-negative aerobes |
94.0
70.1%
|
95.0
70.9%
|
| All Enterobacteriaceae |
93.8
70%
|
95.0
70.9%
|
| Citrobacter freundii complex |
100.0
74.6%
|
|
| Citrobacter koseri |
100.0
74.6%
|
|
| Enterobacter aerogenes |
100.0
74.6%
|
|
| Enterobacter cloacae complex |
100.0
74.6%
|
|
| Other Enterobacter spp. |
100.0
74.6%
|
|
| Escherichia coli |
93.8
70%
|
95.7
71.4%
|
| Klebsiella oxytoca |
100.0
74.6%
|
|
| Klebsiella pneumoniae |
100.0
74.6%
|
90.9
67.8%
|
| Morganella morganii |
100.0
74.6%
|
|
| Proteus mirabilis |
50.0
37.3%
|
|
| Aeromonas hydrophila |
100.0
74.6%
|
|
| Pseudomonas aeruginosa |
75.0
56%
|
100.0
74.6%
|
| Gram-positive aerobes |
80.0
59.7%
|
88.2
65.8%
|
| Gram-negative anaerobes |
100.0
74.6%
|
|
| Gram-positive anaerobes |
100.0
74.6%
|
100.0
74.6%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Ceftolozane/Tazobactam + Metronidazole, Meropenem + Placebo |
|---|---|---|
| Comments | Gram-negative aerobes comparison: Based on unstratified Miettinen and Nurminen method. | |
| Type of Statistical Test | Other | |
| Comments | Difference in percentage was based on unstratified Miettinen and Nurminen method. Confidence Interval is displayed only when there are at least 4 participants in at least one treatment group. | |
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Difference in percentages |
| Estimated Value | -1.0 | |
| Confidence Interval |
(2-Sided) 95% -11.9 to 8.7 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Ceftolozane/Tazobactam + Metronidazole, Meropenem + Placebo |
|---|---|---|
| Comments | All enterobacteriaceae comparison: Based on unstratified Miettinen and Nurminen method. | |
| Type of Statistical Test | Other | |
| Comments | Difference in percentage was based on unstratified Miettinen and Nurminen method. Confidence Interval is displayed only when there are at least 4 participants in at least one treatment group. | |
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Difference in percentages |
| Estimated Value | -1.2 | |
| Confidence Interval |
(2-Sided) 95% -12.5 to 8.5 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
Statistical Analysis 3
| Statistical Analysis Overview | Comparison Group Selection | Ceftolozane/Tazobactam + Metronidazole, Meropenem + Placebo |
|---|---|---|
| Comments | Gram-positive aerobes comparison: Based on unstratified Miettinen and Nurminen method. | |
| Type of Statistical Test | Other | |
| Comments | Difference in percentage was based on unstratified Miettinen and Nurminen method. Confidence Interval is displayed only when there are at least 4 participants in at least one treatment group. | |
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Difference in percentages |
| Estimated Value | -8.2 | |
| Confidence Interval |
(2-Sided) 95% -42.2 to 20.0 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Percentage of Participants Who Experienced 1 or More Adverse Events (AEs) |
|---|---|
| Description | 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. |
| Time Frame | Up to approximately Day 30 |
Outcome Measure Data
| Analysis Population Description |
|---|
| The All Participants as Treated (APaT) population was used for the analysis of safety data in this study. The APaT population consisted of all randomized participants who received at least one dose of study treatment. |
| Arm/Group Title | Ceftolozane/Tazobactam + Metronidazole | Meropenem + Placebo |
|---|---|---|
| Arm/Group Description | Participants received ceftolozane/tazobactam 1500 mg (ceftolozane 1000 mg + tazobactam 500 mg) plus metronidazole 500 mg administered as an intravenous (IV) infusion every 8 hours for 4 to 14 days (per protocol, ceftolozane/tazobactam could be adjusted to 500 mg/250 mg if CrCL was 30 to ≤50 mL/min). | Participants received meropenem 1000 mg plus saline administered as an IV infusion every 8 hours for 4 to 14 days (per protocol, meropenem could be adjusted to every 12 hours if CrCL was 30 to ≤50 mL/min). |
| Measure Participants | 134 | 134 |
| Number [Percentage of Participants] |
50.0
37.3%
|
50.7
37.8%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Ceftolozane/Tazobactam + Metronidazole, Meropenem + Placebo |
|---|---|---|
| Comments | Difference in percentage was based on Miettinen & Nurminen method. | |
| Type of Statistical Test | Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Difference in Percentages |
| Estimated Value | -0.7 | |
| Confidence Interval |
(2-Sided) 95% -12.6 to 11.2 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Percentage of Participants That Discontinued Study Treatment Due to an AE |
|---|---|
| Description | 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. |
| Time Frame | Up to Day 14 |
Outcome Measure Data
| Analysis Population Description |
|---|
| The APaT population was used for the analysis of safety data in this study. The APaT population consisted of all randomized participants who received at least one dose of study treatment. |
| Arm/Group Title | Ceftolozane/Tazobactam + Metronidazole | Meropenem + Placebo |
|---|---|---|
| Arm/Group Description | Participants received ceftolozane/tazobactam 1500 mg (ceftolozane 1000 mg + tazobactam 500 mg) plus metronidazole 500 mg administered as an intravenous (IV) infusion every 8 hours for 4 to 14 days (per protocol, ceftolozane/tazobactam could be adjusted to 500 mg/250 mg if CrCL was 30 to ≤50 mL/min). | Participants received meropenem 1000 mg plus saline administered as an IV infusion every 8 hours for 4 to 14 days (per protocol, meropenem could be adjusted to every 12 hours if CrCL was 30 to ≤50 mL/min). |
| Measure Participants | 134 | 134 |
| Number [Percentage of Participants] |
2.2
1.6%
|
2.2
1.6%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Ceftolozane/Tazobactam + Metronidazole, Meropenem + Placebo |
|---|---|---|
| Comments | Difference in percentage was based on Miettinen & Nurminen method. | |
| Type of Statistical Test | Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Difference in Percentages |
| Estimated Value | 0.0 | |
| Confidence Interval |
(2-Sided) 95% -4.4 to 4.4 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
Adverse Events
| Time Frame | Up to approximately Day 30 | |||
|---|---|---|---|---|
| Adverse Event Reporting Description | The analysis population consisted of all randomized participants who received at least one dose of study treatment. | |||
| Arm/Group Title | Ceftolozane/Tazobactam + Metronidazole | Meropenem + Placebo | ||
| Arm/Group Description | Participants received ceftolozane/tazobactam 1500 mg (ceftolozane 1000 mg + tazobactam 500 mg) plus metronidazole 500 mg administered as an intravenous (IV) infusion every 8 hours for 4 to 14 days (per protocol, ceftolozane/tazobactam could be adjusted to 500 mg/250 mg if CrCL was 30 to ≤50 mL/min). | Participants received meropenem 1000 mg plus saline administered as an IV infusion every 8 hours for 4 to 14 days (per protocol, meropenem could be adjusted to every 12 hours if CrCL was 30 to ≤50 mL/min). | ||
All Cause Mortality |
||||
| Ceftolozane/Tazobactam + Metronidazole | Meropenem + Placebo | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 0/134 (0%) | 1/134 (0.7%) | ||
Serious Adverse Events |
||||
| Ceftolozane/Tazobactam + Metronidazole | Meropenem + Placebo | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 7/134 (5.2%) | 7/134 (5.2%) | ||
| Cardiac disorders | ||||
| Atrial fibrillation | 0/134 (0%) | 0 | 1/134 (0.7%) | 1 |
| Gastrointestinal disorders | ||||
| Small intestinal obstruction | 1/134 (0.7%) | 1 | 0/134 (0%) | 0 |
| General disorders | ||||
| Death | 0/134 (0%) | 0 | 1/134 (0.7%) | 1 |
| Hepatobiliary disorders | ||||
| Cholecystitis | 1/134 (0.7%) | 1 | 1/134 (0.7%) | 1 |
| Cholelithiasis | 1/134 (0.7%) | 1 | 0/134 (0%) | 0 |
| Hepatic function abnormal | 0/134 (0%) | 0 | 1/134 (0.7%) | 1 |
| Infections and infestations | ||||
| Abdominal infection | 2/134 (1.5%) | 2 | 2/134 (1.5%) | 2 |
| Peritonitis | 1/134 (0.7%) | 1 | 0/134 (0%) | 0 |
| Pneumonia | 1/134 (0.7%) | 1 | 0/134 (0%) | 0 |
| Pulmonary mycosis | 1/134 (0.7%) | 1 | 0/134 (0%) | 0 |
| Respiratory, thoracic and mediastinal disorders | ||||
| Pleural effusion | 0/134 (0%) | 0 | 1/134 (0.7%) | 1 |
| Pneumothorax | 1/134 (0.7%) | 1 | 0/134 (0%) | 0 |
| Vascular disorders | ||||
| Deep vein thrombosis | 0/134 (0%) | 0 | 1/134 (0.7%) | 1 |
Other (Not Including Serious) Adverse Events |
||||
| Ceftolozane/Tazobactam + Metronidazole | Meropenem + Placebo | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 28/134 (20.9%) | 33/134 (24.6%) | ||
| Gastrointestinal disorders | ||||
| Constipation | 1/134 (0.7%) | 1 | 8/134 (6%) | 9 |
| Diarrhoea | 8/134 (6%) | 8 | 11/134 (8.2%) | 12 |
| General disorders | ||||
| Pyrexia | 9/134 (6.7%) | 11 | 14/134 (10.4%) | 15 |
| Metabolism and nutrition disorders | ||||
| Hypokalaemia | 7/134 (5.2%) | 7 | 2/134 (1.5%) | 2 |
| Respiratory, thoracic and mediastinal disorders | ||||
| Cough | 7/134 (5.2%) | 7 | 9/134 (6.7%) | 9 |
Limitations/Caveats
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
If publication activity is not directed by the Sponsor, the investigator agrees to submit all manuscripts or abstracts to the Sponsor before submission. This allows the Sponsor to protect proprietary information and to provide comments.
Results Point of Contact
| Name/Title | Senior Vice President, Global Clinical Development |
|---|---|
| Organization | Merck Sharp & Dohme Corp. |
| Phone | 1-800-672-6372 |
| ClinicalTrialsDisclosure@merck.com |
- 7625A-015
- MK-7625A-015