A Phase 3 interventional study of MK-7625A 1.5 g (ceftolozane 1 g/tazobactam 0.5 g) in Urinary Tract Infection (UTI), Complicated Urinary Tract Infection and Pyelonephritis, sponsored by Merck Sharp & Dohme LLC. Completed. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2019-02-05.
Sponsored by Merck Sharp & Dohme LLC · Phase 3, Interventional, and Treatment
This is a Phase 3, multi-site, non-randomized, open-label study evaluating the safety and efficacy of MK-7625A 1.5 g (ceftolozane 1 g/tazobactam 0.5 g) for the treatment of complicated urinary tract infection (cUTI) including pyelonephritis (uncomplicated or complicated pyelonephritis and complicated lower urinary tract infection) in Japanese participants. Efficacy will be primarily assessed by microbiological response defined as eradication of the baseline pathogen or pathogens.
Clinical signs and/or symptoms of urinary tract infection (UTI) at screening visit, either one of the following:
Exclusion Criteria:
MK-7625A 1.5 g (ceftolozane 1 g/tazobactam 0.5 g) administered as an intravenous (IV) infusion every 8 hours for 7 days. The dose may be reduced to 750 mg (ceftolozane 500 mg/tazobactam 250 mg) for participants with a creatinine clearance (CrCl) of 30-50 mL/min.
Drug: MK-7625A 1.5 g (ceftolozane 1 g/tazobactam 0.5 g)
MK-7625A 1.5 g (ceftolozane 1 g/tazobactam 0.5 g) administered as an intravenous (IV) infusion
Percentage of Participants With Microbiological Response of Eradication at Test of Cure (TOC)
The per-pathogen microbiological outcome was determined for each uropathogen isolated at baseline at TOC (14 days post first dose). Microbiological outcome was classified as "eradication", "persistence" or "indeterminate." A successful microbiological response was "eradication" which was defined as urine culture showed all uropathogens found at baseline at ≥10\^5 colony-forming unit (CFU)/mL were reduced to \<10\^4 CFU/mL. If the outcome for any uropathogen was" persistence" (CFU/mL not reduced the result was classified as unsuccessful. Participants with responses reported as "indeterminate" were excluded.
Time frame: Day 14 (14 days post first dose of study drug)
Percentage of Participants Who Report 1 or More Adverse Event (AE)
An AE was defined as any untoward medical occurrence in a participant which does not necessarily have a causal relationship with the treatment. An AE was any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with use of a medicinal product, regardless of whether or not it was considered related to the medicinal product. The percentage of participants that reported at least 1 AE was summarized.
Time frame: Up to 42 days post first dose of study drug
Percentage of Participants Discontinuing Study Drug Due to an AE
An AE was defined as any untoward medical occurrence in a participant which does not necessarily have a causal relationship with the treatment. An AE was any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with use of a medicinal product, regardless of whether or not considered related to the medicinal product. The percentage of participants that had study drug discontinued during the study due to an AE was summarized.
Time frame: Up to 7 days after the first dose of study drug
Percentage of Participants With Microbiological Response of Eradication at End Of Therapy (EOT)
The per-pathogen microbiological outcome was determined for each uropathogen isolated at baseline at EOT (7 days post first dose of study drug). Microbiological outcome was classified as "eradication", "persistence" or "indeterminate." A successful microbiological response was "eradication" which was defined as urine culture showed all uropathogens found at baseline at ≥10\^5 colony-forming unit (CFU)/mL were reduced to \<10\^4 CFU/mL. If the outcome for any uropathogen was" persistence" (CFU/mL not reduced the result was classified as unsuccessful. Participants with responses reported as "indeterminate" were excluded.
Time frame: Day 7 (7 days post first dose of study drug)
Percentage of Participants With Microbiological Response of Eradication at Late Follow-up (LFU)
The per-pathogen microbiological outcome was determined for each uropathogen isolated at baseline at LFU (42 days post first dose of study drug). Microbiological outcome was classified as "eradication", "persistence" or "indeterminate." A successful microbiological response was "eradication" which was defined as urine culture showed all uropathogens found at baseline at ≥10\^5 colony-forming unit (CFU)/mL were reduced to \<10\^4 CFU/mL. If the outcome for any uropathogen was" persistence" (CFU/mL not reduced the result was classified as unsuccessful. Participants with responses reported as "indeterminate" were excluded.
Time frame: Day 42 (42 days post first dose of study drug)
Percentage of Participants With Clinical Response of Clinical Cure at TOC
The Investigator classified clinical outcome as "clinical cure", "clinical failure", or "indeterminate". A favorable clinical response is "clinical cure" defined as complete resolution of, marked improvement in (where clinical improvement was defined as a reduction in severity of all baseline signs and symptoms with worsening of none and with no requirement for additional antibiotic therapy after EOT), or return to pre-infection signs and symptoms and no use of additional or nonstudy antimicrobial therapy for the treatment of the current UTI. Outcomes reported as "indeterminate" were excluded. Percentage of participants with clinical response of clinical cure at TOC was summarized
Time frame: Day 14 (14 days post first dose of study drug)
Percentage of Participants With Clinical Response of Clinical Cure at EOT
The Investigator classified clinical outcome as "clinical cure", "clinical failure", or "indeterminate". A favorable clinical response is "clinical cure" defined as complete resolution of, marked improvement in (where clinical improvement was defined as a reduction in severity of all baseline signs and symptoms with worsening of none and with no requirement for additional antibiotic therapy after EOT), or return to pre-infection signs and symptoms and no use of additional or nonstudy antimicrobial therapy for the treatment of the current UTI. Outcomes reported as "indeterminate" were excluded. Percentage of participants with clinical response of clinical cure at EOT was summarized
Time frame: Day 7 (7 days post first dose of study drug)
Percentage of Participants With Clinical Response of Clinical Cure at LFU
The Investigator classified clinical outcome as "clinical cure", "clinical failure", or "indeterminate". A favorable clinical response is "clinical cure" defined as complete resolution of, marked improvement in (where clinical improvement was defined as a reduction in severity of all baseline signs and symptoms with worsening of none and with no requirement for additional antibiotic therapy after EOT), or return to pre-infection signs and symptoms and no use of additional or nonstudy antimicrobial therapy for the treatment of the current UTI. Outcomes reported as "indeterminate" were excluded. Percentage of participants with clinical response of clinical cure at LFU was summarized.
Time frame: Day 42 (42 days post first dose of study drug)
Percentage of Participants With a Composite Response of Both Eradication and Clinical Cure at TOC
The percentage of participants that met requirements for both eradication and clinical cure at TOC was summarized.
Time frame: Day 14 (14 days post first dose of study drug)
Percentage of Participants With Microbiological Response of Eradication, by Pathogen at EOT
The per-pathogen microbiological outcome was determined for each uropathogen isolated at baseline. Microbiological outcome was classified as "Eradication", "Persistence" or "Indeterminate." A successful microbiological response was "Eradication" which was defined as urine culture showed the specific pathogen found at baseline at ≥10\^5 colony-forming unit (CFU)/mL was reduced to \<10\^4 CFU/mL. If the outcome for any uropathogen was persistence (CFU/mL not reduced the result was classified as a failure. Outcomes reported as "indeterminate" were excluded. The percentage of participants that achieved eradication for each uropathogen at EOT (7 days post first dose of study drug) was summarized.
Time frame: Day 7 (7 days post first dose of study drug)
Percentage of Participants With Microbiological Response of Eradication by Pathogen at TOC
The per-pathogen microbiological outcome was determined for each uropathogen isolated at baseline. Microbiological outcome was classified as "Eradication", "Persistence" or "Indeterminate." A successful microbiological response was "Eradication" which was defined as urine culture showed the specific pathogen found at baseline at ≥10\^5 colony-forming unit (CFU)/mL was reduced to \<10\^4 CFU/mL. If the outcome for any uropathogen was persistence (CFU/mL not reduced), the result was classified as a failure. Outcomes reported as "indeterminate" were excluded. The percentage of participants that achieved eradication for each uropathogen at TOC (14 days post first dose of study drug) was summarized.
Time frame: Day 14 (14 days post first dose of study drug)
Percentage of Participants With Microbiological Response of Eradication by Pathogen at LFU
The per-pathogen microbiological outcome was determined for each uropathogen isolated at baseline. Microbiological outcome was classified as "Eradication", "Persistence" or "Indeterminate." A successful microbiological response was "Eradication" which was defined as urine culture showed the specific pathogen found at baseline at ≥10\^5 colony-forming unit (CFU)/mL was reduced to \<10\^4 CFU/mL. If the outcome for any uropathogen was persistence (CFU/mL not reduced the result was classified as a failure. Outcomes reported as "indeterminate" were excluded. The percentage of participants that achieved eradication for each uropathogen LFU (42 days post first dose of study drug) was summarized. .
Time frame: Day 42 (42 days post first dose of study drug)
| Milestone | MK-7625A |
|---|---|
| Started | 115 |
| Treated | 114 |
| Completed | 112 |
| Not completed | 3 |
| Withdrew: Physician decision | 2 |
| Withdrew: Withdrawal by subject | 1 |
The per-pathogen microbiological outcome was determined for each uropathogen isolated at baseline at TOC (14 days post first dose). Microbiological outcome was classified as "eradication", "persistence" or "indeterminate." A successful microbiological response was "eradication" which was defined as urine culture showed all uropathogens found at baseline at ≥10\^5 colony-forming unit (CFU)/mL were reduced to \<10\^4 CFU/mL. If the outcome for any uropathogen was" persistence" (CFU/mL not reduced the result was classified as unsuccessful. Participants with responses reported as "indeterminate" were excluded.
| Percentage of participants | MK-7625A |
|---|---|
| Percentage of Participants With Microbiological Response of Eradication at Test of Cure (TOC) | 80.7 (70.9 to 88.3) |
An AE was defined as any untoward medical occurrence in a participant which does not necessarily have a causal relationship with the treatment. An AE was any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with use of a medicinal product, regardless of whether or not it was considered related to the medicinal product. The percentage of participants that reported at least 1 AE was summarized.
| Percentage of participants | MK-7625A |
|---|---|
| Percentage of Participants Who Report 1 or More Adverse Event (AE) | 58.8 (49.2 to 67.9) |
An AE was defined as any untoward medical occurrence in a participant which does not necessarily have a causal relationship with the treatment. An AE was any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with use of a medicinal product, regardless of whether or not considered related to the medicinal product. The percentage of participants that had study drug discontinued during the study due to an AE was summarized.
| Percentage of participants | MK-7625A |
|---|---|
| Percentage of Participants Discontinuing Study Drug Due to an AE | 1.8 (0.2 to 6.2) |
The per-pathogen microbiological outcome was determined for each uropathogen isolated at baseline at EOT (7 days post first dose of study drug). Microbiological outcome was classified as "eradication", "persistence" or "indeterminate." A successful microbiological response was "eradication" which was defined as urine culture showed all uropathogens found at baseline at ≥10\^5 colony-forming unit (CFU)/mL were reduced to \<10\^4 CFU/mL. If the outcome for any uropathogen was" persistence" (CFU/mL not reduced the result was classified as unsuccessful. Participants with responses reported as "indeterminate" were excluded.
| Percentage of participants | MK-7625A |
|---|---|
| Percentage of Participants With Microbiological Response of Eradication at End Of Therapy (EOT) | 100.0 (95.8 to 100.0) |
The per-pathogen microbiological outcome was determined for each uropathogen isolated at baseline at LFU (42 days post first dose of study drug). Microbiological outcome was classified as "eradication", "persistence" or "indeterminate." A successful microbiological response was "eradication" which was defined as urine culture showed all uropathogens found at baseline at ≥10\^5 colony-forming unit (CFU)/mL were reduced to \<10\^4 CFU/mL. If the outcome for any uropathogen was" persistence" (CFU/mL not reduced the result was classified as unsuccessful. Participants with responses reported as "indeterminate" were excluded.
| Percentage of participants | MK-7625A |
|---|---|
| Percentage of Participants With Microbiological Response of Eradication at Late Follow-up (LFU) | 61.0 (49.6 to 71.6) |
The Investigator classified clinical outcome as "clinical cure", "clinical failure", or "indeterminate". A favorable clinical response is "clinical cure" defined as complete resolution of, marked improvement in (where clinical improvement was defined as a reduction in severity of all baseline signs and symptoms with worsening of none and with no requirement for additional antibiotic therapy after EOT), or return to pre-infection signs and symptoms and no use of additional or nonstudy antimicrobial therapy for the treatment of the current UTI. Outcomes reported as "indeterminate" were excluded. Percentage of participants with clinical response of clinical cure at TOC was summarized
| Percentage of participants | MK-7625A |
|---|---|
| Percentage of Participants With Clinical Response of Clinical Cure at TOC | 96.6 (90.5 to 99.3) |
The Investigator classified clinical outcome as "clinical cure", "clinical failure", or "indeterminate". A favorable clinical response is "clinical cure" defined as complete resolution of, marked improvement in (where clinical improvement was defined as a reduction in severity of all baseline signs and symptoms with worsening of none and with no requirement for additional antibiotic therapy after EOT), or return to pre-infection signs and symptoms and no use of additional or nonstudy antimicrobial therapy for the treatment of the current UTI. Outcomes reported as "indeterminate" were excluded. Percentage of participants with clinical response of clinical cure at EOT was summarized
| Percentage of participants | MK-7625A |
|---|---|
| Percentage of Participants With Clinical Response of Clinical Cure at EOT | 97.8 (92.1 to 99.7) |
The Investigator classified clinical outcome as "clinical cure", "clinical failure", or "indeterminate". A favorable clinical response is "clinical cure" defined as complete resolution of, marked improvement in (where clinical improvement was defined as a reduction in severity of all baseline signs and symptoms with worsening of none and with no requirement for additional antibiotic therapy after EOT), or return to pre-infection signs and symptoms and no use of additional or nonstudy antimicrobial therapy for the treatment of the current UTI. Outcomes reported as "indeterminate" were excluded. Percentage of participants with clinical response of clinical cure at LFU was summarized.
| Percentage of participants | MK-7625A |
|---|---|
| Percentage of Participants With Clinical Response of Clinical Cure at LFU | 78.2 (68.0 to 86.3) |
The percentage of participants that met requirements for both eradication and clinical cure at TOC was summarized.
| Percentage of participants | MK-7625A |
|---|---|
| Percentage of Participants With a Composite Response of Both Eradication and Clinical Cure at TOC | 80.7 (70.9 to 88.3) |
The per-pathogen microbiological outcome was determined for each uropathogen isolated at baseline. Microbiological outcome was classified as "Eradication", "Persistence" or "Indeterminate." A successful microbiological response was "Eradication" which was defined as urine culture showed the specific pathogen found at baseline at ≥10\^5 colony-forming unit (CFU)/mL was reduced to \<10\^4 CFU/mL. If the outcome for any uropathogen was persistence (CFU/mL not reduced the result was classified as a failure. Outcomes reported as "indeterminate" were excluded. The percentage of participants that achieved eradication for each uropathogen at EOT (7 days post first dose of study drug) was summarized.
| Percentage of participants | MK-7625A |
|---|---|
| Enterobacter aerogenes | 100.0 (2.5 to 100.0) |
| Escherichia coli | 100.0 (95.3 to 100.0) |
| Klebsiella pneumoniae | 100.0 (59.0 to 100.0) |
| Proteus mirabilis | 100.0 (15.8 to 100.0) |
| Proteus vulgaris | 100.0 (15.8 to 100.0) |
| Pseudomonas aeruginosa | 100.0 (2.5 to 100.0) |
The per-pathogen microbiological outcome was determined for each uropathogen isolated at baseline. Microbiological outcome was classified as "Eradication", "Persistence" or "Indeterminate." A successful microbiological response was "Eradication" which was defined as urine culture showed the specific pathogen found at baseline at ≥10\^5 colony-forming unit (CFU)/mL was reduced to \<10\^4 CFU/mL. If the outcome for any uropathogen was persistence (CFU/mL not reduced), the result was classified as a failure. Outcomes reported as "indeterminate" were excluded. The percentage of participants that achieved eradication for each uropathogen at TOC (14 days post first dose of study drug) was summarized.
| Percentage of participants | MK-7625A |
|---|---|
| Citrobacter koseri | 100.0 (2.5 to 100.0) |
| Enterobacter aerogenes | 100.0 (2.5 to 100.0) |
| Escherichia coli | 82.9 (72.5 to 90.6) |
| Klebsiella pneumoniae | 42.9 (9.9 to 81.6) |
| Proteus mirabilis | 100.0 (29.2 to 100.0) |
| Proteus vulgaris | 100.0 (15.8 to 100.0) |
| Pseudomonas aeruginosa | 100.0 (2.5 to 100.0) |
The per-pathogen microbiological outcome was determined for each uropathogen isolated at baseline. Microbiological outcome was classified as "Eradication", "Persistence" or "Indeterminate." A successful microbiological response was "Eradication" which was defined as urine culture showed the specific pathogen found at baseline at ≥10\^5 colony-forming unit (CFU)/mL was reduced to \<10\^4 CFU/mL. If the outcome for any uropathogen was persistence (CFU/mL not reduced the result was classified as a failure. Outcomes reported as "indeterminate" were excluded. The percentage of participants that achieved eradication for each uropathogen LFU (42 days post first dose of study drug) was summarized. .
| Percentage of participants | MK-7625A |
|---|---|
| Citrobacter koseri | 100.0 (2.5 to 100.0) |
| Enterobacter aerogenes | 100.0 (2.5 to 100.0) |
| Escherichia coli | 62.9 (50.5 to 74.1) |
| Klebsiella pneumoniae | 37.5 (8.5 to 75.5) |
| Proteus mirabilis | 66.7 (9.4 to 99.2) |
| Proteus vulgaris | 100.0 (2.5 to 100.0) |
| Pseudomonas aeruginosa | 100.0 (2.5 to 100.0) |
Collected over up to 35 post last dose of study drug (up to 42 days total). Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| MK-7625A | 0/114 (0%) | 13/114 (11.4%) | 26/114 (22.8%) |
| Event | MK-7625A |
|---|---|
| Pyelonephritis acuteInfections and infestations | 3/114 |
| Cardiac failureCardiac disorders | 1/114 |
| GastritisGastrointestinal disorders | 1/114 |
| IleusGastrointestinal disorders | 1/114 |
| Rectal prolapseGastrointestinal disorders | 1/114 |
| CholelithiasisHepatobiliary disorders | 1/114 |
| Pneumonia bacterialInfections and infestations | 1/114 |
| PyelonephritisInfections and infestations | 1/114 |
| Pyelonephritis chronicInfections and infestations | 1/114 |
| Patella fractureInjury, poisoning and procedural complications | 1/114 |
| Event | MK-7625A |
|---|---|
| ConstipationGastrointestinal disorders | 9/114 |
| DiarrhoeaGastrointestinal disorders | 9/114 |
| Alanine aminotransferase increasedInvestigations | 9/114 |
| Aspartate aminotransferase increasedInvestigations | 7/114 |
| Age, Continuous(Years) | MK-7625A |
|---|---|
| Mean | 68.2 ± 13.8 |
| Sex: Female, Male(Participants) | MK-7625A |
|---|---|
| Female | 77 |
| Male | 38 |
| Race (NIH/OMB)(Participants) | MK-7625A |
|---|---|
| American Indian or Alaska Native | 0 |
| Asian | 115 |
| Native Hawaiian or Other Pacific Islander | 0 |
| Black or African American | 0 |
| White | 0 |
| More than one race | 0 |
| Unknown or Not Reported | 0 |
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