A Phase II, Randomized, Active Comparator-Controlled Clinical Trial to Study the Safety, Tolerability, and Efficacy of MK-7655 + Imipenem/Cilastatin Versus Imipenem/Cilastatin Alone in Patients With Complicated Urinary Tract Infection (cUTI)
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 302
- 主要终点
- Percentage of Participants With Specific AEs With Incidence of >= 4 Participants in One Treatment Group
研究概览
简要总结
The purpose of this study is to evaluate the efficacy, safety and tolerability of adding 125 mg or 250 mg doses of MK-7655 (relebactam) to imipenem/cilastatin in adults 18 years or older with complicated urinary tract infection (cUTI). The primary hypothesis is that the relebactam + imipenem/cilastatin treatment regimen is non-inferior to imipenem/cilastatin with respect to the proportion of participants with a favorable microbiological response at completion of intravenous (IV) study therapy.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Clinically suspected and/or bacteriologically documented cUTI or acute
- •pyelonephritis judged by the investigator to be serious (requiring hospitalization and treatment with IV antibiotic therapy)
- •Pyuria, determined by a midstream clean-catch (MSCC) or catheterized
- •(indwelling or straight catheter) urine specimen with greater than or equal to 10 white blood cells (WBCs) per high-power field (hpf) on standard examination of urine sediment or greater than or equal to 10 WBCs/mm3 in unspun urine
- •One positive urine culture within 48 hours of enrollment
排除标准
- •Complete obstruction of any portion of the urinary tract (requiring a
- •permanent indwelling urinary catheter or instrumentation), a known ileal loop, or intractable vesico-ureteral reflux
- •A temporary indwelling urinary catheter is in place and cannot be removed at study entry.
- •Perinephric or intrarenal abscess or known or suspected prostatitis
- •Uncomplicated UTI
- •Any history of recent accidental trauma to the pelvis or urinary tract
- •Any amount of effective antibiotic therapy after obtaining the urine culture for admission to this study and prior to the administration of the first dose of IV study therapy
- •An infection which has been treated with greater than 24 hours of systemic antibiotic therapy known to be effective against the presumed or documented etiologic pathogen(s) within the 72-hour period immediately prior to consideration for entry into the study
- •History of serious allergy, hypersensitivity (e.g., anaphylaxis), or any
- •serious reaction to carbapenem antibiotics, any cephalosporins, penicillins, or other beta (β)-lactam agents
- •History of serious allergy, hypersensitivity (e.g., anaphylaxis), or any serious reaction to other beta-lactam inhibitors (e.g., tazobactam, sulbactam, clavulanic acid)
- •History of a seizure disorder
- •Currently being treated with valproic acid or has received treatment with
- •valproic acid in the 2 weeks prior to screening.
- •Rapidly progressive or terminal illness unlikely to survive the approximately 6 to 8 week study period
- •Pregnant or expecting to conceive, breast feeding, or plans to breast feed
- •during the study
- •A response to all study therapy (IV study therapy or subsequent oral
- •ciprofloxacin) within the timeframe of treatment specified in this protocol is
- •considered unlikely.
- •Concurrent infection that would interfere with evaluation of response to
- •the study antibiotics
- •Need for concomitant systemic antimicrobial agents in addition to those
- •designated in the various study treatment groups (use of vancomycin, daptomycin, or linezolid is allowed for certain infections)
- •cUTI due to a confirmed fungal pathogen
- •Currently receiving immunosuppressive therapy, including use of high-dose
- •corticosteroids
- •Prior recipient of a renal transplantation
- •Laboratory abnormalities as specified in protocol
- •History of any other illness that, in the opinion of the investigator, might
- •confound the results of the study or pose additional risk in administering the study drug
- •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 presentation or during the previous 30 days prior to screening or is anticipated to participate in such a clinical study during the course of this trial
- •Estimated or actual creatinine clearance of <5 mL/minute, or is currently undergoing hemodialysis
研究组 & 干预措施
Relebactam 250 mg with imipenem/cilastatin
Relebactam 250 mg IV co-administered with 500 mg of imipenem/cilastatin once every 6 hours for a minimum of 96 hours. After 96 hours of IV treatment, participants may be switched to 500 mg ciprofloxacin (as optional oral therapy following minimum duration of IV study drug), administered orally, twice daily for the remainder of the study. Antibiotic therapy (IV and oral combined) should not exceed 14 days.
干预措施: Relebactam 250 mg (Drug)
Relebactam 250 mg with imipenem/cilastatin
Relebactam 250 mg IV co-administered with 500 mg of imipenem/cilastatin once every 6 hours for a minimum of 96 hours. After 96 hours of IV treatment, participants may be switched to 500 mg ciprofloxacin (as optional oral therapy following minimum duration of IV study drug), administered orally, twice daily for the remainder of the study. Antibiotic therapy (IV and oral combined) should not exceed 14 days.
干预措施: imipenem/cilastatin 500 mg (Drug)
Relebactam 250 mg with imipenem/cilastatin
Relebactam 250 mg IV co-administered with 500 mg of imipenem/cilastatin once every 6 hours for a minimum of 96 hours. After 96 hours of IV treatment, participants may be switched to 500 mg ciprofloxacin (as optional oral therapy following minimum duration of IV study drug), administered orally, twice daily for the remainder of the study. Antibiotic therapy (IV and oral combined) should not exceed 14 days.
干预措施: Ciprofloxacin (Drug)
Relebactam 125 mg with imipenem/cilastatin
Relebactam 125 mg IV co-administered with 500 mg of imipenem/cilastatin once every 6 hours for a minimum of 96 hours. After 96 hours of IV treatment, participants may be switched to 500 mg ciprofloxacin (as optional oral therapy following minimum duration of IV study drug), administered orally, twice daily for the remainder of the study. Antibiotic therapy (IV and oral combined) should not exceed 14 days.
干预措施: Relebactam 125 mg (Drug)
Relebactam 125 mg with imipenem/cilastatin
Relebactam 125 mg IV co-administered with 500 mg of imipenem/cilastatin once every 6 hours for a minimum of 96 hours. After 96 hours of IV treatment, participants may be switched to 500 mg ciprofloxacin (as optional oral therapy following minimum duration of IV study drug), administered orally, twice daily for the remainder of the study. Antibiotic therapy (IV and oral combined) should not exceed 14 days.
干预措施: imipenem/cilastatin 500 mg (Drug)
Relebactam 125 mg with imipenem/cilastatin
Relebactam 125 mg IV co-administered with 500 mg of imipenem/cilastatin once every 6 hours for a minimum of 96 hours. After 96 hours of IV treatment, participants may be switched to 500 mg ciprofloxacin (as optional oral therapy following minimum duration of IV study drug), administered orally, twice daily for the remainder of the study. Antibiotic therapy (IV and oral combined) should not exceed 14 days.
干预措施: Ciprofloxacin (Drug)
Relebactam placebo with imipenem/cilastatin
Matching placebo for relebactam (0.9% normal saline) IV co-administered with 500 mg dose of imipenem/cilastatin once every 6 hours for a minimum of 96 hours. After 96 hours of IV treatment, participants may be switched to 500 mg ciprofloxacin (as optional oral therapy following minimum duration of IV study drug), administered orally, twice daily for the remainder of the study. Antibiotic therapy (IV and oral combined) should not exceed 14 days.
干预措施: imipenem/cilastatin 500 mg (Drug)
Relebactam placebo with imipenem/cilastatin
Matching placebo for relebactam (0.9% normal saline) IV co-administered with 500 mg dose of imipenem/cilastatin once every 6 hours for a minimum of 96 hours. After 96 hours of IV treatment, participants may be switched to 500 mg ciprofloxacin (as optional oral therapy following minimum duration of IV study drug), administered orally, twice daily for the remainder of the study. Antibiotic therapy (IV and oral combined) should not exceed 14 days.
干预措施: Placebo to relebactam (Drug)
Relebactam placebo with imipenem/cilastatin
Matching placebo for relebactam (0.9% normal saline) IV co-administered with 500 mg dose of imipenem/cilastatin once every 6 hours for a minimum of 96 hours. After 96 hours of IV treatment, participants may be switched to 500 mg ciprofloxacin (as optional oral therapy following minimum duration of IV study drug), administered orally, twice daily for the remainder of the study. Antibiotic therapy (IV and oral combined) should not exceed 14 days.
干预措施: Ciprofloxacin (Drug)
结局指标
主要结局
Percentage of Participants With Specific AEs With Incidence of >= 4 Participants in One Treatment Group
时间窗: Up to 14 days following completion of all study therapy (up to 28 days)
An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which did not necessarily have to have a causal relationship with this treatment. An AE could therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product/protocol-specified procedure, whether or not considered related to the medicinal product/protocol-specified procedure. Any worsening of a preexisting condition temporally associated with the use of the product was also an AE. Analysis includes specific adverse events with an incidence of ≥4 participants in one treatment group or system organ class.
Percentage of Participants Who Discontinued IV Study Therapy Due to an AE
时间窗: Up to 14 days
An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which did not necessarily have to have a causal relationship with this treatment. An AE could therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product/protocol-specified procedure, whether or not considered related to the medicinal product/protocol-specified procedure. Any worsening of a pre-existing condition temporally associated with the use of the product was also an AE.
Percentage of Participants With a Favorable Microbiological Response at Completion of IV Study Therapy
时间窗: At time of last IV dose of study drug (up to post-randomization day 14)
Microbiological response (MR) was assessed based on results of bacterial cultures obtained at completion of IV study medication relative to cultures obtained at baseline. A favorable microbiological response was defined as eradication of all pathogens identified at baseline. Microbiological response was assessed separately for each participant and pathogen identified in the Microbiologically Evaluable (ME) population that included participants with a urine culture confirmed to be positive for at least 1 gram-negative and/or anaerobic pathogen(s) commonly isolated in UTI. The overall microbiological response was determined as "favorable" if all pathogens isolated from a participant at baseline demonstrated a "favorable" response (eradication) at the time point evaluated.
Percentage of Participants With a Drug-related SAE
时间窗: Up to 42 days following completion of all study therapy (up to 56 days)
A serious, drug-related (DR) AE was an AE that resulted in death, was life threatening, resulted in persistent or significant disability/incapacity, resulted in or prolonged an existing inpatient hospitalization, was a congenital anomaly/birth defect, was a cancer, was associated with an overdose, was another important medical event. The SAE was determined to be possibly, probably, or definitely related to the treatment by the investigator.
Percentage of Participants With an Elevated Aspartate Aminotransferase (AST) or Alanine Aminotransferase (ALT) Laboratory Value That Was Greater Than or Equal to 5 Times the Upper Limit of Normal (ULN)
时间窗: Up to 14 days following completion of all study therapy (up to 28 days)
All randomized participants who received ≥1 dose of study treatment had AST and ALT levels measured up to 14 days following completion of all study medication. Participants who had 2 confirmed elevations of either AST or ALT that were 5 times ULN or greater were recorded.
Percentage of Participants With Elevated AST or ALT Laboratory Values ≥ 3 Times the ULN, as Well as Elevated Total Bilirubin ≥ 2 Times the ULN, and Alkaline Phosphatase Values That Were < 2 Times the ULN
时间窗: Up to 14 days following completion of all study therapy (up to 28 days)
All randomized participants who received ≥1 dose of study treatment had AST, ALT, total bilirubin, and Alkaline Phosphatase (ALP) levels measured up to 14 days following completion of all study medication. Participants who had elevations of AST or ALT that were ≥3 times ULN, total bilirubin measurements that were ≥2 times ULN and, at the same time, an ALP measurement of \< 2X ULN were recorded.
Percentage of Participants With at Least 1 Adverse Event (AE)
时间窗: Up to 14 days following completion of all study therapy (up to 28 days)
An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which did not necessarily have to have a causal relationship with this treatment. An AE could therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product/protocol-specified procedure, whether or not considered related to the medicinal product/protocol-specified procedure. Any worsening of a preexisting condition temporally associated with the use of the product was also an AE.
Percentage of Participants With Any Serious Adverse Event (SAE)
时间窗: Up to 14 days following completion of all study therapy (up to 28 days)
A SAE was an AE that resulted in death, was life threatening, resulted in persistent or significant disability/incapacity, resulted in or prolonged an existing inpatient hospitalization, was a congenital anomaly/birth defect, was a cancer, was associated with an overdose, was another important medical event.
Percentage of Participants With Any Drug-related AE
时间窗: Up to 14 days following completion of all study therapy (up to 28 days)
An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which did not necessarily have to have a causal relationship with this treatment. An AE could therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product/protocol-specified procedure, whether or not considered related to the medicinal product/protocol-specified procedure. Any worsening of a preexisting condition temporally associated with the use of the product was also an AE. A drug-related (DR) AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product that the investigator determined to be possibly, probably, or definitely related to the treatment.
Percentage of Participants Who Discontinued IV Study Therapy Due to a Drug-related AE
时间窗: Up to 14 days
An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which did not necessarily have to have a causal relationship with this treatment. An AE could therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product/protocol-specified procedure, whether or not considered related to the medicinal product/protocol-specified procedure. Any worsening of a preexisting condition temporally associated with the use of the product was also an AE. A drug-related AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product that the investigator determined to be possibly, probably, or definitely related to the treatment.
次要结局
- Percentage of Participants With a Favorable Microbiological Response at Early Follow-up(Up to 9 days following completion of all study IV and oral therapy (up to Day 23))
- Percentage of Participants With a Favorable Clinical Response at Late Follow-up(Up to 42 days following completion of all study IV and oral therapy (up to Day 56))
- Percentage of Participants With a Favorable Clinical Response at Completion of IV Study Therapy(At time of last IV dose of study drug (up to postrandomization day 14))
- Percentage of Participants With a Favorable Microbiological Response at Completion of IV Study Therapy Who Had Imipenem-resistant, Gram-negative cUTI Infections.(At time of last IV dose of study drug (up to post-randomization day 14))
- Percentage of Participants With a Favorable Clinical Response at Early Follow-up(Up to 9 days following completion of all study IV and oral therapy (up to Day 23))
- Percentage of Participants With a Favorable Microbiological Response at Late Follow-up(Up to 42 days following completion of all study IV and oral therapy (up to Day 56))