Efficacy/Safety of Meropenem-Vaborbactam Compared to Piperacillin-Tazobactam in Adults With cUTI and AP
Condition: Urinary Tract Infection Complicated; Acute Pyelonephritis
MeSH terms: Infections; Urinary Tract Infections; Pyelonephritis
Intervention: Meropenem-Vaborbactam; Piperacillin-Tazobactam; Levofloxacin; Saline
Intervention description: Meropenem-vaborbactam; Piperacillin-tazobactam; Levofloxacin; Saline
Intervention MeSH terms: Anti-Bacterial Agents; Levofloxacin; Meropenem; Tazobactam; Piperacillin; Piperacillin, Tazobactam Drug Combination; Vaborbactam; beta-Lactamase Inhibitors
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Masking description: Double blind-double dummy
Enrollment: 550.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      Meropenem-vaborbactam is being compared to piperacillin-tazobactam in the treatment of adults
      with complicated urinary tract infection (cUTI) or acute pyelonephritis (AP).
    

Eligibility criteria:

        Inclusion Criteria:

          1. A signed informed consent form, the ability to understand the study conduct and tasks
             that are required for study participation, and a willingness to cooperate with all
             tasks, tests, and examinations as required by the protocol.

          2. Male or female ≥18 years of age.

          3. Weight ≤185 kilograms (kg).

          4. Expectation, in the judgment of the Investigator, that the participant's cUTI or AP
             requires initial treatment with at least 5 days of IV antibiotics.

          5. Documented or suspected cUTI or AP as defined below:

             cUTI

             Signs or symptoms evidenced by at least 2 of the following:

               -  Chills, rigors, or fever (fever must be documented within 24 hours of the
                  screening visit with a temperature of ≥38.0 degrees Celsius [°C] [≥100.4 degrees
                  Fahrenheit (°F)] or rectal/core temperature ≥38.3°C [≥100.9°F], observed and
                  documented by a health care provider);

               -  Elevated white blood cell count (>10,000/ cubic millimeters [mm^3]) or left shift
                  (>15% immature polymorphonuclear leukocytes [PMNs]);

               -  Nausea or vomiting;

               -  Dysuria, increased urinary frequency, or urinary urgency;

               -  Lower abdominal pain or pelvic pain

             Pyuria evidenced by 1 of the following:

               -  Positive leukocyte esterase (LCE) on urinalysis;

               -  White blood cell count ≥10 cells/mm^3 in unspun urine;

               -  White blood cell count ≥10 cells/high-power field (hpf) in urine sediment

             At least 1 of the following associated risks:

               -  Indwelling urinary catheter;

               -  Neurogenic bladder with presence or history of urine residual volume of ≥100 mL;

               -  Obstructive uropathy (such as, nephrolithiasis, tumor, fibrosis) that is expected
                  to be medically or surgically treated within 48 hours post randomization;

               -  Azotemia due to intrinsic renal disease;

               -  Urinary retention in men due to previously diagnosed benign prostatic hypertrophy

             AP

             Signs or symptoms evidenced by at least 2 of the following:

               -  Chills, rigors, or fever (fever must be documented within 24 hours of the
                  screening visit with a temperature of ≥38.0°C [≥100.4°F] or rectal/core
                  temperature ≥38.3°C [≥100.9°F], observed and documented by a health care
                  provider);

               -  Elevated white blood cell count (>10,000/mm^3), or left shift (>15% immature
                  PMNs);

               -  Nausea or vomiting;

               -  Dysuria, increased urinary frequency, or urinary urgency;

               -  Flank pain;

               -  Costo-vertebral angle tenderness on physical examination

             Pyuria evidenced by 1 of the following:

               -  Positive LCE on urinalysis;

               -  White blood cell count ≥10 cells/mm^3 in unspun urine;

               -  White blood cell count ≥10 cells/hpf in urine sediment

          6. Expectation, in the judgment of the Investigator, that any indwelling urinary catheter
             or instrumentation (including nephrostomy tubes and/or indwelling stents) will be
             removed or replaced (if removal is not clinically acceptable) before or as soon as
             possible, but not longer than 12 hours, after randomization.

          7. Expectation, in the judgment of the Investigator that the participant will survive
             with effective antibiotic therapy and appropriate supportive care for the anticipated
             duration of the study.

          8. Women of childbearing potential must have a negative pregnancy test before
             randomization and be willing to use a highly effective method of contraception between
             randomization and for 7 days after the completion of the study. A highly effective
             method of contraception includes 2 of the following: hormonal implants/patch,
             injectable hormones, oral hormonal contraceptives, prior bilateral oophorectomy, prior
             hysterectomy, prior bilateral tubal ligation, intra-uterine device, approved cervical
             ring, condom, true abstinence (if approved by the Investigator), or a vasectomized
             partner.

          9. Willingness to comply with all the study procedures, whether in the hospital or after
             discharge, for the duration of the study.

        Exclusion Criteria:

          1. Presence of any of the following conditions:

               1. Perinephric abscess;

               2. Renal corticomedullary abscess;

               3. Uncomplicated urinary tract infection;

               4. Polycystic kidney disease;

               5. Chronic vesicoureteral reflux;

               6. Previous or planned renal transplantation;

               7. Participants receiving hemodialysis;

               8. Previous or planned cystectomy or ileal loop surgery; or

               9. Known candiduria.

          2. Presence of suspected or confirmed acute bacterial prostatitis, orchitis,
             epididymitis, or chronic bacterial prostatitis as determined by history and/or
             physical examination.

          3. Gross hematuria requiring intervention other than administration of study drug.

          4. Urinary tract surgery within 7 days prior to randomization or urinary tract surgery
             planned during the study period (except surgery required to relieve an obstruction or
             place a stent or nephrostomy).

          5. Renal function at screening as estimated by creatinine clearance <50 mL/minute (min)
             using the Cockcroft-Gault formula.

          6. Known non-renal source of infection such as endocarditis, osteomyelitis, abscess,
             meningitis, or pneumonia diagnosed within 7 days prior to randomization.

          7. Any of the following signs of severe sepsis:

               1. Shock or profound hypotension defined as systolic blood pressure <90 millimeters
                  mercury (mmHg) or a decrease of >40 mmHg from baseline (if known) that is not
                  responsive to fluid challenge;

               2. Hypothermia (temperature <35.6°C or <96.1°F); or

               3. Disseminated intravascular coagulation as evidenced by prothrombin time or
                  partial thromboplastin time ≥2 × the upper limit of normal (ULN) or platelets
                  <50% of the lower limit of normal.

          8. Pregnant or breastfeeding women.

          9. History of epilepsy or known seizure disorder requiring current treatment with
             anti-seizure medication.

         10. Treatment within 30 days prior to enrollment with valproic acid.

         11. Treatment within 30 days prior to enrollment with probenecid.

         12. Treatment within 30 days prior to enrollment with any cancer chemotherapy,
             immunosuppressive medications for transplantation, or medications for rejection of
             transplantation.

         13. Evidence of significant hepatic disease or dysfunction, including known acute viral
             hepatitis or hepatic encephalopathy.

         14. Aspartate aminotransferase or alanine aminotransferase >5 × ULN or total bilirubin >3
             × ULN.

         15. Receipt of any potentially therapeutic antibiotic agent within 48 hours before
             randomization. Participants with a pathogen-causing cUTI or AP that is resistant to
             the prior therapy may be enrolled in this study (assuming the organism is known to be
             sensitive to piperacillin/tazobactam). Participants who develop signs and symptoms of
             cUTI or AP while on antibiotics may also be enrolled.

         16. Prior exposure to vaborbactam alone or in combination with another product.

         17. Receipt of any potentially therapeutic antibiotic agent within 48 hours before
             randomization.

             EXCEPTIONS:

               -  Participants who received a single dose of a short-acting oral or IV antibiotic
                  (an antibiotic that is typically dosed every 4 hours, every 6 hours, or q8h in a
                  participant with normal renal function). No more than 25% of participants will be
                  enrolled who meet this criterion.

               -  Participants who received >48 hours of prior systemic antibiotic therapy for the
                  current episode of cUTI with unequivocal clinical evidence of treatment failure
                  (that is, worsening signs and symptoms).

               -  Participants who develop signs and symptoms of cUTI or AP while on antibiotics
                  for another indication.

         18. Requirement at time of enrollment for any reason for additional systemic antibiotic
             therapy (other than study drug) or antifungal therapy. Topical antifungal or a single
             oral dose of any antifungal treatment for vaginal candidiasis will be allowed.

         19. Likely to require the use of an antibiotic for cUTI prophylaxis during the
             participant's participation in the study (from enrollment through the last follow up
             visit).

         20. Known history of human immunodeficiency virus infection and known recent cluster of
             differentiation 4 count <200/mm^3.

         21. Presence of immunodeficiency or an immunocompromised condition including hematologic
             malignancy, bone marrow transplant, or receiving immunosuppressive therapy such as
             cancer chemotherapy, medications for the rejection of transplantation, and long-term
             (≥2 weeks) use of systemic corticosteroids.

         22. Presence of neutropenia (<1,000 PMNs/mm^3).

         23. Presence of thrombocytopenia (<60,000 platelets/mm^3).

         24. A corrected QT with Fridericia's Formula >480 milliseconds.

         25. History of significant hypersensitivity or allergic reaction to meropenem/vaborbactam,
             piperacillin/tazobactam, any of the excipients used in the respective formulations, or
             any beta-lactam antibiotics (such as, cephalosporins, penicillins, carbapenems, or
             monobactams).

         26. Known hypersensitivity or inability to tolerate all of the following: fluoroquinolones
             (including levofloxacin), trimethoprim/ sulfamethoxazole, cefdinir, cefixime, or
             cefpodoxime, based on prescribing information.

         27. Unable or unwilling, in the judgment of the Investigator, to comply with the protocol.

         28. An employee of the Investigator or study center with direct involvement in the
             proposed study or other studies under the direction of that Investigator or study
             center, or a family member of the employee or the Investigator.

         29. Acute Physiology and Chronic Health Evaluation II score >30 (if clinically indicated)

         30. Inability to tolerate intravenous fluids, due to medical reasons, of 1050 mL per day
             required for study drug administration.

         31. Any recent history of trauma to the pelvis or urinary tract.