Efficacy/Safety of Meropenem-Vaborbactam Compared to Piperacillin-Tazobactam in Adults With cUTI and AP

Phase III, Randomized, Double-Blind, Study Evaluating Efficacy/Safety/Tolerability of Meropenem-Vaborbactam Compared to Piperacillin/Tazobactam in Adult Patients With Complicated Urinary Tract Infections, Including Acute Pyelonephritis

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

In the current era of increased resistance to extended spectrum cephalosporins, carbapenem antimicrobial agents are frequently the antibiotics of "last defense" for the most resistant pathogens in serious infections, including those found in cUTIs. The recent dissemination of serine carbapenemases in Enterobacteriaceae in many hospitals worldwide now poses a considerable threat to the carbapenems and other members of the beta-lactam class of antimicrobial agents.

Rempex is developing meropenem-vaborbactam administered as a fixed combination by intravenous infusion to treat serious Gram-negative infections such as cUTIs, including those infections caused by bacteria resistant to currently available carbapenems.

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.