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