Efficacy, Safety, Tolerability of Vabomere Compared to Best Available Therapy in Treating Serious Infections in Adults
Condition: Urinary Tract Infection Complicated; Acute Pyelonephritis; Hospital Acquired Bacterial Pneumonia; Ventilator-associated Bacterial Pneumonia; Bacteremia; Abdominal Infection
MeSH terms: Infections; Communicable Diseases; Pneumonia; Urinary Tract Infections; Bacteremia; Intraabdominal Infections; Pneumonia, Bacterial; Pyelonephritis
Intervention: Vabomere; Best Available Therapy
Intervention description: Vabomere for IV injection, administered as a 2 g/2 g dose; Antibiotic(s) chosen by Investigator
Intervention MeSH terms: Anti-Bacterial Agents; Meropenem; Vaborbactam; Antibiotics, Antitubercular; beta-Lactamase Inhibitors
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Masking description: Blinded adjudication committee
Enrollment: 77.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      Vabomere™, (meropenem-vaborbactam) is being compared to the Best Available Therapy in the
      treatment of adults with selected serious infections due to Carbapenem Resistant
      Enterobacteriaceae
    

Eligibility criteria:

        -  Inclusion Criteria:

               1. Willingness to comply with all study activities and procedures and to provide
                  signed, written informed consent prior to any study procedures. If a subject is
                  unable to provide informed consent due to their medical condition, the subject's
                  legal representative will be provided with study information in order for consent
                  to be obtained.

               2. Hospitalized male or female, ≥18 years of age.

               3. Weight ≤185 kg.

               4. Have a confirmed diagnosis of a serious infection, specifically cUTI or AP, cIAI,
                  HABP, VABP, and/or bacteremia, requiring administration of IV antibacterial
                  therapy.

               5. Have a known or suspected Carbapenem-Resistant Enterobacteriaceae (CRE)
                  infection.

               6. Expectation, in the opinion of the Investigator, that the subject's infection
                  will require treatment with IV antibiotics for a minimum of 7 days.

               7. Expectation that subjects with an estimated creatinine clearance <10 ml/min
                  (Cockcroft-Gault) will receive hemodialysis at least 2 times per week.

               8. For cUTI & AP subjects only: 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.

                  For cIAI subjects only: • Expectation, in the judgment of the investigator, that
                  operative drainage/debridement/removal (including open laparotomy, percutaneous
                  drainage, or laparoscopic surgery) of any intra-abdominal collection or other
                  potential source of intra abdominal infection will be performed;

                  • Expectation that cultures from the aforementioned procedure (including open
                  laparotomy, percutaneous drainage, or laparoscopic surgery) will be sent for
                  microbiological evaluation, including gram stain, culture and susceptibility
                  testing, and Vabomere susceptibility testing.

               9. Female subjects of childbearing potential, including those who are less than 2
                  years post menopausal, must agree to, and comply with, using 2 highly effective
                  methods of birth control (i.e., condom plus spermicide, combined oral
                  contraceptive, implant, injectable, indwelling intrauterine device, sexual
                  abstinence, or a vasectomized partner) while participating in this study. In
                  addition, all women of childbearing potential must agree to continue to use 2
                  forms of birth control throughout the study and for at least 30 days after
                  administration of the last dose of study drug.

          -  Exclusion Criteria:

               1. History of any significant hypersensitivity or severe allergic reaction to any
                  beta-lactam antibiotics (e.g., cephalosporins, penicillins, carbapenems, or
                  monobactams).

               2. Known or suspected likely infection with New Delhi metallo- (NDM), Verona
                  integron-encoded metallo- (VIM), or IMP-metallo-beta-lactamases or oxacillinase-
                  (OXA)-beta-lactamases (i.e., Class B or Class D beta-lactamases).

               3. For subjects to be enrolled with the primary indication of cUTI or AP, any of the
                  following urologic conditions:

                    1. Likely to receive ongoing antibacterial drug prophylaxis after treatment of
                       cUTI (e.g., subjects with vesico-ureteral reflux);

                    2. Suspected or confirmed prostatitis;

                    3. Requirement for bladder irrigation with antibiotics or for antibiotics to be
                       administered directly via urinary catheter;

                    4. Previous or planned cystectomy or ileal loop surgery;

                    5. Uncomplicated urinary tract infection (for example, female subjects with
                       urinary frequency, urgency or pain or discomfort without systemic symptoms
                       or signs of infection);

                    6. Complete, permanent obstruction of the urinary tract;

                    7. Suspected or confirmed perinephric or renal corticomedullary abscess;

                    8. Polycystic kidney disease; or

                    9. Any recent history of trauma to the pelvis or urinary tract.

               4. For subjects to be enrolled with the primary indication of cIAI, any of the
                  following conditions:

                    1. Incomplete drainage of suspected or known intra-abdominal source;

                    2. Likely to receive ongoing antibacterial drug prophylaxis or chronic
                       suppressive therapy after intravenous treatment of cIAI;

                    3. Source of infection thought to be related to or involving a non-removable
                       prosthesis (e.g. intra-abdominal mesh) or implantable device, line (e.g.
                       peritoneal catheter) or stent (e.g. biliary stent);

                    4. Uncomplicated intra-abdominal infection, such as simple appendicitis, simple
                       cholecystitis or gangrenous cholecystitis without rupture;

                    5. Patients with infected necrotizing pancreatitis or pancreatic abscess;

                    6. Patients whose surgery will include staged abdominal repair or "open
                       abdomen" technique, or marsupialization (i.e. patients who undergo a
                       surgical procedure where fascial closure is performed are eligible. The skin
                       incision may be left open for purposes of wound management as long as
                       fascial closure is accomplished);

                    7. Patients in whom the intra-abdominal process is deemed not likely to be
                       infectious in origin (e.g. bowel obstruction, ischemic bowel without
                       perforation, traumatic bowel perforation within past 12 hours, perforated
                       gastroduodenal ulcer within 24 hours); or

                    8. Non-intra-abdominal infection (e.g. infection or abscess of the abdominal
                       wall without extension into the intra-abdominal cavity).

               5. For subjects to be enrolled with the primary indication of HABP or VABP, any of
                  the following conditions:

                    1. Diagnosis of ventilator-associated tracheobronchitis

                    2. Inability to obtain proper respiratory specimens for culture.

               6. For subjects to be enrolled with the indication of bacteremia unrelated to cUTI
                  or AP, cIAI, HABP, and VABP, any of the following:

                    1. Unverified CRE infection

                    2. Source of infection thought to be related to or involving a non-removable or
                       implantable device or line.

               7. Evidence of immediately life-threatening disease where in the opinion of the
                  Investigator, the subject is unlikely to survive more than 72 hours from
                  randomization.

               8. Acute Physiology and Chronic Health Evaluation (APACHE) II score >30.

               9. Known or suspected endocarditis, meningitis, intra-abdominal infection, or
                  osteomyelitis.

              10. Irremovable or implantable device or line thought to be the potential source of
                  infection.

              11. Evidence of significant hepatic, hematological, or immunologic disease or
                  dysfunction.

              12. Women who are pregnant or breastfeeding.

              13. Require the use of inhaled antibiotics.

              14. Participation in any study involving administration of an investigational agent
                  or device within 30 days prior to randomization into this study or previous
                  participation in the current study.

              15. Previous participation in a study of vaborbactam.

              16. Any condition that, in the opinion of the Investigator, would compromise the
                  safety of the subject or the quality of the data.