Efficacy, Safety, Tolerability of Vabomere Compared to Best Available Therapy in Treating Serious Infections in Adults

In the current era of increased resistance to extended spectrum cephalosporins and penicillin/beta-lactamase inhibitor combinations, carbapenem antimicrobial agents are frequently the antibiotics of "last defense" for the most resistant pathogens in serious infections. However, the recent dissemination of serine carbapenemases (e.g. KPC) in Enterobacteriaceae within many hospitals worldwide now poses a considerable threat to carbapenems and other members of the beta-lactam class of antimicrobial agents.

Infections caused by Carbapenem-Resistant Enterobacteriaceae (CRE) are associated with high mortality rates and have limited treatment options. The loss of the carbapenem class of antimicrobial agents for treatment of Enterobacteriaceae (the most frequently occurring pathogens in the hospital setting), Acinetobacter baumannii, and Pseudomonas aeruginosa represents a critical setback in modern patient care.

As a result of the current lack of an optimal treatment for patients who have infections due to a CRE, physicians manage these patients with the limited anti-infective options available, including aminoglycosides, polymyxin B, colistin, tigecycline, or various combinations of these. There are limited efficacy data available for many of these therapies when used to treat serious CRE infections, particularly in combination, but with limited or no alternative therapies currently available, such treatments have become the Best Available Therapy despite the toxicities associated with many of them.

Vaborbactam is a novel beta-lactamase inhibitor that has inhibitory activity against many serine beta-lactamases and was optimized for inhibition of the KPC beta-lactamase and the potentiation of carbapenems against Enterobacteriaceae. Vaborbactam is being developed for use with meropenem (a broad spectrum injectable carbapenem antibiotic) to address the challenges of treatment of serious infections caused by pathogens increasingly resistant to available treatments.

Vabomere, (meropenem-vaborbactam) administered as a fixed combination by intravenous (IV) infusion, is being developed to treat serious gram-negative infections, such as complicated urinary tract infections (cUTI), acute pyelonephritis (AP), hospital-acquired bacterial pneumonia (HABP), ventilator-associated bacterial pneumonia (VABP), and bacteremia, including those infections caused by bacteria resistant to currently available carbapenems.

• Inclusion Criteria:

• 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.
• Hospitalized male or female, ≥18 years of age.
• Weight ≤185 kg.
• Have a confirmed diagnosis of a serious infection, specifically cUTI or AP, cIAI, HABP, VABP, and/or bacteremia, requiring administration of IV antibacterial therapy.
• Have a known or suspected Carbapenem-Resistant Enterobacteriaceae (CRE) infection.
• Expectation, in the opinion of the Investigator, that the subject's infection will require treatment with IV antibiotics for a minimum of 7 days.
• Expectation that subjects with an estimated creatinine clearance <10 ml/min (Cockcroft-Gault) will receive hemodialysis at least 2 times per week.
• 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.
• 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:

• History of any significant hypersensitivity or severe allergic reaction to any beta-lactam antibiotics (e.g., cephalosporins, penicillins, carbapenems, or monobactams).
• 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).
• For subjects to be enrolled with the primary indication of cUTI or AP, any of the following urologic conditions:

• Likely to receive ongoing antibacterial drug prophylaxis after treatment of cUTI (e.g., subjects with vesico-ureteral reflux);
• Suspected or confirmed prostatitis;
• Requirement for bladder irrigation with antibiotics or for antibiotics to be administered directly via urinary catheter;
• Previous or planned cystectomy or ileal loop surgery;
• Uncomplicated urinary tract infection (for example, female subjects with urinary frequency, urgency or pain or discomfort without systemic symptoms or signs of infection);
• Complete, permanent obstruction of the urinary tract;
• Suspected or confirmed perinephric or renal corticomedullary abscess;
• Polycystic kidney disease; or
• Any recent history of trauma to the pelvis or urinary tract.
• For subjects to be enrolled with the primary indication of cIAI, any of the following conditions:

• Incomplete drainage of suspected or known intra-abdominal source;
• Likely to receive ongoing antibacterial drug prophylaxis or chronic suppressive therapy after intravenous treatment of cIAI;
• 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);
• Uncomplicated intra-abdominal infection, such as simple appendicitis, simple cholecystitis or gangrenous cholecystitis without rupture;
• Patients with infected necrotizing pancreatitis or pancreatic abscess;
• 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);
• 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
• Non-intra-abdominal infection (e.g. infection or abscess of the abdominal wall without extension into the intra-abdominal cavity).
• For subjects to be enrolled with the primary indication of HABP or VABP, any of the following conditions:

• Diagnosis of ventilator-associated tracheobronchitis
• Inability to obtain proper respiratory specimens for culture.
• For subjects to be enrolled with the indication of bacteremia unrelated to cUTI or AP, cIAI, HABP, and VABP, any of the following:

• Unverified CRE infection
• Source of infection thought to be related to or involving a non-removable or implantable device or line.
• 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.
• Acute Physiology and Chronic Health Evaluation (APACHE) II score >30.
• Known or suspected endocarditis, meningitis, intra-abdominal infection, or osteomyelitis.
• Irremovable or implantable device or line thought to be the potential source of infection.
• Evidence of significant hepatic, hematological, or immunologic disease or dysfunction.
• Women who are pregnant or breastfeeding.
• Require the use of inhaled antibiotics.
• 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.
• Previous participation in a study of vaborbactam.
• Any condition that, in the opinion of the Investigator, would compromise the safety of the subject or the quality of the data.