Determine the PK and Safety and Tolerability of ATM-AVI for the Treatment of cIAIs in Hospitalized Adults (REJUVENATE)

A PHASE IIA PROSPECTIVE, OPEN-LABEL, MULTICENTER STUDY TO DETERMINE THE PHARMACOKINETICS (PK) AND SAFETY AND TOLERABILITY OF AZTREONAM-AVIBACTAM (ATM-AVI) FOR THE TREATMENT OF COMPLICATED INTRA-ABDOMINAL INFECTIONS (CIAIS) IN HOSPITALIZED ADULTS

Determine the PK and safety and tolerability of aztreonam-avibactam (ATM-AVI) in the treatment of hospitalized adults with cIAI

A Phase IIa prospective, open-label, multicenter study to determine the pharmacokinetics (PK) and safety and tolerability of aztreonam-avibactam (ATM-AVI) for the treatment of complicated Intra-Abdominal Infections (cIAIs) in hospitalized adults.

Inclusion Criteria:

1. Provision of informed consent

2. Male or female from 18 to 90 years

3. Female patients are authorized to participate in this clinical study if criteria concerning pregnancy avoidance stated in the protocol are met

4. Diagnosis of cIAI

   EITHER:

   Intra-operative/postoperative enrolment with visual confirmation of cIAI. OR Preoperative enrollment with evidence of systemic inflammatory response, physical and radiological findings consistent with cIAI; confirmation of cIAI at time of surgery within 24 hours of study entry

5. Patients who failed prior antibacterial treatment for their current cIAI can be enrolled but must:

   • Have a known or suspected pathogen causing cIAI that is resistant to the prior therapy
   • Require surgical intervention.

6. Patient must have or will have a surgical intervention within 24 hours (before or after) the administration of the first dose of study drug

Exclusion criteria:

1. Involvement in the planning and/or conduct of the study

2. Patient has been previously enrolled in this study, previously treated with ATM-AVI or previously participated in an investigational study containing AVI

3. Patient has participated or intends to participate in any other clinical study that involves the administration of a study drug during the course of the study, or during the 30 days prior to study start.

4. History of serious allergy, hypersensitivity (eg, anaphylaxis), or any serious reaction to aztreonam, carbapenem,monobactam or other β-lactam antibiotics, avibactam, nitroimidazoles or metronidazole, or any of the excipients of the study drugs

5. Diagnosis of abdominal wall abscess; small bowel obstruction or ischemic bowel disease without perforation; traumatic bowel perforation with surgery within 12 hours of diagnosis; perforation of gastroduodenal ulcer with surgery within 24 hours of diagnosis primary etiology is not likely to be infectious

6. Simple cholecystitis, gangrenous cholecystitis without rupture, simple appendicitis, acute suppurative cholangitis, infected necrotizing pancreatitis, pancreatic abscess or ischaemic/necrotic intestine without perforation

7. Staged abdominal repair (STAR), open abdomen technique or where infection source control is not likely to be achieved; unlikely to solely respond to antimicrobial therapy

8. Infection due to a pathogen that is unlikely to respond to ATM-AVI plus metronidazole

9. Rapidly progressive or terminal illness

10. Systemic antibacterial agents received within the 72- hour period prior to study entry, unless:

    1. A new infection and no more than 24 hours of prior antibiotic treatment received within the 72 hour period prior to study entry or
    2. Patient is considered to have failed the previous treatment

11. Concurrent infection that may interfere with the evaluation of clinical cure for the study therapy

12. requirement for effective concomitant systemic antibacterials or antifungals

13. Creatinine clearance ≤30 ml/min or requirement for renal replacement therapy

14. Acute hepatitis in the prior 6 months, chronic hepatitis, cirrhosis, acute hepatic failure, or acute decompensation of chronic hepatic failure

15. Hepatic disease as indicated by AST or ALT >3 × ULN. Patients with AST and/or ALT >3 × ULN and < 5 × ULN are eligible if acute, not accompanied by a total bilirubin ≥ 2xULN and documented by the investigator as being directly related to cIAI.

16. Patient has a total bilirubin >3 × ULN, unless isolated hyperbilirubinemia is directly related to cIAI or due to known Gilbert's disease

17. ALP >3 × ULN. Patients with values >3 × ULN and <5 x ULN are eligible if acute and directly related to the infectious process being treated.

18. Immunocompromising illness

19. Active Clostridium difficile associated diarrhoea

20. Any other condition that may confound the results of the study or pose additional risks

21. Do not resuscitate order

22. Absolute neutrophil count <1000/μL

23. Hematocrit <25% or hemoglobin <8 gm/dL.

24. Platelet count <75,000/μL.

25. Currently receiving probenecid.

26. Pregnant or breastfeeding or if of child bearing potential, not using a medically accepted effective method of birth control.

27. Unlikely to comply with protocol,

28. Currently receiving anti-convulsant therapy to prevent recurrence of a past history of seizures.

29. Prior liver, pancreas or small-bowel transplant.