Sulopenem Versus Ertapenem for Complicated Intra-abdominal Infection (cIAI)
Condition: Intra Abdominal Infections
MeSH terms: Infections; Intraabdominal Infections
Intervention: Ertapenem; Sulopenem-Etzadroxil/Probenecid; Ciprofloxacin; Metronidazole; Amoxicillin-Clavulanate; Sulopenem
Intervention description: Antibiotic for complicated intra-abdominal infection; Antibiotic for complicated intra-abdominal infection; Antibiotic for complicated intra-abdominal infection; Antibiotic for complicated intra-abdominal infection; Antibiotic for complicated intra-abdominal infection; Antibiotic for complicated intra-abdominal infection
Intervention MeSH terms: Amoxicillin; Metronidazole; Ciprofloxacin; Clavulanic Acid; Clavulanic Acids; Amoxicillin-Potassium Clavulanate Combination; Ertapenem; Lactams; Probenecid
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 674.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      This is a prospective, Phase 3, randomized, multi-center, double-blind study of the efficacy,
      tolerability and safety of sulopenem followed by sulopenem-etzadroxil/probenecid versus
      ertapenem followed by ciprofloxacin-metronidazole for treatment of complicated
      intra-abdominal infections in adults.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Patient or the patient's legally acceptable representative able to provide a signed
             written informed consent prior to any study-specific procedures.

          2. Adult patients ≥18 years of age

          3. EITHER:

             a. Intra-operative/post-operative enrollment with visual confirmation (presence of pus
             within the abdominal cavity) of an intra-abdominal infection associated with
             peritonitis including at least 1 of the following diagnosed during the surgical
             intervention: i. Cholecystitis with gangrenous rupture or perforation or progression
             of the infection beyond the gallbladder wall ii. Diverticular disease with perforation
             or abscess iii. Appendiceal perforation or peri-appendiceal abscess iv. Traumatic
             perforation of the intestines, only if operated on >12 hours after perforation occurs
             v. Secondary peritonitis (but not spontaneous bacterial peritonitis associated with
             cirrhosis and chronic ascites) vi. Intra-abdominal abscess (including of liver or
             spleen provided that there was extension beyond the organ with evidence of
             intraperitoneal involvement).

             OR:

             b. Pre-operative enrollment where one of the following surgical procedures are planned
             within 24 hours prior to the first dose of study drug: i. Open laparotomy,
             percutaneous drainage of an intra-abdominal abscess, or laparoscopic surgery.

          4. Evidence of systemic inflammatory indicators, with at least one of the following:

             i. Fever (defined as body temperature >38°C) or hypothermia with a core body
             temperature <35°C ii. Elevated white blood cell count (>12,000 cells/mm3) iii. Drop in
             blood pressure (systolic BP must be <90 mmHg without pressor support) iv. Increased
             heart rate (>90 bpm) and respiratory rate (>20 breaths/min) v. Hypoxia (oxygen
             saturation ≤90 percent on room air)

          5. Physical findings or symptoms consistent with intra-abdominal infection, with at least
             one of the following:

             i. Abdominal pain and/or tenderness, with or without rebound ii. Localized or diffuse
             abdominal wall rigidity iii. Abdominal mass iv. Nausea/vomiting v. Altered Mental
             Status

          6. Specimen/s from the surgical intervention were sent for culture.

        Exclusion Criteria:

          1. Patient diagnosed with traumatic bowel perforation undergoing surgery within 12 hours;
             perforation of gastroduodenal ulcers undergoing surgery within 24 hours. Other
             intra-abdominal processes in which the primary etiology was not likely to be
             infectious.

          2. Patient has abdominal wall abscess or bowel obstruction without perforation or
             ischemic bowel without perforation.

          3. Patient has simple cholecystitis or gangrenous cholecystitis without rupture, or
             simple appendicitis, or acute suppurative cholangitis; or infected necrotizing
             pancreatitis or pancreatic abscess.

          4. Patient whose surgery included staged abdominal repair, or "open abdomen" technique,
             or marsupialization.

          5. Patient known at study entry to have a complicated intra-abdominal infection caused by
             pathogens resistant to the study antimicrobial agents.

          6. Patient needed effective concomitant systemic antibacterials (oral, IV, or
             intramuscular) or antifungals in addition to those designated in the 2 study groups,
             except vancomycin, linezolid, or daptomycin if started for known or suspected
             methicillin-resistant Staphylococcus aureus (MRSA) or Enterococcus spp. as per
             clinical study protocol (CSP).

          7. Patient has perinephric infections or an indwelling peritoneal dialysis catheter.

          8. Patient has suspected intra-abdominal infections due to fungus, parasites (e.g.,
             amoebic liver abscess), virus, or tuberculosis.

          9. Patient has a known history of serious allergy, hypersensitivity or any serious
             reaction to carbapenem antibiotics, or to other β-lactam antibiotics

         10. Patient known to have any of the following laboratory values as defined below:

               1. Hematocrit <25% or hemoglobin <8 g/dL

               2. Absolute neutrophil count <1000/mm3

               3. Platelet count <75,000/mm3

               4. Bilirubin >3 x the upper limit of normal (ULN), unless isolated
                  hyperbilirubinemia was directly related to the acute infection or known Gilbert's
                  disease

               5. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >3 x ULN
                  values at Screening. Patients with elevations of AST and/or ALT up to 5 x ULN
                  will be eligible if these elevations are acute and directly related to the
                  infectious process being treated. This must be documented

               6. Alkaline phosphatase (ALP) >3 x ULN. Patients with values >3.0 x ULN and <5.0 x
                  ULN are eligible if this value is acute and directly related to the infectious
                  process being treated. This must be documented.

               7. Estimated creeatinine clearance <50 mL/min

         11. Patient has a body mass index >45 kg/m2.

         12. Patient has APACHE II score >30.

         13. Patient considered unlikely to survive the 4-week study period or has a rapidly
             progressive or terminal illness, including septic shock that was associated with a
             high risk of mortality.

         14. Patient unlikely to respond to 10-14 days of treatment with antibiotics.

         15. Patient received systemic antibacterial agents within the 72-hour period prior to
             study entry, unless either of the following pertained:

             a. Patient has a new infection (not considered a treatment failure) and both of the
             following were met: i. Patient received no more than 24 hours of total prior
             antibiotic therapy ii. Patient received ≤1 dose of a treatment regimen
             post-operatively and antibiotics were not received more than 6 hours post-procedure.

             b. Patient considered to have failed the previous treatment regimen i.e.,
             pre-operative treatment of any duration with non-study systemic antimicrobial therapy
             for peritonitis or abscess permitted provided that all of the following are met: i.
             The treatment regimen had been administered for at least 72 hours and was judged to
             have been inadequate ii. The patient had an operative intervention that was just
             completed or was intended no more than 24 hours after study entry iii. Findings of
             infection were documented at surgery iv. Specimens for bacterial cultures and
             susceptibility testing were taken at operative intervention v. No further non-study
             antibacterials were administered after randomization.

         16. Patient has a concurrent infection that may interfere with the evaluation of response
             to the study antibiotic.

         17. Patient receiving hemodialysis or peritoneal dialysis.

         18. Patient has a history of acute hepatitis in the recent past (3 months prior to study
             entry), chronic hepatitis, cirrhosis, acute hepatic failure, or acute decompensation
             of chronic hepatic failure.

         19. Patient has past or current history of epilepsy or seizure disorders excluding febrile
             seizures of childhood.

         20. Patient immunocompromised as evidenced by any of the following:

               1. Human immunodeficiency virus infection, with either a recent (in the past 6
                  months) acquired immune deficiency syndrome-defining condition or a CD4 + T
                  lymphocyte count <200/mm3

               2. Systemic or hematological malignancy requiring chemotherapeutic or
                  radiologic/immunologic interventions within 6 weeks prior to randomization, or
                  anticipated to begin prior to completion of study

               3. Immunosuppressive therapy, including maintenance corticosteroid therapy (>40
                  mg/day equivalent prednisolone) for 5 days or more.

         21. Patient participating in any other clinical study that involved the administration of
             an investigational medication at the time of presentation, during the course of the
             study, or who had received treatment with an investigational medication in the 30 days
             prior to study enrollment, or had previously been enrolled in this study or had been
             treated with sulopenem.

         22. Patient is in a situation or has a condition that, in the investigator's opinion, may
             interfere with optimal participation in the study.

         23. Patient unlikely to comply with protocol e.g., uncooperative attitude, inability to
             return for follow-up visits, and unlikely to complete the study.

         24. Patient has known inflammatory bowel disease (ulcerative colitis or Crohn's disease)
             or Clostridium difficile-associated diarrhea.

         25. Patients with a history of blood dyscrasias

         26. Patients with a history of uric acid kidney stones

         27. Patients with acute gouty attack

         28. Patients on chronic methotrexate therapy

         29. Females of child-bearing potential who are unable to take adequate contraceptive
             precautions, have a positive pregnancy test result within 24 hours of study entry, are
             otherwise known to be pregnant, or are currently breastfeeding an infant.

         30. Male subjects who do not agree to use an effective barrier method of contraception
             during the study and for 14 days post treatment.