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Sulopenem Versus Ertapenem for Complicated Intra-abdominal Infection (cIAI)

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ClinicalTrials.gov Identifier: NCT03358576
Recruitment Status : Recruiting
First Posted : November 30, 2017
Last Update Posted : October 3, 2018
Sponsor:
Information provided by (Responsible Party):
Iterum Therapeutics, US Limited

Brief 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.

Condition or disease Intervention/treatment Phase
Intra Abdominal Infections Drug: Ertapenem Drug: Sulopenem-Etzadroxil/Probenecid Drug: Ciprofloxacin Drug: Metronidazole Drug: Amoxicillin-Clavulanate Drug: Sulopenem Phase 3

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 670 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Prospective, Phase 3, Randomized, Multi-center, Double-blind Study of Efiicacy, Tolerability & Safety of Sulopenem & Sulopenem-etzadroxil/Probenecid vs Ertapenem Followed by Cipro-metronidazole for Treatment of cIAI in Adults
Actual Study Start Date : September 18, 2018
Estimated Primary Completion Date : October 2019
Estimated Study Completion Date : December 2019

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Sulopenem
Sulopenem 1000 mg IV once daily for at least 5 days, followed by Sulopenem-Etzadroxil/Probenecid 500 mg PO twice daily to complete 7-10 days of treatment
Drug: Sulopenem-Etzadroxil/Probenecid
Antibiotic for complicated intra-abdominal infection

Drug: Sulopenem
Antibiotic for complicated intra-abdominal infection

Active Comparator: Ertapenem
Ertapenem 1000 mg IV once daily for at least 5 days, followed by ciprofloxacin 500 mg PO twice daily along with metronidazole 500 mg PO four times daily. If patient is found to have causative pathogens that are resistant to ciprofloxacin they will receive amoxicillin-clavulanate 875 mg PO twice daily instead
Drug: Ertapenem
Antibiotic for complicated intra-abdominal infection
Other Name: Invanz

Drug: Ciprofloxacin
Antibiotic for complicated intra-abdominal infection
Other Name: Cipro

Drug: Metronidazole
Antibiotic for complicated intra-abdominal infection
Other Name: Flagyl

Drug: Amoxicillin-Clavulanate
Antibiotic for complicated intra-abdominal infection
Other Name: Augmentin




Primary Outcome Measures :
  1. Clinical response in each treatment group in the micro-MITT population [ Time Frame: Day 28 +/- 1 day ]
    Clinical response is defined as resolution in signs and symptoms of the index infection and no new symptoms, without the need for additional antibiotics or interventions


Secondary Outcome Measures :
  1. Clinical response in each treatment group at the end of therapy in the micro-MITT population [ Time Frame: Day 11-14 +/- 1 day ]
    Clinical response is defined as resolution in signs and symptoms of the index infection and no new symptoms, without the need for additional antibiotics or interventions



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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 6- to 8-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 5-14 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, 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 current acquired immune deficiency syndrome-defining condition or a CD4 + T lymphocyte count <200/mm3 at the time of study entry
    2. Metastatic or hematological malignancy requiring chemotherapeutic interventions within 6 weeks prior to randomization
    3. Immunosuppressive therapy, including maintenance corticosteroid therapy (>40 mg/day equivalent prednisolone).
  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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03358576


Contacts
Contact: Steven Aronin 8606614035 saronin@iterumtx.com

Locations
United States, Idaho
Medical Facility Recruiting
Idaho Falls, Idaho, United States, 83404
United States, Montana
Medical Facility Recruiting
Butte, Montana, United States, 59701
Sponsors and Collaborators
Iterum Therapeutics, US Limited

Responsible Party: Iterum Therapeutics, US Limited
ClinicalTrials.gov Identifier: NCT03358576     History of Changes
Other Study ID Numbers: IT001-303
First Posted: November 30, 2017    Key Record Dates
Last Update Posted: October 3, 2018
Last Verified: September 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
Infection
Intraabdominal Infections
Amoxicillin
Ciprofloxacin
Clavulanic Acid
Clavulanic Acids
Ertapenem
Amoxicillin-Potassium Clavulanate Combination
Lactams
Metronidazole
Probenecid
Anti-Bacterial Agents
Anti-Infective Agents
Antiprotozoal Agents
Antiparasitic Agents
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Cytochrome P-450 CYP1A2 Inhibitors
Cytochrome P-450 Enzyme Inhibitors
beta-Lactamase Inhibitors
Uricosuric Agents
Gout Suppressants
Antirheumatic Agents
Renal Agents