E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Complicated intra-abdominal infection |
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E.1.1.1 | Medical condition in easily understood language |
Complicated intra-abdominal infection |
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E.1.1.2 | Therapeutic area | Diseases [C] - Bacterial Infections and Mycoses [C01] |
MedDRA Classification |
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To compare the efficacy of sulopenem followed by sulopenem etzadroxil with probenecid versus ertapenem followed by ciprofloxacin and metronidazole or amoxicillin-clavulanate for treatment of complicated intra-abdominal infection in adults, on Day 28 (test of cure [TOC]) post randomization. |
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E.2.2 | Secondary objectives of the trial |
To compare the efficacy outcomes at other relevant time points as well as the safety profile of treatment with sulopenem followed by sulopenem etzadroxil plus probenecid versus ertapenem followed by ciprofloxacin and metronidazole or amoxicillin-clavulanate for treatment of complicated intra-abdominal infection in adults.
To assess the population PK profile of sulopenem when administered either intravenously or as the prodrug, sulopenem etzadroxil, co-administered with probenecid. |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
POPULATION PK SUBSTUDY
Date and Version: August 14, 2018 Amendment #1
This study will be conducted within the context of an ongoing Phase 3 sulopenem clinical trial in order to generate confirmatory data for the population PK profile of both the IV and oral pro-drug regimens of sulopenem. |
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E.3 | Principal inclusion criteria |
1. Patient 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 of 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:
a. Fever (defined as body temperature >38°C) or hypothermia with a core body temperature <35°C
b. Elevated white blood cell count (>12,000 cells/mm3) or leukopenia (defined as white blood cell count <4,000 cells/mm3)
c. Drop in blood pressure (systolic BP must be <90 mmHg without pressor support)
d. Increased heart rate (>90 bpm) and respiratory rate (>20 breaths/min)
e. 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:
a. Abdominal pain and/or tenderness, with or without rebound
b. Localized or diffuse abdominal wall rigidity
c. Abdominal mass
d. Nausea and/or vomiting
e. Altered Mental Status
6. Specimen/s from the surgical intervention were sent or planned to be sent for culture.
Microbiologic specimens collected during routine operative care prior to subject providing informed consent may be used for study purposes. |
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E.4 | Principal 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 non-susceptible to the study antimicrobial agents.
6. Patient needed effective concomitant systemic antibacterials or antifungals in addition to those designated in the 2 study groups, except vancomycin, linezolid, or daptomycin if started for known or suspected MRSA or Enterococcus spp.
7. Patient has perinephric infections or an indwelling peritoneal dialysis catheter.
8. Patient has suspected intra-abdominal infections due to fungus, parasites, virus, or tuberculosis.
9. Patient with known history of serious allergy, hypersensitivity or any serious reaction to carbapenem antibiotics, other β-lactam antibiotics, quinolones, metronidazole, or probenecid, as formulated with their excipients.
10. Patient is known to have a history of any of the following laboratory abnormalities
a.Hematocrit <25% or hemoglobin <8 g/dL
b. Absolute neutrophil count <1000/mm3
c. Platelet count <75,000/mm3
d. Bilirubin >3 x the ULN, unless isolated hyperbilirubinemia was directly related to the acute infection or known Gilbert’s disease
e. ALT or 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
f. 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.
11. Patient has a body mass index >45 kg/m2.
12. Patient has APACHE II score >30 (serum bicarbonate may be used in place of arterial blood gases).
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 7-10 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 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 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 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
16. Patient has concurrent infection that interfere with the evaluation of response to the study antibiotic.
17. Patient receiving hemodialysis, hemofiltration, or peritoneal dialysis.
18. Patient has 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:
a. HIV infection, with either a recent (in the past 6 months) acquired immune deficiency syndrome-defining condition or a CD4 + T lymphocyte count <200/mm3
b. 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
c. Immunosuppressive therapy, including maintenance corticosteroid therapy (>40 mg/day equivalent prednisolone for 5 days or more).
21. Patient has known inflammatory bowel disease (ulcerative colitis or Crohn’s disease) or Clostridium difficile-associated diarrhea.
22. Patients with history of blood dyscrasias |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary outcome measure for efficacy evaluation on Day 28 will be the resolution of the symptoms of cIAI present at trial entry.
A patient’s outcome will be programmatically defined as a clinical cure if the following criteria are met:
• Patient is alive
• Resolution of baseline signs and symptoms of the index infection
o No new symptoms
• No new antibiotics or interventions for treatment failure are required
Clinical failure, defined as:
• death due to cIAI
• Surgical site wound infection requiring non-study systemic antibiotic therapy
• Unplanned surgical procedures or percutaneous drainage procedures for complication or recurrence of cIAI based on documented worsening symptoms or signs of cIAI
• Initiation of non-trial antibacterial drug therapy for treatment of cIAI based on documented worsening symptoms or signs of cIAI
If data are unavailable to determine if the patient is a cure or a failure, the patient outcome will be considered an indeterminate response.
For the primary efficacy evaluation, the proportions of patients achieving cure, failure or indeterminate will be determined in the microbiologic-modified intent to treat population (m-MITT). The m-MITT population will comprised of all randomized patients who received at least one dose of study drug and had a baseline pathogen causing cIAI isolated from a culture specimen taken at baseline, prior to initiation of study drug therapy. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
The primary outcome measure for efficacy evaluation on Day 28 |
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E.5.2 | Secondary end point(s) |
Same clinical endpoint as the primary endpoint but at EOT instead of TOC/day 28. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 32 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Bulgaria |
Czech Republic |
Estonia |
Georgia |
Hungary |
Latvia |
Poland |
Russian Federation |
Serbia |
Ukraine |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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LVLS |
Poslední návštěva posledního subjektu hodnocení. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 1 |