| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Complicated Intraabdominal Infections |
|
| E.1.1.1 | Medical condition in easily understood language |
| Intraabdominal infections in complicated conditions like Peritonitis |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Bacterial Infections and Mycoses [C01] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10056570 |
| E.1.2 | Term | Intra-abdominal infection |
| E.1.2 | System Organ Class | 10021881 - Infections and infestations |
|
| 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 demonstrate the non-inferiority of CXA-201 and metronidazole vs. meropenem in adult subjects with complicated intraabdominal infection (cIAI) based on the 95% confidence interval (CI) around the difference in clinical cure rates at the TOC visit (26 to 30 days after the initiation of study drug administration) in the microbiological intent-to-treat (MITT) population. |
|
| E.2.2 | Secondary objectives of the trial |
• To demonstrate the non-inferiority of CXA-201 and metronidazole vs. meropenem in adult subjects with cIAI based on the 95% CI around the difference in clinical cure rates at the TOC visit (26 to 30 days after the initiation of study drug administration) in the microbiologically evaluable (ME) population .
• To compare the clinical response of CXA-201 and metronidazole to that of meropenem at the TOC visit in the clinically evaluable (CE) population.
• To compare the microbiological response of CXA-201 and metronidazole to that of meropenem at the TOC visit.
• To compare the clinical and microbiological responses of CXA-201 and metronidazole versus meropenem at the EOT (within 24 hours of last dose of treatment) and LFU visit (38-45 days post
first dose of study drug)
• To evaluate the safety and tolerability of CXA-201 in adult subjects with cIAI. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Provide written informed consent prior to any study-related procedure not part of normal medical care (2. Be males or females ≥ 18 years of age.
3. If female, subject is non-lactating, and is either:
a. Not of childbearing potential, defined as postmenopausal for at least 1 year or surgically sterile due to bilateral tubal ligation, bilateral oophorectomy, or hysterectomy; or
b. Of childbearing potential and is practicing a barrier method of birth control (e.g., a diaphragm or contraceptive sponge) along with 1 of the following methods: oral or parenteral contraceptives (for 3 months prior to study drug administration), or a vasectomized partner. Or practice these methods for the duration of the trial and for at least 35 days after last dose of study medication.
4. Males are required to practice reliable birth control methods (condom or other barrier device) during the conduct of the study and for at least 35 days after last dose of study medication.
5. One of the following diagnoses (in which there is evidence of intraperitoneal infection) including:
a. Cholecystitis (including gangrenous cholecystitis) with rupture, perforation, or progression of the infection beyond the gallbladder wall;
b. Diverticular disease with perforation or abscess;
c. Appendiceal perforation or periappendiceal abscess;
d. Acute gastric or duodenal perforation, only if operated on > 24 hours after perforation occurs;
e. Traumatic perforation of the intestine, only if operated on > 12 hours after perforation occurs;
f. Peritonitis due to other perforated viscus or following a prior operative procedure;
i. Subjects with inflammatory bowel disease or ischemic bowel disease are eligible provided there is bowel perforation.
g. Intraabdominal abscess (including liver or spleen).
6. Subject requires surgical intervention (e.g., laparotomy, laparoscopic surgery, or percutaneous draining of an abscess) within 24 hours of (before or after) the first dose of study drug.
7. If subject is to be enrolled preoperatively, the subject should have radiographic evidence of bowel perforation or intraabdominal abscess.
8. Subjects who failed prior antibacterial treatment for the current cIAI can be enrolled but must: (a) have a positive culture (from an intraabdominal site) and (b) require surgical intervention. Such
subjects can be enrolled before the results of the culture are known; however, if the culture is negative, study drug administration must be discontinued.
9. Willing and able to comply with all study procedures and restrictions. |
|
| E.4 | Principal exclusion criteria |
1. Diagnosis of abdominal wall abscess; small bowel obstruction or ischemic bowel disease without perforation.
2. Simple appendicitis; acute suppurative cholangitis; infected necrotizing pancreatitis; pancreatic abscess; or pelvic infections.
3. Spontaneous [primary] bacterial peritonitis associated with cirrhosis and chronic ascites.
4. Complicated intraabdominal infection managed by staged abdominal repair (STAR), open abdomen technique including temporary closure of the abdomen, or any situation where infection source control is not likely to be achieved.
5. Known prior to randomization to have an IAI or postoperative infection caused by pathogen(s) resistant to meropenem.
6. Use of systemic antibiotic therapy for IAI for more than 24 hours prior to the first dose of study drug, unless there is a documented treatment failure with such therapy.
7. More than one dose of an active non-study antibacterial regimen given postoperatively. For subjects enrolled preoperatively, no postoperative non-study antibacterial therapy is allowed.
8. Subjects who previously received imipenem, meropenem, doripenem or cefepime for the current intraabdominal infection.
9. Have a concomitant infection at the time of randomization, which requires non-study systemic antibacterial therapy in addition to IV study drug therapy. (Drugs with only gram-positive activity [e.g., daptomycin, vancomycin, linezolid] are allowed).
10. Severe impairment of renal function (estimated creatinine clearance [CrCl] < 30 mL/min), or requirement for peritoneal dialysis, hemodialysis or hemofiltration, or oliguria (< 20 mL/h urine output over 24 hours).
11. The presence of hepatic disease at baseline as defined by any of the following:
a. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 4 x upper limit of normal (ULN)
b. Total bilirubin > 2 x ULN, unrelated to cholecystitis
c. Alkaline phosphatase > 4 x ULN. Subjects with a value > 4 x ULN and < 5 x ULN are eligible if this value is historically stable
d. Acute or chronic hepatitis, cirrhosis, acute hepatic failure, acute decompensation of chronic hepatic failure.
12. Hematocrit < 25% or hemoglobin < 8 gm/dL.
13. Neutropenia with absolute neutrophil count < 1000 /mm3.
14. Platelet count < 75,000 /mm3. Subjects with a platelet count as low as 50,000 /mm3 are permitted if the reduction is historically stable.
15. Considered unlikely to survive the 4- to 5-week study period.
16. Any rapidly-progressing disease or immediately life-threatening illness (including respiratory failure and septic shock).
17. Immunocompromising condition, including established Acquired Immune Deficiency Syndrome (AIDS), hematological malignancy, or bone marrow transplantation, or immunosuppressive therapy including cancer chemotherapy, medications for prevention of organ transplantation rejection, or the administration of corticosteroids equivalent to or greater than 40 mg of prednisone per day administered continuously for more than 14 days preceding randomization.
18. Have a documented history of any moderate or severe hypersensitivity or allergic reaction to any β-lactam antibacterial (a history of a mild rash followed by uneventful re-exposure is not a
contraindication to enrollment), including cephalosporins, carbapenems, penicillins, or ß-lactamase inhibitors, or metronidazole, or nitroimidazole derivatives.
19. Any condition or circumstance that, in the opinion of the Investigator, would compromise the safety of the subject or the quality of study data.
20. Participation in any clinical study of an investigational product within days prior to the proposed first day of study drug.
21. Previous participation in any study of CXA-101 or CXA-201.
22. Subjects who have received disulfiram in the past 14 days or who are currently receiving probenecid.
23. Women who are pregnant or nursing. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Clinical cure rate at the TOC visit in the primary MITT population. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The primary statistical goal of this study is to establish non-inferiority of CXA-201 plus metronidazole to meropenem with respect to proportion of subjects in the MITT primary analysis population who achieve clinical cure at TOC visit. A 95% CI (normal approximation to the binomial distribution) around the difference in clinical cure rate (CXA-201 minus meropenem) will be calculated. CXA-201 plus metronidazole will be considered non-inferior to meropenem if the lower limit of the 95% CI if the difference in cure rate (CXA-201 minus meropenem) at TOC among subjects in the MITT population is greater than minus 12.5%. |
|
| E.5.2 | Secondary end point(s) |
Additional secondary goals are to compare CXA-201 plus metronidazole to meropenem with respect to following end points:
(1) clinical cure rate at TOC in the CE population,
(2) microbiological eradication rate (per-subject) at TOC in the ME population,
(3) perpathogen microbiological eradication rate at TOC in the ME population, and
(4) proportion of subjects with superinfections or new infections in the MITT population. A 95% CI will be obtained for the difference in rates between CXA-201 and meropenem. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
For the secondary statistical goal, a 95% CI will also be obtained for the difference in the clinical cure rate at TOC in the ME population. CXA-201 plus metronidazole will be considered non-inferior to meropenem if the lower limit of the 95% CI if the difference in cure rate (CXA-201 minus meropenem) at TOC among subjects in the ME population is greater than minus 12.5%.
|
|
| 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 | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| 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 | No |
| 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 | No |
| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 41 |
| 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 |
| Australia |
| Brazil |
| Georgia |
| Mexico |
| Peru |
| Romania |
| Russian Federation |
| South Africa |
| Spain |
| Ukraine |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | No |
| 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
|
| The study will be stopped when the last subject completes the study or when the last ongoing subject has discontinued treatment, whichever occurs first. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 0 |
| E.8.9.1 | In the Member State concerned months | 20 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 20 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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