| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Complicated intra-abdominal infection (cIAI) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Complicated intra-abdominal infection (cIAI) |
|
| 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 | 20.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10056570 |
| E.1.2 | Term | Intra-abdominal infection |
| E.1.2 | System Organ Class | 100000004862 |
|
| 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 evaluate the safety and tolerability of ceftolozane/tazobactam plus metronidazole compared with that of meropenem |
|
| E.2.2 | Secondary objectives of the trial |
1. To evaluate the efficacy of ceftolozane/tazobactam plus metronidazole compared with that of meropenem with respect to clinical response at the EOT and TOC Visits
2. To evaluate the efficacy of ceftolozane/tazobactam plus metronidazole compared with that of meropenem with respect to per-subject microbiological response at the EOT and TOC Visits |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Have a legal representative who provides written informed consent for the trial on the subject’s behalf and provides age-appropriate written informed assent (as applicable) for the trial
2. Be a male or female from birth (defined as >32 weeks gestational age and ≥7 days postnatal) to <18 years of age
3. Be able to comply with the protocol for the duration of the trial
4. Require IV antibacterial therapy for the treatment of presumed or documented cIAI as demonstrated by either:
Operative diagnosis (laparotomy, laparoscopy or percutaneous drainage) of cIAI, defined as evidence of infection within the abdominal cavity extending beyond the hollow viscus of origin into the peritoneal space as demonstrated by either abscess formation or peritonitis
OR
Preoperative diagnosis of cIAI, defined as meeting both of the criteria below:
a) Clinical evidence of cIAI as indicated by one or more systemic signs or symptoms that accompany cIAI, such as fever, leukocytosis, hypotension, abdominal pain, nausea/vomiting, anorexia, abdominal mass on clinical examination, or altered mental status
b) Radiographic evidence consistent with intra-abdominal abscess or peritonitis
NOTE: The number of subjects with complicated appendicitis will be limited to a maximum of 60% of the randomized population
5. Have an operative procedure for the current diagnosis and management of cIAI planned or completed within 24 hours of the first dose of an antibacterial drug
6. Have baseline intra-abdominal specimen collection in compliance with protocol Section 7.1.3.4 – Intra-abdominal Samples for Culture. Subjects enrolled preprocedure should have a sample obtained during the interventional procedure performed to comply with protocol Section 7.1.3.4
7. Meet one of the following categories:
a) The subject is a male who is not of reproductive potential, defined as a male who has azoospermia (whether due to being prepubertal, having had a vasectomy, or an underlying medical condition)
b) The subject is a female not of reproductive potential, defined as a female who either: (1) Has not undergone menarche, (2) has had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy, or bilateral tubal ligation/occlusion at least 6 weeks prior to screening, or (3) has a congenital or acquired condition that prevents childbearing
c) The subject is a female or a male of reproductive potential who agrees to avoid becoming pregnant or impregnating a partner during screening, while receiving study treatment and for at least 30 days after the last dose of study treatment by complying with one of the following: (1) Practice abstinence from heterosexual activity OR (2) use (or have their partner use) acceptable contraception during heterosexual activity
8. Meet the following criteria for a female subject who is of reproductive potential:
a) The subject is not pregnant (as confirmed by serum pregnancy test at screening) and not planning to become pregnant within 30 days of the last day of treatment administration,
AND
b) The subject is nonlactating
|
|
| E.4 | Principal exclusion criteria |
1. Is currently participating in or has participated in an interventional clinical trial with an investigational compound or device within 30 days prior to the first dose of study treatment in this current trial
2. Has previously participated in any trial of ceftolozane or ceftolozane/tazobactam or has enrolled previously in the current trial and been discontinued
3. Has a history or current evidence of any condition, therapy, laboratory abnormality, or other circumstance that, in the opinion of the investigator, might expose the subject to increased risk by participating in the trial, confound the results of the trial, or interfere with the subject’s participation for the full duration of the trial
4. Has a history of any moderate or severe hypersensitivity (eg, anaphylaxis), allergic reaction, or other contraindication to any of the following: β-lactam antibiotics (eg, penicillins, cephalosporins, and carbapenems), β-lactamase inhibitors (eg, tazobactam, sulbactam, clavulanic acid, avibactam), or metronidazole
5. Has an IAI within the past 1 year prior to randomization known to be caused by a pathogen resistant to either IV study treatment
6. Has a concomitant infection at the time of randomization that requires nonstudy systemic antibacterial therapy in addition to IV study treatment or oral step-down therapy (medications with only gram-positive activity [eg, vancomycin, linezolid] are allowed)
7. Has received potentially therapeutic antibacterial therapy (eg, with gram-negative activity) for a duration more than 24 hours during the 48 hours preceding the first dose of study treatment, unless the subject is considered to be failing antibiotic therapy for cIAI
NOTE: A subject considered to be failing a previous antibiotic regimen must meet all of the following criteria:
a) Has received the systemic antibacterial treatment for at least 48 hours
b) Has clinical and operative or radiographic findings clearly indicating ongoing infection
c) Has planned operative intervention no more than 24 hours after first dose of study treatment
d) Has not received any further nonstudy antibiotics postoperatively
8. Has any of the following:
a) Intractable cIAI that the investigator anticipates would require more than 14 days of study treatment
b) Abdominal wall abscess
c) Small bowel obstruction
d) Ischemic bowel disease without perforation
e) Traumatic bowel perforation with surgery within 12 hours of perforation
f) Perforation of gastroduodenal ulcers requiring surgery within 24 hours of perforation (these are considered situations of peritoneal soiling before the infection has become established)
g) Suspected uncomplicated intra-abdominal infection (eg, cholecystitis without rupture or extension beyond the gallbladder wall)
h) Acute suppurative cholangitis
i) Infected necrotizing pancreatitis
j) Pancreatic abscess
9. Has severe impairment of renal function, defined as an estimated creatinine clearance <50 mL/min/1.73 m2 based on the Schwartz equation or requirement for peritoneal dialysis, hemodialysis, or hemofiltration
10. Has one or more of the following laboratory abnormalities in a specimen obtained at baseline:
a) Absolute neutrophil count <1000/mm3
b) Aspartate aminotransferase or alanine aminotransferase ≥3 × the upper limit of normal (ULN)
c) Total bilirubin ≥2 × ULN (if 7 to ≤28 days of age and breastfeeding, total bilirubin >10 mg/dL OR ≥2 × ULN)
11. Has a seizure disorder or is anticipated to be treated with divalproex sodium or valproic acid during the course of study treatment
12. Is receiving, or is expected to receive, any of the following medications:
a) Immunosuppressive agents
b) Probenecid
c) Valproic acid or divalproex sodium
d) Disulfiram
e) Ergot derivatives
f) Ethanol-containing medications
g) Nonstudy systemic (IV or oral) antibacterial treatments
13. Has any rapidly progressing disease or immediately life-threatening illness, including acute hepatic failure, respiratory failure, or septic shock
14. Has an immunocompromising condition, including established acquired immune deficiency syndrome, 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 the systemic equivalent of ≥2 mg/kg total daily dose of prednisone for more than 14 days preceding randomization
15. Has a history of malignancy ≤5 years prior to signing informed consent except for adequately treated basal cell or squamous cell skin cancer or in situ cervical cancer
16. Planned receipt of suppressive/prophylactic antibiotics with gram-negative activity after completion of study treatment
17. Is or has an immediate family member (e.g., spouse, parent/legal guardian, sibling or child) who is investigational site or Sponsor staff directly involved with this trial |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
1. Adverse events (AEs)
2. Clinical laboratory tests
3. Vital signs |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Safety evaluation all study visits |
|
| E.5.2 | Secondary end point(s) |
1. Clinical success at the End of Treatment (EOT) and Test of Cure (TOC)
Visits
2. Per-subject microbiological eradication at the EOT and TOC Visits |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| End of IV treatment (EOIV), End of treatment (EOT), Test of cure (TOC) |
|
| 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 | 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| 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 | Yes |
| E.8.1.7.1 | Other trial design description |
| open label Oral step down therapy / Standard of Care |
|
| 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 | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 15 |
| 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 |
| Brazil |
| Hungary |
| Lithuania |
| Malaysia |
| Mexico |
| Romania |
| Russian Federation |
| South Africa |
| Spain |
| Turkey |
| Ukraine |
| United States |
|
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
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