| 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 |
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| 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 | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10056570 |
| E.1.2 | Term | Intra-abdominal infection |
| E.1.2 | System Organ Class | 100000016609 |
|
| 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 |
| Evaluate the safety and tolerability of CAZ AVI plus metronidazole given at the selected dose regimen versus meropenem in paediatric patients aged ≥3 months to <18 years with cIAI |
|
| E.2.2 | Secondary objectives of the trial |
Evaluate the descriptive efficacy of CAZ AVI plus metronidazole versus meropenem in paediatric patients aged ≥3 months to <18 years with cIAI
Evaluate the PK of CAZ AVI in paediatric patients aged ≥3 months to <18 years with cIAI |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Must be ≥3 calendar months to <18 years of age. Patient aged ≥3 calendar months to <1 year must have been born at term (defined as gestational age ≥37 weeks).
2. Written informed consent from parent(s) or other legally acceptable representative(s), and informed assent from patient (if age appropriate according to local regulations)
3. If female and has reached menarche, or has reached Tanner stage 3 development (even if not having reached menarche) (refer to Appendix E for further details on Tanner staging), the patient is authorised to participate in this clinical study if the following criteria are met:
At screening:
(i) (a) Patient reports sexual abstinence for the prior 3 months or reports use of at least one of the acceptable methods of contraception, including an intrauterine device (with copper banded coil), levonorgestrel intrauterine system (eg, Mirena®), or regular medroxyprogesterone injections (Depo-Provera®); or (b) Patient agrees to initiate sexual abstinence from the time of screening until 7 days after end of treatment with study drug; and
(ii) Patient is advised to avoid conception from the time of screening until 7 days after receipt of study drug and agrees not to attempt pregnancy from the time of screening until 7 days after end of treatment with study drug; and
(iii) Patient is provided guidelines regarding continuation of abstinence, initiation of abstinence, or about allowed contraception; and
(iv) Patient has a negative serum ß-human chorionic gonadotropin (β-hCG) test just prior to study entry. Since serum tests may miss an early pregnancy, relevant menstrual history and sexual history, including methods of contraception, should be considered. Note: if the result of the serum β-hCG test cannot be obtained prior to dosing of investigational product, a patient may be enrolled on the basis of a negative urine pregnancy test, though a serum β-hCG test result must still be obtained.
4. Must, based on the judgment of the Investigator, require hospitalisation initially and antibacterial therapy for 7 to 15 days in addition to surgical intervention for the treatment of the current cIAI
5. Require surgical intervention (eg, laparotomy, laparoscopic surgery or percutaneous drainage) to manage the cIAI
6. Must have clinical evidence of cIAI as follows:
(i) Pre-operative enrolment inclusion:
(a) Requires surgical intervention that is expected to be completed within 24 hours of enrolment
Laparotomy, laparoscopy, or percutaneous drainage
(b) Evidence of a systemic inflammatory response (at least one):
Fever (defined as oral temperature >38.5°C, or equivalent to method used) or hypothermia (with a core body or rectal temperature <35°C, or equivalent to method used)
Elevated white blood cells (WBC) (>15000 cells/mm3)
C-reactive protein (CRP) levels (>10 mg/L)
(c) Physical Findings consistent with intra-abdominal infection, such as:
Abdominal pain and/or tenderness
Localised or diffuse abdominal wall rigidity
Abdominal mass
(d) Intention to send specimens from the surgical intervention for culture
(e) (Optional) Supportive radiologic findings of intra-abdominal infection, such as perforated intraperitoneal abscess detected on:
Computed tomography (CT) scan or
Magnetic resonance imaging (MRI) or
Ultrasound or
(ii) Intra-operative/postoperative enrolment inclusion (in cases of postoperative enrolment, must be within 24 hours after the time of incision):
Visual confirmation of intra-abdominal infection associated with peritonitis at laparotomy, laparoscopy or percutaneous drainage (to be confirmed pending feasibility); must have one of these diagnoses:
(a) Appendiceal perforation or peri-appendiceal abscess
(b) Cholecystitis with gangrenous rupture or perforation or progression of the infection beyond the gallbladder wall
(c) Acute gastric or duodenal perforations, only if operated on >24 hours after singular perforation occurs
(d) Traumatic perforation of the intestines, only if operated on >12 hours after perforation occurs
(e) Secondary peritonitis (but not spontaneous bacterial peritonitis associated with cirrhosis and chronic ascites)
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|
| E.4 | Principal exclusion criteria |
1. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site)
2. Previous enrolment or randomisation in the present study
3. Participation in another clinical study with an investigational product (IP) during the last 30 days before the first dose of IV study drug or have previously participated in the current study or in another study of CAZ-AVI (in which an active agent was received)
4. History of hypersensitivity reactions to carbapenems, cephalosporins, penicillin, other β lactam antibiotics or metronidazole or to nitroimidazole derivates
5. Concurrent infection, that may interfere with the evaluation of response to the study antibiotics at the time of randomisation
6. Patient needs effective concomitant systemic antibacterials (oral, IV, or intramuscular) in addition to those designated in the 2 study groups(CAZ-AVI plus metronidazole group or meropenem group) (see Section 7.8)
7. Receipt of non-study systemic antibiotic therapy for cIAI for a continuous duration of more than 24 hours during the 72 hours preceding the first dose of IV drug, except in proven resistant organisms and/or worsening of the clinical condition for more than 24 hours. More than 2 consecutive doses are not permitted if the individual doses are expected to give >12 hours' cover (ie, giving a total cover of > 24 hours). For patients enrolled after a surgical procedure, only 1 dose of non study antibiotics is permitted postoperatively.
8. Patient is considered unlikely to survive the 6 to 8 week study period
9. Patient is unlikely to respond to 7 to 15 days of treatment with antibiotics
10. Patient is receiving haemodialysis or peritoneal dialysis
11. Diagnosis of abdominal wall abscess confined to musculature of the abdominal wall or ischaemic bowel disease without perforation, traumatic bowel perforation requiring surgery within 12 hours of perforation, or perforation of gastroduodenal ulcers requiring surgery within 24 hours of perforation (these are considered situations of peritoneal soiling before the infection has become established)
12. Simple (uncomplicated), non-perforated appendicitis or gangrenous appendicitis without rupture into the peritoneal cavity identified during a surgical procedure OR presence of primary peritonitis (ie, spontaneous bacterial peritonitis) or peritonitis associated with cirrhosis or chronic ascites
13. At the time of randomisation, patient is known to have a cIAI caused by pathogens resistant to the study antimicrobials planned to be used in the study
14. Presence of any of the following clinically significant laboratory abnormalities:
(a) Haematocrit <25% or haemoglobin <8 g/dL (<80g/L , <4.9mmol/L)
(b) Serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >3×the age-specific upper limit of normal (ULN), or total bilirubin >2×ULN (except known Gilbert’s disease).
For a) and b): unless if these values are acute and directly related to the infectious process being treated.
15. Creatinine clearance < 30 mL/min/1.73 m2 calculated using the child’s measured height (length) and serum creatinine within the updated “bedside” Schwartz formula (Schwartz et al, 2009): CrCl (mL/min/1.73m2)=0.413×height (length) (cm)/serum creatinine (mg/dL)
16. History of seizures, excluding well-documented febrile seizure of childhood.
17. Any situation or condition that would make the patient, in the opinion of the Investigator, unsuitable for the study (eg. would place a patient at risk or compromise the quality of the data) or may interfere with optimal participation in the study.
18. If female, currently pregnant or breast feeding
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|
| E.5 End points |
| E.5.1 | Primary end point(s) |
To assess the safety and tolerability by :
a) adverse events (AEs) and serious adverse events(SAEs)
b) vital signs (pulse , blood pressure , respiratory rate, temperature)
c) ECG (electrocardiogram)
d) laboratory tests(complete blood count with differential and comprehensive metabolic panel )
e) creatinine clearance (CrCl) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
a) from ICF to LFU visit (27 to 50 days after start of study treatment)
b)from ICF to LFU visit (27 to 50 days after start of study treatment)
c) baseline, Day 1, TOC
d)baseline , Days 4 to 15, EoIV (end of intravenous treatment) and TOC (test of cure); if clinically indicated (Days2 and 3; EOT and LFU)
e)baseline, Days 4 to 15, EoIV (end of intravenous treatment) and TOC (test of cure); if clinically indicated (Days2 and 3; EOT and LFU) |
|
| E.5.2 | Secondary end point(s) |
1.To assess the efficacy by:
a) clinical outcomes
b)microbiological response
c)clinical relapse
d) emergent infections
2. To evaluate the PK of CAZ-AVI in pediatric patients aged aged ≥3 months to <18 years with cIAI
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1
a)end of 72 hours' treatment, end of intravenous treatment (EOIV), end of treatment (EOT) and test of cure (TOC)
b) EOIV, EOT, TOC and LFU
c)LFU
d)study duration
2. Days 2 and 3 |
|
| 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 | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| 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 | Yes |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| 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) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
|
| 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 | 7 |
| 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 |
| Argentina |
| Chile |
| Czech Republic |
| Greece |
| Hungary |
| Poland |
| Romania |
| Russian Federation |
| Spain |
| Taiwan |
| Turkey |
| 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 | 2 |
| E.8.9.1 | In the Member State concerned months | 10 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 10 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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