Evaluation of Safety,Pharmacokinetics and Efficacy of CAZ-AVI With Metronidazole in Children Aged 3 Months to 18 Years Old With Complicated Intra-abdominal Infections (cIAIs).
Condition: Complicated Intra-abdominal Infections
MeSH terms: Infections; Communicable Diseases; Intraabdominal Infections
Intervention: Ceftazidime -avibactam; Meropenem; Metronidazole
Intervention description: Randomisation (3:1) to ceftazidime -avibactam plus metronidazole or meropenem treatment; Randomisation (3:1) to CAZ AVI plus metronidazole or meropenem treatment; Randomisation (3:1) to ceftazidime -avibactam plus metronidazole or meropenem treatment
Intervention MeSH terms: Metronidazole; Meropenem; Ceftazidime; Avibactam; Avibactam, ceftazidime drug combination
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Enrollment: 83.0
Sex: All
Minimum age: 3 Months
Maximum age: 17 Years
Healthy volunteers: No

Summary:

      This study will assess the safety , efficacy and pharmacokinetics of ceftazidime avibactam
      and metronidazole versus meropenem in paediatric population (from 3 months to less than 18
      years of age )with complicated intra-abdominal infections (cIAIs)
    

Eligibility criteria:

        Inclusion Criteria:

          1. Must be ≥3 calendar months to <18 years of age. Patients 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) Patient reports sexual abstinence for the prior 3 months or reports use of at least 1
        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 β-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:

          1. Requires surgical intervention that is expected to be completed within 24 hours of
             enrolment Laparotomy, laparoscopy, or percutaneous drainage

          2. Evidence of a systemic inflammatory response (at least 1): 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)

          3. Physical Findings consistent with intra-abdominal infection, such as:

             Abdominal pain and/or tenderness Localised or diffuse abdominal wall rigidity
             Abdominal mass

          4. Intention to send specimens from the surgical intervention for culture

          5. (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 (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 1 of
        these diagnoses:

          1. Appendiceal perforation or peri-appendiceal abscess

          2. Cholecystitis with gangrenous rupture or perforation or progression of the infection
             beyond the gallbladder wall

          3. Acute gastric or duodenal perforations, only if operated on >24 hours after singular
             perforation occurs

          4. Traumatic perforation of the intestines, only if operated on >12 hours after
             perforation occurs

          5. Secondary peritonitis (but not spontaneous bacterial peritonitis associated with
             cirrhosis and chronic ascites)

        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 metronidazole or to nitroimidazole derivatives

          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 antibacterial drug 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:

               1. Haematocrit <25% or haemoglobin <8 g/dL (<80g/L , <4.9 mmol/L)

               2. 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) to 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