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).

• Register: ClinicalTrials.gov
• Last refreshed on: 12 December 2020
• Main ID: NCT02475733
• Date of registration: 25/05/2015
• Prospective Registration: Yes
• Primary sponsor: Pfizer
• Public title: 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).
• Scientific title: A Single Blind, Randomised, Multi-centre, Active Controlled, Trial To Evaluate Safety, Tolerability, Pharmacokinetics And Efficacy Of Ceftazidime And Avibactam When Given In Combination With Metronidazole, Compared With Meropenem, In Children From 3 Months To Less Than 18 Years Of Age With Complicated Intra-abdominal Infections (cIAIs)
• Date of first enrolment: August 1, 2015
• Target sample size: 83
• Recruitment status: Completed
• URL: https://clinicaltrials.gov/show/NCT02475733
• Study type: Interventional
• Study design: Allocation: Randomized. Intervention model: Parallel Assignment. Primary purpose: Treatment. Masking: Single (Outcomes Assessor).
• Phase: Phase 2

Countries of recruitment

Argentina, Chile, Czech Republic, Czechia, Greece, Hungary, Poland, Romania, Russian Federation, Spain, Taiwan, Turkey, United States

Contacts

• Name: Pfizer CT.gov Call Center
• Affiliation: Pfizer

Key inclusion & exclusion 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 ß-human chorionic gonadotropin (ß-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 ß-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 ß-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 ß 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


Age minimum: 3 Months
Age maximum: 17 Years
Gender: All

Health Condition(s) or Problem(s) studied

Complicated Intra-abdominal Infections

Intervention(s)

Drug: Ceftazidime -avibactam

Drug: Metronidazole

Drug: Meropenem

Primary Outcome(s)

Change From Baseline in Body Weight at End of Intravenous Therapy (EOIV) Visit [Time Frame: Baseline, EOIV visit (anytime from Day 4 up to 16)]

Change From Baseline in Pulse Rate at End of Intravenous Therapy (EOIV) Visit [Time Frame: Baseline, EOIV visit (anytime from Day 4 up to 16)]

Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at End of Intravenous Therapy (EOIV) Visit [Time Frame: Baseline, EOIV visit (anytime from Day 4 up to 16)]

Percentage of Participants With Potentially Clinically Significant Abnormalities in Laboratory Parameters [Time Frame: Baseline until the LFU visit (up to a maximum study duration of 50 days)]

Percentage of Participants With Creatinine Clearance (CrCl) at Day 7 [Time Frame: Day 7]

Change From Baseline in Respiratory Rate at End of Intravenous Therapy (EOIV) Visit [Time Frame: Baseline, EOIV visit (anytime from Day 4 up to 16)]

Percentage of Participants With Creatinine Clearance (CrCl) at Test of Cure (TOC) Visit [Time Frame: TOC visit (up to a maximum study duration of 50 days)]

Percentage of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) [Time Frame: Baseline until the LFU visit (up to a maximum study duration of 50 days)]

Change From Baseline in Body Temperature at End of Intravenous Therapy (EOIV) Visit [Time Frame: Baseline, EOIV visit (anytime from Day 4 up to 16)]

Percentage of Participants With Creatinine Clearance (CrCl) at Late Follow-up (LFU) Visit [Time Frame: LFU visit (up to a maximum study duration of 50 days)]

Percentage of Participants With Cephalosporin Class Effects and Additional Adverse Events (AEs) [Time Frame: Baseline until the LFU visit (up to a maximum study duration of 50 days)]

Percentage of Participants With Electrocardiogram (ECG) Parameter QTcF: > 450, >480 and >500 Millisecond (ms) [Time Frame: Baseline until the EOIV visit (anytime from Day 4 to 16)]

Percentage of Participants With Creatinine Clearance (CrCl) at End of Intravenous Therapy (EOIV) Visit [Time Frame: EOIV visit (anytime from Day 4 up to 16)]

Percentage of Participants With Abnormal Physical Examination Findings at End of Intravenous Therapy (EOIV) Visit [Time Frame: EOIV visit (anytime from Day 4 up to 16)]

Secondary Outcome(s)

Percentage of Participants With Emergent Infections: Microbiological Intent-to-treat (Micro-ITT) Population [Time Frame: Baseline up to 50 days]

Percentage of Participants With Favorable Clinical Response (CR) at End of 72 Hours Treatment: Intent-to-treat (ITT) Analysis Population [Time Frame: End of 72 hours study drug treatment on Day 1]

Percentage of Participants With Favorable Microbiological Response: Microbiological Intent-to-treat (Micro-ITT) Population [Time Frame: EOIV visit (Day 4 up to 16), EOT visit (up to Day 17), TOC visit (up to a maximum study duration of 50 days) and LFU visit (up to a maximum study duration of 50 days)]

Percentage of Participants With Clinical Relapse at Late Follow-up (LFU) Visit: Microbiologically Evaluable (ME) Population [Time Frame: LFU visit (up to a maximum study duration of 50 days)]

Percentage of Participants With Favorable Clinical Response (CR) at End of Intravenous Therapy (EOIV) Visit: Intent-to-treat (ITT) Analysis Population [Time Frame: EOIV visit (anytime from Day 4 up to 16)]

Percentage of Participants With Favorable Clinical Response (CR) at End of Treatment (EOT) Visit: Intent-to-treat (ITT) Analysis Population [Time Frame: EOT visit (up to Day 17)]

Percentage of Participants With Clinical Relapse at Late Follow-up (LFU) Visit: Clinically Evaluable (CE) Population [Time Frame: LFU visit (up to a maximum study duration of 50 days)]

Percentage of Participants With Favorable Clinical Response (CR): Clinically Evaluable (CE) Analysis Population [Time Frame: End of 72 hours study drug treatment on Day 1, EOIV (anytime from Day 4 up to 16), EOT visit (up to Day 17) and TOC visit (up to a maximum study duration of 50 days)]

Percentage of Participants With Favorable Clinical Response (CR) at Test of Cure (TOC) Visit: Intent-to-treat (ITT) Analysis Population [Time Frame: TOC visit (up to a maximum study duration of 50 days)]

Percentage of Participants With Favorable Microbiological Response: Microbiologically Evaluable (ME) Population [Time Frame: EOIV visit (Day 4 up to 16), EOT visit (up to Day 17), TOC visit (up to a maximum study duration of 50 days) and LFU visit (up to a maximum study duration of 50 days)]

Plasma Concentrations of Ceftazidime and Avibactam [Time Frame: 15, 30-90, 300-360 minutes post-dose on Day 3]

Percentage of Participants With Emergent Infections at Test of Cure (TOC) Visit: Microbiologically Evaluable Population [Time Frame: TOC visit (up to a maximum study duration of 50 days)]

Secondary ID(s)

C3591004

2014-003242-28

D4280C00015

Source(s) of Monetary Support

Please refer to primary and secondary sponsors

Results

• Results available: Yes
• Date Posted: 09/08/2018
• URL: https://clinicaltrials.gov/ct2/show/results/NCT02475733