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Evaluation of Safety,Pharmacokinetics and Efficacy of CAZ-AVI With Metronidazole in Childern Aged 3 Months to 18 Years Old With Complicated Intra-abdominal Infections (cIAIs).

Last updated on May 11, 2018

FOR MORE INFORMATION
Study Location
CHOC Children's
Orange, California, 92868 United States
Contact
1-800-718-1021
Eligibility criteria
Condition
The disease, disorder, syndrome, illness, or injury that is being studied.
Complicated Intra-abdominal Infections
Sex
Females and Males
Age
Pediatric Trials: 0-17 Years
Adult Trials: 18+ Years
3-17 months
Inclusion criteria
The factors, or reasons, that allow a person to participate in a clinical study.
Show details

1. Must be ≥3 calendar months to 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 (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
The factors, or reasons, that prevent a person from participating in a clinical study.
Show details

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 ? 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

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 (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

NCT02475733
Pfizer
Completed
Evaluation of Safety,Pharmacokinetics and Efficacy of CAZ-AVI With Metronidazole in Childern Aged 3 Months to 18 Years Old With Complicated Intra-abdominal Infections (cIAIs).

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Evaluation of Safety,Pharmacokinetics and Efficacy of CAZ-AVI With Metronidazole in Childern Aged 3 Months to 18 Years Old With Complicated Intra-abdominal Infections (cIAIs).
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)
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)
This is a multicentre, multinational, single blind, randomised and active controlled trial of intravenous ceftazidime avibactam in combination with metronidazole versus meropenem. Patients will receive intravenous (IV) treatment for a minimum of 72 hours (3 full days, ie, 9 doses) before having the option to switch to an oral therapy. The decision to switch to oral therapy is entirely at the Investigator's discretion, if the patient has good or sufficient clinical response, and the patient is tolerating oral fluids or food.Patients will be assessed for safety and efficacy throughout the study, and blood samples will be taken for pharmacokinetic (PK) assessment. The duration of each patient's participation in the study will be a minimum of 27 days to a maximum of 50 days after start of study treatment (defined as the time point at which first dose of study treatment is administered) at which time there will be a late follow up (LFU) assessment visit. The LFU is to be performed 20 to 35 days after the last dose of any treatment.The assessments at the test of cure (TOC) visit should be performed in person 8 to 15 days after last dose of any study drug (IV or oral). The maximum duration of IV study drug or oral switch therapy is up to Day 15.
Interventional
Phase 2
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Primary Purpose: Treatment
Complicated Intra-abdominal Infections
  • Drug: Ceftazidime -avibactam
    Randomisation (3:1) to ceftazidime -avibactam plus metronidazole or meropenem treatment
  • Drug: Meropenem
    Randomisation (3:1) to CAZ AVI plus metronidazole or meropenem treatment
  • Drug: Metronidazole
    Randomisation (3:1) to ceftazidime -avibactam plus metronidazole or meropenem treatment
  • Experimental: CAZ-AVI and metronidazole
    CAZ-AVI to be administered every 8 hours as a 2 hour infusion (CAZ-AVI dose and frequency of IV administration will depend upon body weight and renal function) followed by metronidazole (no later than 30 minutes after CAZ-AVI infusion ) to be administered every 8 hours as 20 to 30 minutes infusion
    Interventions:
    • Drug: Ceftazidime -avibactam
    • Drug: Metronidazole
  • Active Comparator: Meropenem
    administered every 8 hours infused over 15 to 30 minutes or up to 1 hour or infusion duration as per local guidelines.
    Intervention: Drug: Meropenem
Not Provided


*   Includes publications given by the data provider as well as publications
identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
83
June 1, 2017
June 1, 2017   (Final data collection date for primary outcome measure)

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 ?-human chorionic gonadotropin (?-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 ?-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 ?-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 ? 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
Sexes Eligible for Study: All
3 Months to 17 Years   (Child)
No
Contact information is only displayed when the study is recruiting subjects
Czechia,   Greece,   Hungary,   Poland,   Romania,   Russian Federation,   Spain,   Taiwan,   Turkey,   United States
Argentina,   Chile,   Czech Republic
 
NCT02475733
D4280C00015
C3591004 ( Other Identifier: Alias Study Number )
2014-003242-28 ( EudraCT Number )
Not Provided
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Not Provided
Pfizer
Pfizer
Not Provided
Study Director: Pfizer CT.gov Call Center Pfizer
Pfizer
August 2017

ICMJE     Data element required by the

International Committee of Medical Journal Editors
and the
World Health Organization ICTRP

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