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).

NCT ID: NCT02475733

Last Updated: 2018-08-09

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 83 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2015-08-01
• Study Completion Date: 2017-06-01

Brief 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)

Detailed Description

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.

Conditions

Complicated Intra-abdominal Infections

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: SINGLE

Study Groups

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

Group Type: EXPERIMENTAL

Ceftazidime -avibactam

Intervention Type: DRUG

Randomisation (3:1) to ceftazidime -avibactam plus metronidazole or meropenem treatment

Metronidazole

Intervention Type: DRUG

Randomisation (3:1) to ceftazidime -avibactam plus metronidazole or meropenem treatment

Meropenem

administered every 8 hours infused over 15 to 30 minutes or up to 1 hour or infusion duration as per local guidelines.

Group Type: ACTIVE_COMPARATOR

Meropenem

Intervention Type: DRUG

Randomisation (3:1) to CAZ AVI plus metronidazole or meropenem treatment

Interventions

Ceftazidime -avibactam

Randomisation (3:1) to ceftazidime -avibactam plus metronidazole or meropenem treatment

Intervention Type: DRUG

Meropenem

Randomisation (3:1) to CAZ AVI plus metronidazole or meropenem treatment

Intervention Type: DRUG

Metronidazole

Randomisation (3:1) to ceftazidime -avibactam plus metronidazole or meropenem treatment

Intervention Type: DRUG

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

• Minimum Eligible Age: 3 Months
• Maximum Eligible Age: 17 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Pfizer

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Pfizer CT.gov Call Center

Role: STUDY_DIRECTOR

Pfizer

Locations

CHOC Children's

Orange, California, United States

Rady Children's Hospital San Diego

San Diego, California, United States

ProMedica Toledo Children's Hospital

Toledo, Ohio, United States

The Children's Hospital at Saint Francis

Tulsa, Oklahoma, United States

Oblastni Nemocnice Kolin, a.s., Nemocnice Stredoceskeho Kraje, Detske oddeleni

Kolin III, , Czechia

Lekarna Oblastni Nemocnice Kolin, a.s.

Kolin III, , Czechia

Krajska zdravotni, a.s. - Nemocnice Most, o.z., Detske a dorostove oddeleni

Most, , Czechia

Lekarna Nemocnice Most, o.z.

Most, , Czechia

Fakultni Nemocnice Ostrava - Klinika Detskeho Lekarstvi

Ostrava - Poruba, , Czechia

Lekarna Fakultni Nemocnice Ostrava

Ostrava - Poruba, , Czechia

Lekarna Thomayerovy Nemocnice

Praha 4 - Krc, , Czechia

Thomayerova Nemocnice, Klinika detske chirurgie a traumatologie 3.LF UK a TN

Praha 4 - Krc, , Czechia

Lekarna Nemocnice Strakonice

Strakonice, , Czechia

Nemocnice Strakonice, a.s. - Detske oddeleni

Strakonice, , Czechia

General Children's Hospital of Athens "P. & A.Kyriakou"

Athens, Attica, Greece

General Hospital of Thessaloniki "Hippokratio"

Thessaloniki, Macedonia, Greece

Semmelweis Egyetem, II. sz. Gyermekgyogyaszati Klinika

Budapest, , Hungary

Kanizsai Dorottya Korhaz, Csecsemo es Gyermekgyogyaszati Osztaly

Nagykanizsa, , Hungary

Pecsi Tudomanyegyetem, AOK, Klinikai Kozpont, Gyermekgyogyaszati Klinika

Pécs, , Hungary

Szegedi Tudomanyegyetem, Szent-Gyorgyi Albert Klinikai Kozpont

Szeged, , Hungary

Tolna Megyei Balassa Janos Korhaz, Gyermekgyogyaszati Osztaly

Szekszárd, , Hungary

Uniwersytecki Szpital Dzieciecy w Lublinie

Lublin, , Poland

Spitalul Clinic de Urgenta pentru Copii "Sf. Maria" Iasi, Sectia Chirurgie Pediatrica II

Iași, , Romania

State Budgetary Educational Institution of Higher Professional Education

Smolensk, Smolensk Oblast, Russia

Hospital Universitario Germans Trias i Pujol

Badalona, Barcelona, Spain

Hospital de Sant Joan de Deu

Esplugues de Llobregat, Barcelona, Spain

Hospital Clinico San Carlos

Madrid, , Spain

Hospital Universitario Fundacion Jimenez Diaz

Madrid, , Spain

Hospital Universitario y Politecnico la Fe

Valencia, , Spain

Kaohsiung Veterans General Hospital

Kaohsiung City, , Taiwan

Taichung Veterans General Hospital

Taichung, , Taiwan

Department of Pediatrics, Mackay Memorial Hospital

Taipei, , Taiwan

Cukurova Universitesi Tip Fakultesi Balcali Hastanesi

Adana, , Turkey (Türkiye)

Eskisehir Osmangazi Universitesi Saglik Uygulama ve Arastirma Hastanesi

Eskişehir, , Turkey (Türkiye)

Celal Bayar Universitesi Hafsa Sultan Hastanesi

Manisa, , Turkey (Türkiye)

Countries

United States; Czechia; Greece; Hungary; Poland; Romania; Russia; Spain; Taiwan; Turkey (Türkiye)

References

Franzese RC, McFadyen L, Watson KJ, Riccobene T, Carrothers TJ, Vourvahis M, Chan PLS, Raber S, Bradley JS, Lovern M. Population Pharmacokinetic Modeling and Probability of Pharmacodynamic Target Attainment for Ceftazidime-Avibactam in Pediatric Patients Aged 3 Months and Older. Clin Pharmacol Ther. 2022 Mar;111(3):635-645. doi: 10.1002/cpt.2460. Epub 2021 Nov 22.

Reference Type: DERIVED

PMID: 34687548 (View on PubMed)

Bradley JS, Broadhurst H, Cheng K, Mendez M, Newell P, Prchlik M, Stone GG, Talley AK, Tawadrous M, Wajsbrot D, Yates K, Zuzova A, Gardner A. Safety and Efficacy of Ceftazidime-Avibactam Plus Metronidazole in the Treatment of Children >/=3 Months to <18 Years With Complicated Intra-Abdominal Infection: Results From a Phase 2, Randomized, Controlled Trial. Pediatr Infect Dis J. 2019 Aug;38(8):816-824. doi: 10.1097/INF.0000000000002392.

Reference Type: DERIVED

PMID: 31306396 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

C3591004

Identifier Type: OTHER

Identifier Source: secondary_id

2014-003242-28

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

D4280C00015

Identifier Type: -

Identifier Source: org_study_id