Clinical trial NCT02475733: 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).
Official 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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Complicated Intra-abdominal Infections
Lead sponsor: Pfizer
Sponsor class: INDUSTRY
First posted: 2015-06-19
Enrollment: 83
Sex: ALL
Minimum age (years): 3
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Percentage of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)
timeFrame: Baseline until the LFU visit (up to a maximum study duration of 50 days)
measure: Percentage of Participants With Cephalosporin Class Effects and Additional Adverse Events (AEs)
timeFrame: Baseline until the LFU visit (up to a maximum study duration of 50 days)
measure: Change From Baseline in Pulse Rate at End of Intravenous Therapy (EOIV) Visit
timeFrame: Baseline, EOIV visit (anytime from Day 4 up to 16)
measure: Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at End of Intravenous Therapy (EOIV) Visit
timeFrame: Baseline, EOIV visit (anytime from Day 4 up to 16)
measure: Change From Baseline in Respiratory Rate at End of Intravenous Therapy (EOIV) Visit
timeFrame: Baseline, EOIV visit (anytime from Day 4 up to 16)
measure: Change From Baseline in Body Weight at End of Intravenous Therapy (EOIV) Visit
timeFrame: Baseline, EOIV visit (anytime from Day 4 up to 16)
measure: Change From Baseline in Body Temperature at End of Intravenous Therapy (EOIV) Visit
timeFrame: Baseline, EOIV visit (anytime from Day 4 up to 16)
measure: Percentage of Participants With Abnormal Physical Examination Findings at End of Intravenous Therapy (EOIV) Visit
timeFrame: EOIV visit (anytime from Day 4 up to 16)
measure: Percentage of Participants With Potentially Clinically Significant Abnormalities in Laboratory Parameters
timeFrame: Baseline until the LFU visit (up to a maximum study duration of 50 days)
measure: Percentage of Participants With Electrocardiogram (ECG) Parameter QTcF: > 450, >480 and >500 Millisecond (ms)
timeFrame: Baseline until the EOIV visit (anytime from Day 4 to 16)
measure: Percentage of Participants With Creatinine Clearance (CrCl) at Day 7
timeFrame: Day 7
measure: Percentage of Participants With Creatinine Clearance (CrCl) at End of Intravenous Therapy (EOIV) Visit
timeFrame: EOIV visit (anytime from Day 4 up to 16)
measure: Percentage of Participants With Creatinine Clearance (CrCl) at Test of Cure (TOC) Visit
timeFrame: TOC visit (up to a maximum study duration of 50 days)
measure: Percentage of Participants With Creatinine Clearance (CrCl) at Late Follow-up (LFU) Visit
timeFrame: LFU visit (up to a maximum study duration of 50 days)
Secondary outcomes:
measure: Plasma Concentrations of Ceftazidime and Avibactam
timeFrame: 15, 30-90, 300-360 minutes post-dose on Day 3
measure: Percentage of Participants With Favorable Clinical Response (CR) at End of 72 Hours Treatment: Intent-to-treat (ITT) Analysis Population
timeFrame: End of 72 hours study drug treatment on Day 1
measure: Percentage of Participants With Favorable Clinical Response (CR) at End of Intravenous Therapy (EOIV) Visit: Intent-to-treat (ITT) Analysis Population
timeFrame: EOIV visit (anytime from Day 4 up to 16)
measure: Percentage of Participants With Favorable Clinical Response (CR) at End of Treatment (EOT) Visit: Intent-to-treat (ITT) Analysis Population
timeFrame: EOT visit (up to Day 17)
measure: Percentage of Participants With Favorable Clinical Response (CR) at Test of Cure (TOC) Visit: Intent-to-treat (ITT) Analysis Population
timeFrame: TOC visit (up to a maximum study duration of 50 days)
measure: Percentage of Participants With Favorable Clinical Response (CR): Clinically Evaluable (CE) Analysis Population
timeFrame: 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)
measure: Percentage of Participants With Favorable Microbiological Response: Microbiological Intent-to-treat (Micro-ITT) Population
timeFrame: 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)
measure: Percentage of Participants With Favorable Microbiological Response: Microbiologically Evaluable (ME) Population
timeFrame: 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)
measure: Percentage of Participants With Clinical Relapse at Late Follow-up (LFU) Visit: Clinically Evaluable (CE) Population
timeFrame: LFU visit (up to a maximum study duration of 50 days)
measure: Percentage of Participants With Clinical Relapse at Late Follow-up (LFU) Visit: Microbiologically Evaluable (ME) Population
timeFrame: LFU visit (up to a maximum study duration of 50 days)
measure: Percentage of Participants With Emergent Infections: Microbiological Intent-to-treat (Micro-ITT) Population
timeFrame: Baseline up to 50 days
measure: Percentage of Participants With Emergent Infections at Test of Cure (TOC) Visit: Microbiologically Evaluable Population
timeFrame: TOC visit (up to a maximum study duration of 50 days)
Other outcomes:
Locations:
city: Orange
country: United States
facility: CHOC Children's
state: California
city: San Diego
country: United States
facility: Rady Children's Hospital San Diego
state: California
city: Toledo
country: United States
facility: ProMedica Toledo Children's Hospital
state: Ohio
city: Tulsa
country: United States
facility: The Children's Hospital at Saint Francis
state: Oklahoma
city: Kolin III
country: Czechia
facility: Oblastni Nemocnice Kolin, a.s., Nemocnice Stredoceskeho Kraje, Detske oddeleni
city: Kolin III
country: Czechia
facility: Lekarna Oblastni Nemocnice Kolin, a.s.
city: Most
country: Czechia
facility: Krajska zdravotni, a.s. - Nemocnice Most, o.z., Detske a dorostove oddeleni
city: Most
country: Czechia
facility: Lekarna Nemocnice Most, o.z.
city: Ostrava - Poruba
country: Czechia
facility: Fakultni Nemocnice Ostrava - Klinika Detskeho Lekarstvi
city: Ostrava - Poruba
country: Czechia
facility: Lekarna Fakultni Nemocnice Ostrava
city: Praha 4 - Krc
country: Czechia
facility: Lekarna Thomayerovy Nemocnice
city: Praha 4 - Krc
country: Czechia
facility: Thomayerova Nemocnice, Klinika detske chirurgie a traumatologie 3.LF UK a TN
city: Strakonice
country: Czechia
facility: Lekarna Nemocnice Strakonice
city: Strakonice
country: Czechia
facility: Nemocnice Strakonice, a.s. - Detske oddeleni
city: Athens
country: Greece
facility: General Children's Hospital of Athens "P. & A.Kyriakou"
state: Attica
city: Thessaloniki
country: Greece
facility: General Hospital of Thessaloniki "Hippokratio"
state: Macedonia
city: Budapest
country: Hungary
facility: Semmelweis Egyetem, II. sz. Gyermekgyogyaszati Klinika
city: Nagykanizsa
country: Hungary
facility: Kanizsai Dorottya Korhaz, Csecsemo es Gyermekgyogyaszati Osztaly
city: Pecs
country: Hungary
facility: Pecsi Tudomanyegyetem, AOK, Klinikai Kozpont, Gyermekgyogyaszati Klinika
city: Szeged
country: Hungary
facility: Szegedi Tudomanyegyetem, Szent-Gyorgyi Albert Klinikai Kozpont
city: Szekszard
country: Hungary
facility: Tolna Megyei Balassa Janos Korhaz, Gyermekgyogyaszati Osztaly
city: Lublin
country: Poland
facility: Uniwersytecki Szpital Dzieciecy w Lublinie
city: Iasi
country: Romania
facility: Spitalul Clinic de Urgenta pentru Copii "Sf. Maria" Iasi, Sectia Chirurgie Pediatrica II
city: Smolensk
country: Russian Federation
facility: State Budgetary Educational Institution of Higher Professional Education
state: Smolensk Region
city: Badalona
country: Spain
facility: Hospital Universitario Germans Trias i Pujol
state: Barcelona
city: Esplugues de LLobregat
country: Spain
facility: Hospital de Sant Joan de Deu
state: Barcelona
city: Madrid
country: Spain
facility: Hospital Clinico San Carlos
city: Madrid
country: Spain
facility: Hospital Universitario Fundacion Jimenez Diaz
city: Valencia
country: Spain
facility: Hospital Universitario y Politecnico la Fe
city: Kaohsiung
country: Taiwan
facility: Kaohsiung Veterans General Hospital
city: Taichung
country: Taiwan
facility: Taichung Veterans General Hospital
city: Taipei
country: Taiwan
facility: Department of Pediatrics, Mackay Memorial Hospital
city: Adana
country: Turkey
facility: Cukurova Universitesi Tip Fakultesi Balcali Hastanesi
city: Eskisehir
country: Turkey
facility: Eskisehir Osmangazi Universitesi Saglik Uygulama ve Arastirma Hastanesi
city: Manisa
country: Turkey
facility: Celal Bayar Universitesi Hafsa Sultan Hastanesi
Study officials:
affiliation: Pfizer
name: Pfizer CT.gov Call Center
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.