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).

NCT02475733 | Completed Phase 2 Results FDA Drug

• 3 other identifiers: D4280C00015C35910042014-003242-28
• Study Type: interventional
• Target: 83
• Locations: 10 countries
• Sites: 35

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)

Conditions

Complicated Intra-abdominal Infections

Outcome Measures

Primary Outcomes (14)

• Percentage of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)

  An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged in-patient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent AEs were events between first dose of study drug and up to late follow-up (LFU) visit (20 to 35 days after last dose of study treatment \[IV or oral\]) that were absent before treatment or that worsened relative to pretreatment state. AEs included both SAE and non-SAE.

  Baseline until the LFU visit (up to a maximum study duration of 50 days)

• Percentage of Participants With Cephalosporin Class Effects and Additional Adverse Events (AEs)

  Percentage of participants with Cephalosporin class effects (defined as adverse event of special interest (AEoSI) within the safety topics (ST) of hypersensitivity/anaphylaxis) and additional AEs (which included AEs of seizures, diarrhea, renal disorder, and liver disorder relevant to the cephalosporin class within the ST and AEs with preferred term in the system organ class of nervous system disorder system organ class based on MedDRA 20.0) were reported in this outcome measure.

  Baseline until the LFU visit (up to a maximum study duration of 50 days)

• Change From Baseline in Pulse Rate at End of Intravenous Therapy (EOIV) Visit

  EOIV visit occurred within 24 hours after completion of last infusion of the study drug.

  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

  EOIV visit occurred within 24 hours after completion of last infusion of the study drug.

  Baseline, EOIV visit (anytime from Day 4 up to 16)

• Change From Baseline in Respiratory Rate at End of Intravenous Therapy (EOIV) Visit

  EOIV visit occurred within 24 hours after completion of last infusion of the study drug.

  Baseline, EOIV visit (anytime from Day 4 up to 16)

• Change From Baseline in Body Weight at End of Intravenous Therapy (EOIV) Visit

  EOIV visit occurred within 24 hours after completion of last infusion of the study drug.

  Baseline, EOIV visit (anytime from Day 4 up to 16)

• Change From Baseline in Body Temperature at End of Intravenous Therapy (EOIV) Visit

  EOIV visit occurred within 24 hours after completion of last infusion of the study drug.

  Baseline, EOIV visit (anytime from Day 4 up to 16)

• Percentage of Participants With Abnormal Physical Examination Findings at End of Intravenous Therapy (EOIV) Visit

  Physical examination included an assessment of the following: general appearance, skin, head and neck (including ears, eyes, nose and throat), lymph nodes, thyroid, respiratory system, cardiovascular system, abdomen, musculoskeletal system (including spine and extremities), and neurological system. Participants with new or aggravated abnormal physical examination findings with regard to baseline findings were reported. Abnormality in physical examinations were based on blinded observer's discretion. EOIV visit occurred within 24 hours after completion of last infusion of the study drug.

  EOIV visit (anytime from Day 4 up to 16)

• Percentage of Participants With Potentially Clinically Significant Abnormalities in Laboratory Parameters

  Criteria for potentially clinically significant laboratory abnormalities: Chemistry (calcium: \<0.7\*lower limit of normal range \[LLN\] and \>30 percent decrease from baseline \[DFB\]; alanine aminotransferase \[ALT\]: \>3\*upper limit of normal range \[ULN\] and \>300 percent IFB; alanine aminotransferase \[AST\]: \>3\*ULN and \>300 percent IFB) and hematology (platelets: \>2\*ULN and \>100 percent IFB). LFU visit occurred within 20 to 35 days after last dose of study treatment (IV or oral).

  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)

  ECG parameters included maximum QT intervals using Fridericia's correction (QTcF). Maximum QTcF \>450 millisecond (ms); maximum QTcF \>480 ms; and maximum QTcF \>500 ms. EOIV visit occurred within 24 hours after completion of last infusion of the study drug.

  Baseline until the EOIV visit (anytime from Day 4 to 16)

• Percentage of Participants With Creatinine Clearance (CrCl) at Day 7

  CrCl is a measure of glomerular filtration rate (GMFR), an index of kidney function. It is the volume of blood plasma that is cleared of creatinine by the kidneys per unit time. Percentage of participants with CrCl in the following categories were reported: \<30 mL/min/1.73 m\^2, \>=30 to \<50 mL/min/1.73 m\^2, \>=50 mL/min/1.73 m\^2 to \<80 mL/min/1.73 m\^2, and \>=80 mL/min/1.73 m\^2.

  Day 7

• Percentage of Participants With Creatinine Clearance (CrCl) at End of Intravenous Therapy (EOIV) Visit

  CrCl is a measure of GMFR, an index of kidney function. It is the volume of blood plasma that is cleared of creatinine by the kidneys per unit time. Percentage of participants with CrCl in the following categories were reported: \<30 mL/min/1.73 m\^2, \>=30 to \<50 mL/min/1.73 m\^2, \>=50 mL/min/1.73 m\^2 to \<80 mL/min/1.73 m\^2, and \>=80 mL/min/1.73 m\^2. EOIV visit occurred within 24 hours after completion of last infusion of the study drug.

  EOIV visit (anytime from Day 4 up to 16)

• Percentage of Participants With Creatinine Clearance (CrCl) at Test of Cure (TOC) Visit

  CrCl is a measure of GMFR, an index of kidney function. It is the volume of blood plasma that is cleared of creatinine by the kidneys per unit time. Percentage of participants with CrCl in the following categories were reported: \<30 mL/min/1.73 m\^2, \>=30 to \<50 mL/min/1.73 m\^2, \>=50 mL/min/1.73 m\^2 to \<80 mL/min/1.73 m\^2, and \>=80 mL/min/1.73 m\^2. TOC visit occurred within 8 to 15 days after last dose of any study drug (IV or oral).

  TOC visit (up to a maximum study duration of 50 days)

• Percentage of Participants With Creatinine Clearance (CrCl) at Late Follow-up (LFU) Visit

  CrCl is a measure of GMFR, an index of kidney function. It is the volume of blood plasma that is cleared of creatinine by the kidneys per unit time. Percentage of participants with CrCl in the following categories were reported: \<30 mL/min/1.73 m\^2, \>=30 to \<50 mL/min/1.73 m\^2, \>=50 mL/min/1.73 m\^2 to \<80 mL/min/1.73 m\^2, and \>=80 mL/min/1.73 m\^2. LFU visit occurred within 20 to 35 days after last dose of study treatment (IV or oral).

  LFU visit (up to a maximum study duration of 50 days)

Secondary Outcomes (12)

• Plasma Concentrations of Ceftazidime and Avibactam

  15, 30-90, 300-360 minutes post-dose on Day 3

• Percentage of Participants With Favorable Clinical Response (CR) at End of 72 Hours Treatment: Intent-to-treat (ITT) Analysis Population

  End of 72 hours study drug treatment on Day 1

• Percentage of Participants With Favorable Clinical Response (CR) at End of Intravenous Therapy (EOIV) Visit: Intent-to-treat (ITT) Analysis Population

  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

  EOT visit (up to Day 17)

• Percentage of Participants With Favorable Clinical Response (CR) at Test of Cure (TOC) Visit: Intent-to-treat (ITT) Analysis Population

  TOC visit (up to a maximum study duration of 50 days)

Study Arms (2)

CAZ-AVI and metronidazole

EXPERIMENTAL

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

Drug: Ceftazidime -avibactam; Drug: Metronidazole

Meropenem

ACTIVE COMPARATOR

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

Drug: Meropenem

Interventions

Ceftazidime -avibactam DRUG

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

CAZ-AVI and metronidazole

Meropenem DRUG

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

Meropenem

Metronidazole DRUG

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

CAZ-AVI and metronidazole

Eligibility Criteria

• Age: 3 Months - 17 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• 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).
• Written informed consent from parent(s) or other legally acceptable representative(s), and informed assent from patient (if age appropriate according to local regulations)
• 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.
• Requires surgical intervention that is expected to be completed within 24 hours of enrolment Laparotomy, laparoscopy, or percutaneous drainage
• 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)
• Physical Findings consistent with intra-abdominal infection, such as:
• Abdominal pain and/or tenderness Localised or diffuse abdominal wall rigidity Abdominal mass
• Intention to send specimens from the surgical intervention for culture
• 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:
• Appendiceal perforation or peri-appendiceal abscess
• Cholecystitis with gangrenous rupture or perforation or progression of the infection beyond the gallbladder wall
• Acute gastric or duodenal perforations, only if operated on \>24 hours after singular perforation occurs
• Traumatic perforation of the intestines, only if operated on \>12 hours after perforation occurs

You may not qualify if:

• Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site)
• Previous enrolment or randomisation in the present study
• 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)
• History of hypersensitivity reactions to carbapenems, cephalosporins, penicillin, other β lactam antibiotics metronidazole or to nitroimidazole derivatives
• Concurrent infection, that may interfere with the evaluation of response to the study antibiotics at the time of randomisation
• 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)
• 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
• Patient is considered unlikely to survive the 6 to 8 week study period
• Patient is unlikely to respond to 7 to 15 days of treatment with antibiotics
• Patient is receiving haemodialysis or peritoneal dialysis
• 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)
• 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
• 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
• Presence of any of the following clinically significant laboratory abnormalities:
• Haematocrit \<25% or haemoglobin \<8 g/dL (\<80g/L , \<4.9 mmol/L)

Sponsors & Collaborators

• Pfizer: lead

Study Sites (35)

CHOC Children's

Orange, California, 92868, United States

Location

Rady Children's Hospital San Diego

San Diego, California, 92123, United States

Location

ProMedica Toledo Children's Hospital

Toledo, Ohio, 43606, United States

Location

The Children's Hospital at Saint Francis

Tulsa, Oklahoma, 74136, United States

Location

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

Kolin III, 280 00, Czechia

Location

Lekarna Oblastni Nemocnice Kolin, a.s.

Kolin III, 280 02, Czechia

Location

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

Most, 434 64, Czechia

Location

Lekarna Nemocnice Most, o.z.

Most, 434 64, Czechia

Location

Fakultni Nemocnice Ostrava - Klinika Detskeho Lekarstvi

Ostrava - Poruba, 708 52, Czechia

Location

Lekarna Fakultni Nemocnice Ostrava

Ostrava - Poruba, 708 52, Czechia

Location

Lekarna Thomayerovy Nemocnice

Praha 4 - Krc, 140 59, Czechia

Location

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

Praha 4 - Krc, 140 59, Czechia

Location

Lekarna Nemocnice Strakonice

Strakonice, 386 29, Czechia

Location

Nemocnice Strakonice, a.s. - Detske oddeleni

Strakonice, 386 29, Czechia

Location

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

Athens, Attica, 11527, Greece

Location

General Hospital of Thessaloniki "Hippokratio"

Thessaloniki, Macedonia, 54642, Greece

Location

Semmelweis Egyetem, II. sz. Gyermekgyogyaszati Klinika

Budapest, 1094, Hungary

Location

Kanizsai Dorottya Korhaz, Csecsemo es Gyermekgyogyaszati Osztaly

Nagykanizsa, 8800, Hungary

Location

Pecsi Tudomanyegyetem, AOK, Klinikai Kozpont, Gyermekgyogyaszati Klinika

Pécs, 7623, Hungary

Location

Szegedi Tudomanyegyetem, Szent-Gyorgyi Albert Klinikai Kozpont

Szeged, 6720, Hungary

Location

Tolna Megyei Balassa Janos Korhaz, Gyermekgyogyaszati Osztaly

Szekszárd, 7100, Hungary

Location

Uniwersytecki Szpital Dzieciecy w Lublinie

Lublin, 20-093, Poland

Location

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

Iași, 700309, Romania

Location

State Budgetary Educational Institution of Higher Professional Education

Smolensk, Smolensk Oblast, 214019, Russia

Location

Hospital Universitario Germans Trias i Pujol

Badalona, Barcelona, 08916, Spain

Location

Hospital de Sant Joan de Deu

Esplugues de Llobregat, Barcelona, 08950, Spain

Location

Hospital Clinico San Carlos

Madrid, 28040, Spain

Location

Hospital Universitario Fundacion Jimenez Diaz

Madrid, 28040, Spain

Location

Hospital Universitario y Politecnico la Fe

Valencia, 46026, Spain

Location

Kaohsiung Veterans General Hospital

Kaohsiung City, 81362, Taiwan

Location

Taichung Veterans General Hospital

Taichung, 40705, Taiwan

Location

Department of Pediatrics, Mackay Memorial Hospital

Taipei, 10449, Taiwan

Location

Cukurova Universitesi Tip Fakultesi Balcali Hastanesi

Adana, 01330, Turkey (Türkiye)

Location

Eskisehir Osmangazi Universitesi Saglik Uygulama ve Arastirma Hastanesi

Eskişehir, 26040, Turkey (Türkiye)

Location

Celal Bayar Universitesi Hafsa Sultan Hastanesi

Manisa, 45030, Turkey (Türkiye)

Location

Related Publications (2)

• 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.

  PMID: 34687548 DERIVED

• 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.

  PMID: 31306396 DERIVED

MeSH Terms

Interventions

avibactam, ceftazidime drug combination; Meropenem; Metronidazole

Intervention Hierarchy (Ancestors)

Thienamycins; Carbapenems; beta-Lactams; Lactams; Amides; Organic Chemicals; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Nitroimidazoles; Nitro Compounds; Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring

Results Point of Contact

• Title: Pfizer ClinicalTrials.gov Call Center
• Organization: Pfizer, Inc.

ClinicalTrials.gov_Inquiries@pfizer.com

1-800-718-1021

Study Officials

• Pfizer CT.gov Call Center

  Pfizer

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 25, 2015
• First Posted: June 19, 2015
• Study Start: August 1, 2015
• Primary Completion: June 1, 2017
• Study Completion: June 1, 2017
• Last Updated: August 9, 2018
• Results First Posted: August 9, 2018

Record last verified: 2018-07

Locations

HU (5); TU (3); RO (1); ES (5); RU (1); GR (2); US (4); TW (3); CZ (10); PL (1)