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    Summary
    EudraCT Number:2014-003242-28
    Sponsor's Protocol Code Number:D4280C00015
    National Competent Authority:Czechia - SUKL
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2015-05-06
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedCzechia - SUKL
    A.2EudraCT number2014-003242-28
    A.3Full title of the trial
    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)
    Jednoduše zaslepené, randomizované, multicentrické klinické hodnocení s aktivní kontrolou hodnotící bezpečnost, snášenlivost, farmakokinetiku a účinnost ceftazidimu a avibaktamu v kombinaci s metronidazolem, ve srovnání se meropenem u dětí od 3 měsíců do 18 let věku s komplikovanou nitrobřišní infekcí (kNBI)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    This study will assess the safety, efficacy and pharmacokinetics of ceftazidime avibactam +metronidazole vs meropenem in pediatric population with complicated Intra-abdominal infections
    A.4.1Sponsor's protocol code numberD4280C00015
    A.7Trial is part of a Paediatric Investigation Plan Yes
    A.8EMA Decision number of Paediatric Investigation PlanP/133/2014
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorPfizer Inc.
    B.1.3.4CountryUnited States
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportPfizer Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationPfizer Inc.
    B.5.2Functional name of contact pointClinical Trials.gov Call Center
    B.5.3 Address:
    B.5.3.1Street Address235 East 42nd Street
    B.5.3.2Town/ cityNew York
    B.5.3.3Post codeNY 10017
    B.5.3.4CountryUnited States
    B.5.4Telephone number1800718 1021
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameceftazidime avibactam
    D.3.2Product code CAZ104
    D.3.4Pharmaceutical form Powder for concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation Yes
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNceftazidime pentahydrate
    D.3.9.1CAS number 78439-06-2
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number2000
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNAvibactam
    D.3.9.1CAS number 1192491-61-4
    D.3.9.2Current sponsor codeNXL104
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number500
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleComparator
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Meronem
    D.2.1.1.2Name of the Marketing Authorisation holderAstraZeneca
    D.2.1.2Country which granted the Marketing AuthorisationUnited Kingdom
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product namemeropenem
    D.3.4Pharmaceutical form Powder for solution for injection/infusion
    D.3.4.1Specific paediatric formulation Yes
    D.3.7Routes of administration for this IMPIntramuscular and intravenous use (Noncurrent)
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNmeropenem
    D.3.9.2Current sponsor code119478-56-7
    D.3.9.3Other descriptive nameMeropenem trihydrate
    D.3.10 Strength
    D.3.10.1Concentration unit g gram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Complicated Intra-Abdominal Infection (cIAI)
    E.1.1.1Medical condition in easily understood language
    Abdominal infection
    E.1.1.2Therapeutic area Diseases [C] - Bacterial Infections and Mycoses [C01]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10056570
    E.1.2Term Intra-abdominal infection
    E.1.2System Organ Class 100000016609
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Evaluate the safety and tolerability of CAZ AVI plus metronidazole given at the selected dose regimen versus meropenem in paediatric patients aged ≥3 months to <18 years with cIAI
    E.2.2Secondary objectives of the trial
    Evaluate the descriptive efficacy of CAZ AVI plus metronidazole versus meropenem in paediatric patients aged ≥3 months to <18 years with cIAI

    Evaluate the PK of CAZ AVI in paediatric patients aged ≥3 months to <18 years with cIAI
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Must be ≥3 calendar months to <18 years of age. Patient 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) (a) Patient reports sexual abstinence for the prior 3 months or reports use of at least one 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 (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:
    (a) Requires surgical intervention that is expected to be completed within 24 hours of enrolment
     Laparotomy, laparoscopy, or percutaneous drainage
    (b) Evidence of a systemic inflammatory response (at least one):
     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)
    (c) Physical Findings consistent with intra-abdominal infection, such as:
     Abdominal pain and/or tenderness
     Localised or diffuse abdominal wall rigidity
     Abdominal mass
    (d) Intention to send specimens from the surgical intervention for culture
    (e) (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 or
    (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 one of these diagnoses:
    (a) Appendiceal perforation or peri-appendiceal abscess
    (b) Cholecystitis with gangrenous rupture or perforation or progression of the infection beyond the gallbladder wall
    (c) Acute gastric or duodenal perforations, only if operated on >24 hours after singular perforation occurs
    (d) Traumatic perforation of the intestines, only if operated on >12 hours after perforation occurs
    (e) Secondary peritonitis (but not spontaneous bacterial peritonitis associated with cirrhosis and chronic ascites)
    E.4Principal 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 or metronidazole or to nitroimidazole derivates
    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 antibiotic 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:
    (a) Haematocrit <25% or haemoglobin <8 g/dL (<80g/L , <4.9mmol/L)
    (b) 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) and 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

    E.5 End points
    E.5.1Primary end point(s)
    To assess the safety and tolerability by :
    a) adverse events (AEs) and serious adverse events(SAEs)
    b) vital signs (pulse , blood pressure , respiratory rate, temperature)
    c) ECG (electrocardiogram)
    d) laboratory tests(complete blood count with differential and comprehensive metabolic panel )
    e) creatinine clearance (CrCl)
    E.5.1.1Timepoint(s) of evaluation of this end point
    a) from ICF to LFU visit (27 to 50 days after start of study treatment)
    b)from ICF to LFU visit (27 to 50 days after start of study treatment)
    c) baseline, Day 1, TOC
    d)baseline , Days 4 to 15, EoIV (end of intravenous treatment) and TOC (test of cure); if clinically indicated (Days2 and 3; EOT and LFU)
    e)baseline, Days 4 to 15, EoIV (end of intravenous treatment) and TOC (test of cure); if clinically indicated (Days2 and 3; EOT and LFU)
    E.5.2Secondary end point(s)
    1.To assess the efficacy by:
    a) clinical outcomes
    b)microbiological response
    c)clinical relapse
    d) emergent infections

    2. To evaluate the PK of CAZ-AVI in pediatric patients aged aged ≥3 months to <18 years with cIAI
    E.5.2.1Timepoint(s) of evaluation of this end point
    1
    a)end of 72 hours' treatment, end of intravenous treatment (EOIV), end of treatment (EOT) and test of cure (TOC)
    b) EOIV, EOT, TOC and LFU
    c)LFU
    d)study duration

    2. Days 2 and 3
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    tolerability
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind Yes
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    meropenem
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned7
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA41
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Argentina
    Chile
    Czech Republic
    Greece
    Hungary
    Poland
    Romania
    Russian Federation
    Spain
    Taiwan
    Turkey
    United States
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    last patient last visit
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months10
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months10
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) Yes
    F.1.1.4.1Number of subjects for this age range: 14
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 54
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 34
    F.1.2Adults (18-64 years) No
    F.1.3Elderly (>=65 years) No
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    subjects below the age of consent
    F.3.3.7Others Yes
    F.3.3.7.1Details of other specific vulnerable populations
    children from 3 months to 18 years old
    F.4 Planned number of subjects to be included
    F.4.1In the member state25
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 70
    F.4.2.2In the whole clinical trial 102
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    standard of care
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2015-05-05
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-03-11
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2017-06-01
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