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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)

Information source: AstraZeneca
ClinicalTrials.gov processed this data on August 23, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Complicated Intra-abdominal Infections (cIAIs)

Intervention: Ceftazidime -avibactam (Drug); Meropenem (Drug); Metronidazole (Drug)

Phase: Phase 2

Status: Recruiting

Sponsored by: AstraZeneca

Official(s) and/or principal investigator(s):
Paul Newell, MD, Study Director, Affiliation: Medical Sciences Director

Overall contact:
AstraZeneca Clinical Study Information Center, Phone: 1-877-240-9479, Email: information.center@astrazeneca.com

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)

Clinical Details

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 design: Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Single Blind (Outcomes Assessor), Primary Purpose: Treatment

Primary outcome:

Number of patients with adverse events as a measure of safety and tolerability

Number of patients with serious adverse events as a measure of safety and tolerability

Number of patients with laboratory tests as a measure of safety and tolerability

Number of patients with laboratory tests as a measure of safety and tolerability

Number of patients with laboratory tests as a measure of safety and tolerability

Number of patients with laboratory tests as a measure of safety and tolerability

Number of patients with vital signs as a measure of safety and tolerability

Number of patients with ECGs as a measure of safety and tolerability

Number of patients with ECGs as a measure of safety and tolerability

Number of patients with ECGs as a measure of safety and tolerability

Secondary outcome:

Number of patients with each clinical outcome

Number of patients with each microbiological response

Number of patients with clinical relapse

Plasma concentration of CAZ-AVI from blood sampling

Number of patients with each clinical outcome

Number of patients with each clinical outcome

Number of patients with each clinical outcome

Number of patients with each microbiological response

Number of patients with each microbiological response

Number of patients with each microbiological response

Plasma concentration of CAZ-AVI from blood sampling

Plasma concentration of CAZ-AVI from blood sampling

Number of patients with emergent infections

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 as specified below, at the Investigator's discretion. 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

Minimum age: 3 Months. Maximum age: 18 Years. Gender(s): Both.

Criteria:

Inclusion Criteria: 1. Must be ≥3 calendar months to <18 years of age. 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: 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 or metronidazole 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 more than 24 hours immediately preceding the start of the infusion of the first dose of IV study drug therapy, except in proven resistant organisms and or worsening of the clinical condition 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. Absolute neutrophil count <500/mm3 3. Platelet count <50,000/mm3 4. 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 d): unless if these values are acute and directly related to the infectious process being treated. 15. Creatinine clearance ≤50 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. Patient has: 1. Evidence of immunocompromising condition 2. Concomitant medications that could interfere with the evaluation of antibacterial drug efficacy (e. g., immunosuppressant therapy) 3. Requirement for high-dose (eg, ≥2 mg/kg/day or a maximum of 20 mg/day of prednisone or equivalent) or prolonged systemic corticosteroid therapy. (Short courses of corticosteroids, such as those for currently worsening asthma, are permitted.) 17. History of seizures, excluding well-documented febrile seizure of childhood 18. Any situation or condition (eg, cystic fibrosis, severe burns, malignancy, hepatitis B virus, hepatitis C virus, or human immunodeficiency virus) 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 19. If female, currently pregnant or breast feeding

Locations and Contacts

AstraZeneca Clinical Study Information Center, Phone: 1-877-240-9479, Email: information.center@astrazeneca.com

Research Site, Buenos Aires, Argentina; Not yet recruiting

Research Site, Ciudad Autónoma de Buenos Aire, Argentina; Not yet recruiting

Research Site, Cordoba, Argentina; Not yet recruiting

Research Site, Gral. Pacheco, Argentina; Not yet recruiting

Research Site, Rosario, Argentina; Not yet recruiting

Research Site, Talar, Argentina; Not yet recruiting

Research Site, Puente Alto, Chile; Not yet recruiting

Research Site, Santiago de Chile, Chile; Not yet recruiting

Research Site, Kolín III, Czech Republic; Not yet recruiting

Research Site, Most, Czech Republic; Not yet recruiting

Research Site, Ostrava - Poruba, Czech Republic; Not yet recruiting

Research Site, Plzeň-Lochotín, Czech Republic; Not yet recruiting

Research Site, Prague 4 - Krc, Czech Republic; Not yet recruiting

Research Site, Strakonice I, Czech Republic; Not yet recruiting

Research Site, Vyškov, Czech Republic; Not yet recruiting

Research Site, Athens, Greece; Not yet recruiting

Research Site, Thessaloniki, Greece; Not yet recruiting

Research Site, Budapest, Hungary; Not yet recruiting

Research Site, Cegléd, Hungary; Not yet recruiting

Research Site, Nagykanizsa, Hungary; Not yet recruiting

Research Site, Nyíregyháza, Hungary; Not yet recruiting

Research Site, Pecs, Hungary; Not yet recruiting

Research Site, Szeged, Hungary; Not yet recruiting

Research Site, Szekszárd, Hungary; Not yet recruiting

Research Site, Szombathely, Hungary; Not yet recruiting

Research Site, Székesfehérvár, Hungary; Not yet recruiting

Research Site, Lublin, Poland; Not yet recruiting

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Research Site, Rzeszów, Poland; Not yet recruiting

Research Site, Brasov, Romania; Not yet recruiting

Research Site, Constanta, Romania; Not yet recruiting

Research Site, Iasi, Romania; Not yet recruiting

Research Site, Targu-Mures, Romania; Not yet recruiting

Research Site, Timisoara, Romania; Not yet recruiting

Research Site, Kemerovo, Russian Federation; Not yet recruiting

Research Site, Smolensk, Russian Federation; Not yet recruiting

Research Site, Barcelona, Spain; Recruiting

Research Site, Esplugues de Llobregat (Barc), Spain; Not yet recruiting

Research Site, Madrid, Spain; Not yet recruiting

Research Site, Valencia, Spain; Not yet recruiting

Research Site, Kaohsiung, Taiwan; Not yet recruiting

Research Site, Taichung, Taiwan; Not yet recruiting

Research Site, Taipei, Taiwan; Not yet recruiting

Research Site, Adana, Turkey; Not yet recruiting

Research Site, Diyarbakir, Turkey; Not yet recruiting

Research Site, Eskisehir, Turkey; Not yet recruiting

Research Site, Istanbul, Turkey; Not yet recruiting

Research Site, Manisa, Turkey; Not yet recruiting

Research Site, Long Beach, California, United States; Not yet recruiting

Research Site, Los Angeles, California, United States; Not yet recruiting

Research Site, Orange, California, United States; Not yet recruiting

Research Site, San Diego, California, United States; Not yet recruiting

Research Site, West Palm Beach, Florida, United States; Not yet recruiting

Research Site, Augusta, Georgia, United States; Not yet recruiting

Research Site, Louisville, Kentucky, United States; Not yet recruiting

Research Site, Royal Oak, Michigan, United States; Not yet recruiting

Research Site, Las Vegas, Nevada, United States; Not yet recruiting

Research Site, New Brunswick, New Jersey, United States; Not yet recruiting

Research Site, New York, New York, United States; Not yet recruiting

Research Site, Toledo, Ohio, United States; Not yet recruiting

Research Site, Tulsa, Oklahoma, United States; Not yet recruiting

Research Site, Austin, Texas, United States; Not yet recruiting

Research Site, Houston, Texas, United States; Not yet recruiting

Research Site, Richmond, Virginia, United States; Not yet recruiting

Additional Information

Starting date: July 2015
Last updated: August 19, 2015

Page last updated: August 23, 2015

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