A Study Comparing Ceftazidime-Avibactam+Metronidazole Versus Meropenem in Adults With Complicated Intra-abdominal Infections

Complicated Intra-Abdominal Infection Clinical Trial

Official title:

A Phase III, Randomized, Multicenter, Double Blind, Double-Dummy, Parallel-Group, Comparative Study to Determine the Efficacy, Safety, and Tolerability of Ceftazidime Avibactam Plus Metronidazole Versus Meropenem in the Treatment of Complicated Intra-Abdominal Infections In Hospitalized Adults

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01500239
• Other study ID #: D4280C00005
• Secondary ID: 2011-003895-35
• Status: Completed
• Phase: Phase 3
• First received: December 22, 2011
• Last updated: January 29, 2016
• Start date: April 2012
• Est. completion date: April 2014

Study information

• Verified date: January 2016
• Source: AstraZeneca
• Contact: n/a
• Is FDA regulated: No
• Health authority: Argentina: Administracion Nacional de Medicamentos, Alimentos y Tecnologia MedicaBelgium: Federal Agency for Medicinal Products and Health ProductsBrazil: National Health Surveillance AgencyBulgaria: Bulgarian Drug AgencyChile: Instituto de Salud Pública de ChileCzech Republic: State Institute for Drug ControlFrance: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)Germany: Federal Institute for Drugs and Medical DevicesGreece: National Organization of MedicinesIndia: Drugs Controller General of IndiaIsrael: Ministry of HealthItaly: National Institute of HealthRomania: National Medicines AgencyRussia: Ministry of Health of the Russian FederationSpain: Spanish Agency of MedicinesThailand: Food and Drug AdministrationTurkey: Ministry of HealthUkraine: State Pharmacological Center - Ministry of HealthUnited States: Food and Drug AdministrationCanada: Health Canada
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to evaluate the effects of Ceftazidime Avibactam plus Metronidazole compared to Meropenem for treating hospitalized patients with complicated intra-abdominal infections.

Description:

A Phase III, Randomized, Multicenter, Double Blind, Double-Dummy, Parallel-Group, Comparative Study to Determine the Efficacy, Safety, and Tolerability of Ceftazidime Avibactam Plus Metronidazole Versus Meropenem in the Treatment of Complicated Intra-Abdominal Infections In Hospitalized Adults

Recruitment information / eligibility

• Status: Completed
• Enrollment: 577
• Est. completion date: April 2014
• Est. primary completion date: April 2014
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 90 Years

Eligibility

Inclusion Criteria:

• 18 to 90 years of age inclusive

• Female patient is authorized to participate if at least one of the following criteria are met: (a) Surgical sterilization (b) Age =50 years and postmenopausal as defined by amenorrhea for 12 months or more following cessation of all exogenous hormonal treatments (c) Age <50 years and postmenopausal as defined by documented LH and FSH levels in the postmenopausal range PLUS amenorrhea for 12 months or more following cessation of all exogenous hormonal treatments (d) Patient has a negative serum pregnancy test (serum ß-human chorionic gonadotropin [ß-hCG]) within 1 day prior to study entry, and agrees to use highly effective contraception methods during treatment and for at least 7 days after last dose of IV study therapy - Intraoperative/postoperative enrollment with confirmation (presence of pus within the abdominal cavity) of an intra-abdominal infection associated with peritonitis

• Confirmation of infection by surgical intervention within 24 hours of entry: evidence of systemic inflammatory response; physical findings consistent with intra-abdominal infection; supportive radiologic imaging findings of intra-abdominal infections

Exclusion Criteria:

• Patient is diagnosed with traumatic bowel perforation undergoing surgery within 12 hours; perforation of gastroduodenal ulcers undergoing surgery within 24 hours. Other intra-abdominal processes in which primary etiology is not likely to be infectious

• Patient has abdominal wall abscess or bowel obstruction without perforation or ischemic bowel without perforation

• Patient has suspected intra-abdominal infections due to fungus, parasites, virus or tuberculosis - Patient is considered unlikely to survive the 6 to 8 week study period or has a rapidly progressive or terminal illness, including septic shock that is associated with a high risk of mortality

Study Design

Allocation: Randomized, Endpoint Classification: Safety Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Complicated Intra-Abdominal Infection
• Infection
• Intraabdominal Infections

Intervention

Drug:
• CAZ-AVI
Ceftazidime 2000 mg and 500 mg of avibactam
• Metronidazole
500 mg of Metronidazole
• Meropenem
1 gram of Meropenem

Locations

Country	Name	City	State
Argentina	Research Site	Córdoba
Argentina	Research Site	Mendoza
Argentina	Research Site	Rosario
Argentina	Research Site	Santa Fe
Belgium	Research Site	Antwerpen
Belgium	Research Site	Brussels (Jette)
Brazil	Research Site	Belo Horizonte
Brazil	Research Site	Curitiba
Brazil	Research Site	Passo Fundo
Bulgaria	Research Site	Plovdiv
Bulgaria	Research Site	Ruse
Bulgaria	Research Site	Sofia
Bulgaria	Research Site	Varna
Canada	Research Site	Greenfield Park	Quebec
Chile	Research Site	Vina del MAr
Croatia	Research Site	Zagreb
Czech Republic	Research Site	Decin
Czech Republic	Research Site	Hradec Kralove
Czech Republic	Research Site	Jihlava
Czech Republic	Research Site	Kolin
Czech Republic	Research Site	Kyjov
Czech Republic	Research Site	Melnik
Czech Republic	Research Site	Olomouc
Czech Republic	Research Site	Praha 10
Czech Republic	Research Site	Praha 10, Prague
Czech Republic	Research Site	Praha 4
Czech Republic	Research Site	Praha 5
Czech Republic	Research Site	Praha 6
Czech Republic	Research Site	Teplice
France	Research Site	Argenteuil
France	Research Site	Clermont-ferrand
France	Research Site	Limoges
France	Research Site	Marseille
France	Research Site	Nantes
Germany	Research Site	Heidelberg
Germany	Research Site	Leipzig
Greece	Research Site	Athens
Greece	Research Site	Thessaloniki
Hungary	Research Site	Budapest
Hungary	Research Site	Székesfehérvár
India	Research Site	Ahmedabad
India	Research Site	Bangalore
India	Research Site	Hyderabad
India	Research Site	Lucknow
India	Research Site	New Delhi
India	Research Site	Pune
India	Research Site	Trivandrum
India	Research Site	Vadodara
Israel	Research Site	Hadera
Israel	Research Site	Haifa
Israel	Research Site	Holon
Israel	Research Site	Jerusalem
Israel	Research Site	Rehovot
Italy	Research Site	Rozzano
Latvia	Research Site	Riga
Lithuania	Research Site	Kaunas
Lithuania	Research Site	Klaipeda
Lithuania	Research Site	Klajpeda
Malaysia	Research Site	Alor Setar
Mexico	Research Site	Durango
Mexico	Research Site	Guadalajara, Jalisco
Mexico	Research Site	Mexico City
Netherlands	Research Site	Enschede
Netherlands	Research Site	s-Hertogenbosch
Peru	Research Site	Arequipa
Peru	Research Site	Cercardo de Lima
Peru	Research Site	Lima
Peru	Research Site	Trujillo
Romania	Research Site	Bucharest
Romania	Research Site	Cluj-Napoca
Romania	Research Site	Iasi
Romania	Research Site	Timisoara
Russian Federation	Research Site	Kemerovo
Russian Federation	Research Site	Moscow
Russian Federation	Research Site	Perm
Russian Federation	Research Site	Saratov
Russian Federation	Research Site	Smolensk
Russian Federation	Research Site	Vsevolozhsk
South Africa	Research Site	Pretoria
Spain	Research Site	Alcorcón
Spain	Research Site	Alicante
Spain	Research Site	Alzira (Valencia)
Spain	Research Site	Barcelona
Spain	Research Site	Elche
Spain	Research Site	Granollers
Spain	Research Site	Madrid
Spain	Research Site	Sabadell(Barcelona)
Spain	Research Site	Terrassa
Taiwan	Research Site	Kaohsiung
Taiwan	Research Site	Taichung
Taiwan	Research Site	Tainan
Taiwan	Research Site	Taipei
Thailand	Research Site	Bangkok
Thailand	Research Site	Khon Kaen
Thailand	Research Site	Phisanulok
Thailand	Research Site	Songkla
Turkey	Research Site	Antalya
Turkey	Research Site	Trabzon
Ukraine	Research Site	Chernivtsi
Ukraine	Research Site	Dnipropetrovsk
Ukraine	Research Site	Ivano-Frankivsk
Ukraine	Research Site	Kharkov
Ukraine	Research Site	Kyiv
Ukraine	Research Site	Odesa
Ukraine	Research Site	Poltava
Ukraine	Research Site	Zaporizhzhya
United States	Research Site	Boston	Massachusetts
United States	Research Site	Chula Vista	California
United States	Research Site	Denver	Colorado
United States	Research Site	Minneapolis	Minnesota
United States	Research Site	San Diego	California
United States	Research Site	Somers Point	New Jersey
United States	Research Site	St. Louis	Missouri
United States	Research Site	Stanford	California
United States	Research Site	Torrance	California

Sponsors (2)

Lead Sponsor	Collaborator
AstraZeneca	Forest Laboratories

Countries where clinical trial is conducted

United States,  Argentina,  Belgium,  Brazil,  Bulgaria,  Canada,  Chile,  Croatia,  Czech Republic,  France,  Germany,  Greece,  Hungary,  India,  Israel,  Italy,  Latvia,  Lithuania,  Malaysia,  Mexico,  Netherlands,  Peru,  Romania,  Russian Federation,  South Africa,  Spain,  Taiwan,  Thailand,  Turkey,  Ukraine, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Clinical Response at the Test of Cure (TOC) Visit in the Microbiologically Modified Intent-To-Treat (mMITT) Analysis Set (Primary Outcome for FDA).	The number of patients meeting the cure criteria: complete resolution or significant improvement of signs and symptoms of the index infection such that no further antibacterial therapy, drainage, or surgical intervention is necessary. Indeterminate response are where study data were not available for evaluation of efficacy for any reason, including patient lost to follow-up or assessment not undertaken such that a determination of clinical response could not be made, death where cIAI was clearly noncontributory or circumstances that precluded classification as a cure or failure. Results from two identical protocols D4280C00001 and D4280C00005 combined into a single database with agreement from FDA and EMA.	TOC: 28 to 35 days after start of study drug	No
Primary	Clinical Response at the TOC Visit in the Modified Intent-To-Treat Analysis Set (Co-primary Outcome for Rest of World [ROW]).	The number of patients meeting the cure criteria: complete resolution or significant improvement of signs and symptoms of the index infection such that no further antibacterial therapy, drainage, or surgical intervention was necessary. Indeterminate response are where study data were not available for evaluation of efficacy for any reason, including patient lost to follow-up or assessment not undertaken such that a determination of clinical response could not be made, dDeath where cIAI was clearly noncontributory or circumstances that precluded classification as a cure or failure.	TOC: 28 to 35 days after start of study drug	No
Primary	Clinical Response at the TOC Visit in the Clinically Evaulable (CE) Analysis Set (Co-primary Outcome for Rest of World [ROW]).	The number of patients meeting the cure criteria: complete resolution or significant improvement of signs and symptoms of the index infection such that no further antibacterial therapy, drainage, or surgical intervention was necessary.	TOC: 28 to 35 days after start of study drug	No
Secondary	Clinical Cure at TOC in the Microbiologically Evaluable Analysis Set	The number of patients meeting the cure criteria: complete resolution or significant improvement of signs and symptoms of the index infection such that no further antibacterial therapy, drainage, or surgical intervention was necessary.	TOC: 28 to 35 days after start of study drug	No
Secondary	Clinical Cure at TOC in the Extended Microbiologically Evaluable Analysis Set	The number of patients meeting the cure criteria: complete resolution or significant improvement of signs and symptoms of the index infection such that no further antibacterial therapy, drainage, or surgical intervention was necessary.	TOC: 28 to 35 days after start of study drug	No
Secondary	Clinical Response by Visit in the Primary Population: Microbiologically Modified Intent-to-Treat (mMITT)	Complete resolution or significant improvement of signs and symptoms of the index infection such that no further antibacterial therapy, drainage, or surgical intervention was necessary. Indeterminate response are where study data were not available for evaluation of efficacy for any reason, including patient lost to follow-up or assessment not undertaken such that a determination of clinical response could not be made, dDeath where cIAI was clearly noncontributory or circumstances that precluded classification as a cure or failure.	EOT: within 24 hours after last dose of study drug. TOC: 28 to 35 days after start of study drug. LFU: 42 to 49 days after start of study drug	No
Secondary	Per-patient Microbiological Response in the Microbiologically Modified Intent- To-Treat Analysis Set	Microbiological responses as per the protocoled criteria: responses other than "indeterminate" were classified as "favorable" or "unfavorable." Favorable microbiological response assessments included "eradication" and "presumed eradication." Unfavorable microbiological response assessments included "persistence," "persistence with increasing minimum inhibitory concentration (MIC)," and "presumed persistence." Indeterminate microbiologic response assessments included cases where the clinical response was changed to indeterminate due to an SRP assessment of inadequate source control (ie, circumstances that preclude classification as eradication, presumed eradication, persistence, persistence with increasing MIC, and presumed persistence).	EOT: within 24 hours after last dose of study drug. TOC: 28 to 35 days after start of study drug. LFU 42 to 49 days after start of study drug	No
Secondary	Per-pathogen Microbiological Response at TOC in the Microbiologically Modified Intent-To-Treat Analysis Set.	The number of patients with a favorable per-pathogen microbiological response: favourable microbiological response includes: Eradication Absence of causative pathogen from specimens at the site of infection. Presumed eradication where, repeat cultures were not performed/clinically indicated in a patient who had a clinical response of cure.	TOC: 28 to 35 days after start of study drug.	No
Secondary	Clinical Response by Pathogen at TOC for Patients Infected With Ceftazidime-resistant Pathogens in Microbiological Modified Intent to Treat Analysis Set	Complete resolution or significant improvement of signs and symptoms of the index infection such that no further antibacterial therapy, drainage, or surgical intervention was necessary.	Test of Cure: 28 to 35 days after start of study drug	No
Secondary	Favorable Per-pathogen Microbiological Response for Patients Infected With Ceftazidime-resistant Pathogens in mMITT Analysis Set	The number of patients with a favorable per-pathogen microbiological response: favourable microbiological response includes: Eradication Absence of causative pathogen from specimens at the site of infection. Presumed eradication where, repeat cultures were not performed/clinically indicated in a patient who had a clinical response of cure.	TOC: 28 to 35 days after start of study drug	No
Secondary	Per-patient Microbiological Response at TOC for Patients Infected With Ceftazidime-resistant Pathogens in mMITT Analysis Set	Microbiological responses other than "indeterminate" were classified as "favorable" or "unfavorable." Favorable microbiological response assessments included "eradication" and "presumed eradication." Unfavorable microbiological response assessments included "persistence," "persistence with increasing minimum inhibitory concentration (MIC)," and "presumed persistence." Indeterminate microbiologic response assessments included cases where the clinical response was changed to indeterminate due to a surgical review panel (SRP) assessment of inadequate source control (ie, circumstances that preclude classification as eradication, presumed eradication, persistence, persistence with increasing MIC, and presumed persistence).	Test of Cure: 28 to 35 days after start of study drug	No
Secondary	Number of Patients Afebrile at Last Observation in the Clinically Evaluable Analysis Set for Patients Who Have Fever at Study Entry	Time to first defervescence was calculated for patients with a fever (>38ºC) at baseline.; Defervescence (=37.8ºC) was defined as the absence of fever based on the highest temperature recorded on each study day.	Test of Cure: 1 to 14 days after start of study drug	No
Secondary	Plasma Concentrations for Ceftazidime and Avibactam	Blood samples were taken from all patients on Day 3 for the pharmacokinetic evaluation of ceftazidime and avibactam plasma concentrations	Anytime within 15 minutes prior to or after stopping study drug, anytime between 30 and 90 minutes after stopping study drug, anytime between 300 minutes and 360 minutes after stopping study drug	No