Compare Ceftazidime-Avibactam + Metronidazole Versus Meropenem for Hospitalized Adults With Complicated Intra-Abdominal Infections

• ClinicalTrials.gov Identifier: NCT01499290
• Recruitment Status: Completed
• First Posted: December 26, 2011
• Results First Posted: March 1, 2016
• Last Update Posted: September 6, 2017
• Sponsor: Pfizer
• Collaborator: Forest Laboratories
• Information provided by (Responsible Party): Pfizer

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Complicated Intra-Abdominal Infection
• Interventions: Drug: CAZ-AVI; Drug: Metronidazole; Drug: Meropenem
• Enrollment: 493

Participant Flow

Recruitment Details	Results from two identical protocols D4280C00001 and D4280C00005 combined into a single database with agreement from FDA and EMA. First patient enrolled 22 March 2012 and last patient's last visit was 07 April 2014. Patients were adults hospitalised with complicated intra-abdominal infection (cIAI) that required surgery and IV antibiotics.
Pre-assignment Details	After obtaining written informed consent patients underwent a preliminary evaluation for eligibility within the 24-hour period prior to initiation of IV study therapy. eligible patients were randomized to 1 of 2 treatment groups in a 1:1 ratio according to the central randomization schedule.

Arm/Group Title	CAZ-AVI + Metronidazole	Meropenem
Arm/Group Description	CAZ (2000mg)/AVI (500mg): IV treatment	1000 mg: IV treatment
Period Title: Overall Study
Started	529 [1]	529 [1]
Completed	474 [2]	494 [2]
Not Completed	55	35
Reason Not Completed
Withdrawal by Subject	22	15
Not specified in study report	11	5
Condition improved/subject recovered	1	0
Lack of Efficacy	7	8
Adverse Event	14	7
[1] Patients dosed in pooled protocols D4280C00001/D4280C00005 (NCT01499290/NCT01500239) agreed with FDA; [2] (Numbers indicate patients who completed treatment)

Baseline Characteristics

Arm/Group Title		CAZ-AVI + Metronidazole	Meropenem	Total
Arm/Group Description		CAZ (2000mg)/AVI (500mg): IV treatment	1000 mg: IV treatment	Total of all reporting groups
Overall Number of Baseline Participants		520	523	1043
Baseline Analysis Population Description		The MITT analysis set includes all patients who met the disease definition for cIAI and received at least 1 dose of study drug. 15 patients excluded received at least one dose of study drug but failed the minimum disease criteria.
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	520 participants	523 participants	1043 participants
		49.8 (17.48)	50.3 (18.29)	50.0 (17.88)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	520 participants	523 participants	1043 participants
	Female	194 37.3%	191 36.5%	385 36.9%
	Male	326 62.7%	332 63.5%	658 63.1%

Outcome Measures

1. Primary Outcome

Title	Clinical Response at the Test of Cure (TOC) Visit in the Microbiologically Modified Intent-To-Treat (mMITT) Analysis Set (Primary Outcome for FDA).
Description	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.
Time Frame	TOC: 28 to 35 days after start of study drug

Outcome Measure Data

Analysis Population Description

The mMITT analysis set included all randomized patients who met the disease definition of cIAI and had at least 1 etiologic pathogen identified at study entry (regardless of isolate susceptibilities). Patients with a bacterial species typically not expected to respond to both study drugs were excluded.

Arm/Group Title	CAZ-AVI + Metronidazole	Meropenem
Arm/Group Description:	CAZ (2000mg)/AVI (500mg): IV treatment	1000 mg: IV treatment
Overall Number of Participants Analyzed	413	410
Measure Type: Number; Unit of Measure: Participants
Clinical cure	337	349
Clinical failure	37	30
Indeterminate	39	31

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	CAZ-AVI + Metronidazole, Meropenem
	Comments	The primary objective of this study (FDA agreed) was to determine the noninferiority in the clinical cure rate for CAZ-AVI compared to that for Meropenem at TOC in the mMITT in adult subjects with cIAI.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Non-inferiority was determined by comparing the lower limit of the 95% confidence interval for risk difference (corresponding to a 97.5% 1-sided lower bound) to the non-inferiority marging of -12.5%
Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	-3.5
	Confidence Interval	(2-Sided) 95%; -8.64 to 1.58
	Estimation Comments	[Not Specified]

2. Primary Outcome

Title	Clinical Response at the TOC Visit in the Modified Intent-To-Treat Analysis Set (Co-primary Outcome for Rest of World [ROW]).
Description	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.
Time Frame	TOC: 28 to 35 days after start of study drug

Outcome Measure Data

Analysis Population Description

The MITT analysis set included all randomized patients who met the disease definition of cIAI and who received any amount of study drug.

Arm/Group Title	CAZ-AVI + Metronidazole	Meropenem
Arm/Group Description:	CAZ (2000mg)/AVI (500mg): IV treatment	1000 mg: IV treatment
Overall Number of Participants Analyzed	520	523
Measure Type: Number; Unit of Measure: Participants
Clinical cure	429	444
Clinical failure	47	39
Indeterminate	44	40

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	CAZ-AVI + Metronidazole, Meropenem
	Comments	The co-primary objective of this study (ROW agreed) was to determine the noninferiority in the clinical cure rate for CAZ-AVI compared to that for Meropenem at TOC in the MITT in adult subjects with cIAI.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Non-inferiority was determined by comparing the lower limit of the 95% confidence interval for risk difference (corresponding to a 97.5% 1-sided lower bound) to the non-inferiority marging of -12.5%
Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	-2.4
	Confidence Interval	(2-Sided) 95%; -6.90 to 2.10
	Estimation Comments	[Not Specified]

3. Primary Outcome

Title	Clinical Response at the TOC Visit in the Clinically Evaulable (CE) Analysis Set (Co-primary Outcome for Rest of World [ROW]).
Description	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.
Time Frame	TOC: 28 to 35 days after start of study drug

Outcome Measure Data

Analysis Population Description

The CE analysis set included all patients who met the disease definition of cIAI and met the stringent criteria for clinical evaluation described in the protocol regarding dosing, concomitant medication, evaluation, etc.

Arm/Group Title	CAZ-AVI + Metronidazole	Meropenem
Arm/Group Description:	CAZ (2000mg)/AVI (500mg): IV treatment	1000 mg: IV treatment
Overall Number of Participants Analyzed	410	416
Measure Type: Number; Unit of Measure: Participants
Clinical cure	376	385
Clinical failure	34	31

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	CAZ-AVI + Metronidazole, Meropenem
	Comments	The co-primary objective of this study (ROW agreed) was to determine the noninferiority in the clinical cure rate for CAZ-AVI compared to that for Meropenem at TOC in the CE in adult subjects with cIAI.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Non-inferiority was determined by comparing the lower limit of the 95% confidence interval for risk difference (corresponding to a 97.5% 1-sided lower bound) to the non-inferiority marging of -12.5%
Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	-0.8
	Confidence Interval	(2-Sided) 95%; -4.61 to 2.89
	Estimation Comments	[Not Specified]

4. Secondary Outcome

Title	Clinical Cure at TOC in the Microbiologically Evaluable Analysis Set
Description	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.
Time Frame	TOC: 28 to 35 days after start of study drug

Outcome Measure Data

Analysis Population Description

ME analysis set defined as all patients included in the CE set with at least 1 Gram negative, aerobic, susceptible pathogen in the initial/prestudy culture.

Arm/Group Title	CAZ-AVI + Metronidazole	Meropenem
Arm/Group Description:	CAZ (2000mg)/AVI (500mg): IV treatment	1000 mg: IV treatment
Overall Number of Participants Analyzed	265	287
Measure Type: Number; Unit of Measure: Participants
Clinical cure	244	272
Clinical failure	21	15

5. Secondary Outcome

Title	Clinical Cure at TOC in the Extended Microbiologically Evaluable Analysis Set
Description	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.
Time Frame	TOC: 28 to 35 days after start of study drug

Outcome Measure Data

Analysis Population Description

Extended ME analysis set defined as all patients included in the CE set with at least 1 Gram negative, aerobic, pathogen in the initial/prestudy culture, regardless of susceptibility.

Arm/Group Title	CAZ-AVI + Metronidazole	Meropenem
Arm/Group Description:	CAZ (2000mg)/AVI (500mg): IV treatment	1000 mg: IV treatment
Overall Number of Participants Analyzed	270	294
Measure Type: Number; Unit of Measure: Participants
Clinical cure	248	278
Clinical failure	22	16

6. Secondary Outcome

Title	Clinical Response by Visit in the Primary Population: Microbiologically Modified Intent-to-Treat (mMITT)
Description	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.
Time Frame	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

Outcome Measure Data

Analysis Population Description

The mMITT analysis set included all randomized patients who met the disease definition of cIAI and had at least 1 etiologic pathogen identified at study entry (regardless of isolate susceptibilities). Patients with a bacterial species typically not expected to respond to both study drugs were excluded.

Arm/Group Title	CAZ-AVI + Metronidazole (EOT)	Meropenem (EOT)	CAZ-AVI + Metronidazole (TOC)	Meropenem (TOC)	CAZ-AVI + Metronidazole (LFU)	Meropenem (LFU)
Arm/Group Description:	EOT - within 24 hours of last dose of study drug	EOT - within 24 hours of last dose of study drug	TOC - 28 to 35 days after start of study drug	TOC - 28 to 35 days after start of study drug	LFU - 42 to 49 days after start of study drug	LFU - 42 to 49 days after start of study drug
Overall Number of Participants Analyzed	413	410	413	410	413	410
Measure Type: Number; Unit of Measure: Participants
Clinical cure	361	379	337	349	340	347
Clinical failure	30	19	37	30	38	31
Indeterminate	22	12	39	31	35	32

7. Secondary Outcome

Title	Per-patient Microbiological Response in the Microbiologically Modified Intent- To-Treat Analysis Set
Description	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 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).
Time Frame	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

Outcome Measure Data

Analysis Population Description

The mMITT analysis set included all randomized patients who met the disease definition of cIAI and had at least 1 etiologic pathogen identified at study entry (regardless of isolate susceptibilities). Patients with a bacterial species typically not expected to respond to both study drugs were excluded.

Arm/Group Title	CAZ-AVI + Metronidazole (EOT)	Meropenem (EOT)	CAZ-AVI + Metronidazole (TOC)	Meropenem (TOC)	CAZ-AVI + Metronidazole (LFU)	Meropenem (LFU)
Arm/Group Description:	EOT - within 24 hours after last dose of study drug	EOT - within 24 hours after last dose of study drug	TOC - 28 to 35 days after start of study drug	TOC - 28 to 35 days after start of study drug	LFU - 42 to 49 days after start of study drug	LFU - 42 to 49 days after start of study drug
Overall Number of Participants Analyzed	413	410	413	410	413	410
Measure Type: Number; Unit of Measure: Participants
Favourable response	362	379	337	349	340	347
Unfavourable response	30	19	37	31	38	32
Indeterminate	21	12	39	30	35	31

8. Secondary Outcome

Title	Per-pathogen Microbiological Response at TOC in the Microbiologically Modified Intent-To-Treat Analysis Set.
Description	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.
Time Frame	TOC: 28 to 35 days after start of study drug.

Outcome Measure Data

Analysis Population Description

The mMITT analysis set included all randomized patients who met the disease definition of cIAI and had at least 1 etiologic pathogen identified at study entry (regardless of isolate susceptibilities). Patients with a bacterial species typically not expected to respond to both study drugs were excluded.

Arm/Group Title	CAZ-AVI + Metronidazole	Meropenem	CAZ-AVI + Metronidazole (Denominator)	Meropenem (Denominator)
Arm/Group Description:	CAZ (2000mg)/AVI (500mg): IV treatment Number of favourable responses	1000 mg: IV treatment. Number of favourable responses	Total number of patiets with each pathogen at baseline (summary only shows pathogens where N>/=10)	Number of patients with pathogen at baseline
Overall Number of Participants Analyzed	413	410	413	410
Measure Type: Number; Unit of Measure: Participants
Citrobacter freundii complex	14	9	18	12
Enterobacter aerogenes	4	5	5	5
Enterobacter cloacae	11	16	13	19
Escherichia coli	218	249	271	285
Klebsiella oxytoca	14	12	18	15
Klebsiella pneumoniae	40	37	51	49
Proteus mirabilis	5	7	8	9
Pseudomonas aeruginosa	30	34	35	36
Enterococcus avium	8	10	8	15
Enterococcus faecalis	22	23	31	28
Enterococcus faecium	13	18	16	22
Staphylococcus aureus	17	14	18	14
Streptococcus anginosus group	59	50	72	61
Streptococcus bovis group	2	6	3	7
Streptococcus mitis group	10	9	15	11
Bacteroides fragilis	45	38	52	47
Bacteroides ovatus	17	17	22	20
Bacteroides stercoris	9	1	10	1
Bacteroides thetaiotaomicron	18	21	22	25
Bacteroides uniformis	4	6	7	7
Bacteroides vulgatus	6	6	8	9
Clostridium perfringens	7	4	10	4
Eggerthella lenta	5	7	5	8
Parabacteroides distasonis	13	12	16	13
Parvimonas micra	7	8	7	10

9. Secondary Outcome

Title	Clinical Response by Pathogen at TOC for Patients Infected With Ceftazidime-resistant Pathogens in Microbiological Modified Intent to Treat Analysis Set
Description	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.
Time Frame	Test of Cure: 28 to 35 days after start of study drug

Outcome Measure Data

Analysis Population Description

The mMITT analysis set included all randomized patients who met the disease definition of cIAI and had at least 1 etiologic pathogen identified at study entry (regardless of isolate susceptibilities). Patients with a bacterial species typically not expected to respond to both study drugs were excluded.

Arm/Group Title	CAZ-AVI + Metronidazole	Meropenem	CAZ-AVI + Metronidazole (Denominator)	Meropenem (Denominator)
Arm/Group Description:	CAZ (2000mg)/AVI (500mg): IV treatment	1000 mg: IV treatment	Number of patients with pathogen at baseline	Number of patients with pathogen at baseline
Overall Number of Participants Analyzed	413	410	413	410
Measure Type: Number; Unit of Measure: Participants
All	39	55	47	64
Citrobacter freundii complex	1	2	1	2
Enterobacter aerogenes	0	1	0	1
Enterobacter cloacae	2	7	3	7
Escherichia coli	19	31	24	37
Klebsiella pneumoniae	10	9	13	13
Morganella morganii	1	1	2	1
Proteus mirabilis	2	3	2	3
Serratia marcescens	1	0	1	0
Alcaligenes faecalis	1	2	1	2
Comamonas testosteroni	1	0	1	0
Pseudomonas aeruginosa	2	4	2	4

10. Secondary Outcome

Title	Favorable Per-pathogen Microbiological Response for Patients Infected With Ceftazidime-resistant Pathogens in mMITT Analysis Set
Description	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.
Time Frame	TOC: 28 to 35 days after start of study drug

Outcome Measure Data

Analysis Population Description

The mMITT analysis set included all randomized patients who met the disease definition of cIAI and had at least 1 etiologic pathogen identified at study entry (regardless of isolate susceptibilities). Patients with a bacterial species typically not expected to respond to both study drugs were excluded.

Arm/Group Title	CAZ-AVI + Metronidazole	Meropenem	CAZ-AVI + Metronidazole (Denominator)	Meropenem (Denominator)
Arm/Group Description:	CAZ (2000mg)/AVI (500mg): IV treatment	1000 mg: IV treatment	Number of patients with pathogen at baseline	Number of patients with pathogen at baseline
Overall Number of Participants Analyzed	48	64	48	64
Measure Type: Number; Unit of Measure: Participants
Citrobacter freundii complex	1	2	2	2
Enterobacter aerogenes	0	1	0	1
Enterobacter cloacae	2	7	3	7
Escherichia coli	19	31	24	37
Klebsiella pneumoniae	10	9	13	13
Morganella morganii	1	1	2	1
Proteus mirabilis	2	3	2	3
Serratia marcescens	1	0	1	0
Alcaligenes faecalis	1	2	1	2
Comamonas testosteroni	1	0	1	0
Pseudomonas aeruginosa	2	4	2	4

11. Secondary Outcome

Title	Per-patient Microbiological Response at TOC for Patients Infected With Ceftazidime-resistant Pathogens in mMITT Analysis Set
Description	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 an SRP assessment of inadequate source control (ie, circumstances that preclude classification as eradication, presumed eradication, persistence, persistence with increasing MIC, and presumed persistence).
Time Frame	Test of Cure: 28 to 35 days after start of study drug

Outcome Measure Data

Analysis Population Description

The mMITT analysis set included all randomized patients who met the disease definition of cIAI and had at least 1 etiologic pathogen identified at study entry (regardless of isolate susceptibilities). Patients with a bacterial species typically not expected to respond to both study drugs were excluded.

Arm/Group Title	CAZ-AVI + Metronidazole	Meropenem
Arm/Group Description:	CAZ (2000mg)/AVI (500mg): IV treatment	1000 mg: IV treatment
Overall Number of Participants Analyzed	48	64
Measure Type: Number; Unit of Measure: Participants
Favourable	39	55
Unfavourable	7	1
indeterminate	2	8

12. Secondary Outcome

Title	Number of Patients Afebrile at Last Observation in the Clinically Evaluable Analysis Set for Patients Who Have Fever at Study Entry
Description	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.
Time Frame	Test of Cure: 1 to 14 days after start of study drug

Outcome Measure Data

Analysis Population Description

Clinically evaluable (CE) with fever, defined as >38ºC at study entry.

Arm/Group Title	CAZ-AVI + Metronidazole	Meropenem
Arm/Group Description:	CAZ (2000mg)/AVI (500mg): IV treatment	1000 mg: IV treatment
Overall Number of Participants Analyzed	84	78
Measure Type: Number; Unit of Measure: Participants
	84	72

13. Secondary Outcome

Title	Plasma Concentrations for Ceftazidime and Avibactam
Description	Blood samples were taken from all patients on Day 3 for the pharmacokinetic evaluation of ceftazidime and avibactam plasma concentrations
Time Frame	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

Outcome Measure Data

Analysis Population Description

PK analysis set

Arm/Group Title	CAZ (1)	AVI (1)	CAZ (2)	AVI (2)	CAZ (3)	AVI (3)
Arm/Group Description:	30 mins before/after dose	30 min before/after dose	30-90 mins after dose	30-90 mins after dose	300-360 mins after dose	300-360 mins after dose
Overall Number of Participants Analyzed	486	493	484	489	481	484
Geometric Mean (Full Range); Unit of Measure: (NG/ML)
	50823.0; (171 to 3110000)	9229.4; (13 to 693000)	40053.1; (155 to 235000)	7163.9; (15 to 46800)	10967.6; (159 to 151000)	1690.7; (14 to 30800)

Adverse Events

Time Frame	Adverse event data were collected from the screening/consent visit until the late follow-up visit (ie Day -1/0 to Day 42).
Adverse Event Reporting Description	AEs spontaneously reported by the patient or care provider or reported in response to the open question from the study center personnel, or revealed by observation were to be collected and recorded in the eCRF.
Arm/Group Title	CAZ-AVI + Metronidazole	Meropenem
Arm/Group Description	CAZ (2000mg)/AVI (500mg): IV treatment.	1000 mg: IV treatment
All-Cause Mortality
	CAZ-AVI + Metronidazole	Meropenem
	Affected / at Risk (%)	Affected / at Risk (%)
Total	--/--	--/--
Serious Adverse Events
	CAZ-AVI + Metronidazole	Meropenem
	Affected / at Risk (%)	Affected / at Risk (%)
Total	17/529 (3.21%)	15/529 (2.84%)
Blood and lymphatic system disorders
Bone marrow failure † 1	0/529 (0.00%)	1/529 (0.19%)
Disseminated intravascular coagulation † 1	1/529 (0.19%)	0/529 (0.00%)
Cardiac disorders
Myocardial infarction † 1	1/529 (0.19%)	2/529 (0.38%)
Cardiac failure † 1	2/529 (0.38%)	1/529 (0.19%)
Acute myocardial infarction † 1	1/529 (0.19%)	1/529 (0.19%)
Atrial fibrillation † 1	0/529 (0.00%)	1/529 (0.19%)
Cardiac failure congestive † 1	1/529 (0.19%)	1/529 (0.19%)
Cardio-respiratory arrest † 1	0/529 (0.00%)	1/529 (0.19%)
Left ventricular failure † 1	1/529 (0.19%)	0/529 (0.00%)
Right ventricular failure † 1	1/529 (0.19%)	0/529 (0.00%)
Gastrointestinal disorders
Abdominal pain † 1	2/529 (0.38%)	0/529 (0.00%)
Colonic fistula † 1	0/529 (0.00%)	1/529 (0.19%)
Duodenal ulcer haemorrhage † 1	1/529 (0.19%)	0/529 (0.00%)
Gastrointestinal haemorrhage † 1	1/529 (0.19%)	0/529 (0.00%)
Gastrointestinal hypomotility † 1	1/529 (0.19%)	0/529 (0.00%)
Ileal perforation † 1	1/529 (0.19%)	0/529 (0.00%)
Ileus † 1	1/529 (0.19%)	0/529 (0.00%)
Intestinal obstruction † 1	0/529 (0.00%)	1/529 (0.19%)
Large intestine perforation † 1	1/529 (0.19%)	0/529 (0.00%)
Localised intraabdominal fluid collection † 1	1/529 (0.19%)	0/529 (0.00%)
Rectal haemorrhage † 1	0/529 (0.00%)	1/529 (0.19%)
Small intestine perforation † 1	1/529 (0.19%)	0/529 (0.00%)
Subileus † 1	0/529 (0.00%)	1/529 (0.19%)
Upper gastrointestinal haemorrhage † 1	0/529 (0.00%)	1/529 (0.19%)
Volvulus † 1	0/529 (0.00%)	1/529 (0.19%)
Small intestinal obstruction † 1	1/529 (0.19%)	1/529 (0.19%)
General disorders
Multi-organ failure † 1	1/529 (0.19%)	0/529 (0.00%)
Sudden death † 1	1/529 (0.19%)	1/529 (0.19%)
Hepatobiliary disorders
Bile duct obstruction † 1	1/529 (0.19%)	1/529 (0.19%)
Biloma † 1	1/529 (0.19%)	0/529 (0.00%)
Immune system disorders
Hypersensitivity † 1	1/529 (0.19%)	0/529 (0.00%)
Infections and infestations
Abdominal abscess † 1	0/529 (0.00%)	2/529 (0.38%)
Bronchopneumonia † 1	2/529 (0.38%)	2/529 (0.38%)
Candida sepsis † 1	2/529 (0.38%)	0/529 (0.00%)
Colonic abscess † 1	0/529 (0.00%)	1/529 (0.19%)
Diverticulitis † 1	1/529 (0.19%)	0/529 (0.00%)
Empyema † 1	1/529 (0.19%)	0/529 (0.00%)
Enterococcal bacteraemia † 1	1/529 (0.19%)	1/529 (0.19%)
Pneumonia † 1	1/529 (0.19%)	1/529 (0.19%)
Sepsis † 1	0/529 (0.00%)	1/529 (0.19%)
Septic enceohalopathy † 1	1/529 (0.19%)	0/529 (0.00%)
Septic shock † 1	0/529 (0.00%)	1/529 (0.19%)
Systematic candida † 1	0/529 (0.00%)	1/529 (0.19%)
Injury, poisoning and procedural complications
Gastrointestinal stoma necrosis † 1	2/529 (0.38%)	0/529 (0.00%)
Abdominal wound dehiscence † 1	1/529 (0.19%)	1/529 (0.19%)
Anastomotic leak † 1	1/529 (0.19%)	0/529 (0.00%)
Gastrointestinal stoma complication † 1	1/529 (0.19%)	1/529 (0.19%)
Laceration † 1	0/529 (0.00%)	1/529 (0.19%)
Pneumothorax traumatic † 1	1/529 (0.19%)	0/529 (0.00%)
Post procedural bile leak † 1	0/529 (0.00%)	1/529 (0.19%)
Postoperative wound complication † 1	1/529 (0.19%)	0/529 (0.00%)
Procedural pain † 1	1/529 (0.19%)	0/529 (0.00%)
Suture related complication † 1	1/529 (0.19%)	0/529 (0.00%)
Wound dehiscence † 1	0/529 (0.00%)	1/529 (0.19%)
Wound evisceration † 1	0/529 (0.00%)	1/529 (0.19%)
Investigations
Transaminases increased † 1	0/529 (0.00%)	2/529 (0.38%)
Metabolism and nutrition disorders
Hypoglycaemia † 1	0/529 (0.00%)	2/529 (0.38%)
Dehydration † 1	1/529 (0.19%)	0/529 (0.00%)
Musculoskeletal and connective tissue disorders
Critical illness myopathy † 1	0/529 (0.00%)	1/529 (0.19%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Adenocarcinoma gastric † 1	0/529 (0.00%)	1/529 (0.19%)
Nervous system disorders
Ischaemic stroke † 1	0/529 (0.00%)	1/529 (0.19%)
Polyneuropathy † 1	0/529 (0.00%)	1/529 (0.19%)
Psychiatric disorders
Delirium tremens † 1	1/529 (0.19%)	0/529 (0.00%)
Renal and urinary disorders
Renal failure acute † 1	5/529 (0.95%)	0/529 (0.00%)
Renal failure † 1	1/529 (0.19%)	0/529 (0.00%)
Respiratory, thoracic and mediastinal disorders
Respiratory failure † 1	3/529 (0.57%)	3/529 (0.57%)
Pulmonary embolism † 1	3/529 (0.57%)	1/529 (0.19%)
Atelectasis † 1	0/529 (0.00%)	1/529 (0.19%)
Chronic obstructive pulmonary disease † 1	0/529 (0.00%)	1/529 (0.19%)
Pleural effusion † 1	1/529 (0.19%)	1/529 (0.19%)
Pneumothorax † 1	0/529 (0.00%)	1/529 (0.19%)
Pulmonary congestion † 1	0/529 (0.00%)	1/529 (0.19%)
Respiratory distress † 1	1/529 (0.19%)	1/529 (0.19%)
Skin and subcutaneous tissue disorders
Drug eruption † 1	0/529 (0.00%)	1/529 (0.19%)
Vascular disorders
Shock † 1	1/529 (0.19%)	0/529 (0.00%)
† Indicates events were collected by systematic assessment; 1 Term from vocabulary, (MedDRA)
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	2%
	CAZ-AVI + Metronidazole	Meropenem
	Affected / at Risk (%)	Affected / at Risk (%)
Total	184/529 (34.78%)	152/529 (28.73%)
Blood and lymphatic system disorders
Anaemia † 1	11/529 (2.08%)	9/529 (1.70%)
Gastrointestinal disorders
Diarrhoea † 1	40/529 (7.56%)	17/529 (3.21%)
Nausea † 1	36/529 (6.81%)	24/529 (4.54%)
Vomiting † 1	24/529 (4.54%)	10/529 (1.89%)
Constipation † 1	8/529 (1.51%)	20/529 (3.78%)
Abdominal distension † 1	10/529 (1.89%)	11/529 (2.08%)
General disorders
Pyrexia † 1	24/529 (4.54%)	24/529 (4.54%)
Asthenia † 1	10/529 (1.89%)	12/529 (2.27%)
Infections and infestations
Wound infection † 1	13/529 (2.46%)	11/529 (2.08%)
Nervous system disorders
Headache † 1	15/529 (2.84%)	9/529 (1.70%)
Respiratory, thoracic and mediastinal disorders
Cough † 1	11/529 (2.08%)	13/529 (2.46%)
Vascular disorders
Hypertension † 1	15/529 (2.84%)	24/529 (4.54%)
Hypotension † 1	12/529 (2.27%)	12/529 (2.27%)
Phlebitis † 1	10/529 (1.89%)	11/529 (2.08%)
† Indicates events were collected by systematic assessment; 1 Term from vocabulary, (MedDRA)

Limitations and Caveats

This summary describes data collected from two identical CSPs (D4280C00001 and D4280C00005). With agreement from the EMA and the FDA the data have been combined into a single study database.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

The PI shall not publish results until the earliest of (i) date of the 1st study publication (joint between PI, sponsor and study sites) (ii) 18 months after study completion, or (iii) sponsor notification that no multi-center publication is to be made. The PI submits the publication for review 60 days before submission. Sponsor may embargo for a further 90 days to protect IP rights. Sponsor may request removal of confidential and/or proprietry information.

Results Point of Contact

• Name/Title: Paul Newell, Medical Science Director
• Organization: AstraZeneca
• Phone: +44 1625 515727
• EMail: paul.newell@astrazeneca.com

Publications:

Mazuski JE, Gasink LB, Armstrong J, Broadhurst H, Stone GG, Rank D, Llorens L, Newell P, Pachl J. Efficacy and Safety of Ceftazidime-Avibactam Plus Metronidazole Versus Meropenem in the Treatment of Complicated Intra-abdominal Infection: Results From a Randomized, Controlled, Double-Blind, Phase 3 Program. Clin Infect Dis. 2016 Jun 1;62(11):1380-1389. doi: 10.1093/cid/ciw133. Epub 2016 Mar 8.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Cheng K, Newell P, Chow JW, Broadhurst H, Wilson D, Yates K, Wardman A. Safety Profile of Ceftazidime-Avibactam: Pooled Data from the Adult Phase II and Phase III Clinical Trial Programme. Drug Saf. 2020 Aug;43(8):751-766. doi: 10.1007/s40264-020-00934-3.

Kongnakorn T, Eckmann C, Bassetti M, Tichy E, Di Virgilio R, Baillon-Plot N, Charbonneau C. Cost-effectiveness analysis comparing ceftazidime/avibactam (CAZ-AVI) as empirical treatment comparing to ceftolozane/tazobactam and to meropenem for complicated intra-abdominal infection (cIAI). Antimicrob Resist Infect Control. 2019 Dec 21;8:204. doi: 10.1186/s13756-019-0652-x. eCollection 2019.

Li J, Lovern M, Green ML, Chiu J, Zhou D, Comisar C, Xiong Y, Hing J, MacPherson M, Wright JG, Riccobene T, Carrothers TJ, Das S. Ceftazidime-Avibactam Population Pharmacokinetic Modeling and Pharmacodynamic Target Attainment Across Adult Indications and Patient Subgroups. Clin Transl Sci. 2019 Mar;12(2):151-163. doi: 10.1111/cts.12585. Epub 2018 Sep 28.

Nichols WW, Stone GG, Newell P, Broadhurst H, Wardman A, MacPherson M, Yates K, Riccobene T, Critchley IA, Das S. Ceftazidime-Avibactam Susceptibility Breakpoints against Enterobacteriaceae and Pseudomonas aeruginosa. Antimicrob Agents Chemother. 2018 Oct 24;62(11):e02590-17. doi: 10.1128/AAC.02590-17. Print 2018 Nov.

Stone GG, Newell P, Gasink LB, Broadhurst H, Wardman A, Yates K, Chen Z, Song J, Chow JW. Clinical activity of ceftazidime/avibactam against MDR Enterobacteriaceae and Pseudomonas aeruginosa: pooled data from the ceftazidime/avibactam Phase III clinical trial programme. J Antimicrob Chemother. 2018 Sep 1;73(9):2519-2523. doi: 10.1093/jac/dky204.

Stone GG, Newell P, Bradford PA. In Vitro Activity of Ceftazidime-Avibactam against Isolates from Patients in a Phase 3 Clinical Trial for Treatment of Complicated Intra-abdominal Infections. Antimicrob Agents Chemother. 2018 Jun 26;62(7):e02584-17. doi: 10.1128/AAC.02584-17. Print 2018 Jul.

Mendes RE, Castanheira M, Woosley LN, Stone GG, Bradford PA, Flamm RK. Molecular beta-Lactamase Characterization of Aerobic Gram-Negative Pathogens Recovered from Patients Enrolled in the Ceftazidime-Avibactam Phase 3 Trials for Complicated Intra-abdominal Infections, with Efficacies Analyzed against Susceptible and Resistant Subsets. Antimicrob Agents Chemother. 2017 May 24;61(6):e02447-16. doi: 10.1128/AAC.02447-16. Print 2017 Jun.

• Responsible Party: Pfizer
• ClinicalTrials.gov Identifier: NCT01499290
• Obsolete Identifiers: NCT01500239
• Other Study ID Numbers: D4280C00001; 2011-003893-97
• First Submitted: December 19, 2011
• First Posted: December 26, 2011
• Results First Submitted: November 6, 2015
• Results First Posted: March 1, 2016
• Last Update Posted: September 6, 2017