To Compare Safety and Efficacy of Doripenem Versus Imipenem-Cilastatin in Patients With Ventilator-Associated Pneumonia

• Sponsor: Johnson & Johnson Pharmaceutical Research & Development, L.L.C. (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT00589693
• Collaborator: (none)
• Enrollment: 274
• Locations: 102
• Arms: 2
• Duration (Months): 38
• Patients Per Site: 2.7
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The purpose of this study is to show that doripenem is as effective as imipenem-cilastatin in the treatment of patients with ventilator-associated pneumonia.

Condition or Disease	Intervention/Treatment	Phase
Ventilator-Associated Pneumonia	Drug: Doripenem; Drug: Imipenem-Cilastatin; Drug: Placebo	Phase 3

Detailed Description

This is a randomized (the study medication is assigned by chance), double-blind (neither physician nor patient knows the treatment that the patient receives), active-controlled (agent that is compared with a study medication to test whether the study medication has a real effect in a clinical study), double-dummy (placebo [inactive substance that is compared with a medication to test whether the medication has a real effect in a clinical study] is administered to maintain the blind when the comparator medication cannot be made identical to the study medication), parallel-group (each group of patients will be treated at the same time), multicenter study to assess the effectiveness and safety of 7 day course of doripenem, compared with 10 day course of imipenem-cilastatin in patients with ventilator-associated pneumonia. This study will consists of 3 phases: (1) a pretreatment phase with a maximum of 24 hours for the screening/baseline visit, (2) a double blind, double dummy, treatment phase of 10 days (Day 1 to Day 10) and an end-of-treatment (EOT) assessment within 24 hours after the last dose of study medication therapy administered on Day 10 or at the time of early withdrawal from study medication, and (3) a post treatment (follow-up) phase consisting of an early follow-up (EFU) visit within 7 to 14 days after the last dose of study medication, and last follow-up (LFU) visit within 28 to 35 days after the last dose of study medication for all patients including those who discontinued study medication early. Two hundred and seventy four patients will be randomly assigned to receive either doripenem or imipenem with placebo of the other medication given simultaneously to maintain the blind (eg, 1 group will receive blinded doripenem from Days 1 to 7 and imipenem placebo Days 1 to 10, other group will receive blinded imipenem Days 1 to 10 and doripenem placebo Days 1 to 7). A sample of secretions from the lower respiratory tract will be obtained by bronchoalveolar lavage (BAL) or mini-BAL within 36 hours prior to administration of study medication from the enrolled patients and sent for culture. Patients, whose baseline BAL or mini-BAL culture results will yield at least 1 qualifying pneumonia pathogen will continue to receive study medication therapy and patients, whose baseline BAL or mini-BAL culture results did not yield at least 1 qualifying pneumonia pathogen will be discontinued from study medication therapy but will remain enroll in the study and will be followed for safety. Safety evaluations including adverse events, clinical laboratory evaluations, vital signs and physical examinations will be monitored throughout the study period. The total duration of an individual patient's participation in the study will be approximately 5 to 6 weeks.

Study Design

• Study Type: Interventional
• Actual Enrollment: 274 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Prospective, Randomized, Double-Blind, Double-Dummy, Multicenter Study to Assess the Safety and Efficacy of Doripenem Compared With Imipenem-Cilastatin in the Treatment of Subjects With Ventilator-Associated Pneumonia
• Study Start Date: Apr 1, 2008
• Actual Primary Completion Date: Jun 1, 2011
• Actual Study Completion Date: Jun 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Doripenem Doripenem from Days 1 to 7 and imipenem-cilastatin placebo from Days 1 to 10	Drug: Doripenem; Type=exact number, number=1, unit=g, form=solution for injection, route=intravenously. 1 gram 4-hour infusion of doripenem will be administered every 8 hours for 7 days.; Drug: Placebo; Form=solution, route=intravenous. Doripenem pacebo will be administered from Days 1 to 7 in imipenem-cilastatin arm and imipenem-cilastatin placebo will be administered in doripenem arm.
Active Comparator: Imipenem-Cilastatin Imipenem-Cilastatin Days 1 to 10 and doripenem placebo from Days 1 to 7	Drug: Imipenem-Cilastatin; Type=exact number, number=1, unit=g, form=solution for injection, route=intravenously. 1 gram 1-hour infusion of imipenem-cilastatin will be administered every 8 hours for 10 days.; Drug: Placebo; Form=solution, route=intravenous. Doripenem pacebo will be administered from Days 1 to 7 in imipenem-cilastatin arm and imipenem-cilastatin placebo will be administered in doripenem arm.

Outcome Measures

Primary Outcome Measures

1. Clinical Cure Rate at the End-of-treatment (EOT) Visit [End-of-treatment (Day 10 or Day 11)]

   The number of patients who achieved clinical cure at the EOT visit on Day 10. The patient's were classified as clinical cure if they had resolution of signs and symptoms and objective findings of pneumonia to such an extent that no further antimicrobial therapy was necessary.

Secondary Outcome Measures

1. Clinical Cure Rate at the End-of-treatment (EOT) Visit in Patients From Whom a Qualifying P. Aeruginosa Was Isolated at Baseline [End-of-treatment (Day 10 or Day 11)]

   The clinical cure rate at the EOT visit in patients, whose bronchoalveolar lavage (BAL) or mini-BAL culture results yielded qualifying pneumonia pathogen P. aeruginosa at baseline.

2. Clinical Cure Rate at the End-of-treatment (EOT) Visit in Patients From Whom at Least 1 of the Gram-negative Qualifying Pneumonia Pathogens (Enterobacteriaceae, P. Aeruginosa, and Acinetobacter Spp) Was Isolated at Baseline [End-of-treatment (Day 10 or Day 11)]

   The clinical cure rate at the EOT visit in patients whose BAL or mini-BAL culture results yielded at least 1 of the following Gram-negative qualifying pneumonia pathogens was isolated at baseline: any Enterobacteriaceae, P. aeruginosa, and Acinetobacter Spp.

3. Number of Patients Who Had Emergence of P. Aeruginosa Resistance [Up to 6 weeks]

   Number of patients who had P. aeruginosa isolates with a 4 fold or greater increase in minimum inhibitory concentration (MIC) at anytime during the study (after the study medication is received) from baseline

4. 28-day All-cause Mortality Rate [Up to 28 days]

   Number of deaths which occured up to 28 days of the study period due to all causes

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Patients must have new or worsening radiographic infiltrates consistent with ventilator-associated pneumonia that was not related to cardiac or other disease processes

• Have at least 1 of the following: fever (core body temperature greater than 39.0°C); hypothermia (core body temperature of less than 35.0°C); leukocytosis (increased WBC count); and leukopenia (decreased WBC count)

• Have developed ventilator-associated pneumonia and have been on mechanical ventilation for more than or equal to 48 hours and on mechanical ventilation at the time that study medication is assigned

• Have been hospitalized or been in a chronic care facility for consecutive 5 days or more within the last 90 days

• Have a baseline Clinical Pulmonary Infection Score (CPIS) more than or equal to 6 and an Acute Physiology and Chronic Health Evaluation (APACHE) II score more than 8 and less than 35

Exclusion Criteria:

• Have received antibiotics for this episode of ventilator-associated pneumonia for more than 24 hours before study medication administration

• Known presence at baseline of only methicillin-resistant Staphylococcus aureus or Stenotrophomonas infection

• Acute respiratory distress syndrome

• Has any of the following conditions: chest trauma with severe lung bruising or loss of stability of the thoracic cage following a fracture of the sternum, ribs, or both, increased amounts of fluid in the lung cavities requiring drainage or pus in the cavity

• Has active seizure disorder within the last 2 years or brain injury such that imipenem cilastatin would not be administered to the patient in usual practice

• Has lung cancer within the last 2 years, chronic bronchitis with an increase in severity within the last 30 days, chronic enlargement of the bronchi or bronchioles related to inflammatory disease or obstruction, lung abscess(s), anatomical bronchial obstruction, respiratory tuberculosis on treatment, suspected atypical pneumonia, chemical pneumonitis, cystic fibrosis, congestive heart failure, severe burns to greater than 15% of the body, evidence of severe and chronic liver disease

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Jonesboro	Arkansas	United States
2		Newark	Delaware	United States
3		Washington	District of Columbia	United States
4		Jacksonville	Florida	United States
5		Moline	Illinois	United States
6		Hazard	Kentucky	United States
7		Biddeford	Maine	United States
8		Baltimore	Maryland	United States
9		Detroit	Michigan	United States
10		Butte	Montana	United States
11		Buffalo	New York	United States
12		Winston Salem	North Carolina	United States
13		Cincinnati	Ohio	United States
14		Oklahoma City	Oklahoma	United States
15		Nashville	Tennessee	United States
16		Houston	Texas	United States
17		Milwaukee	Wisconsin	United States
18		Buenos Aires		Argentina
19		Cordoba		Argentina
20		Entre Rios		Argentina
21		Monte Grande		Argentina
22		Rio Negro		Argentina
23		Rosario		Argentina
24		Adelaide		Australia
25		Box Hill		Australia
26		Clayton		Australia
27		Melbourne		Australia
28		Parkville N/A		Australia
29		Brussel		Belgium
30		Gent		Belgium
31		Belo Horizonte		Brazil
32		Curitiba		Brazil
33		Fortaleza		Brazil
34		Porto Alegre		Brazil
35		Rio De Janeiro		Brazil
36		Santo Andre		Brazil
37		Sao Jose Do Rio Preto		Brazil
38		Sao Paulo		Brazil
39		Halifax	Nova Scotia	Canada
40		Ottawa	Ontario	Canada
41		Greenfield Park N/A	Quebec	Canada
42		Argenteuil		France
43		Limoges Cedex 1		France
44		Paris Cedex 15		France
45		Pierre - Benite Cedex		France
46		Tours		France
47		Dresden		Germany
48		Halle/Saale		Germany
49		Homburg/Saar		Germany
50		Lübeck		Germany
51		Mannheim		Germany
52		Ulm		Germany
53		Cuilapa		Guatemala
54		Escuintla Escuintla		Guatemala
55		Guatemala		Guatemala
56		Budapest N/A		Hungary
57		Budapest Na		Hungary
58		Budapest		Hungary
59		Székesfehérvár		Hungary
60		Bangalore		India
61		Coimbatore		India
62		Ludhiana		India
63		New Delhi		India
64		Pune		India
65		Afula		Israel
66		Petah Tikva		Israel
67		Ramat-Gan		Israel
68		Chihuahua		Mexico
69		Guadalajara		Mexico
70		Monterrey		Mexico
71		San Luis Potosi		Mexico
72		Zapopan		Mexico
73		Manila		Philippines
74		Quezon City		Philippines
75		Lisboa		Portugal
76		Porto		Portugal
77		Brasov		Romania
78		Targu Mures		Romania
79		Timisoara		Romania
80		Moscow		Russian Federation
81		Saratov		Russian Federation
82		Smolensk		Russian Federation
83		St Petersburg		Russian Federation
84		Yaroslavl		Russian Federation
85		Barcelona		Spain
86		L'Hospitalet De Llobregat		Spain
87		Las Palmas De Gran Canaria		Spain
88		Madrid N/A		Spain
89		Madrid		Spain
90		Tarragona		Spain
91		Chiang Mai		Thailand
92		Khon Kaen		Thailand
93		Nakhonratchasima		Thailand
94		Adana		Turkey
95		Ankara		Turkey
96		Istanbul		Turkey
97		Kayseri		Turkey
98		Samsun		Turkey
99		Trabzon		Turkey
100		Kharkov		Ukraine
101		Kiev		Ukraine
102		Odessa		Ukraine

Sponsors and Collaborators

• Johnson & Johnson Pharmaceutical Research & Development, L.L.C.

Investigators

• Study Director: Johnson & Johnson Pharmaceutical Research & Development, L.L. C. Clinical Trial, Johnson & Johnson Pharmaceutical Research & Development, L.L.C.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Johnson & Johnson Pharmaceutical Research & Development, L.L.C.
• ClinicalTrials.gov Identifier: NCT00589693
• Other Study ID Numbers: CR014038; DORINOS3008; 2007-004646-33
• First Posted: Jan 10, 2008
• Last Update Posted: Dec 28, 2012
• Last Verified: Dec 1, 2012

• Keywords provided by Johnson & Johnson Pharmaceutical Research & Development, L.L.C.: Ventilator-Associated Pneumonia; Pneumonia, hospital-acquired; Doripenem; Imipenem-cilastatin
• Additional relevant MeSH terms: Pneumonia; Pneumonia, Ventilator-Associated; Imipenem; Doripenem; Cilastatin, Imipenem Drug Combination; Cilastatin

Study Results

Participant Flow

Recruitment Details	274 enrolled patients were randomnly assigned to the 127 study centers. 524 patients were to be enrolled, however as the study was terminated early only 274 patients were actually enrolled.
Pre-assignment Detail	Out of 274 randomized patients, 41 patients were excluded (as their sites were GCP Non-Compliant) and 6 patients were not treated. Treated patients=227 (115 doripenem and 112 imipenem-cilastatin).

Arm/Group Title	Doripenem	Imipenem-cilastatin
Arm/Group Description	1 g 4-hour infusion intravenously every 8 hour for 7 days	1 g 1-hour infusion intravenously every 8 hour for 10 days
Period Title: Overall Study
STARTED	115	112
COMPLETED	71	83
NOT COMPLETED	44	29

Baseline Characteristics

Arm/Group Title	Doripenem	Imipenem-cilastatin	Total
Arm/Group Description	1 g 4-hour infusion intravenously every 8 hour for 7 days	1 g 1-hour infusion intravenously every 8 hour for 10 days	Total of all reporting groups
Overall Participants	115	112	227
Age (Count of Participants)
<=18 years	0 0%	1 0.9%	1 0.4%
Between 18 and 65 years	72 62.6%	72 64.3%	144 63.4%
>=65 years	43 37.4%	39 34.8%	82 36.1%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	57.5 (16.53)	54.6 (18.46)	56.1 (17.53)
Sex: Female, Male (Count of Participants)
Female	43 37.4%	37 33%	80 35.2%
Male	72 62.6%	75 67%	147 64.8%
Region Enroll (participants) [Number]
EUROPE	69 60%	71 63.4%	140 61.7%
NORTH AMERICA	16 13.9%	12 10.7%	28 12.3%
REST OF WORLD	9 7.8%	6 5.4%	15 6.6%
SOUTH AMERICA	21 18.3%	23 20.5%	44 19.4%

Outcome Measures

1. Primary Outcome

Title	Clinical Cure Rate at the End-of-treatment (EOT) Visit
Description	The number of patients who achieved clinical cure at the EOT visit on Day 10. The patient's were classified as clinical cure if they had resolution of signs and symptoms and objective findings of pneumonia to such an extent that no further antimicrobial therapy was necessary.
Time Frame	End-of-treatment (Day 10 or Day 11)

Outcome Measure Data

Analysis Population Description

Microbiological Intent-to-Treat (MITT) - subset of all ITT (all randomized patients who received at least a partial dose of study medication) patients who had at least 1 qualifying pneumonia pathogen.

Arm/Group Title	Doripenem	Imipenem-cilastatin
Arm/Group Description	1 g 4-hour infusion intravenously every 8 hour for 7 days	1 g 1-hour infusion intravenously every 8 hour for 10 days
Measure Participants	79	88
Number [Participants]	36 31.3%	50 44.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Doripenem, Imipenem-cilastatin
	Comments	Null Hypothesis: The clinical cure rate of doripenem assessed at the EOT visit is more than 15% inferior to that of imipenem-cilastatin
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Noninferiority will be established if the lower limit of the 2-sided 95% Confidence Interval (CI) of the difference in clinical cure rate (doripenem minus imipenem-cilastatin) is greater than 15%
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Difference of 2 binomial proportions
	Estimated Value	-11.2
	Confidence Interval	(2-Sided) 95%; -26.3 to 3.8
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Clinical Cure Rate at the End-of-treatment (EOT) Visit in Patients From Whom a Qualifying P. Aeruginosa Was Isolated at Baseline
Description	The clinical cure rate at the EOT visit in patients, whose bronchoalveolar lavage (BAL) or mini-BAL culture results yielded qualifying pneumonia pathogen P. aeruginosa at baseline.
Time Frame	End-of-treatment (Day 10 or Day 11)

Outcome Measure Data

Analysis Population Description

Microbiological Intent-to-Treat (MITT) - subset of all ITT (all randomized patients who received at least a partial dose of study medication) patients who had at least 1 qualifying pneumonia pathogen.

Arm/Group Title	Doripenem	Imipenem-cilastatin
Arm/Group Description	1 g 4-hour infusion intravenously every 8 hour for 7 days	1 g 1-hour infusion intravenously every 8 hour for 10 days
Measure Participants	17	10
Number [Participants]	7 6.1%	6 5.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Doripenem, Imipenem-cilastatin
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Difference of 2 binomial proportions
	Estimated Value	-18.8
	Confidence Interval	(2-Sided) 95%; -57.2 to 19.5
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Clinical Cure Rate at the End-of-treatment (EOT) Visit in Patients From Whom at Least 1 of the Gram-negative Qualifying Pneumonia Pathogens (Enterobacteriaceae, P. Aeruginosa, and Acinetobacter Spp) Was Isolated at Baseline
Description	The clinical cure rate at the EOT visit in patients whose BAL or mini-BAL culture results yielded at least 1 of the following Gram-negative qualifying pneumonia pathogens was isolated at baseline: any Enterobacteriaceae, P. aeruginosa, and Acinetobacter Spp.
Time Frame	End-of-treatment (Day 10 or Day 11)

Outcome Measure Data

Analysis Population Description

Microbiological Intent-to-Treat (MITT) - subset of all ITT (all randomized patients who received at least a partial dose of study medication) patients who had at least 1 qualifying pneumonia pathogen.

Arm/Group Title	Doripenem	Imipenem-cilastatin
Arm/Group Description	1 g 4-hour infusion intravenously every 8 hour for 7 days	1 g 1-hour infusion intravenously every 8 hour for 10 days
Measure Participants	65	62
Number [Participants]	32 27.8%	34 30.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Doripenem, Imipenem-cilastatin
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Difference of 2 binomial proportions
	Estimated Value	-5.6
	Confidence Interval	(2-Sided) 95%; -23.0 to 11.7
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Number of Patients Who Had Emergence of P. Aeruginosa Resistance
Description	Number of patients who had P. aeruginosa isolates with a 4 fold or greater increase in minimum inhibitory concentration (MIC) at anytime during the study (after the study medication is received) from baseline
Time Frame	Up to 6 weeks

Outcome Measure Data

Analysis Population Description

Microbiological Intent-to-Treat (MITT) - subset of all ITT (all randomized patients who received at least a partial dose of study medication) patients who had at least 1 qualifying pneumonia pathogen.

Arm/Group Title	Doripenem	Imipenem-cilastatin
Arm/Group Description	1 g 4-hour infusion intravenously every 8 hour for 7 days	1 g 1-hour infusion intravenously every 8 hour for 10 days
Measure Participants	19	15
Number [Participants]	3 2.6%	6 5.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Doripenem, Imipenem-cilastatin
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.14
	Comments
	Method	Fisher Exact
	Comments

5. Secondary Outcome

Title	28-day All-cause Mortality Rate
Description	Number of deaths which occured up to 28 days of the study period due to all causes
Time Frame	Up to 28 days

Outcome Measure Data

Analysis Population Description

Microbiological Intent-to-Treat (MITT) - subset of all ITT (all randomized patients who received at least a partial dose of study medication) patients who had at least 1 qualifying pneumonia pathogen.

Arm/Group Title	Doripenem	Imipenem-cilastatin
Arm/Group Description	1 g 4-hour infusion intravenously every 8 hour for 7 days	1 g 1-hour infusion intravenously every 8 hour for 10 days
Measure Participants	79	88
Number [Participants]	17 14.8%	13 11.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Doripenem, Imipenem-cilastatin
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Difference of 2 binomial proportions
	Estimated Value	6.7
	Confidence Interval	(2-Sided) 95%; -5.0 to 18.5
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	6 weeks
Adverse Event Reporting Description	Only patients who had at least one of the treatment related adverse events (AEs) was listed in the other (non Serious) AE table and was included as the total number of patients with Non-Serious Adverse Events.
Arm/Group Title	Doripenem		Imipenem-cilastatin
Arm/Group Description	1 g 4-hour infusion intravenously every 8 hour for 7 days		1 g 1-hour infusion intravenously every 8 hour for 10 days
All Cause Mortality
	Doripenem		Imipenem-cilastatin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Doripenem		Imipenem-cilastatin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	55/115 (47.8%)		45/112 (40.2%)
Blood and lymphatic system disorders
Anaemia	1/115 (0.9%)		0/112 (0%)
Cardiac disorders
Cardiac arrest	3/115 (2.6%)		6/112 (5.4%)
Cardiac failure	2/115 (1.7%)		3/112 (2.7%)
Atrial fibrillation	1/115 (0.9%)		0/112 (0%)
Bradyarrhythmia	1/115 (0.9%)		0/112 (0%)
Cardio-respiratory arrest	1/115 (0.9%)		0/112 (0%)
Ventricular fibrillation	1/115 (0.9%)		0/112 (0%)
Bradycardia	0/115 (0%)		2/112 (1.8%)
Endocrine disorders
Diabetes insipidus	1/115 (0.9%)		0/112 (0%)
Gastrointestinal disorders
Duodenal perforation	1/115 (0.9%)		0/112 (0%)
Gastrointestinal haemorrhage	1/115 (0.9%)		0/112 (0%)
Pancreatic necrosis	1/115 (0.9%)		0/112 (0%)
Pancreatitis	1/115 (0.9%)		0/112 (0%)
Peritonitis	1/115 (0.9%)		1/112 (0.9%)
Diarrhoea	0/115 (0%)		1/112 (0.9%)
Gastric haemorrhage	0/115 (0%)		1/112 (0.9%)
Ileus paralytic	0/115 (0%)		1/112 (0.9%)
Lower gastrointestinal haemorrhage	0/115 (0%)		1/112 (0.9%)
General disorders
Multi-organ failure	2/115 (1.7%)		3/112 (2.7%)
Treatment failure	2/115 (1.7%)		0/112 (0%)
Impaired healing	0/115 (0%)		1/112 (0.9%)
Hepatobiliary disorders
Cholecystitis	1/115 (0.9%)		1/112 (0.9%)
Immune system disorders
Hypersensitivity	1/115 (0.9%)		0/112 (0%)
Infections and infestations
Sepsis	8/115 (7%)		3/112 (2.7%)
Septic shock	6/115 (5.2%)		6/112 (5.4%)
Pneumonia	5/115 (4.3%)		3/112 (2.7%)
Device related sepsis	3/115 (2.6%)		2/112 (1.8%)
Urinary tract infection	3/115 (2.6%)		1/112 (0.9%)
Empyema	2/115 (1.7%)		0/112 (0%)
Abscess	1/115 (0.9%)		0/112 (0%)
Bacteraemia	1/115 (0.9%)		2/112 (1.8%)
Central nervous system infection	1/115 (0.9%)		0/112 (0%)
Clostridium difficile colitis	1/115 (0.9%)		0/112 (0%)
Infected skin ulcer	1/115 (0.9%)		0/112 (0%)
Osteomyelitis	1/115 (0.9%)		1/112 (0.9%)
Pneumonia bacterial	1/115 (0.9%)		0/112 (0%)
Staphylococcal sepsis	1/115 (0.9%)		0/112 (0%)
Staphylococcal skin infection	1/115 (0.9%)		0/112 (0%)
Superinfection	1/115 (0.9%)		0/112 (0%)
Abdominal abscess	0/115 (0%)		1/112 (0.9%)
Device related infection	0/115 (0%)		1/112 (0.9%)
Fungal infection	0/115 (0%)		1/112 (0.9%)
Lung infection	0/115 (0%)		1/112 (0.9%)
Mediastinitis	0/115 (0%)		2/112 (1.8%)
Meningitis	0/115 (0%)		1/112 (0.9%)
Pneumonia klebsiella	0/115 (0%)		1/112 (0.9%)
Postoperative wound infection	0/115 (0%)		1/112 (0.9%)
Pulmonary sepsis	0/115 (0%)		2/112 (1.8%)
Tracheobronchitis	0/115 (0%)		1/112 (0.9%)
Injury, poisoning and procedural complications
Traumatic brain injury	3/115 (2.6%)		0/112 (0%)
Fat embolism	1/115 (0.9%)		0/112 (0%)
Incisional hernia	1/115 (0.9%)		0/112 (0%)
Post procedural complication	1/115 (0.9%)		0/112 (0%)
Anaemia postoperative	0/115 (0%)		1/112 (0.9%)
Extradural haematoma	0/115 (0%)		1/112 (0.9%)
Post procedural haemorrhage	0/115 (0%)		1/112 (0.9%)
Spinal cord injury cervical	0/115 (0%)		1/112 (0.9%)
Investigations
Troponin increased	1/115 (0.9%)		0/112 (0%)
Metabolism and nutrition disorders
Hypoglycaemia	0/115 (0%)		1/112 (0.9%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Metastases to pleura	1/115 (0.9%)		0/112 (0%)
Nervous system disorders
Brain oedema	3/115 (2.6%)		4/112 (3.6%)
Intracranial pressure increased	2/115 (1.7%)		1/112 (0.9%)
Brain stem syndrome	1/115 (0.9%)		0/112 (0%)
Convulsion	1/115 (0.9%)		0/112 (0%)
Haemorrhage intracranial	1/115 (0.9%)		0/112 (0%)
Nervous system disorder	1/115 (0.9%)		0/112 (0%)
Subarachnoid haemorrhage	1/115 (0.9%)		0/112 (0%)
Cerebrovascular accident	0/115 (0%)		1/112 (0.9%)
Hydrocephalus	0/115 (0%)		1/112 (0.9%)
Subdural hygroma	0/115 (0%)		1/112 (0.9%)
Transient ischaemic attack	0/115 (0%)		1/112 (0.9%)
Renal and urinary disorders
Renal failure	5/115 (4.3%)		1/112 (0.9%)
Renal failure acute	2/115 (1.7%)		2/112 (1.8%)
Acute prerenal failure	1/115 (0.9%)		0/112 (0%)
Renal tubular acidosis	0/115 (0%)		1/112 (0.9%)
Respiratory, thoracic and mediastinal disorders
Respiratory failure	3/115 (2.6%)		2/112 (1.8%)
Acute respiratory distress syndrome	2/115 (1.7%)		1/112 (0.9%)
Acute respiratory failure	1/115 (0.9%)		2/112 (1.8%)
Atelectasis	1/115 (0.9%)		1/112 (0.9%)
Pleural effusion	1/115 (0.9%)		1/112 (0.9%)
Pulmonary embolism	1/115 (0.9%)		3/112 (2.7%)
Pulmonary haemorrhage	1/115 (0.9%)		0/112 (0%)
Respiratory arrest	1/115 (0.9%)		1/112 (0.9%)
Respiratory disorder	1/115 (0.9%)		0/112 (0%)
Respiratory distress	1/115 (0.9%)		0/112 (0%)
Acute pulmonary oedema	0/115 (0%)		1/112 (0.9%)
Apnoea	0/115 (0%)		1/112 (0.9%)
Hypoxia	0/115 (0%)		4/112 (3.6%)
Pleural disorder	0/115 (0%)		1/112 (0.9%)
Pulmonary oedema	0/115 (0%)		1/112 (0.9%)
Tachypnoea	0/115 (0%)		1/112 (0.9%)
Skin and subcutaneous tissue disorders
Skin haemorrhage	1/115 (0.9%)		0/112 (0%)
Vascular disorders
Circulatory collapse	1/115 (0.9%)		0/112 (0%)
Deep vein thrombosis	1/115 (0.9%)		0/112 (0%)
Hypovolaemic shock	1/115 (0.9%)		0/112 (0%)
Intra-abdominal haemorrhage	1/115 (0.9%)		0/112 (0%)
Shock	1/115 (0.9%)		2/112 (1.8%)
Haemorrhage	0/115 (0%)		1/112 (0.9%)
Hypotension	0/115 (0%)		3/112 (2.7%)
Jugular vein thrombosis	0/115 (0%)		1/112 (0.9%)
Thrombosis	0/115 (0%)		1/112 (0.9%)
Other (Not Including Serious) Adverse Events
	Doripenem		Imipenem-cilastatin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	82/115 (71.3%)		80/112 (71.4%)
Blood and lymphatic system disorders
Anaemia	26/115 (22.6%)		25/112 (22.3%)
Cardiac disorders
Atrial fibrillation	9/115 (7.8%)		8/112 (7.1%)
Bradycardia	3/115 (2.6%)		6/112 (5.4%)
Gastrointestinal disorders
Diarrhoea	11/115 (9.6%)		12/112 (10.7%)
Constipation	9/115 (7.8%)		11/112 (9.8%)
Vomiting	6/115 (5.2%)		6/112 (5.4%)
Nausea	5/115 (4.3%)		7/112 (6.3%)
General disorders
Pyrexia	11/115 (9.6%)		10/112 (8.9%)
Infections and infestations
Urinary tract infection	13/115 (11.3%)		16/112 (14.3%)
Pneumonia	6/115 (5.2%)		9/112 (8%)
Metabolism and nutrition disorders
Hypokalaemia	12/115 (10.4%)		12/112 (10.7%)
Hyperkalaemia	6/115 (5.2%)		6/112 (5.4%)
Hypernatraemia	5/115 (4.3%)		7/112 (6.3%)
Hyponatraemia	5/115 (4.3%)		10/112 (8.9%)
Hypomagnesaemia	4/115 (3.5%)		7/112 (6.3%)
Psychiatric disorders
Depression	14/115 (12.2%)		8/112 (7.1%)
Agitation	11/115 (9.6%)		7/112 (6.3%)
Insomnia	8/115 (7%)		8/112 (7.1%)
Anxiety	2/115 (1.7%)		6/112 (5.4%)
Renal and urinary disorders
Renal impairment	6/115 (5.2%)		4/112 (3.6%)
Respiratory, thoracic and mediastinal disorders
Bronchospasm	4/115 (3.5%)		6/112 (5.4%)
Skin and subcutaneous tissue disorders
Decubitus ulcer	14/115 (12.2%)		11/112 (9.8%)
Vascular disorders
Hypotension	11/115 (9.6%)		8/112 (7.1%)
Hypertension	2/115 (1.7%)		6/112 (5.4%)

Limitations/Caveats

41 patients (21 doripenem, 20 imipenem-cilastatin) were enrolled at 5 sites that were found to be Good Clinical Practice non-compliant and were excluded from the primary efficacy and safety analyses.

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Certain Agreements

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

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.