Study Comparing Tigecycline Versus Ceftriaxone Sodium Plus Metronidazole in Complicated Intra-abdominal Infection

• Sponsor: Wyeth is now a wholly owned subsidiary of Pfizer (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00195351
• Collaborator: (none)
• Enrollment: 467
• Locations: 66
• Arms: 2
• Duration (Months): 29
• Patients Per Site: 7.1
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

This is a phase 3b/4 randomized, open-label, comparative, multicenter study of the safety and efficacy of tigecycline to ceftriaxone sodium plus metronidazole in hospitalized subjects with cIAI (Complicated Intra-Abdominal Infection). Subjects with clinical signs and symptoms of cIAI will be included for enrollment. Subjects will be stratified at randomization for Acute Physiologic and Chronic Health Evaluation scale (APACHE II) score < 10 and > 10. Subjects will be followed for efficacy through the test-of-cure assessment. Safety evaluations will occur through the treatment and post-treatment periods and continue through resolution or stability of the adverse event(s).

Condition or Disease	Intervention/Treatment	Phase
Appendicitis; Cholecystitis; Cross Infection; Diverticulitis; Peritonitis	Drug: tigecycline; Drug: ceftriaxone sodium + metronidazole	Phase 4

Study Design

• Study Type: Interventional
• Actual Enrollment: 467 participants
• Allocation: Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Multicenter, Open-Label, Randomized Comparative Study of Tigecycline vs Ceftriaxone Sodium Plus Metronidazole for the Treatment of Hospitalized Subjects With Complicated Intra-abdominal Infection
• Study Start Date: Sep 1, 2005
• Actual Primary Completion Date: Feb 1, 2008
• Actual Study Completion Date: Feb 1, 2008

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: A	Drug: tigecycline; every 12 hours IV (an initial dose of 100 mg followed by 50 mg every 12 hours)
Active Comparator: B	Drug: ceftriaxone sodium + metronidazole; Ceftriaxone sodium 2 g once daily intravenously plus metronidazole 1 g to 2 g daily given in divided doses intravenously. Test article should be administered for a minimum of 4 days and up to 14 days at the discretion of the investigator.

Outcome Measures

Primary Outcome Measures

1. Number of Clinically Evaluable Patients With Clinical Response of Cure at Test-of-Cure (TOC) Visit. [10-21 days after the last dose of test article]

   The clinical response was assigned by the investigator according to the protocol-specified guidelines. A clinical response of cure was defined as: the test article and the initial intervention (operative and/or radiologically controlled drainage procedure) resolved the intra-abdominal infection.

Secondary Outcome Measures

1. Number of Microbiologically Evaluable Patients With a Clinical Response of Cure at Test-of-Cure (TOC) Visit. [10-21 days after the last dose of test article]

   The clinical response was assigned by the investigator according to the protocol-specified guidelines. A clinical response of cure was defined as: the test article and the initial intervention (operative and/or radiologically controlled drainage procedure) resolved the intra-abdominal infection.

2. Number of Patients by Microbiologic Response at Test-of-Cure (TOC) Visit. [10-21 days after the last dose of test article]

   Microbiologic response assessed at patient level was combined microbiologic responses for all baseline isolates identified in intra-abdominal/blood cultures. Eradication=baseline isolate not recovered from primary infection site/blood; Presumed Eradication=no material available for culture but response was cure; Persistence=baseline isolate recovered from primary infection site/blood; Presumed Persistence=no material available for culture but response was failure; Superinfection=culture from primary infection site was positive for new isolate not identified at baseline & response was failure.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Clinical diagnosis of complicated intra-abdominal infection that requires surgery within 24 hours.

• Fever over 100.4°F (38.0°C) or high white blood cell count plus other symptoms such as nausea, vomiting, abdominal pain.

Exclusion Criteria:

• Cancer

• Medicines that suppress the immune system

• Dialysis

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Mobile	Alabama	United States	36617
2		Laguna Hills	California	United States	92653
3		Los Angeles	California	United States	90033
4		Orange	California	United States	92868
5		Palm Springs	California	United States	92262
6		San Diego	California	United States	92134
7		Torrance	California	United States	90509
8		Denver	Colorado	United States	80204
9		Denver	Colorado	United States	80262
10		Hartford	Connecticut	United States	06102
11		Newark	Delaware	United States	19718
12		Washington	District of Columbia	United States	20037
13		Miami	Florida	United States	33136
14		Atlanta	Georgia	United States	30342
15		Honolulu	Hawaii	United States	96813
16		Chicago	Illinois	United States	60612
17		Indianapolis	Indiana	United States	46202
18		Indianapolis	Indiana	United States	46280
19		Boston	Massachusetts	United States	02118
20		Springfield	Massachusetts	United States	01199
21		West Roxbury	Massachusetts	United States	02132
22		Detroit	Michigan	United States	48201
23		Grand Rapids	Michigan	United States	49506
24		Minneapolis	Minnesota	United States	55422
25		St. Louis	Missouri	United States	63110
26		St. Louis	Missouri	United States	63131
27		Butte	Montana	United States	59701
28		Lincoln	Nebraska	United States	68510
29		Laconia	New Hampshire	United States	03246
30		Buffalo	New York	United States	14215
31		Bismarck	North Dakota	United States	58501
32		Fargo	North Dakota	United States	58122
33		Cleveland	Ohio	United States	44109
34		Columbus	Ohio	United States	43210
35		Columbus	Ohio	United States	43215
36		Toledo	Ohio	United States	43608
37		Zanesville	Ohio	United States	43701
38		Pittsburgh	Pennsylvania	United States	15261
39		Corsiana	Texas	United States	75151
40		Fort Worth	Texas	United States	76135
41		Houston	Texas	United States	77026
42		Houston	Texas	United States	77030
43		Salt Lake City	Utah	United States	84102
44		Charlottesville	Virginia	United States	22906
45		Madison	Wisconsin	United States	53792
46		Milwaukee	Wisconsin	United States	53226
47		Buenos Aires		Argentina	C1118AAT
48		Buenos Aires		Argentina	C1425DUH
49		Buenos Aires		Argentina	C1431FWO
50		Curitiba	PR	Brazil	80810-050
51		Sao Paulo	SP	Brazil	01323-010
52		Sao Paulo	SP	Brazil	04330-020
53		Calgary	Alberta	Canada	T2N 2T9
54		Victoria	British Columbia	Canada	V8T 5G4
55		Ajax	Ontario	Canada	L1S 2J5
56		Oshawa	Ontario	Canada	L1H 1B9
57		Toronto	Ontario	Canada	M1E 5E9
58		Toronto	Ontario	Canada	M5T 2S8
59		Chicoutimi	Quebec	Canada	G7H 5H6
60		Greenfield Park	Quebec	Canada	J4V 2H1
61		Montreal	Quebec	Canada	H2X 3J4
62		Rimouski	Quebec	Canada	G5L 5T1
63		Trois-Rivieres	Quebec	Canada	G8Z 3R9
64		Santiago		Chile
65		Vina del Mar		Chile
66		Mexico D.F. CP		Mexico	03100

Sponsors and Collaborators

• Wyeth is now a wholly owned subsidiary of Pfizer

Investigators

• Study Director: Medical Monitor, Wyeth is now a wholly owned subsidiary of Pfizer

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Wyeth is now a wholly owned subsidiary of Pfizer
• ClinicalTrials.gov Identifier: NCT00195351
• Other Study ID Numbers: 3074A1-400
• First Posted: Sep 19, 2005
• Last Update Posted: Feb 25, 2013
• Last Verified: Feb 1, 2013

• Keywords provided by Wyeth is now a wholly owned subsidiary of Pfizer: Complicated intra-abdominal infection; Appendicitis with abscess; Perforated diverticulitis; Purulent peritonitis; Complicated cholecystitis
• Additional relevant MeSH terms: Infections; Communicable Diseases; Appendicitis; Peritonitis; Intraabdominal Infections; Cross Infection; Cholecystitis; Acalculous Cholecystitis; Diverticulitis; Metronidazole; Ceftriaxone; Tigecycline

Study Results

Participant Flow

Recruitment Details	Subjects were recruited worldwide from September 2005 to February 2008.
Pre-assignment Detail	Subjects were screened up to two days.

Arm/Group Title	Tigecycline	Ceftriaxone Sodium + Metronidazole
Arm/Group Description	Administered intravenously every 12 hours (an initial dose of 100 mg followed by 50 mg every 12 hours).	Ceftriaxone sodium 2 g administered intravenously once daily plus metronidazole 1 g to 2 g daily in divided IV doses.
Period Title: Overall Study
STARTED	236	231
COMPLETED	215	215
NOT COMPLETED	21	16

Baseline Characteristics

Arm/Group Title	Tigecycline	Ceftriaxone Sodium + Metronidazole	Total
Arm/Group Description	Administered intravenously every 12 hours (an initial dose of 100 mg followed by 50 mg every 12 hours).	Ceftriaxone sodium 2 g administered intravenously once daily plus metronidazole 1 g to 2 g daily in divided IV doses.	Total of all reporting groups
Overall Participants	236	231	467
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	48.17 (18.05)	48.79 (17.46)	48.48 (17.74)
Sex: Female, Male (Count of Participants)
Female	93 39.4%	72 31.2%	165 35.3%
Male	143 60.6%	159 68.8%	302 64.7%
Region of Enrollment (participants) [Number]
United States	163 69.1%	169 73.2%	332 71.1%
Mexico	1 0.4%	0 0%	1 0.2%
Canada	39 16.5%	25 10.8%	64 13.7%
Argentina	4 1.7%	2 0.9%	6 1.3%
Brazil	23 9.7%	23 10%	46 9.9%
Chile	6 2.5%	12 5.2%	18 3.9%

Outcome Measures

1. Primary Outcome

Title	Number of Clinically Evaluable Patients With Clinical Response of Cure at Test-of-Cure (TOC) Visit.
Description	The clinical response was assigned by the investigator according to the protocol-specified guidelines. A clinical response of cure was defined as: the test article and the initial intervention (operative and/or radiologically controlled drainage procedure) resolved the intra-abdominal infection.
Time Frame	10-21 days after the last dose of test article

Outcome Measure Data

Analysis Population Description

All patients who received ≥1 dose of study drug, who had clinical evidence of complicated intra-abdominal infection, met all inclusion and exclusion criteria, and completed TOC assessment within 8-44 days after last dose of study drug. Patients with an indeterminate assessment were excluded.

Arm/Group Title	Tigecycline	Ceftriaxone Sodium + Metronidazole
Arm/Group Description	Administered intravenously every 12 hours (an initial dose of 100 mg followed by 50 mg every 12 hours).	Ceftriaxone sodium 2 g administered intravenously once daily plus metronidazole 1 g to 2 g daily in divided IV doses.
Measure Participants	189	187
Number [participants]	133 56.4%	139 60.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Tigecycline, Ceftriaxone Sodium + Metronidazole
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.009
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	-4.0
	Confidence Interval	() 95%; -13.1 to 5.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Number of Microbiologically Evaluable Patients With a Clinical Response of Cure at Test-of-Cure (TOC) Visit.
Description	The clinical response was assigned by the investigator according to the protocol-specified guidelines. A clinical response of cure was defined as: the test article and the initial intervention (operative and/or radiologically controlled drainage procedure) resolved the intra-abdominal infection.
Time Frame	10-21 days after the last dose of test article

Outcome Measure Data

Analysis Population Description

All patients who received ≥1 dose, had clinical evidence of complicated intra-abdominal infection, met all inclusion/exclusion criteria, completed TOC assessment within 8-44 days after last dose, and had a baseline culture with ≥1 identified isolate that was susceptible to both study drugs. Patients with an indeterminate assessment were excluded.

Arm/Group Title	Tigecycline	Ceftriaxone Sodium + Metronidazole
Arm/Group Description	Administered intravenously every 12 hours (an initial dose of 100 mg followed by 50 mg every 12 hours).	Ceftriaxone sodium 2 g administered intravenously once daily plus metronidazole 1 g to 2 g daily in divided IV doses.
Measure Participants	138	137
Number [participants]	91 38.6%	96 41.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Tigecycline, Ceftriaxone Sodium + Metronidazole
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.020
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	-3.4
	Confidence Interval	() 95%; -14.5 to 7.8
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Number of Patients by Microbiologic Response at Test-of-Cure (TOC) Visit.
Description	Microbiologic response assessed at patient level was combined microbiologic responses for all baseline isolates identified in intra-abdominal/blood cultures. Eradication=baseline isolate not recovered from primary infection site/blood; Presumed Eradication=no material available for culture but response was cure; Persistence=baseline isolate recovered from primary infection site/blood; Presumed Persistence=no material available for culture but response was failure; Superinfection=culture from primary infection site was positive for new isolate not identified at baseline & response was failure.
Time Frame	10-21 days after the last dose of test article

Outcome Measure Data

Analysis Population Description

All patients who received ≥1 dose, had clinical evidence of complicated intra-abdominal infection, met all inclusion/exclusion criteria, completed TOC assessment within 8-44 days after last dose, and had baseline culture with ≥1 identified isolate that was susceptible to both study drugs. Patients with an indeterminate assessment were excluded.

Arm/Group Title	Tigecycline	Ceftriaxone Sodium + Metronidazole
Arm/Group Description	Administered intravenously every 12 hours (an initial dose of 100 mg followed by 50 mg every 12 hours).	Ceftriaxone sodium 2 g administered intravenously once daily plus metronidazole 1 g to 2 g daily in divided IV doses.
Measure Participants	138	137
Eradication and presumed eradication	94 39.8%	98 42.4%
Persistence and presumed persistence	44 18.6%	39 16.9%
Superinfection	7 3%	3 1.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Tigecycline, Ceftriaxone Sodium + Metronidazole
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.015
	Comments
	Method	Method of Mehrotra and Railkar
	Comments
Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	-2.9
	Confidence Interval	() 95%; -13.9 to 8.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Arm/Group Title	Tigecycline		Ceftriaxone Sodium + Metronidazole
Arm/Group Description	Administered intravenously every 12 hours (an initial dose of 100 mg followed by 50 mg every 12 hours).		Ceftriaxone sodium 2 g administered intravenously once daily plus metronidazole 1 g to 2 g daily in divided IV doses.
All Cause Mortality
	Tigecycline		Ceftriaxone Sodium + Metronidazole
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Tigecycline		Ceftriaxone Sodium + Metronidazole
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	51/ (NaN)		49/ (NaN)
Blood and lymphatic system disorders
Thrombocythemia	2/236 (0.8%)		0/231 (0%)
Anemia	0/236 (0%)		1/231 (0.4%)
International normalized ratio increased	1/236 (0.4%)		0/231 (0%)
Cardiac disorders
Pulmonary embolus	3/236 (1.3%)		1/231 (0.4%)
Atrial fibrillation	2/236 (0.8%)		0/231 (0%)
Hypotension	1/236 (0.4%)		1/231 (0.4%)
Myocardial infarct	0/236 (0%)		2/231 (0.9%)
Congestive heart failure	0/236 (0%)		1/231 (0.4%)
Coronary artery disorder	0/236 (0%)		1/231 (0.4%)
Heart arrest	1/236 (0.4%)		0/231 (0%)
Gastrointestinal disorders
Ileus	3/236 (1.3%)		3/231 (1.3%)
Intestinal obstruction	2/236 (0.8%)		3/231 (1.3%)
Gastrointestinal carcinoma	2/236 (0.8%)		1/231 (0.4%)
Cholestatic jaundice	2/236 (0.8%)		0/231 (0%)
Constipation	0/236 (0%)		1/231 (0.4%)
Diarrhea	1/236 (0.4%)		0/231 (0%)
Gastrointestinal disorder	0/236 (0%)		1/231 (0.4%)
Gastrointestinal hemorrhage	1/236 (0.4%)		0/231 (0%)
Hematemesis	0/236 (0%)		1/231 (0.4%)
Intestinal necrosis	1/236 (0.4%)		0/231 (0%)
Melena	0/236 (0%)		1/231 (0.4%)
General disorders
Abscess	18/236 (7.6%)		13/231 (5.6%)
Infection	3/236 (1.3%)		4/231 (1.7%)
Abdominal pain	3/236 (1.3%)		3/231 (1.3%)
Lymphocele	0/236 (0%)		4/231 (1.7%)
Peritonitis	1/236 (0.4%)		2/231 (0.9%)
Sepsis	0/236 (0%)		3/231 (1.3%)
Chest pain	1/236 (0.4%)		1/231 (0.4%)
Septic shock	2/236 (0.8%)		0/231 (0%)
Hemoperitoneum	0/236 (0%)		1/231 (0.4%)
Mesenteric fibrosis	1/236 (0.4%)		0/231 (0%)
Retroperitoneal hemorrhage	0/236 (0%)		1/231 (0.4%)
Traumatic hematoma	1/236 (0.4%)		0/231 (0%)
Trauma	0/236 (0%)		1/231 (0.4%)
Metabolism and nutrition disorders
Healing abdominal	3/236 (1.3%)		1/231 (0.4%)
Acidosis	0/236 (0%)		1/231 (0.4%)
Blood urea nitrogen increased	0/236 (0%)		1/231 (0.4%)
Renal and urinary disorders
Acute kidney failure	0/236 (0%)		1/231 (0.4%)
Pyelonephritis	1/236 (0.4%)		0/231 (0%)
Urinary retention	1/236 (0.4%)		0/231 (0%)
Respiratory, thoracic and mediastinal disorders
Respiratory failure	2/236 (0.8%)		5/231 (2.2%)
Pneumonia	1/236 (0.4%)		3/231 (1.3%)
Aspiration pneumonia	1/236 (0.4%)		1/231 (0.4%)
Respiratory distress syndrome	0/236 (0%)		2/231 (0.9%)
Carcinoma of the lung	1/236 (0.4%)		0/231 (0%)
Dyspnea	0/236 (0%)		1/231 (0.4%)
Vascular disorders
Deep vein thrombosis	2/236 (0.8%)		0/231 (0%)
Cerebral ischemia	1/236 (0.4%)		0/231 (0%)
Cerebrovascular accident	1/236 (0.4%)		0/231 (0%)
Hemorrhage	1/236 (0.4%)		0/231 (0%)
Mesenteric venous occousion	1/236 (0.4%)		0/231 (0%)
Other (Not Including Serious) Adverse Events
	Tigecycline		Ceftriaxone Sodium + Metronidazole
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	195/ (NaN)		189/ (NaN)
Blood and lymphatic system disorders
Thrombocythemia	13/236 (5.5%)		15/231 (6.5%)
Anemia	16/236 (6.8%)		8/231 (3.5%)
Leukocytosis	19/236 (8.1%)		4/231 (1.7%)
Cardiac disorders
Hypertension	9/236 (3.8%)		11/231 (4.8%)
Gastrointestinal disorders
Nausea	91/236 (38.6%)		64/231 (27.7%)
Vomiting	55/236 (23.3%)		41/231 (17.7%)
Diarrhea	42/236 (17.8%)		40/231 (17.3%)
Constipation	14/236 (5.9%)		14/231 (6.1%)
Ileus	8/236 (3.4%)		16/231 (6.9%)
Abdominal distension	5/236 (2.1%)		11/231 (4.8%)
Dyspepsia	9/236 (3.8%)		4/231 (1.7%)
Oral moniliasis	8/236 (3.4%)		1/231 (0.4%)
General disorders
Abdominal pain	22/236 (9.3%)		16/231 (6.9%)
Abscess	23/236 (9.7%)		15/231 (6.5%)
Headache	14/236 (5.9%)		22/231 (9.5%)
Fever	17/236 (7.2%)		18/231 (7.8%)
Infection	17/236 (7.2%)		9/231 (3.9%)
Generalized edema	1/236 (0.4%)		7/231 (3%)
Taste perversion	2/236 (0.8%)		9/231 (3.9%)
Metabolism and nutrition disorders
Hypokalemia	16/236 (6.8%)		21/231 (9.1%)
Healing abdominal	9/236 (3.8%)		8/231 (3.5%)
Hyperglycemia	9/236 (3.8%)		8/231 (3.5%)
Peripheral edema	9/236 (3.8%)		7/231 (3%)
Hypoproteinemia	11/236 (4.7%)		4/231 (1.7%)
Amylase increased	8/236 (3.4%)		4/231 (1.7%)
Hypophophatemia	3/236 (1.3%)		9/231 (3.9%)
SGPT increased	7/236 (3%)		5/231 (2.2%)
Nervous system disorders
Insomina	23/236 (9.7%)		24/231 (10.4%)
Anxiety	7/236 (3%)		12/231 (5.2%)
Confusion	8/236 (3.4%)		2/231 (0.9%)
Respiratory, thoracic and mediastinal disorders
Pharyngitis	9/236 (3.8%)		8/231 (3.5%)
Respiratory failure	6/236 (2.5%)		10/231 (4.3%)
Pulmonary physical findings	7/236 (3%)		6/231 (2.6%)
Dyspnea	5/236 (2.1%)		7/231 (3%)
Pleural effusion	4/236 (1.7%)		7/231 (3%)
Atelectasis	0/236 (0%)		7/231 (3%)
Skin and subcutaneous tissue disorders
Pruritus	13/236 (5.5%)		12/231 (5.2%)
Rash	4/236 (1.7%)		7/231 (3%)
Surgical and medical procedures
Local reaction to procedure	18/236 (7.6%)		14/231 (6.1%)
Vascular disorders
Deep vein thrombosis	8/236 (3.4%)		1/231 (0.4%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

The PIs agreed to allow the sponsor 60 days to review and require changes to presentations or publications but only to protect confidential information and intellectual property, and for the sponsor to file a patent application, as applicable. The PIs also agreed for data to be presented first as a joint, multi-center publication.