Appendicitis, Cholecystitis, Cross Infection, Diverticulitis, Peritonitis
Conditions
Keywords
Complicated intra-abdominal infection, Appendicitis with abscess, Perforated diverticulitis, Purulent peritonitis, Complicated cholecystitis
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).
Interventions
DRUGtigecycline
every 12 hours IV (an initial dose of 100 mg followed by 50 mg every 12 hours)
DRUGceftriaxone 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.
Sponsors
Wyeth is now a wholly owned subsidiary of Pfizer
Study design
Allocation
RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
Countries
Argentina, Brazil, Canada, Chile, Mexico, United States
Participant flow
Recruitment details
Subjects were recruited worldwide from September 2005 to February 2008.
Pre-assignment details
Subjects were screened up to two days.
Participants by arm
| Arm | Count |
|---|---|
| Tigecycline Administered intravenously every 12 hours (an initial dose of 100 mg followed by 50 mg every 12 hours). | 236 |
| Ceftriaxone Sodium + Metronidazole Ceftriaxone sodium 2 g administered intravenously once daily plus metronidazole 1 g to 2 g daily in divided IV doses. | 231 |
| Total | 467 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 3 | 1 |
| Overall Study | Lack of Efficacy | 0 | 1 |
| Overall Study | Lost to Follow-up | 9 | 9 |
| Overall Study | Protocol Deviation | 3 | 2 |
| Overall Study | Withdrawal by Subject | 6 | 3 |
Baseline characteristics
| Characteristic | Tigecycline | Ceftriaxone Sodium + Metronidazole | Total |
|---|---|---|---|
| Age Continuous | 48.17 years STANDARD_DEVIATION 18.05 | 48.79 years STANDARD_DEVIATION 17.46 | 48.48 years STANDARD_DEVIATION 17.74 |
| Region of Enrollment Argentina | 4 participants | 2 participants | 6 participants |
| Region of Enrollment Brazil | 23 participants | 23 participants | 46 participants |
| Region of Enrollment Canada | 39 participants | 25 participants | 64 participants |
| Region of Enrollment Chile | 6 participants | 12 participants | 18 participants |
| Region of Enrollment Mexico | 1 participants | 0 participants | 1 participants |
| Region of Enrollment United States | 163 participants | 169 participants | 332 participants |
| Sex: Female, Male Female | 93 Participants | 72 Participants | 165 Participants |
| Sex: Female, Male Male | 143 Participants | 159 Participants | 302 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 195 / — | 189 / — |
| serious Total, serious adverse events | 51 / — | 49 / — |
Outcome results
Primary
Number of Clinically Evaluable Patients With Clinical Response of Cure at Test-of-Cure (TOC) Visit.
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
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| Tigecycline | Number of Clinically Evaluable Patients With Clinical Response of Cure at Test-of-Cure (TOC) Visit. | 133 participants |
| Ceftriaxone Sodium + Metronidazole | Number of Clinically Evaluable Patients With Clinical Response of Cure at Test-of-Cure (TOC) Visit. | 139 participants |
p-value: 0.00995% CI: [-13.1, 5.1]t-test, 2 sided
Secondary
Number of Microbiologically Evaluable Patients With a Clinical Response of Cure at Test-of-Cure (TOC) Visit.
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
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| Tigecycline | Number of Microbiologically Evaluable Patients With a Clinical Response of Cure at Test-of-Cure (TOC) Visit. | 91 participants |
| Ceftriaxone Sodium + Metronidazole | Number of Microbiologically Evaluable Patients With a Clinical Response of Cure at Test-of-Cure (TOC) Visit. | 96 participants |
p-value: 0.0295% CI: [-14.5, 7.8]t-test, 2 sided
Secondary
Number of Patients by Microbiologic Response at Test-of-Cure (TOC) Visit.
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
Population: 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 | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Tigecycline | Number of Patients by Microbiologic Response at Test-of-Cure (TOC) Visit. | Eradication and presumed eradication | 94 participants |
| Tigecycline | Number of Patients by Microbiologic Response at Test-of-Cure (TOC) Visit. | Persistence and presumed persistence | 44 participants |
| Tigecycline | Number of Patients by Microbiologic Response at Test-of-Cure (TOC) Visit. | Superinfection | 7 participants |
| Ceftriaxone Sodium + Metronidazole | Number of Patients by Microbiologic Response at Test-of-Cure (TOC) Visit. | Eradication and presumed eradication | 98 participants |
| Ceftriaxone Sodium + Metronidazole | Number of Patients by Microbiologic Response at Test-of-Cure (TOC) Visit. | Persistence and presumed persistence | 39 participants |
| Ceftriaxone Sodium + Metronidazole | Number of Patients by Microbiologic Response at Test-of-Cure (TOC) Visit. | Superinfection | 3 participants |
p-value: 0.01595% CI: [-13.9, 8.1]Method of Mehrotra and Railkar