Trial Outcomes & Findings for Study Comparing the Safety and Efficacy of Tigecycline With Ampicillin-Sulbactam or Amoxicillin-Clavulanate to Treat Skin Infections (NCT NCT00368537)

Last Updated: 2012-08-09

Results Overview

Investigator assigned clinical response of cure of the cSSSI defined as: resolution of all clinical signs and symptoms of infection (healing of chronic underlying skin ulcer not required) or improvement of signs or symptoms of the infection to such an extent that no further antibacterial therapy was necessary. CE population were those who completed TOC assessment of cure or failure (but not indeterminate) or, in case of premature discontinuation due to lack of efficacy, had completed end of treatment assessment such that assessment of clinical response could be made.

Recruitment status

COMPLETED

Study phase

PHASE4

Target enrollment

550 participants

Primary outcome timeframe

up to 6 weeks

Results posted on

2012-08-09

Participant Flow

Patients were recruited worldwide from September 2006 to August 2008.

Patients were screened according to the inclusion/exclusion criteria. Once informed consent was obtained, the patient was enrolled into the study and assigned a randomization number and a treatment regimen.

Participant milestones

Participant milestones
Measure	Tigecycline Tigecycline every 12 hours IV (an initial dose of 100 mg followed by 50 mg every 12 hours)	Ampicillin-Sulbactam or Amoxicillin-Clavulanate Ampicillin-sulbactam 1.5 g (1 g ampicillin plus 0.5 g sulbactam) to 3 g (2 g ampicillin plus 1 g sulbactam) IV every 6 hours or amoxicillin-clavulanate 1.2 g (1000 mg amoxicillin plus 200 mg clavulanate) IV every 6 to 8 hours.
Randomization STARTED	281	269
Randomization COMPLETED	268	263
Randomization NOT COMPLETED	13	6
Baseline Participants STARTED	268	263
Baseline Participants COMPLETED	244	239
Baseline Participants NOT COMPLETED	24	24

Reasons for withdrawal

Reasons for withdrawal
Measure	Tigecycline Tigecycline every 12 hours IV (an initial dose of 100 mg followed by 50 mg every 12 hours)	Ampicillin-Sulbactam or Amoxicillin-Clavulanate Ampicillin-sulbactam 1.5 g (1 g ampicillin plus 0.5 g sulbactam) to 3 g (2 g ampicillin plus 1 g sulbactam) IV every 6 hours or amoxicillin-clavulanate 1.2 g (1000 mg amoxicillin plus 200 mg clavulanate) IV every 6 to 8 hours.
Randomization No study drug dosed	13	6
Baseline Participants Lost to Follow-up	16	17
Baseline Participants Withdrawal by Subject	6	4
Baseline Participants Death	1	2
Baseline Participants No susceptibility	1	0
Baseline Participants Patient uncompliant	0	1

Baseline Characteristics

Study Comparing the Safety and Efficacy of Tigecycline With Ampicillin-Sulbactam or Amoxicillin-Clavulanate to Treat Skin Infections

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Tigecycline n=268 Participants Tigecycline every 12 hours IV (an initial dose of 100 mg followed by 50 mg every 12 hours)	Ampicillin-Sulbactam or Amoxicillin-Clavulanate n=263 Participants Ampicillin-sulbactam 1.5 g (1 g ampicillin plus 0.5 g sulbactam) to 3 g (2 g ampicillin plus 1 g sulbactam) IV every 6 hours or amoxicillin-clavulanate 1.2 g (1000 mg amoxicillin plus 200 mg clavulanate) IV every 6 to 8 hours.	Total n=531 Participants Total of all reporting groups
Age Continuous	51.10 years STANDARD_DEVIATION 16.11 • n=5 Participants	51.54 years STANDARD_DEVIATION 16.90 • n=7 Participants	51.32 years STANDARD_DEVIATION 16.49 • n=5 Participants
Sex: Female, Male Female	105 Participants n=5 Participants	94 Participants n=7 Participants	199 Participants n=5 Participants
Sex: Female, Male Male	163 Participants n=5 Participants	169 Participants n=7 Participants	332 Participants n=5 Participants

PRIMARY outcome

Timeframe: up to 6 weeks

Population: Clinically Evaluable (CE): Patients with cSSSI, no Pseudomonas aeruginosa as sole baseline isolate, met major inclusion/exclusion criteria, ≤24 hrs antibiotics pre-baseline, had ≥4 days of study drug, compliant with therapy. Excludes indeterminates.

Outcome measures

Outcome measures
Measure	Tigecycline n=209 Participants Tigecycline every 12 hours IV (an initial dose of 100 mg followed by 50 mg every 12 hours)	Ampicillin-Sulbactam or Amoxicillin-Clavulanate n=196 Participants Ampicillin-sulbactam 1.5 g (1 g ampicillin plus 0.5 g sulbactam) to 3 g (2 g ampicillin plus 1 g sulbactam) IV every 6 hours or amoxicillin-clavulanate 1.2 g (1000 mg amoxicillin plus 200 mg clavulanate) IV every 6 to 8 hours.
Number of Clinically Evaluable (CE) Patients With Clinical Response of Cure at the Test-of-cure (TOC) Visit	162 participants	152 participants

SECONDARY outcome

Timeframe: up to 6 weeks

Population: Microbiologically Evaluable patients:Clinically Evaluable (CE) patients who had baseline culture with ≥1 identified pathogen susceptible to both study drugs (ie, the pathogen is susceptible to tigecycline and comparator). Excludes indeterminates.

Investigator assigned clinical response of cure of the cSSSI defined as: resolution of all clinical signs and symptoms of infection (healing of chronic underlying skin ulcer not required) or improvement of signs or symptoms of the infection to such an extent that no further antibacterial therapy was necessary. ME population were subjects who were CE and had baseline culture with at least 1 identified isolate that was susceptible to study drug and comparator. TOC performed 8-50 days after last dose of study drug.

Outcome measures

Outcome measures
Measure	Tigecycline n=120 Participants Tigecycline every 12 hours IV (an initial dose of 100 mg followed by 50 mg every 12 hours)	Ampicillin-Sulbactam or Amoxicillin-Clavulanate n=99 Participants Ampicillin-sulbactam 1.5 g (1 g ampicillin plus 0.5 g sulbactam) to 3 g (2 g ampicillin plus 1 g sulbactam) IV every 6 hours or amoxicillin-clavulanate 1.2 g (1000 mg amoxicillin plus 200 mg clavulanate) IV every 6 to 8 hours.
Number of Microbiologically Evaluable Patients With Clinical Response of Cure at the Test-of-cure (TOC) Visit	96 participants	77 participants

SECONDARY outcome

Timeframe: up to 6 weeks

Population: Microbiologically Evaluable patients:CE patients who had baseline culture with ≥1 identified pathogen susceptible to both study drugs (ie, the pathogen is susceptible to tigecycline and comparator). TOC performed 8-50 days after last dose of study drug.

Microbiological response assessed at patient level. Eradication=baseline isolate not present in repeat culture from the original infection site; Presumed Eradication=clinical response of cure precluded the availability of a specimen for culture; Persistence=baseline isolate present in repeat culture from the original infection site; Presumed Persistence=culture data not available for patients with a clinical response of failure; Superinfection=culture from the primary infection site had new pathogen not identified as a baseline isolate and clinical response was failure.

Outcome measures

Outcome measures
Measure	Tigecycline n=120 Participants Tigecycline every 12 hours IV (an initial dose of 100 mg followed by 50 mg every 12 hours)	Ampicillin-Sulbactam or Amoxicillin-Clavulanate n=99 Participants Ampicillin-sulbactam 1.5 g (1 g ampicillin plus 0.5 g sulbactam) to 3 g (2 g ampicillin plus 1 g sulbactam) IV every 6 hours or amoxicillin-clavulanate 1.2 g (1000 mg amoxicillin plus 200 mg clavulanate) IV every 6 to 8 hours.
Number of Microbiologically Evaluable Patients by Microbiologic Response at Test-of-Cure (TOC) Visit Superinfection	2 participants	1 participants
Number of Microbiologically Evaluable Patients by Microbiologic Response at Test-of-Cure (TOC) Visit Eradication + presumed eradication	95 participants	76 participants
Number of Microbiologically Evaluable Patients by Microbiologic Response at Test-of-Cure (TOC) Visit Persistence + Presumed persistence	25 participants	23 participants

SECONDARY outcome

Timeframe: up to 6 weeks

Population: m-mITT: Patients with ≥1 dose of study drug, had cSSSI and baseline isolate from infection site / blood. MIC reported for isolates present in ≥10 m-mITT patients. In the categories below "n" is the actual number of isolates used to caluculate the MIC 50 and MIC 90.

In vitro activity of the study drugs against a range of pathogenic bacteria that cause complicated skin and skin structure infection (cSSSI) were analyzed using MIC. MIC 50 and MIC 90 are the lowest concentrations of a drug that inhibit the growth of 50% and 90% of a microorganism, respectively. TOC performed 8-50 days after last dose of study drug.

Outcome measures

Outcome measures
Measure	Tigecycline n=120 Participants Tigecycline every 12 hours IV (an initial dose of 100 mg followed by 50 mg every 12 hours)	Ampicillin-Sulbactam or Amoxicillin-Clavulanate n=99 Participants Ampicillin-sulbactam 1.5 g (1 g ampicillin plus 0.5 g sulbactam) to 3 g (2 g ampicillin plus 1 g sulbactam) IV every 6 hours or amoxicillin-clavulanate 1.2 g (1000 mg amoxicillin plus 200 mg clavulanate) IV every 6 to 8 hours.
Minimum Inhibitory Concentration (MIC) 50 and 90 by Baseline Isolate Enterococcus Faecalis MIC50 (n=20,20)	0.12 mcg/mL	1.00 mcg/mL
Minimum Inhibitory Concentration (MIC) 50 and 90 by Baseline Isolate Enterococcus Faecalis MIC90 (n=20,20)	0.25 mcg/mL	1.00 mcg/mL
Minimum Inhibitory Concentration (MIC) 50 and 90 by Baseline Isolate Escherichia Coli MIC50 (n=29,29)	0.25 mcg/mL	8.00 mcg/mL
Minimum Inhibitory Concentration (MIC) 50 and 90 by Baseline Isolate Escherichia Coli MIC90 (n=29,29)	0.50 mcg/mL	32.00 mcg/mL
Minimum Inhibitory Concentration (MIC) 50 and 90 by Baseline Isolate Klebsiella Pneumoniae MIC50 (n=13,13)	0.50 mcg/mL	2.00 mcg/mL
Minimum Inhibitory Concentration (MIC) 50 and 90 by Baseline Isolate Klebsiella Pneumoniae MIC90 (n=13,13)	2.00 mcg/mL	8.00 mcg/mL
Minimum Inhibitory Concentration (MIC) 50 and 90 by Baseline Isolate Staphylococcus Aureus MIC50 (n=176,176)	0.12 mcg/mL	2.00 mcg/mL
Minimum Inhibitory Concentration (MIC) 50 and 90 by Baseline Isolate Staphylococcus Aureus MIC90 (n=176,176)	0.25 mcg/mL	8.00 mcg/mL
Minimum Inhibitory Concentration (MIC) 50 and 90 by Baseline Isolate Streptococcus Agalactiae MIC50 (n=18,18)	0.03 mcg/mL	0.12 mcg/mL
Minimum Inhibitory Concentration (MIC) 50 and 90 by Baseline Isolate Streptococcus Agalactiae MIC90 (n=18,18)	0.06 mcg/mL	0.12 mcg/mL
Minimum Inhibitory Concentration (MIC) 50 and 90 by Baseline Isolate Streptococcus Pyogenes MIC50 (n=18,18)	0.03 mcg/mL	0.06 mcg/mL
Minimum Inhibitory Concentration (MIC) 50 and 90 by Baseline Isolate Streptococcus Pyogenes MIC90 (n=18,18)	0.06 mcg/mL	0.06 mcg/mL

SECONDARY outcome

Timeframe: up to 6 weeks

Population: All patients who received at least 1 dose of study article.

Healthcare resource utilization assessment included intensive care unit (ICU) and non-ICU inpatient hospitalization. TOC performed 8-50 days after last dose of study drug.

Outcome measures

Outcome measures
Measure	Tigecycline n=268 Participants Tigecycline every 12 hours IV (an initial dose of 100 mg followed by 50 mg every 12 hours)	Ampicillin-Sulbactam or Amoxicillin-Clavulanate n=263 Participants Ampicillin-sulbactam 1.5 g (1 g ampicillin plus 0.5 g sulbactam) to 3 g (2 g ampicillin plus 1 g sulbactam) IV every 6 hours or amoxicillin-clavulanate 1.2 g (1000 mg amoxicillin plus 200 mg clavulanate) IV every 6 to 8 hours.
Inpatient Healthcare Resource Utilization on or Before Test-of-Cure - Number of Patients Intensive care unit	6 participants	9 participants
Inpatient Healthcare Resource Utilization on or Before Test-of-Cure - Number of Patients Non-ICU inpatient hospitalization	268 participants	263 participants

Adverse Events

Tigecycline

Serious events: 38 serious events

Other events: 396 other events

Deaths: 0 deaths

Ampicillin-Sulbactam or Amoxicillin-Clavulanate

Serious events: 29 serious events

Other events: 241 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

U. S. Contact Center

Wyeth

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee 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.
Publication restrictions are in place

Restriction type: OTHER

Measure	Tigecycline n=268 participants at risk Tigecycline every 12 hours IV (an initial dose of 100 mg followed by 50 mg every 12 hours)	Ampicillin-Sulbactam or Amoxicillin-Clavulanate n=263 participants at risk Ampicillin-sulbactam 1.5 g (1 g ampicillin plus 0.5 g sulbactam) to 3 g (2 g ampicillin plus 1 g sulbactam) IV every 6 hours or amoxicillin-clavulanate 1.2 g (1000 mg amoxicillin plus 200 mg clavulanate) IV every 6 to 8 hours.
Gastrointestinal disorders Nausea	43.7% 117/268 This data represents the number of times a given adverse event was reported. The given participant may have experienced more than one adverse event. We are looking at the frequency of adverse events based on event and not by participant.	16.7% 44/263 This data represents the number of times a given adverse event was reported. The given participant may have experienced more than one adverse event. We are looking at the frequency of adverse events based on event and not by participant.
Gastrointestinal disorders Vomiting	23.9% 64/268 This data represents the number of times a given adverse event was reported. The given participant may have experienced more than one adverse event. We are looking at the frequency of adverse events based on event and not by participant.	5.3% 14/263 This data represents the number of times a given adverse event was reported. The given participant may have experienced more than one adverse event. We are looking at the frequency of adverse events based on event and not by participant.
Gastrointestinal disorders Diarrhea	14.2% 38/268 This data represents the number of times a given adverse event was reported. The given participant may have experienced more than one adverse event. We are looking at the frequency of adverse events based on event and not by participant.	5.3% 14/263 This data represents the number of times a given adverse event was reported. The given participant may have experienced more than one adverse event. We are looking at the frequency of adverse events based on event and not by participant.
Gastrointestinal disorders Constipation	6.3% 17/268 This data represents the number of times a given adverse event was reported. The given participant may have experienced more than one adverse event. We are looking at the frequency of adverse events based on event and not by participant.	8.4% 22/263 This data represents the number of times a given adverse event was reported. The given participant may have experienced more than one adverse event. We are looking at the frequency of adverse events based on event and not by participant.
Gastrointestinal disorders Dyspepsia	6.3% 17/268 This data represents the number of times a given adverse event was reported. The given participant may have experienced more than one adverse event. We are looking at the frequency of adverse events based on event and not by participant.	2.7% 7/263 This data represents the number of times a given adverse event was reported. The given participant may have experienced more than one adverse event. We are looking at the frequency of adverse events based on event and not by participant.
General disorders Headache	7.5% 20/268 This data represents the number of times a given adverse event was reported. The given participant may have experienced more than one adverse event. We are looking at the frequency of adverse events based on event and not by participant.	8.4% 22/263 This data represents the number of times a given adverse event was reported. The given participant may have experienced more than one adverse event. We are looking at the frequency of adverse events based on event and not by participant.
General disorders Pain	5.6% 15/268 This data represents the number of times a given adverse event was reported. The given participant may have experienced more than one adverse event. We are looking at the frequency of adverse events based on event and not by participant.	6.8% 18/263 This data represents the number of times a given adverse event was reported. The given participant may have experienced more than one adverse event. We are looking at the frequency of adverse events based on event and not by participant.
General disorders Abdominal pain	6.3% 17/268 This data represents the number of times a given adverse event was reported. The given participant may have experienced more than one adverse event. We are looking at the frequency of adverse events based on event and not by participant.	2.7% 7/263 This data represents the number of times a given adverse event was reported. The given participant may have experienced more than one adverse event. We are looking at the frequency of adverse events based on event and not by participant.
General disorders Fever	3.4% 9/268 This data represents the number of times a given adverse event was reported. The given participant may have experienced more than one adverse event. We are looking at the frequency of adverse events based on event and not by participant.	2.3% 6/263 This data represents the number of times a given adverse event was reported. The given participant may have experienced more than one adverse event. We are looking at the frequency of adverse events based on event and not by participant.
General disorders Chest pain	1.9% 5/268 This data represents the number of times a given adverse event was reported. The given participant may have experienced more than one adverse event. We are looking at the frequency of adverse events based on event and not by participant.	3.0% 8/263 This data represents the number of times a given adverse event was reported. The given participant may have experienced more than one adverse event. We are looking at the frequency of adverse events based on event and not by participant.
Nervous system disorders Insomnia	8.2% 22/268 This data represents the number of times a given adverse event was reported. The given participant may have experienced more than one adverse event. We are looking at the frequency of adverse events based on event and not by participant.	6.5% 17/263 This data represents the number of times a given adverse event was reported. The given participant may have experienced more than one adverse event. We are looking at the frequency of adverse events based on event and not by participant.
Nervous system disorders Anxiety	3.4% 9/268 This data represents the number of times a given adverse event was reported. The given participant may have experienced more than one adverse event. We are looking at the frequency of adverse events based on event and not by participant.	2.7% 7/263 This data represents the number of times a given adverse event was reported. The given participant may have experienced more than one adverse event. We are looking at the frequency of adverse events based on event and not by participant.
Nervous system disorders Dizziness	3.4% 9/268 This data represents the number of times a given adverse event was reported. The given participant may have experienced more than one adverse event. We are looking at the frequency of adverse events based on event and not by participant.	2.3% 6/263 This data represents the number of times a given adverse event was reported. The given participant may have experienced more than one adverse event. We are looking at the frequency of adverse events based on event and not by participant.
Metabolism and nutrition disorders Hypokalemia	2.2% 6/268 This data represents the number of times a given adverse event was reported. The given participant may have experienced more than one adverse event. We are looking at the frequency of adverse events based on event and not by participant.	6.5% 17/263 This data represents the number of times a given adverse event was reported. The given participant may have experienced more than one adverse event. We are looking at the frequency of adverse events based on event and not by participant.
Skin and subcutaneous tissue disorders Pruritus	5.6% 15/268 This data represents the number of times a given adverse event was reported. The given participant may have experienced more than one adverse event. We are looking at the frequency of adverse events based on event and not by participant.	6.1% 16/263 This data represents the number of times a given adverse event was reported. The given participant may have experienced more than one adverse event. We are looking at the frequency of adverse events based on event and not by participant.
Vascular disorders Hypertension	3.0% 8/268 This data represents the number of times a given adverse event was reported. The given participant may have experienced more than one adverse event. We are looking at the frequency of adverse events based on event and not by participant.	3.4% 9/263 This data represents the number of times a given adverse event was reported. The given participant may have experienced more than one adverse event. We are looking at the frequency of adverse events based on event and not by participant.
Blood and lymphatic system disorders Anemia	3.0% 8/268 This data represents the number of times a given adverse event was reported. The given participant may have experienced more than one adverse event. We are looking at the frequency of adverse events based on event and not by participant.	2.7% 7/263 This data represents the number of times a given adverse event was reported. The given participant may have experienced more than one adverse event. We are looking at the frequency of adverse events based on event and not by participant.