Comparative Study of Ceftaroline vs. Vancomycin Plus Aztreonam in Adult Subjects With Complicated Skin Infections

• Sponsor: Forest Laboratories (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00423657
• Collaborator: (none)
• Enrollment: 680
• Locations: 54
• Arms: 2
• Duration (Months): 9
• Patients Per Site: 12.6
• Patients Per Site Per Month: 1.4

Study Details

Study Description

Brief Summary

The purpose of this study is to determine whether ceftaroline is effective and safe in the treatment of complicated skin infections in adults.

Condition or Disease	Intervention/Treatment	Phase
Bacterial Infections	Drug: ceftaroline; Drug: vancomycin plus aztreonam; Drug: Placebo	Phase 3

Detailed Description

Additional purpose of this study is to compare ceftaroline effectivity versus Vancomycin plus Aztreonam in the treatment of complicated skin infections in adults.

Study Design

• Study Type: Interventional
• Actual Enrollment: 680 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase 3, Multicenter, Randomized, Double-blind, Comparative Study to Evaluate the Safety and Efficacy of Ceftaroline Versus Vancomycin Plus Aztreonam in Adult Subjects With Complicated Skin and Skin Structure Infection (cSSSI)
• Study Start Date: Mar 1, 2007
• Actual Primary Completion Date: Dec 1, 2007
• Actual Study Completion Date: Dec 1, 2007

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Ceftaroline fosamil for Injection Ceftaroline fosamil 600 mg administered intravenously over 60 minutes every 12 hours, followed by placebo administered over 60 minutes every 12 hours.	Drug: ceftaroline; 600 mg parenteral infused over 60 minutes, every 12 hours for 5 to 14 days; Other Names: Experimental ; Drug: Placebo; Ceftaroline fosamil 600 mg administered intravenously over 60 minutes every 12 hours, followed by placebo administered over 60 minutes every 12 hours.
Active Comparator: IV Vancomycin plus IV Aztreonam Vancomycin 1 g administered over 60 minutes every 12 hours followed by aztreonam 1 g administered over 60 minutes every 12 hours.	Drug: vancomycin plus aztreonam; vancomycin at 1 g parenteral infused over 60 minutes followed by aztreonam 1 g infused over 60 minutes, every 12 hours, for 5 to 14 days.; Other Names: Active Comparator

Outcome Measures

Primary Outcome Measures

1. Clinical Cure Rate at Test of Cure (TOC) (MITT Population) [8-15 days after last dose of study drug administration]

   Cure: Total resolution of all signs and symptoms of the baseline infection, or improvement of the infection such that no further antimicrobial therapy was necessary. Failure: Requirement of alternative antimicrobial therapy for primary infection of complicated skin and skin structure infection (cSSSI) due to inadequate response, recurrence, new infection at the same site; treatment-limiting adverse event (AE); requirement for surgery due to failure of study drug; diagnosis of osteomyelitis after Study Day 8; or death caused by cSSSI. Indeterminate: Inability to determine an outcome

2. The Primary Efficacy Outcome Measure Was the Per-subject Clinical Cure Rate at the TOC Visit in the Clinically Evaluable (CE) Populations. [8-15 days after last dose of study drug]

Secondary Outcome Measures

1. To Evaluate the Microbiological Success Rate at the TOC Visit [8-15 days after the last dose of study drug]

2. To Evaluate the Clinical Response at the End of Therapy (EOT) Visit [last day of study drug administration]

3. To Evaluate the Clinical and Microbiological Response by Pathogen at the TOC Visit [8-15 days after last dose of study drug]

4. To Evaluate Clinical Relapse at the Late Follow Up (LFU) Visit [21 to 35 days after the last dose of study drug]

5. To Evaluate Microbiological Reinfection or Recurrence at the LFU Visit [21-35 days after last dose of study drug]

6. To Evaluate Safety [first study drug dose through TOC]

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Skin and skin structure infection (SSSI) that involves deeper soft tissue or requires significant surgical intervention, or cellulitis or abscess on lower extremity which occurs in subjects with diabetes mellitus or well-documented peripheral vascular disease.

Exclusion Criteria:

• Prior treatment of current complicated skin and skin structure infection (cSSSI) with an antimicrobial.

• Failure of vancomycin or aztreonam as therapy for the current cSSSI, or prior isolation of an organism with in vitro resistance to vancomycin or aztreonam.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Investigational Site	Buena Park	California	United States	90620
2	Investigational Site	Hawaiian Gardens	California	United States	90716
3	Investigational Site	Los Angeles	California	United States	90033
4	Investigational Site	Pasadena	California	United States	91105
5	Investigational Site	San Diego	California	United States	92114
6	Investigational Site	San Jose	California	United States	95124
7	Investigational Site	Atlantis	Florida	United States	33462
8	Investigational Site	Columbus	Georgia	United States	31904
9	Investigational Site	Marietta	Georgia	United States	30060
10	Investigational Site	Springfield	Illinois	United States	62701
11	Investigational Site	Baltimore	Maryland	United States	21201
12	Investigational Site	Minneapolis	Minnesota	United States	55422
13	Investigational Site	Butte	Montana	United States	59701
14	Investigational Site	Somers Point	New Jersey	United States	08244
15	Investigational Site	Toledo	Ohio	United States	43608
16	Investigational Site	Tacoma	Washington	United States	98405
17	Investigational Site	Milwaukee	Wisconsin	United States	53215
18	Investigational Site	Buenos Aires		Argentina
19	Investigational Site	Cordoba		Argentina
20	Investigational Site	Santa Fe		Argentina
21	Investigational Site	Braunau		Austria
22	Investigational Site	Graz		Austria	8036
23	Investigational Site	St. Polten		Austria	3100
24	Investigational Site	Sao Paula		Brazil
25	Investigational Site	Temuco		Chile
26	Investigational Site	Valdivia		Chile
27	Investigational Site	Cottbus		Germany	03048
28	Investigational Site	Dortmund		Germany	44145
29	Investigational Site	Homburg/Saar		Germany	D-66421
30	Investigational Site	Mainz		Germany	D-55101
31	Investigational Site	Wiesbaden		Germany	65191
32	Investigational Site	Riga		Latvia	LV-1001
33	Investigational Site	Guadalajara	Jalisco	Mexico	44280
34	Investigational Site	Seattle Zapopan	Jalisco	Mexico	45170
35	Investigational Site	Bielsko-Biala		Poland	43-316
36	Investigational Site	Krakow		Poland	31-501
37	Investigational Site	Kraków		Poland	31-820
38	Investigational Site	Lodz		Poland	91-425
39	Investigational Site	Lublin		Poland	20-954
40	Investigational Site	Poznań		Poland	61-848
41	Investigational Site	Warszawa		Poland	02-097
42	Investigational Site	Warszawa		Poland	03-401
43	Investigational Site	Wroclaw		Poland	50-326
44	Investigational Site	Moscow Region		Russian Federation	143405
45	Investigational Site	Moscow		Russian Federation	111020
46	Investigational Site	Moscow		Russian Federation	119048
47	Investigational Site	St. Petersburg		Russian Federation	192242
48	Investigational Site	St. Petersburg		Russian Federation
49	Investigational Site	Kharkov		Ukraine	61176
50	Investigational Site	Kyiv		Ukraine	03110
51	Investigational Site	Lviv		Ukraine	79044
52	Investigational Site	Zaporizhya		Ukraine	69000
53	Investigational Site	London		United Kingdom	N19 5LW
54	Investigational Site	London		United Kingdom	SW10 9NH

Sponsors and Collaborators

• Forest Laboratories

Investigators

• Principal Investigator: Mark Wilcox, MD, Old Medical School

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• ClinicalTrials.gov Identifier: NCT00423657
• Other Study ID Numbers: P903-07
• First Posted: Jan 18, 2007
• Last Update Posted: Mar 14, 2017
• Last Verified: Feb 1, 2017

• Keywords provided by , ,: Abscess; Antibacterial; Antibiotic; Antimicrobial; Bacterial infection, skin; Ceftaroline; Ceftaroline acetate; Cellulitis; Cephalosporin; Complicated skin and skin structure infection (cSSSI); cSSSI; Intravenous; Methicillin-resistant Staphylococcus Aureus (MRSA); PPI-0903; Prodrug; Skin disease, bacterial; Skin infection; Staphylococcal skin infection; Staphylococcus aureus; Streptococcal skin infection; Surgical site infection; TAK-599
• Additional relevant MeSH terms: Infections; Communicable Diseases; Bacterial Infections; Vancomycin; Ceftaroline fosamil; Aztreonam

Study Results

Participant Flow

Recruitment Details	Patients were recruited worldwide from March 2007 to December 2007
Pre-assignment Detail	Patients were screened for up to 24 hours

Arm/Group Title	Ceftaroline for Injection	IV Vancomycin Plus IV Aztreonam
Arm/Group Description	Ceftaroline fosamil 600 mg administered intravenously over 60 minutes every 12 hours, followed by placebo administered over 60 minutes every 12 hours.	Vancomycin 1 g administered over 60 minutes every 12 hours followed by aztreonam 1 g administered over 60 minutes every 12 hours.
Period Title: Overall Study
STARTED	342	338
COMPLETED	316	313
NOT COMPLETED	26	25

Baseline Characteristics

Arm/Group Title	Ceftaroline for Injection	IV Vancomycin Plus IV Aztreonam	Total
Arm/Group Description	Ceftaroline fosamil 600 mg administered intravenously over 60 minutes every 12 hours, followed by placebo administered over 60 minutes every 12 hours.	Vancomycin 1 g administered over 60 minutes every 12 hours followed by aztreonam 1 g administered over 60 minutes every 12 hours.	Total of all reporting groups
Overall Participants	342	338	680
Age, Customized (participants) [Number]
<=18 years	0 0%	0 0%	0 0%
>18 and < 65 years	281 82.2%	291 86.1%	572 84.1%
>=65 years	61 17.8%	47 13.9%	108 15.9%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	47.8 (16.98)	47.5 (16.07)	47.7 (16.52)
Sex: Female, Male (Count of Participants)
Female	118 34.5%	137 40.5%	255 37.5%
Male	224 65.5%	201 59.5%	425 62.5%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	63 18.4%	59 17.5%	122 17.9%
Not Hispanic or Latino	279 81.6%	279 82.5%	558 82.1%
Unknown or Not Reported	0 0%	0 0%	0 0%

Outcome Measures

1. Primary Outcome

Title	Clinical Cure Rate at Test of Cure (TOC) (MITT Population)
Description	Cure: Total resolution of all signs and symptoms of the baseline infection, or improvement of the infection such that no further antimicrobial therapy was necessary. Failure: Requirement of alternative antimicrobial therapy for primary infection of complicated skin and skin structure infection (cSSSI) due to inadequate response, recurrence, new infection at the same site; treatment-limiting adverse event (AE); requirement for surgery due to failure of study drug; diagnosis of osteomyelitis after Study Day 8; or death caused by cSSSI. Indeterminate: Inability to determine an outcome
Time Frame	8-15 days after last dose of study drug administration

Outcome Measure Data

Analysis Population Description

MITT (Modified Intent to Treat) - all subjects that received any amount of study drug

Arm/Group Title	Ceftaroline for Injection	IV Vancomycin Plus IV Aztreonam
Arm/Group Description	Ceftaroline fosamil 600 mg administered intravenously over 60 minutes every 12 hours, followed by placebo administered over 60 minutes every 12 hours.	Vancomycin 1 g administered over 60 minutes every 12 hours followed by aztreonam 1 g administered over 60 minutes every 12 hours.
Measure Participants	342	338
Clinical Cure	291 85.1%	289 85.5%
Clinical Failure	25 7.3%	28 8.3%
Indeterminate	26 7.6%	21 6.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ceftaroline for Injection, IV Vancomycin Plus IV Aztreonam
	Comments	The primary objective of this study was to determine the noninferiority in clinical cure rate of ceftaroline in comparison with vancomycin plus aztreonam in adult subjects with cSSSI.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	A two-sided 95% confidence interval (CI) for the observed difference in the primary outcome measure between ceftaroline and vancomycin plus aztreonam was calculated. Noninferiority was concluded if the lower limit of the 95%CI was higher than -10%.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	-0.4
	Confidence Interval	(2-Sided) 95%; -5.8 to 5.0
	Parameter Dispersion	Type: Value:
	Estimation Comments	Risk difference corresponds to Ceftaroline clinical cure rate minus Vancomycin plus Aztreonam clinical cure rate. The confidence interval was calculated using the Miettinen and Nurminen method without adjustment.

2. Primary Outcome

Title	The Primary Efficacy Outcome Measure Was the Per-subject Clinical Cure Rate at the TOC Visit in the Clinically Evaluable (CE) Populations.
Time Frame	8-15 days after last dose of study drug

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

3. Secondary Outcome

Title	To Evaluate the Microbiological Success Rate at the TOC Visit
Time Frame	8-15 days after the last dose of study drug

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

4. Secondary Outcome

Title	To Evaluate the Clinical Response at the End of Therapy (EOT) Visit
Time Frame	last day of study drug administration

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

5. Secondary Outcome

Title	To Evaluate the Clinical and Microbiological Response by Pathogen at the TOC Visit
Time Frame	8-15 days after last dose of study drug

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

6. Secondary Outcome

Title	To Evaluate Clinical Relapse at the Late Follow Up (LFU) Visit
Time Frame	21 to 35 days after the last dose of study drug

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

7. Secondary Outcome

Title	To Evaluate Microbiological Reinfection or Recurrence at the LFU Visit
Time Frame	21-35 days after last dose of study drug

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

8. Secondary Outcome

Title	To Evaluate Safety
Time Frame	first study drug dose through TOC

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Adverse Event Reporting Description	All safety analyses were performed on the Safety Population which consists of all subjects who received any amount of actual study drug.
Arm/Group Title	Ceftaroline for Injection		IV Vancomycin Plus IV Aztreonam
Arm/Group Description	Ceftaroline fosamil 600 mg administered intravenously over 60 minutes every 12 hours, followed by placebo administered over 60 minutes every 12 hours.		Vancomycin 1 g administered over 60 minutes every 12 hours followed by aztreonam 1 g administered over 60 minutes every 12 hours.
All Cause Mortality
	Ceftaroline for Injection		IV Vancomycin Plus IV Aztreonam
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Ceftaroline for Injection		IV Vancomycin Plus IV Aztreonam
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	14/341 (4.1%)		16/339 (4.7%)
Blood and lymphatic system disorders
Anemia	0/341 (0%)	0	1/339 (0.3%)	1
Coagulopathy	0/341 (0%)	0	1/339 (0.3%)	1
Cardiac disorders
Bradycardia	1/341 (0.3%)	1	1/339 (0.3%)	1
Myocardial infarction	1/341 (0.3%)	1	1/339 (0.3%)	1
Sinoatrial block	0/341 (0%)	0	1/339 (0.3%)	1
Gastrointestinal disorders
Abdominal pain	1/341 (0.3%)	1	0/339 (0%)	0
Ileus	0/341 (0%)	0	1/339 (0.3%)	1
General disorders
Multi-organ failure	1/341 (0.3%)	1	0/339 (0%)	0
Condition aggravated	0/341 (0%)	0	1/339 (0.3%)	1
Hepatobiliary disorders
Hepatitis	0/341 (0%)	0	1/339 (0.3%)	1
Immune system disorders
Anaphylactic shock	1/341 (0.3%)	1	0/339 (0%)	0
Anaphylactoid reaction	1/341 (0.3%)	1	0/339 (0%)	0
Infections and infestations
Bacteremia	1/341 (0.3%)	1	0/339 (0%)	0
Central line infection	1/341 (0.3%)	1	0/339 (0%)	0
Wound infection	1/341 (0.3%)	1	0/339 (0%)	0
Osteomyelitis	0/341 (0%)	0	1/339 (0.3%)	1
Pneumonia	0/341 (0%)	0	1/339 (0.3%)	1
Sepsis	0/341 (0%)	0	1/339 (0.3%)	1
Injury, poisoning and procedural complications
Accidental overdose	1/341 (0.3%)	1	0/339 (0%)	0
Dislocation of joint prosthesis	1/341 (0.3%)	1	0/339 (0%)	0
Postprocedural hemorrhage	0/341 (0%)	0	1/339 (0.3%)	1
Metabolism and nutrition disorders
Diabetes mellitus inadequate control	0/341 (0%)	0	1/339 (0.3%)	1
Musculoskeletal and connective tissue disorders
Osteoarthritis	1/341 (0.3%)	1	0/339 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Chronic lymphocytic leukemia recurrent	0/341 (0%)	0	1/339 (0.3%)	1
Nervous system disorders
Convulsion	1/341 (0.3%)	1	0/339 (0%)	0
Loss of consciousness	0/341 (0%)	0	1/339 (0.3%)	1
Renal and urinary disorders
Acute prerenal failure	1/341 (0.3%)	1	0/339 (0%)	0
Renal failure	1/341 (0.3%)	1	0/339 (0%)	0
Renal failure acute	0/341 (0%)	0	1/339 (0.3%)	1
Respiratory, thoracic and mediastinal disorders
Acute pulmonary edema	1/341 (0.3%)	1	0/339 (0%)	0
Pulmonary embolism	1/341 (0.3%)	1	0/339 (0%)	0
Acute respiratory failure	0/341 (0%)	0	1/339 (0.3%)	1
Vascular disorders
Hypotension	1/341 (0.3%)	1	0/339 (0%)	0
Thrombophlebitis	0/341 (0%)	0	1/339 (0.3%)	1
Other (Not Including Serious) Adverse Events
	Ceftaroline for Injection		IV Vancomycin Plus IV Aztreonam
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	144/341 (42.2%)		159/339 (46.9%)
Blood and lymphatic system disorders
Anemia	4/341 (1.2%)	4	8/339 (2.4%)	8
Gastrointestinal disorders
Diarrhea	22/341 (6.5%)	22	15/339 (4.4%)	15
Nausea	21/341 (6.2%)	21	19/339 (5.6%)	19
Vomiting	11/341 (3.2%)	11	9/339 (2.7%)	9
Constipation	10/341 (2.9%)	10	11/339 (3.2%)	11
General disorders
Pyrexia	5/341 (1.5%)	5	7/339 (2.1%)	7
Investigations
Blood pressure increased	7/341 (2.1%)	7	4/339 (1.2%)	4
Alanine aminotransferase increase	5/341 (1.5%)	5	7/339 (2.1%)	7
Metabolism and nutrition disorders
Hypokalemia	5/341 (1.5%)	5	9/339 (2.7%)	9
Nervous system disorders
Headache	18/341 (5.3%)	18	18/339 (5.3%)	18
Psychiatric disorders
Insomnia	12/341 (3.5%)	12	8/339 (2.4%)	8
Skin and subcutaneous tissue disorders
Pruritus	13/341 (3.8%)	13	28/339 (8.3%)	28
Rash	11/341 (3.2%)	11	10/339 (2.9%)	10
Erythema	2/341 (0.6%)	2	8/339 (2.4%)	8
Vascular disorders
Hypertension	8/341 (2.3%)	8	3/339 (0.9%)	3

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

There is NOT 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.