Evaluation of Ceftaroline Fosamil Versus a Comparator in Adult Subjects With Community-acquired Bacterial Pneumonia (CABP) With Risk for Methicillin-resistant Staphylococcus Aureus

• Sponsor: Forest Laboratories (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01645735
• Collaborator: AstraZeneca (Industry)
• Enrollment: 49
• Locations: 31
• Arms: 2
• Duration (Months): 14
• Patients Per Site: 1.6
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The purpose of this study is to determine whether ceftaroline is effective and safe for the treatment of patients with Community-acquired Bacterial Pneumonia (CABP) at risk for infection due to Methicillin-resistant Staphylococcus aureus (MRSA).

Condition or Disease	Intervention/Treatment	Phase
Infections	Drug: Ceftaroline fosamil; Drug: Ceftriaxone plus vancomycin	Phase 4

Detailed Description

A Multicenter, Multinational, Randomized, Double-blind Study to Evaluate the Efficacy and safety of Ceftaroline fosamil Versus Ceftriaxone Plus Vancomycin in Adult Subjects with Community-acquired Bacterial Pneumonia at Risk for Infection Due to Methicillin-resistant Staphylococcus aureus.

Study Design

• Study Type: Interventional
• Actual Enrollment: 49 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Multicenter, Multinational, Randomized, Double-blind Study to Evaluate the Efficacy and Safety of Ceftaroline Fosamil Versus Ceftriaxone Plus Vancomycin in Adult Subjects With Community-acquired Bacterial Pneumonia at Risk for Infection Due to Methicillin-resistant Staphylococcus Aureus
• Study Start Date: Oct 1, 2012
• Actual Primary Completion Date: Dec 1, 2013
• Actual Study Completion Date: Dec 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Ceftaroline Ceftaroline fosamil 600 mg Intravenous (IV) administration over 60 minutes, every 8 hours (q8h); dosing to be adjusted for renal function; treatment duration 5 to 14 days	Drug: Ceftaroline fosamil; Ceftaroline fosamil 600 mg IV over 60 minutes q8h; treatment duration 5 to 14 days; Other Names: Teflaro PPI-0903 TAK-599 TAK599 PPI0903 Teflaro
Active Comparator: Ceftriaxone plus vancomycin Ceftriaxone 2 g IV over 30 minutes once per day (q24h) plus vancomycin 15 mg/kg IV every 12 hours (q12h) initially and then dose adjusted based on trough concentrations; treatment duration 5 to 14 days	Drug: Ceftriaxone plus vancomycin; Ceftriaxone 2g IV over 30 minutes q24h plus vancomycin 15 mg/kg IV q12h initially and then dose adjusted based on trough concentrations; treatment duration 5 to 14 days

Outcome Measures

Primary Outcome Measures

1. Clinical Response at Study Day 4 in the Modified Intent-to-Treat (MITT) Population [Study Day 4]

   Clinical response was defined as meeting all of the following criteria: Symptom Improvement - Improvement in at least 2 and no worsening of any of the following symptoms compared to baseline: Cough Dyspnea Sputum production Chest pain Clinical Stability (per Infectious Diseases Society of America/American Thoracic Society (IDSA/ATS) guidelines; Mandell et al, 2007): Temperature ≤ 37.8°C Heart rate ≤ 100 beats/min Respiratory rate ≤ 24 breaths/min Systolic blood pressure ≥ 90 mmHg Oxygen saturation ≥ 90% Confusion/disorientation absent

2. Clinical Outcome at Test of Cure (TOC) in the MITT Population [Test of Cure, an average of 3 weeks]

   An assessment of clinical outcome was made by the Investigator at TOC. The clinical outcome categories were: Cure: Resolution of all acute signs and symptoms of CABP or improvement to such an extent that no further antimicrobial therapy was required Failure: Subjects who meet either of the following criteria: Incomplete resolution or worsening of CABP signs and symptoms or development of new CABP signs or symptoms requiring alternative nonstudy antimicrobial therapy Death in which CABP is contributory Indeterminate: Study data are not available for evaluation of efficacy for any reason, including: Death in which CABP is clearly noncontributory Lost to follow-up Extenuating circumstances precluding classification as a cure or failure A favorable clinical outcome at Test-of Cure (TOC) was clinical cure.

Other Outcome Measures

1. Microbiological Outcomes by Baseline Pathogen at TOC in the Microbiological Modified Intent-to-Treat (mMITT) Population [Test of Cure, an average of 3 weeks]

   An overall microbiological outcome was derived based on the subject's baseline pathogen. As no follow-up specimens were collected at the TOC visit for any subjects, all microbiological outcomes were derived based strictly on clinical outcomes, as either presumed eradication (ie, source specimen was not available to culture and the subject was assessed as clinical cure) , presumed persistence (ie, source specimen was not available to culture and the subject was assessed as a clinical failure), or indeterminate (ie, source specimen was not available to culture and the subject's clinical response was assessed as indeterminate).

2. Safety Evaluation [Baseline (Day 0) to Day 49]

   Adverse events (AEs), serious adverse events (SAEs), deaths, discontinuation due to AEs

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Subjects are required to meet All of the following inclusion criteria:

1. Male or female, ≥ 18 years old

2. Presence of CABP requiring hospitalization

3. Presence of CABP meeting the following criteria:

1. confirmed pneumonia (new or progressive pulmonary) II. Acute illness (≤ 7 days' duration) with at least 3 clinical signs or symptoms consistent with a lower respiratory tract infection

MRSA Risk Factors

• MRSA-positive blood culture or respiratory specimen or a risk factor for MRSA such as a history of colonization with MRSA

Exclusion Criteria:

• Subjects must Not meet any of the following exclusion criteria at baseline:

1. History of any hypersensitivity or allergic reaction to any β-lactam antimicrobial

2. Suspected or microbiologically-documented infection with a pathogen known to be resistant to any of the study drugs

3. Non-infectious causes of pulmonary infiltrates (eg, pulmonary embolism, chemical pneumonitis from aspiration, hypersensitivity pneumonia, congestive heart failure)

4. More than 24 hours of potentially effective systemic antibacterial therapy for CABP within 96 hours before randomization

5. End-stage renal disease [Creatinine Clearance (CrCl) < 15], including hemodialysis

6. Evidence of significant hepatic, hematological, or immunocompromising condition

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Investigational Site	Phoenix	Arizona	United States	85008
2	Investigational Site	Sylmar	California	United States	91342
3	Investigational Site	DeLand	Florida	United States	32720
4	Investigational Site	Chicago	Illinois	United States	60611
5	Investigational Site	Kansas City	Kansas	United States	66012
6	Investigational Site	Royal Oak	Michigan	United States	48073
7	Investigational Site	Minneapolis	Minnesota	United States	55145
8	Investigational Site	St. Louis	Missouri	United States	63110
9	Investigational Site	Omaha	Nebraska	United States	68131
10	Investigational Site	Laconia	New Hampshire	United States	03246
11	Investigational Site	Columbus	Ohio	United States	43215
12	Investigational Site	Lima	Ohio	United States	45801
13	Investigational Site	Oklahoma City	Oklahoma	United States	73104
14	Investigational Site	Tbilisi		Georgia	0144
15	Investigational Site	Matrahaza		Hungary	3233
16	Investigational Site	Lodz		Poland	90-153
17	Investigational Site	Lublin		Poland	20-954
18	Investigational Site	Wilkowice-Bystra		Poland	43-365
19	Investigational Site	Craiova	Dolj	Romania	200515
20	Investigational Site	Bucharest		Romania	030303
21	Investigational Site	Iasi		Romania	700115
22	Investigational Site	Moscow		Russian Federation	109240
23	Investigational Site	St. Petersburg		Russian Federation	196247
24	Investigational Site	Yaroslavl		Russian Federation	150003
25	Investigational Site	Alicante		Spain	03010
26	Investigational Site	Barcelona		Spain	08304
27	Investigational Site	Dnipropetrovsk		Ukraine	49059
28	Investigational Site	Ivano-Frankivsik		Ukraine	76018
29	Investigational Site	Kharkiv		Ukraine	61115
30	Investigational Site	Kyiv		Ukraine	03680
31	Investigational Site	Zaporizhzhya		Ukraine	69035

Sponsors and Collaborators

• Forest Laboratories
• AstraZeneca

Investigators

• Study Director: Medical Monitor, Forest Laboratories Inc, an affiliate of Allergan plc

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Related Info

Publications

None provided.

• Responsible Party: Forest Laboratories
• ClinicalTrials.gov Identifier: NCT01645735
• Other Study ID Numbers: P903-25
• First Posted: Jul 20, 2012
• Last Update Posted: Feb 1, 2016
• Last Verified: Dec 1, 2015

• Keywords provided by Forest Laboratories: Infections; Teflaro; cephalosporin; Ceftaroline; antibiotics; pneumonia
• Additional relevant MeSH terms: Infections; Pneumonia; Pneumonia, Bacterial; Vancomycin; Ceftriaxone; Ceftaroline fosamil

Study Results

Participant Flow

Arm/Group Title	Ceftaroline	Ceftriaxone Plus Vancomycin
Arm/Group Description	Ceftaroline fosamil 600 mg IV over 60 minutes q8h; treatment duration 5 to 14 days	Ceftriaxone 2 g IV q24 plus vancomycin 15 mg/kg IV q12h initially and then dose adjusted based on trough concentrations; treatment duration 5 to 14 days
Period Title: Overall Study
STARTED	32	17
COMPLETED	28	16
NOT COMPLETED	4	1

Baseline Characteristics

Arm/Group Title	Ceftaroline	Ceftriaxone Plus Vancomycin	Total
Arm/Group Description	Ceftaroline fosamil 600 mg IV over 60 minutes q8h	Ceftriaxone 2g IV over 30 minutes q24h plus vancomycin 15 mg/kg IV q12h initially and then dose adjusted based on trough concentrations	Total of all reporting groups
Overall Participants	32	17	49
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	53.2 (17.09)	68.1 (14.14)	58.3 (17.51)
Sex: Female, Male (Count of Participants)
Female	12 37.5%	4 23.5%	16 32.7%
Male	20 62.5%	13 76.5%	33 67.3%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	3 9.4%	0 0%	3 6.1%
Not Hispanic or Latino	29 90.6%	17 100%	46 93.9%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	1 3.1%	0 0%	1 2%
White	31 96.9%	17 100%	48 98%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Creatinine Clearance (mL/min/1.73 m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mL/min/1.73 m^2]	92.47 (52.190)	66.52 (24.448)	83.47 (45.978)
PORT Score (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	89.8 (33.17)	118.6 (29.47)	99.8 (34.53)

Outcome Measures

1. Primary Outcome

Title	Clinical Response at Study Day 4 in the Modified Intent-to-Treat (MITT) Population
Description	Clinical response was defined as meeting all of the following criteria: Symptom Improvement - Improvement in at least 2 and no worsening of any of the following symptoms compared to baseline: Cough Dyspnea Sputum production Chest pain Clinical Stability (per Infectious Diseases Society of America/American Thoracic Society (IDSA/ATS) guidelines; Mandell et al, 2007): Temperature ≤ 37.8°C Heart rate ≤ 100 beats/min Respiratory rate ≤ 24 breaths/min Systolic blood pressure ≥ 90 mmHg Oxygen saturation ≥ 90% Confusion/disorientation absent
Time Frame	Study Day 4

Outcome Measure Data

Analysis Population Description

MITT Population: all randomized subjects who receive any amount of IV study drug and who have a confirmed diagnosis of Community-Acquired Bacterial Pneumonia (CABP) with risk factors for Methicillin-Resistant Staphylococcus aureus (MRSA) (excluding those that have a sole atypical pathogen)

Arm/Group Title	Ceftaroline	Ceftriaxone Plus Vancomycin
Arm/Group Description	Ceftaroline fosamil 600 mg IV over 60 minutes q8h	Ceftriaxone 2 g IV q24 plus vancomycin 15 mg/kg IV q12h initially and then dose adjusted based on trough concentrations
Measure Participants	32	17
Responder	14 43.8%	8 47.1%
Non-Responder	16 50%	8 47.1%
Incomplete Data	2 6.3%	1 5.9%

2. Primary Outcome

Title	Clinical Outcome at Test of Cure (TOC) in the MITT Population
Description	An assessment of clinical outcome was made by the Investigator at TOC. The clinical outcome categories were: Cure: Resolution of all acute signs and symptoms of CABP or improvement to such an extent that no further antimicrobial therapy was required Failure: Subjects who meet either of the following criteria: Incomplete resolution or worsening of CABP signs and symptoms or development of new CABP signs or symptoms requiring alternative nonstudy antimicrobial therapy Death in which CABP is contributory Indeterminate: Study data are not available for evaluation of efficacy for any reason, including: Death in which CABP is clearly noncontributory Lost to follow-up Extenuating circumstances precluding classification as a cure or failure A favorable clinical outcome at Test-of Cure (TOC) was clinical cure.
Time Frame	Test of Cure, an average of 3 weeks

Outcome Measure Data

Analysis Population Description

MITT Population: all randomized subjects who receive any amount of IV study drug and who have a confirmed diagnosis of CABP with risk factors for MRSA (excluding those that have a sole atypical pathogen)

Arm/Group Title	Ceftaroline	Ceftriaxone Plus Vancomycin
Arm/Group Description	Ceftaroline fosamil 600 mg IV over 60 minutes q8h	Ceftriaxone 2g IV q24 plus vancomycin 15mg/kg IV q12h initially and then dose adjusted based on trough concentrations
Measure Participants	32	17
Clinical Cure	27 84.4%	15 88.2%
Clinical Failure	3 9.4%	2 11.8%
Indeterminate	2 6.3%	0 0%

3. Other Pre-specified Outcome

Title	Microbiological Outcomes by Baseline Pathogen at TOC in the Microbiological Modified Intent-to-Treat (mMITT) Population
Description	An overall microbiological outcome was derived based on the subject's baseline pathogen. As no follow-up specimens were collected at the TOC visit for any subjects, all microbiological outcomes were derived based strictly on clinical outcomes, as either presumed eradication (ie, source specimen was not available to culture and the subject was assessed as clinical cure) , presumed persistence (ie, source specimen was not available to culture and the subject was assessed as a clinical failure), or indeterminate (ie, source specimen was not available to culture and the subject's clinical response was assessed as indeterminate).
Time Frame	Test of Cure, an average of 3 weeks

Outcome Measure Data

Analysis Population Description

mMITT Population: a subset of the MITT Population, including subjects for whom at least 1 typical bacterial pathogen has been identified from an adequate microbiological specimen at baseline

Arm/Group Title	Ceftaroline	Ceftriaxone Plus Vancomycin
Arm/Group Description	Ceftaroline fosamil 600 mg IV over 60 minutes q8h	Ceftriaxone 2 g IV q24 plus vancomycin 15 mg/kg IV q12h initially and then dose adjusted based on trough concentrations
Measure Participants	25	14
Presumed eradication	23 71.9%	12 70.6%
Presumed persistence	0 0%	2 11.8%
Indeterminate	2 6.3%	0 0%

4. Other Pre-specified Outcome

Title	Safety Evaluation
Description	Adverse events (AEs), serious adverse events (SAEs), deaths, discontinuation due to AEs
Time Frame	Baseline (Day 0) to Day 49

Outcome Measure Data

Analysis Population Description

Safety Population: all randomized subjects who received any amount of IV study drug

Arm/Group Title	Ceftaroline	Ceftriaxone Plus Vancomycin
Arm/Group Description	Ceftaroline fosamil 600 mg IV over 60 minutes q8h	Ceftriaxone 2 g IV q24 plus vancomycin 15 mg/kg IV q12h initially and then dose adjusted based on trough concentrations
Measure Participants	32	17
Any TEAE	17 53.1%	9 52.9%
Any study drug-related TEAEs	3 9.4%	2 11.8%
Any SAEs	3 9.4%	2 11.8%
Any study drug-related SAEs	0 0%	0 0%
Discontinuation of IV or oral study drug due to AE	1 3.1%	1 5.9%
Discontinuation of IV study drug only due to AE	1 3.1%	1 5.9%
Deaths	1 3.1%	0 0%

Adverse Events

Arm/Group Title	Ceftaroline		Ceftriaxone Plus Vancomycin
Arm/Group Description	Ceftaroline fosamil 600 mg IV over 60 minutes q8h		Ceftriaxone 2 g IV over 30 minutes q24h plus vancomycin 15 mg/kg IV q12h initially and then dose adjusted based on trough concentrations
All Cause Mortality
	Ceftaroline		Ceftriaxone Plus Vancomycin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Ceftaroline		Ceftriaxone Plus Vancomycin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/32 (9.4%)		2/17 (11.8%)
Cardiac disorders
Angina pectoris	0/32 (0%)		1/17 (5.9%)
Cardiac arrest	1/32 (3.1%)		0/17 (0%)
Myocardial Infarction	1/32 (3.1%)		0/17 (0%)
Infections and infestations
Clostridium difficile colitis	1/32 (3.1%)		0/17 (0%)
Investigations
Computerized tomogram thorax abnormal	0/32 (0%)		1/17 (5.9%)
Renal and urinary disorders
Renal failure	1/32 (3.1%)		0/17 (0%)
Other (Not Including Serious) Adverse Events
	Ceftaroline		Ceftriaxone Plus Vancomycin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	9/32 (28.1%)		9/17 (52.9%)
Blood and lymphatic system disorders
Anemia	0/32 (0%)		1/17 (5.9%)
Leukopenia	0/32 (0%)		2/17 (11.8%)
Gastrointestinal disorders
Abdominal Pain	0/32 (0%)		1/17 (5.9%)
Diarrhea	2/32 (6.3%)		1/17 (5.9%)
Nausea	0/32 (0%)		1/17 (5.9%)
General disorders
Asthenia	0/32 (0%)		1/17 (5.9%)
Non-cardiac chest pain	1/32 (3.1%)		1/17 (5.9%)
Edema Peripheral	0/32 (0%)		1/17 (5.9%)
Injury, poisoning and procedural complications
Procedural pain	2/32 (6.3%)		0/17 (0%)
Investigations
Blood pressure increased	0/32 (0%)		1/17 (5.9%)
Body temperature increased	0/32 (0%)		1/17 (5.9%)
Neutrophil count increased	0/32 (0%)		1/17 (5.9%)
Metabolism and nutrition disorders
Decreased appetite	0/32 (0%)		1/17 (5.9%)
Hypocalcemia	0/32 (0%)		1/17 (5.9%)
Hypokalemia	0/32 (0%)		3/17 (17.6%)
Hypophosphatemia	0/32 (0%)		1/17 (5.9%)
Musculoskeletal and connective tissue disorders
Arthralgia	2/32 (6.3%)		0/17 (0%)
Nervous system disorders
Headache	3/32 (9.4%)		1/17 (5.9%)
Psychiatric disorders
Disorientation	0/32 (0%)		1/17 (5.9%)
Renal and urinary disorders
Renal failure acute	0/32 (0%)		1/17 (5.9%)
Vascular disorders
Hypertension	0/32 (0%)		2/17 (11.8%)

Limitations/Caveats

Small number of subjects enrolled

More Information

Certain Agreements

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

The data generated in this clinical study are the exclusive property of the Sponsor and are confidential. The Sponsor will make all reasonable efforts to publish the results of the study in an appropriate peer-reviewed journal. Authorship on the primary publication of the results from this study will be based on contributions to study design, enrollment, data analysis, and interpretation of results. Publication of results by the PI will be subject to mutual agreement between the PI and Sponsor.