Study to Compare Efficacy and Safety of Daptomycin in Elderly Patients With Complicated Skin and Soft Tissue Infections

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01184872
• Collaborator: (none)
• Enrollment: 120
• Locations: 17
• Arms: 2
• Duration (Months): 12
• Patients Per Site: 7.1
• Patients Per Site Per Month: 0.6

Study Details

Study Description

Brief Summary

The purpose of this study is to provide data documenting the efficacy of daptomycin in elderly patients aged ≥ 65 years with complicated Skin and Soft Tissue Infections.

Condition or Disease	Intervention/Treatment	Phase
Infections	Drug: Daptomycin; Drug: Vancomycin or Semi-Synthetic Penicillins (SSPs)	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 120 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open Label, Multi-center, Randomized, Comparative Phase IIIb Study to Compare Efficacy and Safety of Intravenous (i.v.) Daptomycin With That of Semi-Synthetic Penicillins (SSPs) or Vancomycin in the Treatment of Elderly Patients (Aged ≥ 65 Years) With Complicated Skin and Soft Tissue Infections (cSSTI)
• Study Start Date: Mar 1, 2010
• Actual Primary Completion Date: Mar 1, 2011
• Actual Study Completion Date: Mar 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Daptomycin Patients with bacteremia: Daptomycin 6 mg/Kg intravenous once daily for at least 5 days and up to 28 days. Patients without bacteremia: Daptomycin 4 mg/Kg intravenous once daily for at least 5 days and up to 14 days.	Drug: Daptomycin; Patients with bacteremia: Daptomycin 6 mg/Kg intravenous once daily for at least 5 days and up to 28 days. Patients without bacteremia: Daptomycin 4 mg/Kg intravenous once daily for at least 5 days and up to 14 days.
Active Comparator: Vancomycin or Semi-Synthetic Penicillins (SSPs) Patients with bacteremia: Vancomycin 1 g intravenous twice daily or Semi-Synthetic Penicillins 2 g intravenous every 4 hours for at least 5 days and up to 28 days. Patients without bacteremia: Vancomycin 1 g intravenous twice daily or Semi-Synthetic Penicillins 2 g intravenous every 6 hours for at least 5 days and up to 14 days.	Drug: Vancomycin or Semi-Synthetic Penicillins (SSPs); Patients with bacteremia: Vancomycin 1 g intravenous twice daily or Semi-Synthetic Penicillins 2 g intravenous every 4 hours for at least 5 days and up to 28 days. Patients without bacteremia: Vancomycin 1 g intravenous twice daily or Semi-Synthetic Penicillins 2 g intravenous every 6 hours for at least 5 days and up to 14 days.; Other Names: Oxacillin, Cloxacillin, Flucloxacillin,

Outcome Measures

Primary Outcome Measures

1. Number of Patients With Clinical Success at the Test-Of-Cure (TOC) Visit [Baseline and 7 to 14 days after end of therapy]

   Success: Clinically significant signs and symptoms associated with the skin infection present at the pre-treatment infection site resolved (cure), or improved without need of further antibacterial therapy. Failure: Persistence or progression of signs and symptoms or development of new clinical signs and symptoms at the infection site, or concomitant antibacterial therapy with activity against isolated organisms, or treatment duration longer than pre-specified, or switch back to intravenous therapy due to relapse, or requirement of a major surgical procedure as adjunct or follow-up therapy.

Secondary Outcome Measures

1. Number of Participants With Microbiological Response at Test-of-Cure (TOC) Visit [Baseline and 7 to 14 days after end of therapy]

   Microbiological Success: All infecting Gram-positive pathogens isolated at baseline were eradicated or presumed to be eradicated at the Test-of-Cure (TOC) evaluation and a super infecting pathogen was not isolated either prior to or at the TOC evaluation. Microbiological Failure: Persistence or relapse / re-infection of one or more infecting Gram-positive pathogens or isolation of a super infecting pathogen prior to or at the TOC evaluation.

2. Duration of Treatment (Intravenous) [Up to 28 days]

   Duration of treatment is the interval from first to last intravenous (i.v.) administration. It was preferable that a patient complete the whole antibiotic treatment with the randomized i.v. study drug only. Duration of treatment in patients with bacteremia could be extended up to 28 days.

3. Duration of Treatment (Intravenous and Oral) [Up to 28 days]

   Duration of treatment is the interval from first to last intravenous (i.v.) or to last oral administration if patients switched to an oral antibiotic therapy. It was preferable that a patient complete the whole antibiotic treatment with the randomized i.v. study drug only. Duration of treatment in patients with bacteremia could be extended up to 28 days.

4. Number of Patients With Adverse Events, Serious Adverse Events and Death [Continuously from baseline up to 28 days after end of antibiotic treatment.]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 65 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion criteria:

Patients 65 years or older with infection of sufficient severity to require in-patient hospitalization, with parenteral antimicrobial therapy for at least 96 hours.

Patients who have a diagnosis of Gram-positive complicated Skin and Soft Tissue Infections (cSSTIs) with or without bacteremia:

• Wound infections,

• Major abscesses with or without recognized preceding trauma, that require antibiotic therapy in addition to surgical incision and drainage,

• Severe carbunculosis,

• Infected ulcers (except patients with multiple infected ulcers) associated with: diabetes, vascular insufficiency, pressure (i.e., decubitus ulcers).

Exclusion criteria:

Conditions requiring surgery that in and of itself would cure the infection or remove the infected site (e.g., amputation).

Minor or superficial skin infections (e.g., furuncles, simple abscesses, acne, impetigo).

Cellulitis, including erysipelas, not associated with complicating factors. However, patients with cellulitis associated with more serious infection (e.g., surgical wound, diabetic ulcer, deep tissue) can be enrolled (proportion of these patients will be limited to 30%).

Infections for which outcome is difficult to assess:

• Perirectal abscess,

• Hidradenitis suppurativa,

• Gangrene,

• Infected human or animal bites,

• Multiple infected ulcers at distant sites,

• Infected burns (only third degree burn wound or wound area of more than 10 cm diameter),

• Conditions requiring emergency surgery including necrotizing fasciitis.

Medical conditions:

• History of significant allergy or intolerance to Vancomycin or Daptomycin. Hypersensitivity to SSPs penicillins is not an exclusion criterion,

• Concomitant clinically suspected or confirmed other site of infection or disorder at study entry that may interfere with the evaluation in this protocol,

• Infections associated with a permanent prosthetic device that will not be removed within 24 hours after enrolment,

• Known or suspected HIV infection with a CD4+ T-cell count < 500/μL (HIV testing is not required),

• Severe hepatic disease (Child-Pugh Class C) or ALT and/or AST > 5 times ULN and/ or total bilirubin > 2 times ULN at screening,

• Calculated creatinine clearance by the Cockcroft-Gault equation using actual body weight < 30 mL/min or any type of dialysis,

• Treatment with any investigational agent or device within 30 days of study drug administration.

Exclusion criteria related to medications:

• Previous systemic antibacterial therapy for the treatment of Gram-positive complicated skin and soft tissue infections for more than 24 hours within 48 hours prior to the day of first infusion of study drug unless:

• The previous antibacterial therapy was administered for 3 or more calendar days with either worsening or no improvement in the clinical signs and symptoms of cSSTIs, and was not Vancomycin or SSPs.

Other protocol-defined inclusion/exclusion criteria applied.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novartis Investigative Site	Graz		Austria
2	Novartis Investigative Site	Vienna		Austria
3	Novartis Investigative Site	Bochum		Germany
4	Novartis Investigative Site	Essen		Germany
5	Novartis Investigative Site	Homburg		Germany
6	Novartis Investigative Site	Magdeburg		Germany
7	Novartis Investigative Site	Mannheim		Germany
8	Novartis Investigative Site	Muenster		Germany
9	Novartis Investigative Site	Tuebingen		Germany
10	Novartis Investigative Site	Pisa		Italy
11	Novartis Investigative Site (1)	Moscow		Russian Federation
12	Novartis Investigative Site	Novosibirsk		Russian Federation
13	Novartis Investigative Site (2)	Saint Petersburg		Russian Federation
14	Novartis Investigative Site	Yaroslavi		Russian Federation
15	Novartis Investigative Site (1)	Madrid		Spain
16	Novartis Investigative Site	Santander		Spain
17	Novartis Investigative Site	Seville		Spain

Sponsors and Collaborators

• Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmceuticals, Novartis Pharmceuticals

Study Documents (Full-Text)

None provided.

More Information

Publications

• Arbeit RD, Maki D, Tally FP, Campanaro E, Eisenstein BI; Daptomycin 98-01 and 99-01 Investigators. The safety and efficacy of daptomycin for the treatment of complicated skin and skin-structure infections. Clin Infect Dis. 2004 Jun 15;38(12):1673-81. Epub 2004 May 20.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT01184872
• Other Study ID Numbers: CCBC134A2404; 2009-014391-22
• First Posted: Aug 19, 2010
• Last Update Posted: Jul 13, 2012
• Last Verified: Jul 1, 2012

• Keywords provided by Novartis Pharmaceuticals: Skin infection; Daptomycin; Elderly; Gram positive; Complicated skin and soft tissue infections
• Additional relevant MeSH terms: Infections; Communicable Diseases; Soft Tissue Infections; Vancomycin; Daptomycin; Penicillins; Floxacillin; Cloxacillin; Oxacillin

Study Results

Participant Flow

Arm/Group Title	Daptomycin	Vancomycin or Semi-Synthetic Penicillins (SSPs)
Arm/Group Description	Patients with bacteremia: Daptomycin 6 mg/Kg intravenous once daily for at least 5 days and up to 28 days. Patients without bacteremia: Daptomycin 4 mg/Kg intravenous once daily for at least 5 days and up to 14 days.	Patients with bacteremia: Vancomycin 1 g intravenous twice daily or Semi-Synthetic Penicillins 2 g intravenous every 4 hours for at least 5 days and up to 28 days. Patients without bacteremia: Vancomycin 1 g intravenous twice daily or Semi-Synthetic Penicillins 2 g intravenous every 6 hours for at least 5 days and up to 14 days.
Period Title: Overall Study
STARTED	81	39
Safety Set	80	40
Clinical Evaluable Set (CES)	73	30
Microbiologically Evaluable Set (MES)	65	27
COMPLETED	71	31
NOT COMPLETED	10	8

Baseline Characteristics

Arm/Group Title	Daptomycin	Vancomycin or Semi-Synthetic Penicillins (SSPs)	Total
Arm/Group Description	Patients with bacteremia: Daptomycin 6 mg/Kg intravenous once daily for at least 5 days and up to 28 days. Patients without bacteremia: Daptomycin 4 mg/Kg intravenous once daily for at least 5 days and up to 14 days.	Patients with bacteremia: Vancomycin 1 g intravenous twice daily or Semi-Synthetic Penicillins 2 g intravenous every 4 hours for at least 5 days and up to 28 days. Patients without bacteremia: Vancomycin 1 g intravenous twice daily or Semi-Synthetic Penicillins 2 g intravenous every 6 hours for at least 5 days and up to 14 days.	Total of all reporting groups
Overall Participants	81	39	120
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	74.63 (6.331)	75.28 (5.515)	74.84 (6.063)
Sex: Female, Male (Count of Participants)
Female	47 58%	26 66.7%	73 60.8%
Male	34 42%	13 33.3%	47 39.2%

Outcome Measures

1. Primary Outcome

Title	Number of Patients With Clinical Success at the Test-Of-Cure (TOC) Visit
Description	Success: Clinically significant signs and symptoms associated with the skin infection present at the pre-treatment infection site resolved (cure), or improved without need of further antibacterial therapy. Failure: Persistence or progression of signs and symptoms or development of new clinical signs and symptoms at the infection site, or concomitant antibacterial therapy with activity against isolated organisms, or treatment duration longer than pre-specified, or switch back to intravenous therapy due to relapse, or requirement of a major surgical procedure as adjunct or follow-up therapy.
Time Frame	Baseline and 7 to 14 days after end of therapy

Outcome Measure Data

Analysis Population Description

The clinically evaluable population was used for the efficacy analysis. It included all patients who met the criteria for complicated skin and soft tissue, had no substantive protocol deviation, had a sponsor clinical response assessment of "success" or "failure" at the assessment visit, and had a specified baseline primary site of infection.

Arm/Group Title	Daptomycin	Vancomycin or Semi-Synthetic Penicillins (SSPs)
Arm/Group Description	Patients with bacteremia: Daptomycin 6 mg/Kg intravenous once daily for at least 5 days and up to 28 days. Patients without bacteremia: Daptomycin 4 mg/Kg intravenous once daily for at least 5 days and up to 14 days.	Patients with bacteremia: Vancomycin 1 g intravenous twice daily or Semi-Synthetic Penicillins 2 g intravenous every 4 hours for at least 5 days and up to 28 days. Patients without bacteremia: Vancomycin 1 g intravenous twice daily or Semi-Synthetic Penicillins 2 g intravenous every 6 hours for at least 5 days and up to 14 days.
Measure Participants	73	30
Success	65 80.2%	25 64.1%
Failure	8 9.9%	5 12.8%

2. Secondary Outcome

Title	Number of Participants With Microbiological Response at Test-of-Cure (TOC) Visit
Description	Microbiological Success: All infecting Gram-positive pathogens isolated at baseline were eradicated or presumed to be eradicated at the Test-of-Cure (TOC) evaluation and a super infecting pathogen was not isolated either prior to or at the TOC evaluation. Microbiological Failure: Persistence or relapse / re-infection of one or more infecting Gram-positive pathogens or isolation of a super infecting pathogen prior to or at the TOC evaluation.
Time Frame	Baseline and 7 to 14 days after end of therapy

Outcome Measure Data

Analysis Population Description

Population analyzed consisted of patients from the clinically evaluable population who had independent microbiological assessments.

Arm/Group Title	Daptomycin	Vancomycin or Semi-Synthetic Penicillins (SSPs)
Arm/Group Description	Patients with bacteremia: Daptomycin 6 mg/Kg intravenous once daily for at least 5 days and up to 28 days. Patients without bacteremia: Daptomycin 4 mg/Kg intravenous once daily for at least 5 days and up to 14 days.	Patients with bacteremia: Vancomycin 1 g intravenous twice daily or Semi-Synthetic Penicillins 2 g intravenous every 4 hours for at least 5 days and up to 28 days. Patients without bacteremia: Vancomycin 1 g intravenous twice daily or Semi-Synthetic Penicillins 2 g intravenous every 6 hours for at least 5 days and up to 14 days.
Measure Participants	65	27
Success	54 66.7%	23 59%
Failure	11 13.6%	4 10.3%

3. Secondary Outcome

Title	Duration of Treatment (Intravenous)
Description	Duration of treatment is the interval from first to last intravenous (i.v.) administration. It was preferable that a patient complete the whole antibiotic treatment with the randomized i.v. study drug only. Duration of treatment in patients with bacteremia could be extended up to 28 days.
Time Frame	Up to 28 days

Outcome Measure Data

Analysis Population Description

The Full Analysis Set (FAS) comprised all patients to whom study treatment had been assigned at randomization.

Arm/Group Title	Daptomycin	Vancomycin or Semi-Synthetic Penicillins (SSPs)
Arm/Group Description	Patients with bacteremia: Daptomycin 6 mg/Kg intravenous once daily for at least 5 days and up to 28 days. Patients without bacteremia: Daptomycin 4 mg/Kg intravenous once daily for at least 5 days and up to 14 days.	Patients with bacteremia: Vancomycin 1 g intravenous twice daily or Semi-Synthetic Penicillins 2 g intravenous every 4 hours for at least 5 days and up to 28 days. Patients without bacteremia: Vancomycin 1 g intravenous twice daily or Semi-Synthetic Penicillins 2 g intravenous every 6 hours for at least 5 days and up to 14 days.
Measure Participants	81	39
Mean (Standard Deviation) [Days]	7.8 (3.42)	7.3 (2.42)

4. Secondary Outcome

Title	Duration of Treatment (Intravenous and Oral)
Description	Duration of treatment is the interval from first to last intravenous (i.v.) or to last oral administration if patients switched to an oral antibiotic therapy. It was preferable that a patient complete the whole antibiotic treatment with the randomized i.v. study drug only. Duration of treatment in patients with bacteremia could be extended up to 28 days.
Time Frame	Up to 28 days

Outcome Measure Data

Analysis Population Description

The Full Analysis set (FAS) comprised all patients to whom study treatment had been assigned at randomization.

Arm/Group Title	Daptomycin	Vancomycin or Semi-Synthetic Penicillins (SSPs)
Arm/Group Description	Patients with bacteremia: Daptomycin 6 mg/Kg intravenous once daily for at least 5 days and up to 28 days. Patients without bacteremia: Daptomycin 4 mg/Kg intravenous once daily for at least 5 days and up to 14 days.	Patients with bacteremia: Vancomycin 1 g intravenous twice daily or Semi-Synthetic Penicillins 2 g intravenous every 4 hours for at least 5 days and up to 28 days. Patients without bacteremia: Vancomycin 1 g intravenous twice daily or Semi-Synthetic Penicillins 2 g intravenous every 6 hours for at least 5 days and up to 14 days.
Measure Participants	81	39
intravenous only	7.8 (3.4)	7.3 (2.4)
intravenous + oral	8.7 (4.9)	9.6 (5.4)

5. Secondary Outcome

Title	Number of Patients With Adverse Events, Serious Adverse Events and Death
Time Frame	Continuously from baseline up to 28 days after end of antibiotic treatment.

Outcome Measure Data

Analysis Population Description

The safety set included all patients who received at least one dose of study medication and who had at least one post-baseline safety assessment.

Arm/Group Title	Daptomycin	Vancomycin or Semi-Synthetic Penicillins (SSPs)
Arm/Group Description	Patients with bacteremia: Daptomycin 6 mg/Kg intravenous once daily for at least 5 days and up to 28 days. Patients without bacteremia: Daptomycin 4 mg/Kg intravenous once daily for at least 5 days and up to 14 days.	Patients with bacteremia: Vancomycin 1 g intravenous twice daily or Semi-Synthetic Penicillins 2 g intravenous every 4 hours for at least 5 days and up to 28 days. Patients without bacteremia: Vancomycin 1 g intravenous twice daily or Semi-Synthetic Penicillins 2 g intravenous every 6 hours for at least 5 days and up to 14 days.
Measure Participants	80	40
Adverse Events	50 61.7%	26 66.7%
Serious Adverse Events	7 8.6%	4 10.3%
Death	0 0%	0 0%

Adverse Events

Arm/Group Title	Daptomycin		Vancomycin or Semi-Synthetic Penicillins (SSPs)
Arm/Group Description	Patients with bacteremia: Daptomycin 6 mg/Kg intravenous once daily for at least 5 days and up to 28 days. Patients without bacteremia: Daptomycin 4 mg/Kg intravenous once daily for at least 5 days and up to 14 days.		Patients with bacteremia: Vancomycin 1 g intravenous twice daily or Semi-Synthetic Penicillins 2 g intravenous every 4 hours for at least 5 days and up to 28 days. Patients without bacteremia: Vancomycin 1 g intravenous twice daily or Semi-Synthetic Penicillins 2 g intravenous every 6 hours for at least 5 days and up to 14 days.
All Cause Mortality
	Daptomycin		Vancomycin or Semi-Synthetic Penicillins (SSPs)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Daptomycin		Vancomycin or Semi-Synthetic Penicillins (SSPs)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	7/80 (8.8%)		4/40 (10%)
Blood and lymphatic system disorders
Pancytopenia	0/80 (0%)		1/40 (2.5%)
General disorders
Necrosis	1/80 (1.3%)		0/40 (0%)
Infections and infestations
Klebsiella infection	1/80 (1.3%)		0/40 (0%)
Pneumonia	1/80 (1.3%)		0/40 (0%)
Investigations
Blood creatine phosphokinase increased	1/80 (1.3%)		0/40 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Nasopharyngeal cancer recurrent	1/80 (1.3%)		0/40 (0%)
Squamous cell carcinoma	1/80 (1.3%)		0/40 (0%)
Nervous system disorders
Cerebrovascular accident	0/80 (0%)		1/40 (2.5%)
Renal and urinary disorders
Nephropathy toxic	0/80 (0%)		1/40 (2.5%)
Renal failure acute	0/80 (0%)		1/40 (2.5%)
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease	0/80 (0%)		1/40 (2.5%)
Pulmonary embolism	1/80 (1.3%)		0/40 (0%)
Vascular disorders
Thrombosis	1/80 (1.3%)		0/40 (0%)
Other (Not Including Serious) Adverse Events
	Daptomycin		Vancomycin or Semi-Synthetic Penicillins (SSPs)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	31/80 (38.8%)		14/40 (35%)
Gastrointestinal disorders
Nausea	5/80 (6.3%)		2/40 (5%)
General disorders
Hyperthermia	11/80 (13.8%)		3/40 (7.5%)
Investigations
Blood creatine phosphokinase increased	5/80 (6.3%)		1/40 (2.5%)
Blood creatinine increased	1/80 (1.3%)		2/40 (5%)
Blood pressure increased	5/80 (6.3%)		2/40 (5%)
Metabolism and nutrition disorders
Hypoglycaemia	0/80 (0%)		2/40 (5%)
Respiratory, thoracic and mediastinal disorders
Cough	4/80 (5%)		1/40 (2.5%)
Vascular disorders
Hypertension	6/80 (7.5%)		5/40 (12.5%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (i.e., data from all sites) in the clinical trial or disclosure of trial results in their entirety.