HDSAB: Phase 2 Study of Safety, Efficacy, and Pharmacokinetics of Higher Doses of Daptomycin and Vancomycin in MRSA Bacteremia

• Sponsor: Cubist Pharmaceuticals LLC (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT00695903
• Collaborator: (none)
• Enrollment: 38
• Locations: 2
• Arms: 2
• Actual Duration (Months): 24.4
• Patients Per Site: 19
• Patients Per Site Per Month: 0.8

Study Details

Study Description

Brief Summary

The overall goals of this study are to compare the safety and efficacy of daptomycin monotherapy 10 mg/kg/day and vancomycin monotherapy dosed to achieve vancomycin trough levels of 15 to 20 μg/mL for the treatment of methicillin-resistant S. aureus bacteremia (MRSA), including right-sided infective endocarditis (RIE).

Condition or Disease	Intervention/Treatment	Phase
Endocarditis, Bacterial; Infective Endocarditis	Drug: daptomycin; Drug: vancomycin	Phase 2

Detailed Description

Patients who meet all inclusion criteria and exhibit none of the exclusion criterial will be randomized to one of two treatment arms:

1. daptomycin Intravenously (IV) 10 mg/kg every 24 hours

2. vancomycin IV dosed to maintain trough levels of 15 to 20 μg/mL.

The suggested duration of therapy with daptomycin or vancomycin will be 28 days (or up to 42 days if clinically indicated). Dose adjustments for both drugs will be made by an unblinded pharmacist at each site. To minimize the duration with which patients are treated with antibacterial agents effective against S. aureus prior to enrollment, patients with suspected MRSA bacteremia will be enrolled pending definitive culture results. Suspected MRSA bacteremia will be defined clinically or as initial blood cultures that grow Gram-positive cocci and that were obtained from a patient at increased risk for methicillin-resistant S. aureus infections. However, only patients with confirmed MRSA bacteremia or right-sided infective endocarditis will remain in the study and be evaluated for efficacy. During treatment, regular assessments will be performed. An End-of Therapy (EOT) will be performed 1-3 days after stopping therapy or upon Early Termination (ET). All patients will have a post therapy visit for Test of Cure (TOC) performed 35-49 days following last dose of study drug.

Study Design

• Study Type: Interventional
• Actual Enrollment: 38 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase 2 Multicenter, Randomized, Double-blinded, Study to Describe the Safety, Efficacy, and Pharmacokinetics of Daptomycin 10 mg/kg/Day and Vancomycin for the Treatment of Methicillin-resistant Staphylococcus Aureus Bacteremia
• Actual Study Start Date: Sep 17, 2008
• Actual Primary Completion Date: Aug 24, 2010
• Actual Study Completion Date: Oct 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Experimental: daptomycin 10 mg/kg Daptomycin 10 mg/kg IV every 24 hours	Drug: daptomycin; daptomycin 10 mg/kg IV every 24 hours; Other Names: Cubicin daptomycin for injection
Experimental: vancomycin high-dose Vancomycin 15 mg/kg IV, dosed to maintain trough serum concentrations of 15 to 20 μg/mL	Drug: vancomycin; Vancomycin 15 mg/kg IV, dosed to maintain trough serum concentrations of 15 to 20 μg/mL; Other Names: vancocin

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Treatment-emergent Creatine Phosphokinase (CPK) Elevations [On therapy and up to 3 days post-therapy (treatment duration ranged from 2 to 43 days)]

   Number of participants with treatment-emergent CPK elevations ≥5 x upper limit of normal (≥1,000 U/L) by the EOT visit.

2. Number of Participants With Elevated Serum Creatinine [On therapy and up to 3 days post-therapy (treatment duration ranged from 2 to 43 days)]

   Number of participants with treatment-emergent serum creatinine increases ≥0.5 mg/dL (for patients with a baseline value ≤3.0 mg/dL) or ≥1.0 mg/dL (for patients with a baseline value >3.0 mg/dL) by the EOT visit.

Secondary Outcome Measures

1. Number of Participants With Treatment Cure at End of Therapy (EOT) Visit [End of Therapy (median day 12 and 6.5 in daptomycin and vancomycin modified intent-to treat population, respectively)]

   Investigator's assessment of treatment cure. Treatment Cure includes successful outcomes of both clinical and microbiological assessments. Clinical cure is defined by clinical improvement of symptoms and signs associated with the underlying infection such that no further anti-infective therapy is required. Microbiological Success is defined by the eradication or presumed eradication of baseline infecting methicillin-resistant S. aureus pathogen and no superinfecting pathogen(s) (Gram-positive) or metastatic methicillin-resistant S. aureus pathogens were isolated post therapy.

2. Number of Participants With Treatment Cure at Test of Cure (TOC)/Safety Visit [Test of Cure (TOC) Visit (35 to 49 days post-therapy, approximately week 8)]

   Investigator's assessment of clinical response. Treatment Cure includes successful outcomes of both clinical and microbiological assessments. Clinical cure is defined by clinical improvement of symptoms and signs associated with the underlying infection such that no further anti-infective therapy is required. Microbiological Success is defined by the eradication or presumed eradication of baseline infecting methicillin-resistant S. aureus pathogen and no superinfecting pathogen(s) (Gram-positive) or metastatic methicillin-resistant S. aureus pathogens were isolated post therapy.

Eligibility Criteria

Criteria

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

INCLUSION CRITERIA:

• Written informed consent has been obtained;

• ≥18 years of age;

• Suspected MRSA bacteremia determined by clinical judgment or 2 sets of positive blood cultures;

• Increased risk for an MRSA infection

EXCLUSION CRITERIA:

• Received >48 hours of vancomycin therapy in the 7 days prior to enrollment;

• Received any systemic antibacterial agents potentially effective against MRSA in the 7 days prior to enrollment;

• Anticipated requirement of antibiotics potentially effective against MRSA;

• High likelihood of left-sided infective endocarditis (LIE);

• Known/suspected polymicrobial bacteremia or infection including Gram-negative infections;

• Known pneumonia, osteomyelitis, or meningitis;

• Intravascular foreign material unless material intended removed within 3 days;

• Prosthetic heart valve;

• Cardiac decompensation, valve damage, or both such that high likelihood of valve replacement surgery within first 3 days of study drug treatment;

• Moribund clinical condition such that death likely within first 3 days of study drug treatment;

• Shock or hypotension or oliguria unresponsive to fluids after 4 hours;

• Received investigational drug within 30 days of study entry

• Received statins or other therapy with associated with rhabdomyolysis within 2 days of study entry;

• History of significant allergy or intolerance to vancomycin or daptomycin

• Infecting pathogen with confirmed reduced susceptibility to vancomycin;

• Infecting pathogen with confirmed reduced susceptibility to daptomycin

• Creatinine clearance <30 mL/min (Cockcroft-Gault equation actual body weight)

• Serum creatine phosphokinase (CPK) ≥500 U/L

• Alanine transaminase (ALT) or aspartate aminotransferase (AST) >5 X ULN;

• Total bilirubin ≥3.0 mg/dL;

• Severe neutropenia or expected development severe neutropenia during study;

• Known or suspected HIV infection with a CD4+ T-cell count <200/μL;

• Unlikely to comply with study procedures or return for evaluations;

• Body Mass Index (BMI) ≥40 kg/m2;

• Pregnant or nursing;

• Female of childbearing potential not willing to practice barrier methods of birth control.

CONTINUATION CRITERIA:

• Fulfills A or B or both: A) Confirmed complicated MRSA bacteremia B) Possible or definite RIE caused by MRSA according to modified Duke criteria;

• Infecting S. aureus strain susceptible to vancomycin;

• Infecting S. aureus strain susceptible to daptomycin;

• Appropriate treatment of any foci of infection within first 3 days of study;

• Removal of any intravascular foreign material not allowed per inclusion criteria within first 3 days of study;

• Removal of any percutaneous or implanted catheters not allowed per inclusion criteria within first 3 days of study.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	East Carolina University	Greenville	North Carolina	United States
2	Cleveland Clinic Foundation	Cleveland	Ohio	United States	44195

Sponsors and Collaborators

• Cubist Pharmaceuticals LLC

Investigators

• Study Director: Peter Pertel, MD, Cubist Pharmaceuticals LLC

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Cubist Pharmaceuticals LLC
• ClinicalTrials.gov Identifier: NCT00695903
• Other Study ID Numbers: 3009-013; DAP-HDSAB-07-05
• First Posted: Jun 12, 2008
• Last Update Posted: Dec 24, 2018
• Last Verified: Dec 1, 2018

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Keywords provided by Cubist Pharmaceuticals LLC: Gram-positive bacterial infections; Staph Aureus; Bacteremia; MRSA; Infective Endocarditis; Right-sided Infective endocarditis; SABIE; SAIE; RIE
• Additional relevant MeSH terms: Bacteremia; Endocarditis, Bacterial; Endocarditis; Vancomycin; Daptomycin

Study Results

Participant Flow

Arm/Group Title	Daptomycin 10 mg/kg	Vancomycin High-dose
Arm/Group Description	Daptomycin 10 mg/kg Intravenously (IV) every 24 hours	Vancomycin 15 mg/kg IV, dosed to maintain trough serum concentrations of 15 to 20 μg/mL
Period Title: Had End of Therapy (EOT) Assessment
STARTED	19	19
Met Continuation Criteria	9	6
COMPLETED	7	4
NOT COMPLETED	12	15
Period Title: Had End of Therapy (EOT) Assessment
STARTED	7	4
COMPLETED	5	3
NOT COMPLETED	2	1

Baseline Characteristics

Arm/Group Title	Daptomycin 10 mg/kg	Vancomycin High-dose	Total
Arm/Group Description	Daptomycin 10 mg/kg Intravenously (IV) every 24 hours	Vancomycin 15 mg/kg IV, dosed to maintain trough serum concentrations of 15 to 20 μg/mL	Total of all reporting groups
Overall Participants	19	17	36
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	16 84.2%	15 88.2%	31 86.1%
>=65 years	3 15.8%	2 11.8%	5 13.9%
Sex: Female, Male (Count of Participants)
Female	6 31.6%	4 23.5%	10 27.8%
Male	13 68.4%	13 76.5%	26 72.2%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Treatment-emergent Creatine Phosphokinase (CPK) Elevations
Description	Number of participants with treatment-emergent CPK elevations ≥5 x upper limit of normal (≥1,000 U/L) by the EOT visit.
Time Frame	On therapy and up to 3 days post-therapy (treatment duration ranged from 2 to 43 days)

Outcome Measure Data

Analysis Population Description

All subjects who received at least one dose of study medication (Safety Population). Two patients in the high-dose vancomycin arm were randomized but not treated and therefore not included in the safety population.

Arm/Group Title	Daptomycin 10 mg/kg	Vancomycin High-dose
Arm/Group Description	Daptomycin 10 mg/kg Intravenously (IV) every 24 hours	Vancomycin 15 mg/kg IV, dosed to maintain trough serum concentrations of 15 to 20 μg/mL
Measure Participants	19	17
Number [Participants]	2 10.5%	0 0%

2. Secondary Outcome

Title	Number of Participants With Treatment Cure at End of Therapy (EOT) Visit
Description	Investigator's assessment of treatment cure. Treatment Cure includes successful outcomes of both clinical and microbiological assessments. Clinical cure is defined by clinical improvement of symptoms and signs associated with the underlying infection such that no further anti-infective therapy is required. Microbiological Success is defined by the eradication or presumed eradication of baseline infecting methicillin-resistant S. aureus pathogen and no superinfecting pathogen(s) (Gram-positive) or metastatic methicillin-resistant S. aureus pathogens were isolated post therapy.
Time Frame	End of Therapy (median day 12 and 6.5 in daptomycin and vancomycin modified intent-to treat population, respectively)

Outcome Measure Data

Analysis Population Description

Patients who met the continuation criteria (modified intent-to-treat) and had a EOT assessment of clinical outcome.

Arm/Group Title	Daptomycin 10 mg/kg	Vancomycin High-dose
Arm/Group Description	Daptomycin 10 mg/kg Intravenously (IV) every 24 hours	Vancomycin 15 mg/kg IV, dosed to maintain trough serum concentrations of 15 to 20 μg/mL
Measure Participants	7	4
Number [participants]	6 31.6%	3 17.6%

3. Primary Outcome

Title	Number of Participants With Elevated Serum Creatinine
Description	Number of participants with treatment-emergent serum creatinine increases ≥0.5 mg/dL (for patients with a baseline value ≤3.0 mg/dL) or ≥1.0 mg/dL (for patients with a baseline value >3.0 mg/dL) by the EOT visit.
Time Frame	On therapy and up to 3 days post-therapy (treatment duration ranged from 2 to 43 days)

Outcome Measure Data

Analysis Population Description

All subjects who received at least one dose of study medication (Safety Population). Two patients in the high-dose vancomycin arm were randomized but not treated and therefore not included in the safety population.

Arm/Group Title	Daptomycin 10 mg/kg	Vancomycin High-dose
Arm/Group Description	Daptomycin 10 mg/kg Intravenously (IV) every 24 hours	Vancomycin 15 mg/kg IV, dosed to maintain trough serum concentrations of 15 to 20 μg/mL
Measure Participants	19	17
Number [participants]	0 0%	4 23.5%

4. Secondary Outcome

Title	Number of Participants With Treatment Cure at Test of Cure (TOC)/Safety Visit
Description	Investigator's assessment of clinical response. Treatment Cure includes successful outcomes of both clinical and microbiological assessments. Clinical cure is defined by clinical improvement of symptoms and signs associated with the underlying infection such that no further anti-infective therapy is required. Microbiological Success is defined by the eradication or presumed eradication of baseline infecting methicillin-resistant S. aureus pathogen and no superinfecting pathogen(s) (Gram-positive) or metastatic methicillin-resistant S. aureus pathogens were isolated post therapy.
Time Frame	Test of Cure (TOC) Visit (35 to 49 days post-therapy, approximately week 8)

Outcome Measure Data

Analysis Population Description

Subset of modified intent-to-treat population who completed TOC/Safety visit

Arm/Group Title	Daptomycin 10 mg/kg	Vancomycin High-dose
Arm/Group Description	Daptomycin 10 mg/kg Intravenously (IV) every 24 hours	Vancomycin 15 mg/kg IV, dosed to maintain trough serum concentrations of 15 to 20 μg/mL
Measure Participants	5	3
Number [participants]	5 26.3%	3 17.6%

Adverse Events

Time Frame	Safety assessments were performed throughout the study (an average of 8 weeks). Safety assessments were conducted at the EOT/Early Termination visit (on the day of or within 3 days after therapy was stopped) and TOC visit (35 to 49 days post-therapy).
Adverse Event Reporting Description	On therapy safety assessments included maximum daily temperature, vital signs, physical examination and clinical laboratory tests. Investigators were required to report lab abnormalities (e.g. CPK, serum creatinine) as adverse events only when he/she considered the abnormality clinically significant.
Arm/Group Title	Daptomycin		Vancomycin
Arm/Group Description	Daptomycin 10 mg/kg i.v.q24hr		Vancomycin 15 mg/kg i.v., dosed to maintain trough serum concentrations of 15 to 20 ug/mL
All Cause Mortality
	Daptomycin		Vancomycin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Daptomycin		Vancomycin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/19 (15.8%)		4/17 (23.5%)
Cardiac disorders
Atrioventricular block complete	1/19 (5.3%)	1	0/17 (0%)	0
Congenital, familial and genetic disorders
Atrial septal defect	1/19 (5.3%)	1	0/17 (0%)	0
Gastrointestinal disorders
Abdominal pain	1/19 (5.3%)	1	0/17 (0%)	0
Diarrhoea	2/19 (10.5%)	2	0/17 (0%)	0
Nausea	1/19 (5.3%)	1	0/17 (0%)	0
Pancreatitis acute	1/19 (5.3%)	1	0/17 (0%)	0
Vomiting	1/19 (5.3%)	1	0/17 (0%)	0
Infections and infestations
Endocarditis bacterial	0/19 (0%)	0	1/17 (5.9%)	1
Osteomyelitis	0/19 (0%)	0	1/17 (5.9%)	1
Renal and urinary disorders
Renal failure	0/19 (0%)	0	1/17 (5.9%)	1
Renal failure acute	0/19 (0%)	0	1/17 (5.9%)	1
Respiratory, thoracic and mediastinal disorders
Pulmonary embolism	1/19 (5.3%)	1	0/17 (0%)	0
Other (Not Including Serious) Adverse Events
	Daptomycin		Vancomycin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/19 (31.6%)		10/17 (58.8%)
Eye disorders
Diplopia	1/19 (5.3%)	1	0/17 (0%)	0
Photophobia	1/19 (5.3%)	1	0/17 (0%)	0
Gastrointestinal disorders
Abdominal discomfort	0/19 (0%)	0	1/17 (5.9%)	1
Constipation	0/19 (0%)	0	1/17 (5.9%)	1
Diarrhoea	1/19 (5.3%)	1	0/17 (0%)	0
Nausea	0/19 (0%)	0	1/17 (5.9%)	1
General disorders
Catheter related complication	0/19 (0%)	0	1/17 (5.9%)	1
Catheter site discharge	1/19 (5.3%)	1	0/17 (0%)	0
Catheter site erythema	1/19 (5.3%)	1	0/17 (0%)	0
Catheter site haemorrhage	1/19 (5.3%)	2	0/17 (0%)	0
Catheter site oedema	1/19 (5.3%)	1	0/17 (0%)	0
Catheter site pain	1/19 (5.3%)	1	0/17 (0%)	0
Catheter site related reaction	1/19 (5.3%)	3	0/17 (0%)	0
Pain	1/19 (5.3%)	1	0/17 (0%)	0
Infections and infestations
Pneumonia bacterial	0/19 (0%)	0	1/17 (5.9%)	2
Urinary tract infection bacterial	0/19 (0%)	0	1/17 (5.9%)	2
Vulvovaginal mycotic infection	1/19 (5.3%)	1	0/17 (0%)	0
Investigations
Blood creatine phosphokinase increased	2/19 (10.5%)	2	0/17 (0%)	0
Metabolism and nutrition disorders
Hyperphosphataemia	0/19 (0%)	0	1/17 (5.9%)	1
Hypocalcaemia	0/19 (0%)	0	1/17 (5.9%)	1
Hypoglycaemia	0/19 (0%)	0	1/17 (5.9%)	1
Hypomagnesaemia	1/19 (5.3%)	1	2/17 (11.8%)	2
Musculoskeletal and connective tissue disorders
Back pain	0/19 (0%)	0	1/17 (5.9%)	1
Neck pain	1/19 (5.3%)	1	0/17 (0%)	0
Pain in extremity	1/19 (5.3%)	1	0/17 (0%)	0
Nervous system disorders
Headache	1/19 (5.3%)	1	1/17 (5.9%)	1
Hypoaesthesia	1/19 (5.3%)	1	0/17 (0%)	0
Paraesthesia	1/19 (5.3%)	1	0/17 (0%)	0
Renal and urinary disorders
Renal failure acute	0/19 (0%)	0	1/17 (5.9%)	1
Skin and subcutaneous tissue disorders
Pruritus	0/19 (0%)	0	1/17 (5.9%)	1
Rash	0/19 (0%)	0	2/17 (11.8%)	2
Skin exfoliation	0/19 (0%)	0	1/17 (5.9%)	1
Vascular disorders
Hypertension	0/19 (0%)	0	1/17 (5.9%)	1

Limitations/Caveats

Because the study was terminated early due to lack of enrollment, there were not sufficient patients to provide meaningful analysis for the following secondary outcomes: persistent/recurrent bacteremia and time to defervescence/clearance.

More Information

Certain Agreements

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

The first publication is initiated by Cubist. If first publication not published within 1 year of study conclusion or termination, Investigator has right to publish and disclose the data. Prior to any submission for publication, presentation, or communication of results or information arising from the study, Investigator shall provide Cubist at least 90 days for review and comment upon the manuscript or other material for such publication or presentation.