A Phase 3 Telavancin Staphylococcus Aureus (S. Aureus) Bacteremia Trial

• Sponsor: Cumberland Pharmaceuticals (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT02208063
• Collaborator: (none)
• Enrollment: 121
• Location: 1
• Arms: 2
• Actual Duration (Months): 40.3
• Patients Per Site Per Month: 3

Study Details

Study Description

Brief Summary

This is a multicenter, randomized, open-label, noninferiority trial of telavancin versus standard IV therapy control (e.g., vancomycin, daptomycin, anti-staphylococcal penicillin (PCN), or cefazolin) in the treatment of subjects with complicated Staphylococcus aureus (S. aureus) bacteremia and SA right-sided infective endocarditis (SA-RIE).

Condition or Disease	Intervention/Treatment	Phase
Bacteremia	Drug: Telavancin; Drug: Vancomycin; Drug: Daptomycin; Drug: Synthetic penicillin; Drug: Cefazolin	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 121 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 3 Multicenter, Randomized, Open-label, Clinical Trial of Telavancin Versus Standard Intravenous Therapy in the Treatment of Subjects With Staphylococcus Aureus Bacteremia Including Infective Endocarditis
• Actual Study Start Date: Dec 1, 2014
• Actual Primary Completion Date: Apr 12, 2018
• Actual Study Completion Date: Apr 12, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Telavancin 7.5 mg/kg administered intravenously once every 24 hours daily over 60 minutes	Drug: Telavancin
Active Comparator: Standard of care Vancomycin, Daptomycin, synthetic penicillin or Cefazolin	Drug: Vancomycin; Drug: Daptomycin; Other Names: Cubicin ; Drug: Synthetic penicillin; Other Names: Nafcillin Oxacillin Cloxacillin ; Drug: Cefazolin

Outcome Measures

Primary Outcome Measures

1. Number of Participants With a Clinical Outcome of Cure at Test of Cure (TOC) [Up to 8 weeks]

   The efficacy endpoint of clinical outcome of cure at the test of cure (TOC) was determined by subjects who meet all of the following criteria, as determined by the investigator and adjudicated by the blinded independent efficacy adjudication committee (IEAC). Alive at TOC Resolution of all clinical signed and symptoms of the Staphylococcus aureus (S. aureus) infection at TOC No evidence of microbiological persistence of relapse No new foci of metastatic S. aureus infection after Day 8

Secondary Outcome Measures

1. Number of Participants With an Investigator Clinical Outcome of Cure at TOC in the Microbiological All-treated (mAT) Population [Up to 8 weeks]

   The efficacy endpoint of Investigator clinical outcome of cure at the test of cure (TOC) was determined by the following criteria: Subject alive at TOC Resolution of all clinical signs and symptoms of the S. aureus infection at TOC (unless explained by a more likely alternative diagnosis) No evidence of microbiological persistence or relapse No new foci of metastatic S. aureus infection after Day 8

2. Investigator Clinical Response (Success or Failure) at EOT in the Microbiological All-treated (mAT) Population [Up to 8 weeks]

   This efficacy endpoint was determined to be a clinical failure if the subject switched study antibiotic due to lack of clinical response

3. Number of Participants With the Development of a New Metastatic Foci of S. Aureus Infection at Test of Cure (TOC) in the Microbiological All-treated (mAT) Populations [Day 8]

   After Day 8, any sign or symptom leading to a subsequent confirmed diagnosis of a new metastatic foci of S. aureus infection

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• 18 years of age or older with at least one blood culture positive for S. aureus within 48 hours before randomization

• At least one of the following signs or symptoms of bacteremia:

• Temperature ≥ 38.0°C

• White blood cell (WBC) count > 10,000 or < 4,000 cells/µL or > 10% immature neutrophils (bands)

• Tachycardia (heart rate > 90 bpm)

• Tachypnea (respiratory rate > 20 breaths/min)

• Hypotension (systolic blood pressure < 90 mmHg)

• Signs or symptoms of localized catheter-related infection

• At enrollment, subjects must have either 1) known right-sided infective endocarditis by Modified Duke's criteria 2) known complicated bacteremia, demonstrated as signs or symptoms of metastatic foci of S. aureus infection or 3) at least one risk factor for complicated bacteremia.

Exclusion Criteria:

• Treatment with any potentially effective (anti-staphylococcal) systemic antibiotic for more than 60 hours within 7 days before randomization. EXCEPTION: Documented resistance to the prior systemic antibacterial therapy

• Presence of an infection source that will not be managed or controlled within the first 3 days of study drug treatment

• Presence of prosthetic cardiac valve or cardiac device (eg, implantable cardioverter defibrillator [ICD]), permanent pacemaker, or cardiac valve support ring)

• Known or suspected left-sided infective endocarditis (LIE), by Modified Duke Criteria. NOTE: Right-sided infective endocarditis (RIE) is permitted

• Known or suspected osteomyelitis or meningitis. NOTE: Evidence of metastatic complications related to the primary infection such as right-sided endocarditis, septic arthritis, septic pulmonary emboli are permitted. S. aureus pneumonia is permitted

• Confirmed evidence (identification or gram stain) of a mixed polymicrobial infection with a Gram-negative pathogen that requires non-study antibiotic treatment with agent(s) that have activity against Gram-negative pathogens

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Remington-Davis Clinical Research	Columbus	Ohio	United States	43215

Sponsors and Collaborators

• Cumberland Pharmaceuticals

Investigators

• Study Director: Medical Monitor, Cumberland Pharmaceuticals, Inc.

Study Documents (Full-Text)

• Study Protocol - Jan 16, 2018
• Statistical Analysis Plan - Apr 26, 2018

More Information

Publications

None provided.

• Responsible Party: Cumberland Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT02208063
• Other Study ID Numbers: 0112
• First Posted: Aug 4, 2014
• Last Update Posted: Feb 17, 2020
• Last Verified: Feb 1, 2020

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by Cumberland Pharmaceuticals: Bacteremia; Staphylococcus aureus
• Additional relevant MeSH terms: Bacteremia; Vancomycin; Cefazolin; Daptomycin; Penicillins; Cloxacillin; Oxacillin; Nafcillin; Telavancin

Study Results

Participant Flow

Arm/Group Title	Telavancin	Standard of Care
Arm/Group Description	7.5 mg/kg administered intravenously once every 24 hours daily over 60 minutes Telavancin	Vancomycin, Daptomycin, synthetic penicillin or Cefazolin Vancomycin Daptomycin Synthetic penicillin Cefazolin
Period Title: Overall Study
STARTED	60	61
Randomized and Treated	58	60
Microbiological All Treated	47	52
COMPLETED	48	50
NOT COMPLETED	12	11

Baseline Characteristics

Arm/Group Title	Telavancin	Standard of Care	Total
Arm/Group Description	7.5 mg/kg administered intravenously once every 24 hours daily over 60 minutes Telavancin	Vancomycin, Daptomycin, synthetic penicillin or Cefazolin Vancomycin Daptomycin Synthetic penicillin Cefazolin	Total of all reporting groups
Overall Participants	57	60	117
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	52.3 (16.41)	56.5 (16.33)	54.5 (16.44)
Sex: Female, Male (Count of Participants)
Female	18 31.6%	17 28.3%	35 29.9%
Male	39 68.4%	43 71.7%	82 70.1%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	20 35.1%	19 31.7%	39 33.3%
Not Hispanic or Latino	37 64.9%	41 68.3%	78 66.7%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race/Ethnicity, Customized (Count of Participants)
American Indian or Alaska Native	3 5.3%	3 5%	6 5.1%
Black or African American	8 14%	5 8.3%	13 11.1%
White	44 77.2%	48 80%	92 78.6%
Other	2 3.5%	2 3.3%	4 3.4%
Missing	0 0%	1 1.7%	1 0.9%
Multiple	0 0%	1 1.7%	1 0.9%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With a Clinical Outcome of Cure at Test of Cure (TOC)
Description	The efficacy endpoint of clinical outcome of cure at the test of cure (TOC) was determined by subjects who meet all of the following criteria, as determined by the investigator and adjudicated by the blinded independent efficacy adjudication committee (IEAC). Alive at TOC Resolution of all clinical signed and symptoms of the Staphylococcus aureus (S. aureus) infection at TOC No evidence of microbiological persistence of relapse No new foci of metastatic S. aureus infection after Day 8
Time Frame	Up to 8 weeks

Outcome Measure Data

Analysis Population Description

One subject enrolled was excluded from all summaries and analyses because the subject was randomized to a higher dose of telavancin (10mg/kg) that the remainder of the subjects.

Arm/Group Title	Telavancin	Standard of Care
Arm/Group Description	7.5 mg/kg administered intravenously once every 24 hours daily over 60 minutes Telavancin	Vancomycin, Daptomycin, synthetic penicillin or Cefazolin Vancomycin Daptomycin Synthetic penicillin Cefazolin
Measure Participants	47	52
Cure	22 38.6%	27 45%
Failure	19 33.3%	21 35%
Indeterminate	6 10.5%	4 6.7%

2. Secondary Outcome

Title	Number of Participants With an Investigator Clinical Outcome of Cure at TOC in the Microbiological All-treated (mAT) Population
Description	The efficacy endpoint of Investigator clinical outcome of cure at the test of cure (TOC) was determined by the following criteria: Subject alive at TOC Resolution of all clinical signs and symptoms of the S. aureus infection at TOC (unless explained by a more likely alternative diagnosis) No evidence of microbiological persistence or relapse No new foci of metastatic S. aureus infection after Day 8
Time Frame	Up to 8 weeks

Outcome Measure Data

Analysis Population Description

One subject enrolled was excluded from all summaries and analyses because the subject was randomized to a higher dose of telavancin (10mg/kg) that the remainder of the subjects.

Arm/Group Title	Telavancin	Standard of Care
Arm/Group Description	7.5 mg/kg administered intravenously once every 24 hours daily over 60 minutes Telavancin	Vancomycin, Daptomycin, synthetic penicillin or Cefazolin Vancomycin Daptomycin Synthetic penicillin Cefazolin
Measure Participants	47	52
Cure	26 45.6%	31 51.7%
Failure	15 26.3%	19 31.7%
Indeterminate	3 5.3%	0 0%
Missing	3 5.3%	2 3.3%

3. Secondary Outcome

Title	Investigator Clinical Response (Success or Failure) at EOT in the Microbiological All-treated (mAT) Population
Description	This efficacy endpoint was determined to be a clinical failure if the subject switched study antibiotic due to lack of clinical response
Time Frame	Up to 8 weeks

Outcome Measure Data

Analysis Population Description

One subject enrolled was excluded from all summaries and analyses because the subject was randomized to a higher dose of telavancin (10mg/kg) that the remainder of the subjects.

Arm/Group Title	Telavancin	Standard of Care
Arm/Group Description	7.5 mg/kg administered intravenously once every 24 hours daily over 60 minutes Telavancin	Vancomycin, Daptomycin, synthetic penicillin or Cefazolin Vancomycin Daptomycin Synthetic penicillin Cefazolin
Measure Participants	47	52
Success	28 49.1%	36 60%
Failure	13 22.8%	15 25%
Indeterminate	5 8.8%	0 0%
Missing	1 1.8%	1 1.7%

4. Secondary Outcome

Title	Number of Participants With the Development of a New Metastatic Foci of S. Aureus Infection at Test of Cure (TOC) in the Microbiological All-treated (mAT) Populations
Description	After Day 8, any sign or symptom leading to a subsequent confirmed diagnosis of a new metastatic foci of S. aureus infection
Time Frame	Day 8

Outcome Measure Data

Analysis Population Description

One subject enrolled was excluded from all summaries and analyses because the subject was randomized to a higher dose of telavancin (10mg/kg) that the remainder of the subjects.

Arm/Group Title	Telavancin	Standard of Care
Arm/Group Description	7.5 mg/kg administered intravenously once every 24 hours daily over 60 minutes Telavancin	Vancomycin, Daptomycin, synthetic penicillin or Cefazolin Vancomycin Daptomycin Synthetic penicillin Cefazolin
Measure Participants	47	52
Yes	6 10.5%	3 5%
No	32 56.1%	41 68.3%
Indeterminate	9 15.8%	8 13.3%

Adverse Events

Time Frame	38 months
Arm/Group Title	Telavancin		Standard of Care
Arm/Group Description	7.5 mg/kg administered intravenously once every 24 hours daily over 60 minutes Telavancin		Vancomycin, Daptomycin, synthetic penicillin or Cefazolin Vancomycin Daptomycin Synthetic penicillin Cefazolin
All Cause Mortality
	Telavancin		Standard of Care
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/58 (5.2%)		5/60 (8.3%)
Serious Adverse Events
	Telavancin		Standard of Care
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	16/58 (27.6%)		13/60 (21.7%)
Blood and lymphatic system disorders
Anaemia	0/58 (0%)	0	1/60 (1.7%)	1
Cardiac disorders
Cardiac failure	0/58 (0%)	0	1/60 (1.7%)	1
Cardiovascular insufficiency	1/58 (1.7%)	1	0/60 (0%)	0
General disorders
Multi-organ failure	1/58 (1.7%)	1	1/60 (1.7%)	1
Non-cardiac chest pain	1/58 (1.7%)	1	0/60 (0%)	0
Pyrexia	1/58 (1.7%)	1	0/60 (0%)	0
Unintentional medical device removal	0/58 (0%)	0	1/60 (1.7%)	1
Infections and infestations
Bacteraemia	0/58 (0%)	0	2/60 (3.3%)	2
Osteomyelitis	2/58 (3.4%)	2	0/60 (0%)	0
Sepsis	1/58 (1.7%)	1	1/60 (1.7%)	1
Arthritis bacterial	0/58 (0%)	0	1/60 (1.7%)	1
Cellulitis	1/58 (1.7%)	1	0/60 (0%)	0
Escherichia bacteraemia	0/58 (0%)	0	1/60 (1.7%)	1
Extradural abscess	0/58 (0%)	0	1/60 (1.7%)	1
Pneumonia	0/58 (0%)	0	1/60 (1.7%)	1
Septic shock	1/58 (1.7%)	1	0/60 (0%)	0
Serratia infection	1/58 (1.7%)	1	0/60 (0%)	0
Spinal empyema	1/58 (1.7%)	1	0/60 (0%)	0
Investigations
Blood creatinine increased	1/58 (1.7%)	1	0/60 (0%)	0
Electrocardiogram QT prolonged	1/58 (1.7%)	1	0/60 (0%)	0
Hepatic enzyme increased	0/58 (0%)	0	1/60 (1.7%)	1
Liver function test abnormal	1/58 (1.7%)	1	0/60 (0%)	0
Musculoskeletal and connective tissue disorders
Intervertebral disc protrusion	0/58 (0%)	0	1/60 (1.7%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Malignant peritoneal neoplasm	0/58 (0%)	0	1/60 (1.7%)	1
Nervous system disorders
Brain oedema	1/58 (1.7%)	1	0/60 (0%)	0
Encephalopathy	0/58 (0%)	0	1/60 (1.7%)	1
Renal and urinary disorders
Acute kidney injury	1/58 (1.7%)	1	2/60 (3.3%)	2
Tubulointerstitial nephritis	0/58 (0%)	0	1/60 (1.7%)	1
Urinary retention	0/58 (0%)	0	1/60 (1.7%)	1
Respiratory, thoracic and mediastinal disorders
Dyspnoea	1/58 (1.7%)	1	0/60 (0%)	0
Respiratory failure	1/58 (1.7%)	1	0/60 (0%)	0
Vascular disorders
Haematoma	0/58 (0%)	0	1/60 (1.7%)	1
Shock	0/58 (0%)	0	1/60 (1.7%)	1
Other (Not Including Serious) Adverse Events
	Telavancin		Standard of Care
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	29/58 (50%)		25/60 (41.7%)
Blood and lymphatic system disorders
Anaemia	6/58 (10.3%)	6	7/60 (11.7%)	7
Gastrointestinal disorders
Nausea	6/58 (10.3%)	6	6/60 (10%)	6
Constipation	3/58 (5.2%)	3	7/60 (11.7%)	7
Diarrhoea	3/58 (5.2%)	3	6/60 (10%)	6
Metabolism and nutrition disorders
Hypokalaemia	10/58 (17.2%)	10	8/60 (13.3%)	8
Nervous system disorders
Headache	3/58 (5.2%)	3	3/60 (5%)	3
Psychiatric disorders
Insomnia	5/58 (8.6%)	5	3/60 (5%)	3
Renal and urinary disorders
Acute kidney injury	4/58 (6.9%)	4	8/60 (13.3%)	8

Limitations/Caveats

At the interim analysis, study was deemed to be inadequately powered & terminated prematurely.

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.