Safety & Efficacy of Daptomycin Versus Standard of Care (SOC) in 1 - 17 Year Olds With Staphylococcus Aureus Bacteremia (MK-3009-005)

Study Overview
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Brief Summary
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The intent of this study is to describe the safety and efficacy of daptomycin versus standard of care (SOC) in pediatric participants aged 1-17 years with bacteremia caused by Staphylococcus aureus (S. aureus).

Detailed Description
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S. aureus causes a series of invasive diseases in adults and children, including bacteremia. Infections due to S. aureus in children, particularly those due to methicillin resistant S. aureus (MRSA), are a growing world-wide public health concern. Daptomycin, a cyclic lipopeptide antibacterial agent, shows rapid in vitro bactericidal activity with concentration-dependent killing for Gram-positive organisms, including S. aureus. Surveillance studies have demonstrated a daptomycin MIC90 of 0.5µg/ml for both methicillin-susceptible S. aureus (MSSA) and MRSA with >99% of MRSA isolates being categorized as susceptible by the Food and Drug Administration (FDA), European Committee of antimicrobial susceptibility testing (EUCAST) and Clinical and Laboratory Standards Institute (CLSI) breakpoints (5). Clinical trials in adults demonstrated that daptomycin was safe and efficacious in complicated skin and skin structure infections (cSSSI) and bloodstream infections caused by S. aureus, including right-sided infective endocarditis (RIE). However, information on the safety and efficacy of daptomycin for use in children is lacking. The intent of this study in children is to confirm the safety of daptomycin at mean steady state systemic exposures (AUC) similar to those reported for adults treated at 6 mg/kg for bacteremia.

Official Title
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A Comparative Evaluation of the Safety and Efficacy of Daptomycin Versus Standard of Care in Pediatric Subjects One - Seventeen Years of Age With Bacteremia Caused by Staphylococcus Aureus.

Conditions
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Bacteremia

Intervention / Treatment
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* Drug: Daptomycin
* Drug: Comparator


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: To be included in this study, participants must: Sign a parental consent form; if appropriate, sign an assent form Be between 1 and 17 years of age Have proven or probable bacteremia caused by S. aureus based on the traditional culture result, rapid diagnostic test or Gram stain If female of childbearing potential, must not be pregnant or nursing and take appropriate measures to not get pregnant during the study If male, must take appropriate measures to not get partner pregnant Able to comply with the protocol requirements Exclusion Criteria: Participants will not be allowed into the study if they: Have received a certain amount of antibacterial therapy specific for current bacteremia unless it is demonstrated that the organism is resistant to the given antibacterial; Anticipate to require other antibiotics that may be potentially effective against S. aureus; Have shock or hypotension unresponsive to standard therapy; Have received an investigational product or have participated in an experimental procedure within 30 days; Have an intolerance or hypersensitivity to daptomycin; Have renal insufficiency; Have prior history or current evidence of muscle damage (rhabdomyolysis; significant CPK elevation); Have history of clinically significant muscular disease, nervous system or seizure disorder, including unexplained muscular weakness, history of peripheral neuropathy, Guillain-Barré or spinal cord injury; Have S. aureus pneumonia, empyema, meningitis, or endocarditis

Ages Eligible for Study
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Minimum Age: 1 Year
Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Daptomycin - 12 to 17 year olds<br>Participants ages 12-17 years old were administered daptomycin 7 mg/kg infused once daily, intravenously (IV), over 30 minutes; therapy duration (uncomplicated bacteremia) = 5-28 days, therapy duration (complicated bacteremia) = 7-42 days. After conclusion of IV therapy, can continue on oral therapy (not daptomycin, but at discretion of investigator). | Drug: Daptomycin<br>* Intravenous daptomycin given at 7 mg/kg (ages 12-17 years); 9 mg/kg (ages 7-11 years); 12 mg/kg (ages 1-6 years) infused once daily, intravenously, over 30 or 60 minutes. Participants may be switched to oral therapy following completion of IV study drug administration provided they showed clear clinical improvement and the pathogen was susceptible to an oral agent.<br>* Other names: Cubicin;|
| Active Comparator: Comparator - 12 to 17 year olds<br>Participants ages 12-17 years old received IV vancomycin or semi-synthetic penicillin or first-generation cephalosporins or clindamycin, given as per local guidelines or site-specific prescribing information; therapy duration (uncomplicated bacteremia) = 5-28 days, therapy duration (complicated bacteremia) = 7-42 days. IV comparator and subsequent oral therapy were at the discretion of the investigator. | Drug: Comparator<br>* Vancomycin, Semi-synthetic penicillin, First-generation cephalosporins, Clindamycin: administered per standard of care. Participants may be switched to oral therapy following completion of IV study drug administration provided they showed clear clinical improvement and the pathogen was susceptible to an oral agent.<br>|
| Experimental: Daptomycin - 7 to 11 year olds<br>Participants ages 7 to 11 years old were administered daptomycin 9 mg/kg, infused once daily, IV over 30 minutes; therapy duration (uncomplicated bacteremia) = 5-28 days, therapy duration (complicated bacteremia) = 7-28 days. After conclusion of IV therapy, can continue on oral therapy (not daptomycin, but at discretion of investigator). | Drug: Daptomycin<br>* Intravenous daptomycin given at 7 mg/kg (ages 12-17 years); 9 mg/kg (ages 7-11 years); 12 mg/kg (ages 1-6 years) infused once daily, intravenously, over 30 or 60 minutes. Participants may be switched to oral therapy following completion of IV study drug administration provided they showed clear clinical improvement and the pathogen was susceptible to an oral agent.<br>* Other names: Cubicin;|
| Experimental: Daptomycin - 1 to 6 year olds<br>Participants ages 1 to 6 years old were administered daptomycin 12 mg/kg, infused once daily, IV over 60 minutes; therapy duration (uncomplicated bacteremia) = 5-28 days, therapy duration (complicated bacteremia) = 7-28 days. After conclusion of IV therapy, can continue on oral therapy (not daptomycin, but at discretion of investigator). | Drug: Daptomycin<br>* Intravenous daptomycin given at 7 mg/kg (ages 12-17 years); 9 mg/kg (ages 7-11 years); 12 mg/kg (ages 1-6 years) infused once daily, intravenously, over 30 or 60 minutes. Participants may be switched to oral therapy following completion of IV study drug administration provided they showed clear clinical improvement and the pathogen was susceptible to an oral agent.<br>* Other names: Cubicin;|
| Active Comparator: Comparator - 7 to 11 year olds<br>Participants ages 7-11 years old received IV vancomycin, or semi-synthetic penicillin, or first-generation cephalosporins, clindamycin; given as per local guidelines or site-specific prescribing information; therapy duration (uncomplicated bacteremia) = 5-28 days, therapy duration (complicated bacteremia) = 7-28 days. IV comparator and subsequent oral therapy were at the discretion of the investigator. | Drug: Comparator<br>* Vancomycin, Semi-synthetic penicillin, First-generation cephalosporins, Clindamycin: administered per standard of care. Participants may be switched to oral therapy following completion of IV study drug administration provided they showed clear clinical improvement and the pathogen was susceptible to an oral agent.<br>|
| Active Comparator: Comparator - 1 to 6 year olds<br>Participants ages 1-6 years old received IV vancomycin, or semi-synthetic penicillin, or first-generation cephalosporins, clindamycin; given as per local guidelines or site-specific prescribing information; therapy duration (uncomplicated bacteremia) = 5-28 days, therapy duration (complicated bacteremia) = 7-28 days. IV comparator and subsequent oral therapy were at the discretion of the investigator. | Drug: Comparator<br>* Vancomycin, Semi-synthetic penicillin, First-generation cephalosporins, Clindamycin: administered per standard of care. Participants may be switched to oral therapy following completion of IV study drug administration provided they showed clear clinical improvement and the pathogen was susceptible to an oral agent.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With One or More Adverse Events (AEs) | An AE is any untoward medical occurrence in a participant administered a pharmaceutical product that does not necessarily have to have a causal relationship with the treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not related to the medicinal product. | Administration of first dose through the last follow-up visit (up to 77 days) | 
| Number of Participants With One or More Serious Adverse Events (SAEs) | An SAE is any adverse experience occurring at any dose that results in any of the following outcomes: death, life threatening experience, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability or incapacity, is a congenital anomaly or birth defect, or is considered to be an important medical event. | Administration of first dose through the last follow-up visit (up to 77 days) | 
| Percentage of Participants With Maximum Post-Baseline Creatine Phosphokinase (CPK) Elevations Above Upper Limit of Normal | Blood was drawn from baseline up to the end of therapy visit to determine the percentage of participants with maximum post-baseline CPK elevations above the upper limit of 500 Units Per Liter (U/L) . | Baseline up to end of therapy visit (up to 49 days) | 
| Percentage of Participants With Sustained CPK Elevations | Blood was drawn from baseline up to the end of therapy visit to determine the percentage of participants with sustained CPK elevations, defined as two consecutive post-baseline values above the upper limit of normal (ULN) | Baseline up to end of therapy visit (up to 44 days) | 
| Number of Participants With Abnormal Focused (Peripheral) Neurological Assessments at Test of Cure (TOC) | Focused neurological examinations were done at the TOC/Safety Visit. These examinations include assessments of sensation, pupillary reflex and tracking, peripheral reflexes (biceps, patellar tendon, ankle jerk and plantar response), muscle tone and strength (upper and lower limbs), coordination (finger to nose) and tremor of the hands/fingers. | TOC Safety Visit (up to 56 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Clinical Success at TOC/Safety Visit | Clinical success was determined by assessing resolution/improvement of signs and symptoms. An assessment of cure or improved is considered clinical success. Cure: resolution of clinically significant signs and symptoms associated with admission infection; no further antibiotic therapy is required for the primary infection under study. Improvement: partial resolution of clinical signs/symptoms of infection such that no further antibiotic therapy is required for the primary infection under study. | 7-14 days after the last dose of study medication (up to 56 days) | 
| Percentage of Participants With Overall Success at TOC Visit | Overall success is based on microbiologic responses after initiating study drug and clinical response at TOC/Safety Visit. Overall outcome is a success if both clinical and microbiologic outcomes are successes. An assessment of cure or improved is considered clinical success. Microbiological Success: a participant for whom all baseline infecting pathogens were eradicated (presumed or documented) within 7 days from the start of study drug for uncomplicated bacteremia with no source of infection present, and 10 days for complicated bacteremia or when the source of infection has not been removed. | 7-14 days after the last dose of study medication (up to 56 days) | 
| Trough Plasma Concentration of Daptomycin | Plasma concentrations of daptomycin were measured on Days 3 through 6 of IV dosing. Trough concentrations were collected 22 to 26 hours following the end of the previous day's end of infusion and before the next infusion. Concentrations below the limit of quantification were excluded. | Days 3, 4, 5 or 6 of treatment at pre-dose | 
| Maximum Plasma Concentration (Cmax) of Daptomycin | Plasma concentrations of daptomycin were measured on Days 3 through 6 of IV dosing. Peak concentrations were collected up to 15 minutes following the end of infusion. Concentrations below the limit of quantification were excluded. | Days 3, 4, 5 or 6 of treatment at end of infusion |