Safety and Efficacy Study of Daptomycin in Pediatric Participants (1 to 17 Years-old) With Skin and Skin Structure Infections

Study Overview
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Brief Summary
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This is a multi-center, evaluator-blinded, randomized, comparative study designed to assess the safety, efficacy, and pharmacokinetics (PK) of daptomycin in pediatric subjects ages 1 to 17 years, inclusive, with complicated skin and skin structure infections (cSSSI) caused by Gram-positive pathogens.

Detailed Description
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This is a multi-center, evaluator-blinded, randomized, comparative study designed to assess the safety, efficacy, and PK of daptomycin in pediatric participants ages 1 to 17 years, inclusive, with cSSSI caused by Gram-positive pathogens. Participants will be enrolled into age groups and given age-dependent doses over a period of up to 14 days. Participants will be stratified by age group to receive either daptomycin or SOC (recommended as vancomycin, clindamycin or semisynthetic penicillin) in a ratio of 2:1, respectively. Participants may continue on oral therapy following completion of IV study drug administration and provided that the participant meets all criteria for conversion to oral therapy, including clear clinical improvement and availability of an oral agent to which the pathogen is susceptible. The choice of oral therapy will be left to the discretion of the Investigator. February 11, 2015 released from post marketing requirement to include subjects aged 3 months - < 1 year. Ref ID: 3701325

Official Title
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An Evaluation of the Safety, Efficacy and Pharmacokinetics of Daptomycin in Pediatric Subjects Aged One to Seventeen Years With Complicated Skin and Skin Structure Infections Caused by Gram-Positive Pathogens

Conditions
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Skin Diseases, Infectious

Intervention / Treatment
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* Drug: Daptomycin
* Drug: Standard of Care (SOC)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written parental (or appropriate legal representative) informed consent prior to any study-related procedure not part of normal medical care Written participant assent (as appropriate) Male or female between the ages of 1 and 17 years old, inclusive If female of childbearing potential (defined as post-menarche), not lactating or pregnant, documented negative pregnancy test result within 48 hours prior to study medication administration and willing to practice reliable birth control measures (at the discretion of the Principal Investigator) during study treatment and for at least 28 days after study completion Able to comply with the protocol for the duration of the study Skin and skin structure infections of a complicated nature known or suspected to be caused by Gram-positive pathogen(s) that require IV antibiotic treatment. Complicated infections are defined as infections either involving deep soft tissue or requiring significant surgical intervention (such as, infected ulcers, burns, and major abscesses) or infections in which the participant has a significant underlying disease state that complicates the response to treatment. The Investigator may contact the Medical Monitor to discuss infections not meeting this definition but which otherwise appear appropriate for inclusion At least three of the following clinical signs and symptoms associated with the cSSSI: pain; tenderness to palpation; temperature >37.5 degrees Celsius (C) (99.5 degrees Fahrenheit [F]) oral or >38 degrees C (100.4 degrees F) rectal; white blood count (WBC) >12,000/cubic millimeter (mm^3) or ≥10% bands; swelling and/or induration; erythema (>1 centimeter [cm] beyond edge of wound or abscess); or pus formation Exclusion Criteria: Investigational drug use (including daptomycin) or participation in any experimental procedure in the 30 days preceding study entry Known allergy/hypersensitivity to daptomycin Known infection caused solely by Gram-negative pathogen(s), fungus(i), or virus(es) Previous systemic antimicrobial therapy exceeding 24 hours in duration administered anytime during the 48 hours prior to the first dose of study drug (exception: a participant is eligible if on previous antibiotics without any clinical improvement and/or a wound culture is available and the pathogen is not sensitive to prior therapy) Known or suspected pneumonia, osteomyelitis, meningitis, or endocarditis Known bacteremia (exception: any participant enrolled in the study that is subsequently found to have a blood culture positive for bacteremia may be continued) Participant with current or known clinically significant abnormal laboratory test results (including electrocardiograms [ECGs]) that would expose the participant to unacceptable risk as determined by Investigator History of clinically significant cardiovascular, renal, hepatic, pulmonary (well-controlled asthma is acceptable), gastrointestinal, endocrine, hematological, autoimmune disease, or primary immune deficiency (unless the Investigator considers that the subject would not be at risk by participating in the study [Note: human immunodeficiency virus-infected participants must not be enrolled]) History of or current clinically significant (at the discretion of the Investigator) muscular disease, nervous system, or seizure disorder Unexplained muscular weakness, history of peripheral neuropathy, Guillain-Barre syndrome or spinal cord injury Known or suspected renal insufficiency (that is, estimated creatinine clearance rate [CLcr]<80 mL/min/1.73 squared meter [m^2] History of or current rhabdomyolysis History of (within 1 year prior to first dose of study drug) or current myositis Current septic shock Known or suspected creatine phosphokinase (CPK) elevation

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: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Daptomycin<br>Administered intravenously (IV) every 24 hours for up to 14 days at the following age-dependent dosages. Participants ages 7 to 17 years: daptomycin was dissolved in a volume of 50 milliliters (mL) 0.9% sodium chloride for injection over 30 minutes (min) with an infusion rate of 1.67 mL/min. Participants 1 to 6 years-old: daptomycin was dissolved in a volume of 25 mL 0.9% sodium chloride for injection over 60 min with an infusion rate was 0.42 mL/min. Age Group 1 (for ages 12 to 17 years): 5 milligrams/kilogram (mg/kg) Age Group 2 (for ages 7 to 11 years): 7 mg/kg Age Group 3 (for ages 2 to 6 years): 9 mg/kg Age Group 4 (for ages 1 to <2 years): 10 mg/kg | Drug: Daptomycin<br> <br> * Other names: Cubicin;|
| Active Comparator: Standard of Care (SOC)<br>The comparator agent for this study was the SOC treatment and dosage deemed appropriate by the Investigator. The recommended SOC agents were IV vancomycin, IV clindamycin, and IV semisynthetic penicillins every 24 hours for up to 14 days. | Drug: Standard of Care (SOC)<br> <br> * Other names: nafcillin, oxacillin, cloxacillin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs) | A TEAE was defined as any treatment-emergent adverse event (AE) that occurred from the time of first dose of the study drug through the last study evaluation or pre-existing adverse AEs that were aggravated in severity or frequency during the dosing period. The percentage of participants with at least 1 TEAE, with at least one drug-related AE (drug-related included possibly related or related as deemed by the Investigator; it also included events if causality was missing), and who discontinued from treatment due to a TEAE is presented. A summary of serious and other non-serious adverse events regardless of causality is located in the Reported Adverse Events module. | Baseline through 14 days after last dose of study drug | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With an Overall Therapeutic Response at Test of Cure Visit | The assessment of therapeutic response was determined by comparing a participant's signs and symptoms at the test of cure visit (up to 14 days after last dose) to those recorded at baseline. Participants were classified as Success or Failure by combining their clinical and microbiological efficacy responses. Resolution of clinically significant signs and symptoms associated with the skin infection present at study baseline was considered Success by the Investigator. These participants were deemed both clinically cured and microbiologically eradicated. For participants whose clinical course could not be clearly defined as improved, a clinical outcome of Failure was rendered. In addition, if it was determined that the primary site of infection required additional antibiotic treatment, the assessment of clinical response was Failure. If the Investigator was unable to determine a response because the participant was lost to follow-up, the assessment was Unable to evaluate. | Baseline through 14 days after last dose of study drug | 
| Pharmacokinetics (PK): Area Under the Plasma Concentration-Time Curve for Daptomycin From 0 to the Last Sampling Time Point (AUC[0-t]) | Participants who volunteered for PK sampling had a blood sample collected for analysis at the following time points: Age Group 1; Day 3: Predose, 0.25 hour (hr), 1 hr, 4 hr, and12 hr postdose. Age Group 2; Day 3: Predose, 0.25 hr, 1 hr, 6 hr, and 10 hr postdose. Age Group 3; Day 1, 2, or 3: Predose, 0.25 hr, 1 hr, 6 hr, and 8 hr postdose. Age Group 4; Day 1, 2, or 3: 0, 1, 2, 4, and 6 hr relative to end of infusion. | Predose and 5 timepoints according to age group (up to 12 hours postdose) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Complicated, Skin, Structure