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

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

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.

Study Overview

• Status: Completed
• Conditions: Skin Diseases, Infectious
• Intervention / Treatment: Drug: Daptomycin; Drug: Standard of Care (SOC)

Detailed Description

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

• Study Type: Interventional
• Enrollment (Actual): 396
• Phase: Phase 4

Contacts and Locations

Study Locations

• India
  • Bangalore, India
    • Medisys Hospital
  • Bangalore, India
    • MS Ramaiah
  • Lucknow, India
    • MV hospital and Research Center
  • Mumbai, India
    • BYL Nair Hospital
  • Mumbai, India
    • Lokmanya Tilak Municipal Medical College
  • Pune, India
    • Ruby Hall Clinic
  • Pune, India
    • KEM Hospital
• Panama
  • Panama, Panama
    • Hospital del Niño
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35233
      • University of Alabama at Birmingham
  • California
    • Oakland, California, United States, 94606
      • Children's Hospital Research Center Oakland
    • Orange, California, United States, 92868
      • Children's Hospital of Orange County
    • San Diego, California, United States, 92123
      • Rady Children's Hospital - San Diego
  • Florida
    • Tampa, Florida, United States, 33606
      • University of South Florida College of Medicine
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University
  • Illinois
    • Chicago, Illinois, United States, 60637
      • University of Chicago
  • Michigan
    • Detroit, Michigan, United States, 48201
      • Children's Hospital of Michigan
  • Nebraska
    • Omaha, Nebraska, United States, 68198
      • University of Nebraska Medical Center
  • New Jersey
    • New Brunswick, New Jersey, United States, 08901
      • Robert Wood Johnson Medical School
  • New York
    • Bronx, New York, United States, 10467
      • Montifiore Medical Center
    • Brooklyn, New York, United States, 11203
      • SUNY Downstate Medical Center
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center
  • Ohio
    • Akron, Ohio, United States, 44308
      • Children's Hospital Medical Center of Akron
    • Cleveland, Ohio, United States, 44106
      • University Hospitals Case Medical Center
    • Toledo, Ohio, United States, 43606
      • Toledo Children's Hospital
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • University of Oklahoma Health Sciences Center
  • Tennessee
    • Memphis, Tennessee, United States, 38105
      • LeBonheur Children's Medical Center
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University Medical Center and Children's Hospital
  • Texas
    • Fort Worth, Texas, United States, 76104
      • Cook Children's Medical Center
    • Houston, Texas, United States, 77030
      • Texas Children's Hospital
    • Houston, Texas, United States, 77030
      • The University of Texas Health Science Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year to 17 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Daptomycin; 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; Other Names: Cubicin
Active Comparator: Standard of Care (SOC); 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); Other Names: nafcillin, oxacillin, cloxacillin

What is the study measuring?

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)

Collaborators and Investigators

• Sponsor: Cubist Pharmaceuticals LLC
• Investigators: Study Director: Ellie Hershberger, Cubist Pharmaceuticals LLC

Publications and helpful links

General Publications

• Bradley J, Glasser C, Patino H, Arnold SR, Arrieta A, Congeni B, Daum RS, Kojaoghlanian T, Yoon M, Anastasiou D, Wolf DJ, Bokesch P. Daptomycin for Complicated Skin Infections: A Randomized Trial. Pediatrics. 2017 Mar;139(3):e20162477. doi: 10.1542/peds.2016-2477. Epub 2017 Feb 15.

Study record dates

Study Major Dates

• Study Start (Actual): July 23, 2008
• Primary Completion (Actual): October 11, 2013
• Study Completion (Actual): October 11, 2013

Study Registration Dates

• First Submitted: July 7, 2008
• First Submitted That Met QC Criteria: July 8, 2008
• First Posted (Estimate): July 9, 2008

Study Record Updates

• Last Update Posted (Actual): September 5, 2018
• Last Update Submitted That Met QC Criteria: August 6, 2018
• Last Verified: August 1, 2018

More Information

Terms related to this study

• Keywords: Skin; Complicated; Structure
• Additional Relevant MeSH Terms: Pathologic Processes; Disease Attributes; Infections; Communicable Diseases; Skin Diseases, Infectious; Skin Diseases; Anti-Infective Agents; Anti-Bacterial Agents; Daptomycin; Cloxacillin; Nafcillin; Oxacillin
• Other Study ID Numbers: 3009-017; DAP-PEDS-07-03 (Other Identifier: Cubist Study Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: https://www.merck.com/clinical-trials/pdf/ProcedureAccessClinicalTrialData.pdf