A Multicenter, Randomized, Double-Blinded Comparative Study to Evaluate the Efficacy, Safety, and Pharmacokinetics of Daptomycin Versus Active Comparator in Pediatric Subjects With Acute Hematogenous Osteomyelitis Due to Gram-Positive Organisms
Overview
- Phase
- Phase 3
- Intervention
- Daptomycin
- Conditions
- Acute Hematogenous Osteomyelitis
- Sponsor
- Cubist Pharmaceuticals LLC, a subsidiary of Merck & Co., Inc. (Rahway, New Jersey USA)
- Enrollment
- 149
- Primary Endpoint
- Percentage of Participants With Clinical Improvement in the 3 General Categories of Pain, Inflammation, and Limb Function Based on the Investigator's Overall Assessment of Severity of Each of the Symptom Categories.
- Status
- Completed
- Last Updated
- 7 years ago
Overview
Brief Summary
The purpose of the study is to determine whether daptomycin is effective and safe in the treatment of pediatric participants with AHO when compared to vancomycin (or equivalent) or nafcillin (or β-lactam equivalent). The primary hypothesis is that daptomycin is non-inferior compared with vancomycin (or equivalent) or nafcillin (or β-lactam equivalent) with respect to improvement in Pain, Inflammation, and Limb Function on or before study Day 5.
Detailed Description
Acute hematogenous osteomyelitis is a common problem in the pediatric population, affecting approximately 5/10,000 children each year and accounting for approximately 1% of all pediatric hospitalizations. In children, osteomyelitis arises from bacteremic seeding of the bone metaphysis. Daptomycin, is a cyclic lipopeptide antibacterial active against most clinically significant gram-positive pathogens including drug-resistant strains such as Methicillin Resistant Staphylococcus (S.) aureus (MRSA) and Methicillin Susceptible S. aureus (MSSA). Daptomycin has proven clinical efficacy in adults in the treatment of complicated skin and skin structure infections (cSSSI) caused by aerobic gram-positive pathogens and the treatment of S. aureus bloodstream infections (bacteremia; SAB), including those complicated by right-sided infective endocarditis, caused by MSSA and MRSA. Although not indicated for osteomyelitis, daptomycin has been successfully used to treat osteoarticular infections in adults and children as salvage therapy and at medical centers with increasingly high rates of vancomycin resistant organisms. In addition, more comparative clinical trials are needed in pediatric AHO to better elucidate the optimal treatment regimen and clinical response.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Obtain Informed Consent;
- •Be 1 year to \< 18 years old; a stepwise approach will be implemented to gate enrollment as follows: enrollment will begin with children aged 2-17 years; after an external Drug Safety Monitoring Board (DSMB) review, enrollment will be broadened to 1-17 years.
- •Have diagnosis of suspected or confirmed AHO warranting IV antibacterial therapy as inpatient, based on clinical, imaging and/or microbiological evidence as outlined below:
- •I. Clinical evidence of fever accompanied by symptoms on the affected limb that include but it is not limited to pain, tenderness on palpation, inflammation, warmth, swelling, difficulty bearing weight, motion restriction, loss of function
- •II. Radiologic imaging (magnetic resonance imaging \[MRI\], bone scan, x-ray, or computed tomography \[CT\] scan) consistent with osteomyelitis OR Microbiological evidence (gram stain, culture or polymerase chain reaction (PCR)) from a bone biopsy or bone aspirate (if available), or blood
- •III. Laboratory evidence: C-reactive protein (CRP) elevated, Erythrocyte sedimentation rate (ESR) elevated, leukocytosis or leukopenia, immature neutrophils
- •Confirmed (I, II, and III) OR suspected (I and III) that must be confirmed post-randomization
- •Participants will not be allowed into the study if they:
- •Have documented history of any hypersensitivity or allergic reaction to daptomycin
- •Have septic arthritis only (without AHO)
Exclusion Criteria
- Not provided
Arms & Interventions
Daptomycin
Intravenous (IV) daptomycin was dosed as follows: age 12 years to \<18 years (7 mg/kg); age 7 years to \< 12 years (9 mg/kg); age 24 months to \<7 years (12 mg/kg); age 12 months to \<24 months (12 mg/kg). Drug was infused over 60 minutes ± 10 minutes once daily followed by up to 3 dummy infusions every 6 hours (q6h) infused over 60 (± 10) min to maintain the blind.
Intervention: Daptomycin
Vancomycin or Nafcillin
IV vancomycin (or equivalent), 10 to 15 mg/kg, was infused over 60 (± 10) minutes q6h (± 1 hour) or IV nafcillin (or β-lactam equivalent) at 100-200 mg/kg/day, in divided doses was infused over 60 (± 10) min q6h (± 1 hour)
Intervention: Vancomycin (or equivalent)
Vancomycin or Nafcillin
IV vancomycin (or equivalent), 10 to 15 mg/kg, was infused over 60 (± 10) minutes q6h (± 1 hour) or IV nafcillin (or β-lactam equivalent) at 100-200 mg/kg/day, in divided doses was infused over 60 (± 10) min q6h (± 1 hour)
Intervention: Nafcillin (or equivalent)
Outcomes
Primary Outcomes
Percentage of Participants With Clinical Improvement in the 3 General Categories of Pain, Inflammation, and Limb Function Based on the Investigator's Overall Assessment of Severity of Each of the Symptom Categories.
Time Frame: Up to study Day 5
Clinical improvement was based on the Investigator's overall assessment of severity of each of the 3 general symptom categories of Pain, Inflammation, and Limb Function. Based on this evaluation, a participant was considered to have met criteria for clinical improvement according to the following definition: If 3 general categories are present at baseline: at least a 1-point improvement (i.e. severe to moderate, moderate to mild, mild to absent) in at least 2 of the general categories and no worsening in the other. If 2 general categories are present at baseline: at least a 2-point improvement (i.e. severe to mild, moderate to absent) in at least 1 of the general categories and no worsening or new findings in the others OR at least a 1-point improvement in both and no new findings in the other. If 1 general category is present at baseline: at least a 2-point improvement (i.e., severe to mild, moderate to absent) in that category and no new findings in the others.
Secondary Outcomes
- Percentage of Participants With Clinical Improvement Measured as a Composite End Point of Pain, Inflammation, Limb Function, Body Temperature, and C-reactive Protein at End-of IV (EOIV) Therapy Visit.(Up to study Day 5)
- Percentage of Participants With a Favorable Clinical Outcome(Baseline (within 48 hours prior to first dose of IV study drug) - and up to Test of Cure (21-35 days after last dose of IV study drug) (up to Day 77))
- Percentage of Participants With a Clinical Cure Categorized by Baseline Pathogen at Test of Cure(Baseline (within 48 hours prior to first dose of IV study drug) - and Test of Cure (21-35 days after last dose of IV study drug) (up to Day 77))
- Percentage of Participants With a Favorable Microbiological Response Categorized by Baseline Pathogen at Test of Cure(Baseline (within 48 hours prior to first dose of IV study drug) - and Test of Cure (21-35 days after last dose of IV study drug) (up to Day 77))
- Percentage of Participants With Sustained Clinical Improvement(Baseline (within 48 hours prior to first dose of IV study drug) - up to Test of Cure (21-35 days after last dose of IV study drug) (up to Day 77))