Clinical trial NCT01922011: Safety and Efficacy Study of Daptomycin Compared to Active Comparator in Pediatric Participants With Acute Hematogenous Osteomyelitis (AHO) (MK-3009-006)
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Acute Hematogenous Osteomyelitis
Lead sponsor: Cubist Pharmaceuticals LLC, a subsidiary of Merck & Co., Inc. (Rahway, New Jersey USA)
Sponsor class: INDUSTRY
First posted: 2013-08-14
Enrollment: 149
Sex: ALL
Minimum age (years): 1
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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)
* Have acute hematogenous osteomyelitis that is located in the spine
* Have chronic osteomyelitis (i.e. symptoms of osteomyelitis \> 21 days) or osteomyelitis with complications requiring non-routine surgical treatment (i.e. sequestration).
* Have major trauma, penetrating trauma (including a puncture wound of the foot), postoperative osteomyelitis, foreign body in or adjacent to affected bone or joint, or other iatrogenic bone or joint infections present at the site of infection
* Have acute hematogenous osteomyelitis due to a proven gram-negative organism
* Have transient tenosynovitis, juvenile rheumatoid arthritis (JRA), reactive arthritis, bony tumors, and other osteoarticular diseases suspected to be due to a nonbacterial (eg, fungal or mycobacterial) etiology
* Receive more than 24 hours of effective intravenous antibacterial therapy for osteomyelitis within 96 hours before randomization unless microbiological or clinical failure is documented
* Require any potentially effective concomitant systemic antibacterial therapy for gram-positive infections
* Have history of seizures (except febrile seizure of childhood)
* Have peripheral neuropathy
* Have history of rhabdomyolysis (with the exception of muscle injury due to trauma)
* Have Sickle cell anemia
* Cannot be assessed clinically during the study
* Have any condition (eg, cystic fibrosis, current septic shock) that would make the subject, in the opinion of the Investigator, unsuitable for the study
* Have significant reduced creatinine clearance (CrCl) \< 50 mL/min/1.73 m2
* Have evidence of significant hepatic, hematologic, or immunologic dysfunction
* Have Creatine kinase (CK) elevation ≥ 10 × ULN (upper limit of normal) without symptoms or ≥ 5 × ULN with symptoms
* If female, must not be pregnant or nursing and if required by age and life style take appropriate measures to not get pregnant during the study.
* Have participated in any study involving administration of an investigational agent or device or daptomycin within 30 days
* Are unable or unwilling to adhere to the study-specified procedures and restrictions
* Has suspected or confirmed pneumonia, empyema, meningitis, or endocarditis.

Primary outcomes:
measure: 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.
timeFrame: Up to study Day 5
Secondary outcomes:
measure: 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.
timeFrame: Up to study Day 5
measure: Percentage of Participants With a Favorable Clinical Outcome
timeFrame: 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)
measure: Percentage of Participants With a Clinical Cure Categorized by Baseline Pathogen at Test of Cure
timeFrame: 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)
measure: Percentage of Participants With Sustained Clinical Improvement
timeFrame: 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)
measure: Percentage of Participants With a Favorable Microbiological Response Categorized by Baseline Pathogen at Test of Cure
timeFrame: 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)
Other outcomes:
measure: Number of Participants With 1 or More Adverse Events (AEs)
timeFrame: Administration of first dose up to approximately six and a half months after last dose of study drug
measure: Number of Participants With 1 or More Serious Adverse Events (SAEs)
timeFrame: Administration of first dose through the last follow-up visit; an expected time of up to 6.5 months
measure: Concentration of Serum Creatine Kinase (CK)
timeFrame: Baseline and End of Therapy IV (up to Day 42)
measure: Change From Baseline in Number of Participants With Abnormal Focused (Peripheral) Neurological Assessments
timeFrame: Baseline and up to Test of Cure (21-35 days after last dose of IV study drug) (up to Day 77)
measure: Plasma Concentration of Daptomycin at the End of IV Infusion
timeFrame: Day 3 up to Day 42
measure: Plasma Concentration of Daptomycin at 15 Minutes to 1 Hour After the End of IV Infusion
timeFrame: Day 3 up to Day 42
measure: Plasma Concentration of Daptomycin at 2 to 3 Hours After the End of IV Infusion
timeFrame: Day 3 up to Day 42
measure: Plasma Concentration of Daptomycin at 4 to 5 Hours After the End of IV Infusion
timeFrame: Day 3 up to Day 42
Locations:
Study officials:
affiliation: Merck Sharp & Dohme LLC
name: Medical Director
role: STUDY_DIRECTOR
References:
citation: Bradley JS, Arrieta AC, Digtyar VA, Popejoy MW, Grandhi A, Bokesch P, Hershberger E, Dorr MB, Tan CM, Murata Y, Wolf DJ, Bensaci M. Daptomycin for Pediatric Gram-Positive Acute Hematogenous Osteomyelitis. Pediatr Infect Dis J. 2020 Sep;39(9):814-823. doi: 10.1097/INF.0000000000002790.