Oral-only Antibiotics for Bone and Joint Infections in Children (CHILD@HOME_BJI)

Oral-only Antibiotics for Bone and Joint Infections in Children - A Nationwide Randomized Controlled Trial

A nationwide, multicenter, randomized, non-inferiority trial of children with bone and joint infections. The primary objective is to determine if oral-only antibiotics (experimental arm) is non-inferior to initial intravenous antibiotics followed by oral therapy (control arm). Children will be randomized 1:1. The total treatment duration is identical in both groups. The study is open label with blinding of the primary endpoint assessor.

Study Overview

• Status: Active, not recruiting
• Conditions: Osteomyelitis; Septic Arthritis; Bone Infection; Joint Infection; Bone and Joint Infection
• Intervention / Treatment: Drug: Oral co-amoxiclav or oral dicloxacillin only; Drug: IV ceftriaxon followed by oral co-amoxiclav or oral dicloxacillin

• Study Type: Interventional
• Enrollment (Actual): 180
• Phase: Phase 4

Contacts and Locations

Study Locations

• Denmark
  • Copenhagen, Denmark
    • Copenhagen University Hospital, Rigshospitalet

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 3 months to 17 years (Child)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Children aged 3 months to 18 years with antibiotic treatment of uncomplicated bone or joint infection.

Exclusion Criteria:

1. Severe disease, e.g. septic shock, or any concomitant infection, e.g. necrotizing fasciitis, requiring IV antibiotics in the opinion of the treating clinician.
2. Complicated bone or joint infection, e.g. prosthetic material, infection secondary to or complicated by trauma, severe pyomyositis or other substantial soft tissue infections.
3. Expected need of major surgery within the first 24 hours of treatment, e.g. drilling, debridement, fenestration, surgical drainage, synovectomy. Minor surgery as diagnostic surgical bone biopsy or diagnostic joint fluid aspiration including lavage is not a criterion for exclusion.
4. Significant co-morbidities that might influence the choice of treatment or the course of the infection, e.g. immunodeficiency, immunosuppressive therapy, sickle cell anemia.
5. Previous bone or joint infection.
6. Antibiotic therapy for more than 24 hours before inclusion.
7. Documented pathogen with limited treatment options that do not permit randomization, e.g. the pathogen is only sensitive to intravenous antibiotics.
8. Prior enrolment in the trial

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
Active Comparator: Experimental; < 5 years: High-dose oral co-amoxiclav (1:8) 33 mg amoxicillin/kg/dose (max. 1 g) three-times daily (TDS) until clinical and paraclinical improvement (min. 3 days) followed by oral co-amoxiclav (1:4) 17 mg amoxicillin/kg/dose (max. 500 mg) TDS for 7 days (arthritis) or 21 days (osteomyelitis). =/> 5 years: High-dose oral dicloxacillin 50 mg/kg/dose (max. 2 g) four-times daily (QID) until clinical and paraclinical improvement (min. 3 days) followed by oral dicloxacillin 25 mg/kg/dose (max. 1 g) QID for 7 days (arthritis) or 21 days (osteomyelitis). Treatment will be adjusted according to microbiological findings.	Drug: Oral co-amoxiclav or oral dicloxacillin only; High dose oral treatment followed by standard dose oral treatment
Active Comparator: Standard; IV ceftriaxon 100 mg/kg/dose (max. 4 g) once daily (QD) (all ages) until clinical and paraclinical improvement (min. 3 days) followed by: < 5 years: Oral co-amoxiclav (1:4) 17 mg amoxicillin/kg/dose (max. 500 mg) TDS for 7 days (arthritis) or 21 days (osteomyelitis). >/= 5 years: Oral dicloxacillin 25 mg/kg/dose (max. 1 g) QID for 7 days (arthritis) or 21 days (osteomyelitis). Treatment will be adjusted according to microbiological findings.	Drug: IV ceftriaxon followed by oral co-amoxiclav or oral dicloxacillin; IV treatment followed by standard dose oral treatment

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Sequelae at 6 months	Proportion of children with sequelae 6 months after initiation of treatment defined as abnormal mobility or function of the affected joint/bone. Evaluated by blinded clinical examination by a qualified pediatrician and/or pediatric orthopedic surgeon.	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Non-acute treatment failure.	Proportion of children with change of antibiotic therapy due to non-acute treatment failure. This will be evaluated by two pediatric specialists and is suggested by e.g. 1) temperature above 38,5 after more than 72 hours of antibiotic therapy, 2) increasing CRP ( C-reactive protein) after more than 96 hours of antibiotic therapy and 3) no improvement in mobility or pain after 120 hours of antibiotic therapy.	28 days
Recurrent infection	Proportion of children with recurrence of symptoms and signs (same anatomical location) after completion of antibiotic treatment requiring further antibiotic administration	6 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety Outcome 1: Severe complications during antibiotic treatment.	Proportion of children with severe complications during antibiotic treatment, e.g. need for intensive care, septic shock, organ failure, pyomyositis, endocarditis, deep venous thrombosis.	28 days
Safety Outcome 2: Surgical intervention	Proportion of children with need for surgical intervention during antibiotic treatment. Diagnostic surgical intervention (diagnostic joint aspiration or diagnostic bone biopsy) excluded.	28 days
Safety Outcome 3: Treatment related adverse events	Proportion of children with treatment related adverse events e.g. complications of IV access (infection, need for replacement, extravasation) and drug side effects reported by medical staff or by parents (electronic questionnaire).	3 months
Time to apyrexia from initiation of antibiotic treatment		28 days
Mobility and pain	Level of mobility and pain assessed by daily grading of symptoms by medical staff as well as daily standardized pain scores by participants and/or parents. Score systems: Visual Analog Scale (VAS) or Face Legs Activity Cry Consolability (FLACC) scale, both with scores from 0 (no pain) to 10 (worst pain). [14 days]	14 days
Total duration of antibiotic therapy		3 months
Sequelae at 12 months	Proportion of children with sequelae, e.g. abnormal mobility, growth abnormalities assessed by clinical examination by a qualified pediatrician 12 month after initiation of treatment.	12 months
Radiological abnormalities at 12 months	Proportion of children with radiological abnormalities assessed by a qualified radiologist 12 months after the initiation of treatment.	12 months
Secondary infection	Proportion of children with secondary infection with antimicrobial-resistant organisms or Clostridium difficile	3 months

Collaborators and Investigators

• Sponsor: Rigshospitalet, Denmark
• Collaborators: Innovation Fund Denmark; The research foundation of Copenhagen University Hospital, Rigshospitalet; Copenhagen Health Science Partners
• Investigators: Study Chair: Ulrikka Nygaard, Ass Prof PhD, Rigshospitalet, Denmark; Principal Investigator: Allan Bybeck Nielsen, MD, Rigshospitalet, Denmark

Study record dates

Study Major Dates

• Study Start (Actual): September 15, 2020
• Primary Completion (Estimated): January 1, 2024
• Study Completion (Estimated): September 15, 2024

Study Registration Dates

• First Submitted: September 13, 2020
• First Submitted That Met QC Criteria: September 18, 2020
• First Posted (Actual): September 24, 2020

Study Record Updates

• Last Update Posted (Estimated): January 3, 2024
• Last Update Submitted That Met QC Criteria: December 28, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Disease Attributes; Joint Diseases; Musculoskeletal Diseases; Arthritis; Bone Diseases; Bone Diseases, Infectious; Infections; Communicable Diseases; Arthritis, Infectious; Osteomyelitis; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Anti-Bacterial Agents; beta-Lactamase Inhibitors; Ceftriaxone; Amoxicillin-Potassium Clavulanate Combination; Dicloxacillin
• Other Study ID Numbers: H-20009117

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Study protocol and statistical analysis plan will be shared. The exact plan for sharing Individual Participant Data (IPD) is being prepared.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No