BonE and Joint Infections - Simplifying Treatment in Children Trial

Study Overview
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Brief Summary
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This is a multi- centre trial of children with bone and joint infections (BJIs) at eight major paediatric hospitals in Australia and New Zealand. The primary objective is to establish if in children with acute, uncomplicated BJIs, entirely oral antibiotic treatment is not inferior to initial intravenous (IV) treatment for 1 to 7 days followed by an oral antibiotic course in achieving full recovery 3 months after presentation. Children will be randomly allocated to the 'entirely oral antibiotic' group or the 'standard treatment' group.

Detailed Description
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Children with acute onset BJIs who present to the participating sites will be enrolled into the trial if eligible (see eligibility criteria) and randomly allocated into two groups. Children in the 'standard treatment group' will receive standard treatment for BJIs, which consists of IV antibiotics for 1-7 days followed by 3 weeks of oral antibiotics. Children in the 'entirely oral treatment group' will receive high dose oral antibiotics, followed by the standard dose of oral antibiotics for 3 weeks. The outcomes of children in each of the two groups will be compared to determine whether BJIs can be treated without needing a course of IV antibiotics.

Official Title
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BonE and Joint Infections - Simplifying Treatment in Children Trial

Conditions
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Osteomyelitis, Bone Infection, Septic Arthritis, Bone and Joint Infection

Intervention / Treatment
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* Drug: Oral cefalexin only
* Drug: IV cefazolin or IV flucloxacillin followed by oral cefalexin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Children aged 1 to 18 years with acute, uncomplicated, community-acquired bone and joint infection who fulfil pre-defined clinical criteria. Exclusion Criteria: Infection due to bacteria resistant to cefalexin or atypical infection (e.g. mycobacterial, fungal) Features of sepsis as defined by the presence of organ dysfunction (defined using definitions within the Pediatric Logistic Organ Dysfunction-2 (PELOD-2) score) Concomitant severe, invasive infection e.g. necrosing fasciitis Complicated infection (e.g. presence of prosthetic material; large subperiosteal (>3mm) or soft tissue abscess without surgical intervention; infection secondary to or complicated by trauma) History of allergy to cephalosporin antibiotics or immediate, severe reaction to penicillins Received more than three IV or oral dose of an antibiotic with activity against the likely bacteria causing the current infection Prior episode of OM or SA Prior condition predisposing to poor absorption (e.g. inflammatory bowel disease, current gastrointestinal symptoms) or complicated disease (e.g. immunodeficiency) Prior enrolment in the trial Current recipient of another investigational product as part of a clinical trial

Ages Eligible for Study
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Minimum Age: 1 Year
Maximum Age: 18 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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Intervention<br>Children will receive high-dose oral cefalexin 37.5 mg/kg/dose (max 1.5 g) QID 1 to 7 days followed by oral cefalexin 45 mg/kg/dose (max 1.5 g) TDS for a total course of 3 weeks | Drug: Oral cefalexin only<br>* High-dose oral cefalexin<br>|
| Active Comparator: Standard Therapy<br>Children will receive IV cefazolin 50 mg/kg/dose (max 2 g) three-times daily (TDS) or IV flucloxacillin 50 mg/kg/dise (max 2 g) four-times daily (QID) for 1 to 7 days followed by oral cefalexin 45 mg/kg/dose (max 1.5 g) three-times daily (TDS) for a total course of 3 weeks | Drug: IV cefazolin or IV flucloxacillin followed by oral cefalexin<br>* Standard therapy of IV cefazolin or IV flucloxacillin followed by high dose oral cefalexin<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of children assessed as having made a full recovery 3 months | Full recovery is defined by the absence of: (i) Clinical features of osteomyelitis or septic arthritis (ii) No episodes of disease recurrence requiring further antibiotic administration after initial treatment. Assessment made by a qualified paediatrician. | 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of children with with recurrent disease at 6 months. | Proportion of children with recurrence of symptoms and signs after initial recovery requiring further antibiotic administration assessed at 3 months by an independent committee. | 6 months | 
| Proportion of children with with recurrent disease at 12 months. | Proportion of children with recurrence of symptoms and signs after initial recovery requiring further antibiotic administration assessed at 12 months by an independent committee. | 12 months | 
| Proportion of children with complications of their disease at 3 months. | Complications assessed by an independent committee defined as: (i) residual dysfunction (ii) pain | 3 months | 
| Proportion of children with complications of their disease at 12 months. | Complications assessed by an independent committee defined as: (i) residual poor function (ii) bone death (osteonecrosis) (iii) pain (iv) growth arrest (v) limb deformity | 12 months | 
| Proportion of children with treatment-related adverse effects (AEs). | Adverse effects assessed between days 1-7 including: (i) Complications of IV access (eg need for replacement, infection, extravasation, drug side effects); or (ii) high-dose oral antibiotics (eg. drug side effects, inability to tolerate the full dose) It will be assessed between day 1-7 (can be at any time during the admission while intravenous antibiotics are prescribed) | Between Day 1-7 | 
| Quality of life - Pediatric Quality of Life Inventory (PedsQL) 3 months | PedsQL is an acronym for the Pediatric Quality of Life Inventory. This inventory includes 23 items each scored 0 to 5 . The minimum score is 0 and the maximum score is 92. Lower scores indicate better quality of life. Outcome measures will be reported as median (range). | 3 months | 
| Quality of life - Child Health Utility Scale (CHU9D) Day 8-14 | CHU9D is an acronym for the Child Health Utility scale. It includes 9 domains scored 0 to 5. The minimum score is 0 and the maximum is 5. The minimum score is 0 and the maximum is 45. Lower scores indicate better quality of life. Outcome measures will be reported as median (range). It will be administered once, and completed any day between Day 8 to Day 14. | Once between Day 8 to Day 14 | 
| Quality of life - Child Health Utility Scale (CHU9D) 12 months | CHU9D is an acronym for the Child Health Utility scale. It includes 9 domains scored 0 to 5. The minimum score is 0 and the maximum is 5. The minimum score is 0 and the maximum is 45. Lower scores indicate better quality of life. Outcome measures will be reported as median (range) | 12 months | 
| Quality of life - EQ-5d Day 8-14 | EQ-5D is an acronym for the European Quality of Life Five Dimension, it is an instrument which evaluates the generic quality of life. It is a descriptive system with one question for each of the five dimensions that include mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Outcome measures will be reported as median (range). It will be administered once, and completed any day between Day 8 to Day 14. | Once between Day 8 to Day 14 | 
| Cost effectiveness - cost-effectiveness ratio of all resources at 12 months | The incremental cost-effectiveness ratio will be determined for both arms of the trial. This is a summary measure representing the economic value of the intervention (oral cefalexin), compared with the alternative (IV cefazolin followed by oral cefalexin). Estimated total sum of all hospital and patient/family resources required per patient per treatment course (AUD) collected by the study team at each study visit using a standard questionnaire (e.g. clinical services, medication, hospital and family accommodation, travelling, loss of income, care arrangements for family members). The mean total cost per treatment cost (AUD) will be reported for each arm of the trial. | 12 months | 
| Treatment adherence - medication reconciliation at 3 weeks | Mean percentage of cefalexin doses taken determined by medication reconciliation (ie. return of any remaining cefalexin) at end of treatment (3 weeks) assessed by the study team/trial pharmacist | Week 3 | 
| Treatment adherence - Medication Adherence Response Scale at 3 weeks | Outcome will be reported as median adherence score (range 5-25). | Week 3 |