BonE and Joint Infections - Simplifying Treatment in Children Trial (BEST)

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.

Study Overview

• Status: Recruiting
• Conditions: Osteomyelitis; Septic Arthritis; Bone Infection; Bone and Joint Infection
• Intervention / Treatment: Drug: Oral cefalexin only; Drug: IV cefazolin or IV flucloxacillin followed by oral cefalexin

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 285
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Amanda Gwee, PhD; Phone Number: +61393455522; Email: amanda.gwee@rch.org.au
• Study Contact Backup: Name: Alison Boast, MD; Phone Number: +61393455522; Email: alison.boast@gmail.com

Study Locations

• Australia
  • New South Wales
    • Sydney, New South Wales, Australia, 2031
      • Not yet recruiting
      • Sydney Children's Hospital Network
      • Contact: Brendan Mcmullan, Dr; Phone Number: 293821241; Email: Brendan.Mcmullan@health.nsw.gov.au
    • Sydney, New South Wales, Australia, 2145
      • Not yet recruiting
      • The Children's Hospital at Westmead
      • Contact: Cheryl Jones, Prof; Phone Number: +61418205848; Email: cheryl.jones@sydney.edu.au
  • Northern Territory
    • Darwin, Northern Territory, Australia, 0811
      • Not yet recruiting
      • Royal Darwin Hospital
      • Contact: Joshua R Francis; Phone Number: +61423528381; Email: josh.francis@menzies.edu.au
  • Queensland
    • Brisbane, Queensland, Australia, 4101
      • Not yet recruiting
      • Queensland Children's Hospital
      • Contact: Clare Nourse, Prof; Phone Number: 0413586954; Email: clare.nourse@health.qld.gov.au
  • South Australia
    • Adelaide, South Australia, Australia, 5006
      • Not yet recruiting
      • Women's and Children's Hospital
      • Contact: Celia M Cooper, Dr; Phone Number: (08)81616396; Email: celia.cooper@sa.gov.au
  • Victoria
    • Melbourne, Victoria, Australia, 3051
      • Recruiting
      • The Royal Children's Hospital
      • Contact: Alison Boast, MD; Phone Number: +61395699551; Email: alison.boast@rch.org.au
      • Contact: Amanda Gwee, PhD; Phone Number: +61395699551; Email: amanda.gwee@rch.org.au
  • Western Australia
    • Perth, Western Australia, Australia, 6009
      • Not yet recruiting
      • Perth Children's Hospital
      • Contact: Asha Bowen, A/Prof; Phone Number: 08 64562222; Email: asha.bowen@health.wa.gov.au
• New Zealand
  • Christchurch, New Zealand, 8011
    • Not yet recruiting
    • Christchurch Hospital
    • Contact: Tony Walls, A/Prof; Email: tony.walls@otago.ac.nz

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year to 18 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

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:

1. Infection due to bacteria resistant to cefalexin or atypical infection (e.g. mycobacterial, fungal)
2. Features of sepsis as defined by the presence of organ dysfunction (defined using definitions within the Pediatric Logistic Organ Dysfunction-2 (PELOD-2) score)
3. Concomitant severe, invasive infection e.g. necrosing fasciitis
4. 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)
5. History of allergy to cephalosporin antibiotics or immediate, severe reaction to penicillins
6. Received more than three IV or oral dose of an antibiotic with activity against the likely bacteria causing the current infection
7. Prior episode of OM or SA
8. Prior condition predisposing to poor absorption (e.g. inflammatory bowel disease, current gastrointestinal symptoms) or complicated disease (e.g. immunodeficiency)
9. Prior enrolment in the trial
10. Current recipient of another investigational product as part of a clinical trial

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Intervention; 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; High-dose oral cefalexin
Active Comparator: Standard Therapy; 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; Standard therapy of IV cefazolin or IV flucloxacillin followed by high dose oral cefalexin

What is the study measuring?

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 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
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
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 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

Collaborators and Investigators

• Sponsor: Murdoch Childrens Research Institute
• Investigators: Principal Investigator: Amanda Gwee, PhD, Murdoch Childrens Research Institute

Study record dates

Study Major Dates

• Study Start (Actual): June 1, 2021
• Primary Completion (Estimated): December 1, 2026
• Study Completion (Estimated): December 1, 2026

Study Registration Dates

• First Submitted: July 14, 2020
• First Submitted That Met QC Criteria: September 1, 2020
• First Posted (Actual): September 3, 2020

Study Record Updates

• Last Update Posted (Actual): August 9, 2023
• Last Update Submitted That Met QC Criteria: August 7, 2023
• Last Verified: August 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; Anti-Infective Agents; Anti-Bacterial Agents; Cefazolin; Cephalexin; Floxacillin
• Other Study ID Numbers: 2019.287

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

The de-identified data set collected for this analysis of the BEST trial will be available six months after publication of the primary outcome.

The study protocol, analysis plan and consent forms will also be available. The data may be obtained from the Murdoch Children's Research Institute by emailing amanda.gwee@rch.org.au

• IPD Sharing Time Frame: Time Frame: 6 months after publication of primary outcome
• IPD Sharing Access Criteria: Prior to releasing any data the following are required: a data access agreement must be signed between relevant parties, the BEST Trial Principle and Associate Investigators must see and approve the analysis plan describing how the data will be analysed, there must be an agreement around appropriate acknowledgement and any additional costs involved must be covered. Data will only be shared with a recognised research institution which has approved the proposed analysis plan.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ANALYTIC_CODE; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No