Best Treatment Choice for Osteonecrosis of the Jaw

Study Overview
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Brief Summary
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BETCON is a pragmatic randomized controlled open-label multi-center study in patients with newly diagnosed stage I-II MRONJ designed to answer the question whether minimally invasive management with LPRF membranes or primary surgical treatment is better than the standard of care of conservative therapy alone. The primary end-point is the time to mucosal healing. Secondary end-points consist of supporting measures of efficacy, patient reported symptoms, quality of life, well-being, and functioning.

Detailed Description
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While effective for symptom control and well tolerated, conservative treatment of MRONJ yields highly variable mucosal healing rates ranging between 20 to 50%. In an effort to improve these suboptimal outcomes, many adjunct treatment modalities have been studied, of which the use of minimally invasive surgery with autologous platelet rich plasma (LPRF) to improve wound healing has attracted considerable attention, with reported mucosal closure rates of up to 86% in single arm case series. More recently, improved understanding of the need for pre-operative infection control and adaptation of surgical protocols has renewed the interest in the primary surgical treatment of MRONJ with mucosal closure achieved in up to 90% of patients in some case series. Therapeutic studies of MRONJ have almost exclusively focused on mucosal healing as the desired end-point of MRONJ treatment, with little or no attention to patient symptoms, quality of life, functioning and well-being during treatment, even though the resolution of MRONJ symptoms and limiting treatment related adverse events may be equally important to patients. This comparative effectiveness research (CER) study is a randomized controlled open-label multi-center study in patients with newly diagnosed stage I-II MRONJ and is designed to answer the question whether minimally invasive treatment with LPRF membranes or primary surgical treatment improves outcomes when added to the standard of care of conservative treatment alone. The study also incorporates pragmatic design elements and uses patient reported outcomes (PRO) to determine which treatment offers the best humanistic outcomes considering both efficacy and measures of quality of life, functioning, well-being and symptom control. Indeed, this study will not use an investigational new drug (or drug regimen), device, or surgical technique, but rather evaluate their relative efficacy to guide future clinical management. Finally, plasma and saliva will be collected to identify prognostic and predictive biomarkers of outcome.

Official Title
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A Multicenter Randomized Controlled Open-label Trial of Conservative Management Versus Minimally Invasive Treatment With Leukocyte- and Platelet-rich Fibrin Versus Primary Surgery in Patients With Newly Diagnosed Osteonecrosis of the Jaw

Conditions
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Medication Related Osteonecrosis of the Jaw

Intervention / Treatment
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* Drug: Antibiotics
* Drug: Chlorhexidine mouthwash
* Procedure: Minimally invasive surgery with LPRF
* Procedure: Surgical resection


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: >18 years of age Provision of signed informed consent A history of at least one administration of, or an ongoing treatment with, a bone modifying agent in dose registered for the prevention of skeletal related events in bone metastatic disease or multiple myeloma Diagnosis of stage I-II MRONJ according to AAOMS 2014 criteria not more than 8 weeks prior to the date of screening Exclusion criteria: Any prior treatment for MRONJ other than local antiseptic rinses, systemic antibiotics, or analgesics Prior radiotherapy to the head and neck region Medical contraindication to receive any of the possible study treatments Stage III MRONJ characterized by very extensive bone necrosis, pathological fracture, or fistulas to the skin or sinuses Multiple MRONJ lesions that cannot be closed in a single surgical procedure

Ages Eligible for Study
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Minimum 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: Conservative treatment<br>Amoxicillin-based antibiotics and chlorhexidine oral rinse. Minor debridement. Primary wound closure is not part of this treatment strategy. | Drug: Antibiotics<br>* Antibiotic treatment is the same in all groups. Monotherapy for 4 weeks with: No penicillin contra-indication Amoxicillin-clavulanate 875mg tid PO Penicillin contra-indication or intolerance Clindamycin 300mg tid PO After 4 weeks patients will be switched to consolidation antibiotics: No penicillin contra-indication Amoxicillin 1g bid PO Penicillin contra-indication or intolerance Clindamycin 300mg tid PO Antibiotic treatment can be discontinued after 4 weeks when the MRONJ lesions has healed.<br>* Other names: amoxicillin;Drug: Chlorhexidine mouthwash<br>* Patients in all treatment groups will be prescribed aqueous chlorhexidine 0.12% tid rinse for 2 weeks, with subsequent switch to 0.05% for the duration of the study or until healing of the MRONJ lesion has occurred.<br>* Other names: chlorhexidine;|
| Experimental: Minimally invasive approach + LPRF<br>Amoxicillin-based antibiotics and chlorhexidine oral rinse. Minimally-invasive surgical treatment, including sequestrectomy, debridement of soft tissue, and application of LPRF membranes before tension-free wound closure is obtained. Marginal resection of all necrotic bone is not part of this treatment strategy. | Drug: Antibiotics<br>* Antibiotic treatment is the same in all groups. Monotherapy for 4 weeks with: No penicillin contra-indication Amoxicillin-clavulanate 875mg tid PO Penicillin contra-indication or intolerance Clindamycin 300mg tid PO After 4 weeks patients will be switched to consolidation antibiotics: No penicillin contra-indication Amoxicillin 1g bid PO Penicillin contra-indication or intolerance Clindamycin 300mg tid PO Antibiotic treatment can be discontinued after 4 weeks when the MRONJ lesions has healed.<br>* Other names: amoxicillin;Drug: Chlorhexidine mouthwash<br>* Patients in all treatment groups will be prescribed aqueous chlorhexidine 0.12% tid rinse for 2 weeks, with subsequent switch to 0.05% for the duration of the study or until healing of the MRONJ lesion has occurred.<br>* Other names: chlorhexidine;Procedure: Minimally invasive surgery with LPRF<br>* Minimally-invasive surgical treatment, including sequestrectomy, debridement of soft tissue, and application of LPRF membranes before tension-free wound closure is obtained. Marginal resection of all necrotic bone is not part of this treatment strategy.<br>|
| Experimental: Primary surgical management<br>Amoxicillin-based antibiotics and chlorhexidine oral rinse. Removal of the necrotic bone without excessive resection of healthy bone. Buccal mucoperiosteal flaps will be used to achieve a tension-free mucosal coverage. | Drug: Antibiotics<br>* Antibiotic treatment is the same in all groups. Monotherapy for 4 weeks with: No penicillin contra-indication Amoxicillin-clavulanate 875mg tid PO Penicillin contra-indication or intolerance Clindamycin 300mg tid PO After 4 weeks patients will be switched to consolidation antibiotics: No penicillin contra-indication Amoxicillin 1g bid PO Penicillin contra-indication or intolerance Clindamycin 300mg tid PO Antibiotic treatment can be discontinued after 4 weeks when the MRONJ lesions has healed.<br>* Other names: amoxicillin;Drug: Chlorhexidine mouthwash<br>* Patients in all treatment groups will be prescribed aqueous chlorhexidine 0.12% tid rinse for 2 weeks, with subsequent switch to 0.05% for the duration of the study or until healing of the MRONJ lesion has occurred.<br>* Other names: chlorhexidine;Procedure: Surgical resection<br>* Primary surgical management consisting of the removal of the necrotic bone without excessive resection of healthy bone. Buccal mucoperiosteal flaps will be used to achieve a tension-free mucosal coverage.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to confirmed mucosal healing | Time after randomization until the observation of healed mucosa (without presence of surgical suturing material) at the site of MRONJ, with a first observation of healed mucosa requiring confirmation after 4 weeks. | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mucosal closure | Proportion of patients with mucosal closure 6 months after randomization | 6 months | 
| Time to MRONJ healing | Time to resolution of MRONJ symptoms after start of treatment | 12 months | 
| Relapse rate of MRONJ | Incidence of patients with relapse at the site of MRONJ | 12 months | 
| Antibiotics use | Total duration of exposure to antimicrobial agents | 12 months | 
| Evolution of cancer health-related quality-of-life | Changes over time as measured with the EORTC QLQ-C30 questionnaire. | 12 months | 
| Evolution of general health status | Changes over time as measured with the EUROQOL 5D (EQ-5D-5L) questionnaire. | 12 months | 
| Evolution of oral health-specific quality-of-life | Changes over time as measured with the Oral Health Impacts Profile (OHIP-14) and the SWOG0702 Oral Health and Oral Health-related Quality of Life questionnaires. | 12 months |