Human Amniotic Membrane (hAM) for Stage II Maxillomandibular Osteonecrosis Management

Study Overview
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Brief Summary
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This study aims to demonstrate, during the first standard surgical management of patients with stage II MRONJ, the effect of the implantation of a cryopreserved hAM on the maxillomandibular bone, on the healing of the oral mucosa.

Detailed Description
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Medication-Related Osteonecrosis of the Jaw (MRONJ) is a complication of taking anti-tumor (anti-angiogenic) and bone anti-resorptive treatments (biphosphonates, Denosumab) which impact bone healing and renewal capacities, which can lead to bone necrosis. It affects 1 to 10% of patients and is classified into 4 stages. There is no reference document for their management, which requires antibiotics, local antiseptics and tissue debridement sometimes associated with sequestrectomy. The objective of treatment is very often to obtain healing of the oral mucosa to cover the exposed bone. Without treatment, stage II MRONJ can progress to stage III, with orostoma, pathological fractures and extra-fistula. The human amniotic membrane (hAM) has poor (even no) immunogenicity and exerts an anti-inflammatory, anti-fibrotic, antimicrobial, antiviral and analgesic effect. It is a source of multipotent stem cells and growth factors that promote tissue regeneration. A pioneering, non-comparative study reports the use of hAM in MRONJ with very encouraging results in terms of re-epithelialization, absence of pain and infection (Ragazzo 2018). Recently, the same team published a retrospective study where 49 patients (stage 1 to 3) were included, including 27 treated with hAM (Ragazzo 2021). They report a significant improvement in quality of life and pain in the treated group. hAM would provide a new approach in the treatment of stage II MRONJ by acting on: the quality and speed of mucosal healing, pain, even infection and regeneration of the underlying bone. This study aims to demonstrate, during the first standard surgical management of patients with stage II MRONJ, the effect of the implantation of a cryopreserved hAM on the maxillomandibular bone, on the healing of the oral mucosa three months after the operation. In second objectives will be evaluated: pain, complications at the site of healing of the mucosa (erythema, abscess, purulent discharge, diffuse infection of soft tissues (cellulitis), orostoma, suborbital abscess, mandibular fracture), oral health -dental/quality of life and new bone formation at subsequent visits.

Official Title
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Benefit of Cryopreserved Human Amniotic Membrane (hAM) on Oral Mucosal Healing Among Patients With Stage II Maxillomandibular Osteonecrosis Induced by Antiresorptive and/or Anti-angiogenic Therapies: a Phase II Randomized Trial

Conditions
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Osteonecrosis Due to Drugs, Jaw

Intervention / Treatment
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* Biological: Human Amniotic Membrane
* Other: Conventional/Standard treatment


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA Men and women over the age of 18 Patient treated in the context of a tumor pathology during which he received treatment with bisphosphonates, Denosumab or anti-angiogenics, and/or, very often, switch of treatment or combination. Current treatment or mention of treatment in patient history MRONJ stage II certified clinically and radiologically. Also in the maxilla, stage II MRONJ without bucco-sinus communication after excision of the necrotic bone. Similarly, if a tooth with antral roots must be extracted and creates a bucco-sinus communication, if a MRONJ results, it will be stage II Patients with stage II MRONJ of childbearing age with current contraception or patients already postmenopausal Signature of the informed consent to participate indicating that the subject has understood the purpose and the procedures required by the study, that he agrees to participate in the study as well as to comply with the requirements and restrictions inherent in this study Affiliation to a French social security scheme or beneficiary of such a scheme NON-INCLUSION CRITERIA Life expectancy of less than 6 months assessed by oncologists Existence of an evolving cervico-facial neoplasia or an evolving oral neoplastic process informed by oncologists History of oral and/or cervico-facial radiotherapy Allergy to one of these two antibiotics: amoxicillin-clavulanic acid or clindamycin-metronidazole combination Patient contraindicated for surgery due to his state of health, with general anesthesia or local anesthesia. MRONJ stage I and stage III Stage II MRONJ in patients with only osteoporosis Patients receiving treatments that may affect bone and/or mucous tissue as well as their metabolism: Patients on long-term corticosteroid therapy or immunosuppressants Patients with other diseases that may affect bone and/or mucous tissue as well as their metabolism: Bone diseases (such as brittle bone disease or Osteogenesis imperfecta, primary bone tumors in the maxilla or mandible (osteosarcoma, sarcoma, rhabdomyosarcoma ,…), any other malignant bone tumour; metabolic diseases with bone repercussions (Paget's disease, osteomalacia,…) Patients of childbearing age without contraception Legal incapacity or limited legal capacity Subject unlikely to cooperate in the study and/or low cooperation anticipated by the investigator Subject not affiliated to a social security scheme Patient under guardianship, curatorship or imprisonment Patient who notified his refusal to participate in the research Patient who participates in another clinical research EXCLUSION CRITERIA During surgery: Discovery of an interrupting MRONJ with damage to the basilar edge (which corresponds to stage III). During surgery: Following a sequestrectomy discovery of spontaneous or ongoing healing. During the inclusion period: Patient to benefit from invasive dental surgeries directly related to bone exposure and in conjunction with taking risky molecules (factors favoring the occurrence of MRONJ): dental avulsions, curettage apical granulomas or cysts, endodontic treatments, or alveolar bone procedure (regularization of ridges). During the inclusion period: Patient with metastases all over the mandible. During the inclusion period: State of health of the patient which deteriorates due to his cancer during the inclusion period.

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
Interventional Model Description: Randomization 3:1
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Application of human amniotic membrane (hAM)<br>After conventional/standard treatment, hAM will be applied in a single layer against the bone defect before closure. | Biological: Human Amniotic Membrane<br>* After conventional/standard treatment, hAM will be applied in a single layer against the bone defect with, if possible, a burial of a few millimeters under the mucous edges. With the idea of apprehending a possible dose effect, the hAM will be adapted to the size of the bone/mucous defect, mesenchymal side against the bone. For closure after hAM grafting : 2 options are possible: Edge-to-edge closure if sufficient mucosal laxity, Edge rapprochement by cross points. If necessary: possible incision of the periosteum to give laxity to the mucosa.<br>* Other names: amnion;|
| Active Comparator: Conventional/standard treatment<br>Conventional/standard surgery. | Other: Conventional/Standard treatment<br>* Surgical procedure: Endo-oral approach: Trimming of the mucous edges if they are necrotic or inflamed (granulation tissue) For the bone: either simple sequestrectomy (the mobile sequestered bone is grabbed using forceps); either reaming until bleeding is obtained; either resection with the rongeur; either monobloc resection of the entire necrotic fragment with a saw or with a piezzotome (ultrasound); or a combination of different techniques. Rq: the resection of the necrotic bone (according to the practices of the center) will operate until the appearance of an apparently healthy bone (bone bleeding, clean appearance of the bone site) Closure of the mucosa with possible incision of the periosteum to provide laxity: Suture points by points separated in one plane with non-absorbable braided thread of the 3.0 silk thread type and round needle.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of patients with re-apparition of bone exposure | Number of patients with re-apparition of bone exposure visually observed by the surgeon. Clinical examination: reopening of the scar / reappearance of exposed bone / taking a photograph of the treated area | Between Day 1 post-surgery and Month 3 post-surgery | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of patient with re-opening of the scar / reappearance of the bone exposure added visually during the control visit | Re-apparition of bone exposure visually observed by the surgeon. Clinical examination: reopening of the scar / reappearance of exposed bone / taking a photograph of the treated area | Day 0 (the day of the surgery) or Day 1 post-surgery | 
| Number of patient with re-opening of the scar / reappearance of the bone exposure added visually during the control visit | Re-apparition of bone exposure visually observed by the surgeon. Clinical examination: reopening of the scar / reappearance of exposed bone / taking a photograph of the treated area | Visit 1 (7 to 10 days post-surgery) | 
| Number of patient with re-opening of the scar / reappearance of the bone exposure added visually during the control visit | Re-apparition of bone exposure visually observed by the surgeon. Clinical examination: reopening of the scar / reappearance of exposed bone / taking a photograph of the treated area | Visit 2 (14 to 15 days post-surgery) | 
| Number of patient with re-opening of the scar / reappearance of the bone exposure added visually during the control visit | Re-apparition of bone exposure visually observed by the surgeon. Clinical examination: reopening of the scar / reappearance of exposed bone / taking a photograph of the treated area | Visit 3 (One month post-surgery), | 
| Number of patient with re-opening of the scar / reappearance of the bone exposure added visually during the control visit | Re-apparition of bone exposure visually observed by the surgeon. Clinical examination: reopening of the scar / reappearance of exposed bone / taking a photograph of the treated area | Visit 5 (6 months post-surgery) | 
| Number of patient with re-opening of the scar / reappearance of the bone exposure added visually during the control visit | Re-apparition of bone exposure visually observed by the surgeon. Clinical examination: reopening of the scar / reappearance of exposed bone / taking a photograph of the treated area | Visit 6 (12 months post-surgery) | 
| To assess pain with Visual Analogue Scale | Pain assessed by a Visual Analogue Scale (VAS). This EVA scale will be supplemented by a collection of information on the use of analgesics if necessary. Also patients who would have to take analgesics will fill out a logbook which will specify the class of the drug and the dosage. | Day 0 or Day 1 (if hospitalized patient) | 
| To assess pain with Visual Analogue Scale | Pain assessed by a Visual Analogue Scale (VAS). This EVA scale will be supplemented by a collection of information on the use of analgesics if necessary. Also patients who would have to take analgesics will fill out a logbook which will specify the class of the drug and the dosage. | Visit 1 (7 to 10 days post-surgery) | 
| To assess pain with Visual Analogue Scale | Pain assessed by a Visual Analogue Scale (VAS). This EVA scale will be supplemented by a collection of information on the use of analgesics if necessary. Also patients who would have to take analgesics will fill out a logbook which will specify the class of the drug and the dosage. | Visit 2 (14 to 15 days post-surgery) | 
| To assess pain with Visual Analogue Scale | Pain assessed by a Visual Analogue Scale (VAS). This EVA scale will be supplemented by a collection of information on the use of analgesics if necessary. Also patients who would have to take analgesics will fill out a logbook which will specify the class of the drug and the dosage. | Visit 3 ( 1 Month post-surgery) | 
| To assess pain with Visual Analogue Scale | Pain assessed by a Visual Analogue Scale (VAS). This EVA scale will be supplemented by a collection of information on the use of analgesics if necessary. Also patients who would have to take analgesics will fill out a logbook which will specify the class of the drug and the dosage. | Visit 4 (3 Month post-surgery), | 
| To assess pain with Visual Analogue Scale | Pain assessed by a Visual Analogue Scale (VAS). This EVA scale will be supplemented by a collection of information on the use of analgesics if necessary. Also patients who would have to take analgesics will fill out a logbook which will specify the class of the drug and the dosage. | Visit 5 (6 Month post-surgery) | 
| To assess pain with Visual Analogue Scale | Pain assessed by a Visual Analogue Scale (VAS). This EVA scale will be supplemented by a collection of information on the use of analgesics if necessary. Also patients who would have to take analgesics will fill out a logbook which will specify the class of the drug and the dosage. | Visit 6 ( 12 Month post-surgery) | 
| Proportion of subjects with a complication at the site of mucosal healing | On examination of the area of interest, during each visit, search for the presence of: Minor complications: pain and/or erythema and/or abscess and/or purulent discharge, Major complications: diffuse soft tissue infection (cellulitis), orostoma, suborbital abscess, mandibular fracture. | Day 0 or Day 1 post-surgery (if hospitalized patient) | 
| Proportion of subjects with a complication at the site of mucosal healing | On examination of the area of interest, during each visit, search for the presence of: Minor complications: pain and/or erythema and/or abscess and/or purulent discharge, Major complications: diffuse soft tissue infection (cellulitis), orostoma, suborbital abscess, mandibular fracture. | visit 1 (7 to 10 days post-surgery) | 
| Proportion of subjects with a complication at the site of mucosal healing | On examination of the area of interest, during each visit, search for the presence of: Minor complications: pain and/or erythema and/or abscess and/or purulent discharge, Major complications: diffuse soft tissue infection (cellulitis), orostoma, suborbital abscess, mandibular fracture. | Visit 2 (14 to 15 days post-surgery) | 
| Proportion of subjects with a complication at the site of mucosal healing | On examination of the area of interest, during each visit, search for the presence of: Minor complications: pain and/or erythema and/or abscess and/or purulent discharge, Major complications: diffuse soft tissue infection (cellulitis), orostoma, suborbital abscess, mandibular fracture. | Visit 3 (Month1 post-surgery) | 
| Proportion of subjects with a complication at the site of mucosal healing | On examination of the area of interest, during each visit, search for the presence of: Minor complications: pain and/or erythema and/or abscess and/or purulent discharge, Major complications: diffuse soft tissue infection (cellulitis), orostoma, suborbital abscess, mandibular fracture. | Visit 4 ( 3 Month post-surgery) | 
| Proportion of subjects with a complication at the site of mucosal healing | On examination of the area of interest, during each visit, search for the presence of: Minor complications: pain and/or erythema and/or abscess and/or purulent discharge, Major complications: diffuse soft tissue infection (cellulitis), orostoma, suborbital abscess, mandibular fracture. | Visit 5 (6 Month post-surgery) | 
| Proportion of subjects with a complication at the site of mucosal healing | On examination of the area of interest, during each visit, search for the presence of: Minor complications: pain and/or erythema and/or abscess and/or purulent discharge, Major complications: diffuse soft tissue infection (cellulitis), orostoma, suborbital abscess, mandibular fracture. | Visit 6 (Month 12 post-surgery) | 
| quality of life related to oral health | Oral health impact profile OHIP 14 quality of life score | Day 0 or Day +1 post-surgery (if hospitalized patient) | 
| quality of life related to oral health | Oral health impact profile OHIP 14 quality of life score | Visit1 (7 to10 days post-surgery) | 
| quality of life related to oral health | Oral health impact profile OHIP 14 quality of life score | Visit 2 (14 to 15 days post-surgery) | 
| quality of life related to oral health | Oral health impact profile OHIP 14 quality of life score | V3 (Month 1 post-surgery), | 
| quality of life related to oral health | Oral health impact profile OHIP 14 quality of life score | Visit 4 ( Month 3 post-surgery) | 
| quality of life related to oral health | Oral health impact profile OHIP 14 quality of life score | Visit 5 (Month 6 post-surgery) | 
| quality of life related to oral health | Oral health impact profile OHIP 14 quality of life score | Visit 6 (Month 12 post-surgery) | 
| Proportion of subjects with new bone formation | Presence of newly formed bone assessed by cone-beam imaging | Visit 4 (Month 3) | 
| Proportion of subjects with new bone formation | Presence of newly formed bone assessed by cone-beam imaging | Visit 5 (Month 6) |