Clinical trial NCT05664815: Human Amniotic Membrane (hAM) for Stage II Maxillomandibular Osteonecrosis Management
Official title: 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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Osteonecrosis Due to Drugs, Jaw
Lead sponsor: Centre Hospitalier Universitaire de Besancon
Sponsor class: OTHER
First posted: 2022-12-27
Enrollment: 66
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Randomization 3:1
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Number of patients with re-apparition of bone exposure
timeFrame: Between Day 1 post-surgery and Month 3 post-surgery
Secondary outcomes:
measure: Number of patient with re-opening of the scar / reappearance of the bone exposure added visually during the control visit
timeFrame: Day 0 (the day of the surgery) or Day 1 post-surgery
measure: Number of patient with re-opening of the scar / reappearance of the bone exposure added visually during the control visit
timeFrame: Visit 1 (7 to 10 days post-surgery)
measure: Number of patient with re-opening of the scar / reappearance of the bone exposure added visually during the control visit
timeFrame: Visit 2 (14 to 15 days post-surgery)
measure: Number of patient with re-opening of the scar / reappearance of the bone exposure added visually during the control visit
timeFrame: Visit 3 (One month post-surgery),
measure: Number of patient with re-opening of the scar / reappearance of the bone exposure added visually during the control visit
timeFrame: Visit 5 (6 months post-surgery)
measure: Number of patient with re-opening of the scar / reappearance of the bone exposure added visually during the control visit
timeFrame: Visit 6 (12 months post-surgery)
measure: To assess pain with Visual Analogue Scale
timeFrame: Day 0 or Day 1 (if hospitalized patient)
measure: To assess pain with Visual Analogue Scale
timeFrame: Visit 1 (7 to 10 days post-surgery)
measure: To assess pain with Visual Analogue Scale
timeFrame: Visit 2 (14 to 15 days post-surgery)
measure: To assess pain with Visual Analogue Scale
timeFrame: Visit 3 ( 1 Month post-surgery)
measure: To assess pain with Visual Analogue Scale
timeFrame: Visit 4 (3 Month post-surgery),
measure: To assess pain with Visual Analogue Scale
timeFrame: Visit 5 (6 Month post-surgery)
measure: To assess pain with Visual Analogue Scale
timeFrame: Visit 6 ( 12 Month post-surgery)
measure: Proportion of subjects with a complication at the site of mucosal healing
timeFrame: Day 0 or Day 1 post-surgery (if hospitalized patient)
measure: Proportion of subjects with a complication at the site of mucosal healing
timeFrame: visit 1 (7 to 10 days post-surgery)
measure: Proportion of subjects with a complication at the site of mucosal healing
timeFrame: Visit 2 (14 to 15 days post-surgery)
measure: Proportion of subjects with a complication at the site of mucosal healing
timeFrame: Visit 3 (Month1 post-surgery)
measure: Proportion of subjects with a complication at the site of mucosal healing
timeFrame: Visit 4 ( 3 Month post-surgery)
measure: Proportion of subjects with a complication at the site of mucosal healing
timeFrame: Visit 5 (6 Month post-surgery)
measure: Proportion of subjects with a complication at the site of mucosal healing
timeFrame: Visit 6 (Month 12 post-surgery)
measure: quality of life related to oral health
timeFrame: Day 0 or Day +1 post-surgery (if hospitalized patient)
measure: quality of life related to oral health
timeFrame: Visit1 (7 to10 days post-surgery)
measure: quality of life related to oral health
timeFrame: Visit 2 (14 to 15 days post-surgery)
measure: quality of life related to oral health
timeFrame: V3 (Month 1 post-surgery),
measure: quality of life related to oral health
timeFrame: Visit 4 ( Month 3 post-surgery)
measure: quality of life related to oral health
timeFrame: Visit 5 (Month 6 post-surgery)
measure: quality of life related to oral health
timeFrame: Visit 6 (Month 12 post-surgery)
measure: Proportion of subjects with new bone formation
timeFrame: Visit 4 (Month 3)
measure: Proportion of subjects with new bone formation
timeFrame: Visit 5 (Month 6)
Other outcomes:
Locations:
city: Besançon
country: France
facility: CHU de Besancon
city: Bordeaux
country: France
facility: CHU Bordeaux Pellegrin
city: Dijon
country: France
facility: CHU de Dijon
city: Metz
country: France
facility: CHR Metz Thionville
city: Reims
country: France
facility: CHU de Reims
Study officials:
affiliation: CHU de Besançon
name: Aurélien LOUVRIER, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: