The PENTO Protocol in Medication-related Osteonecrosis of the Jaw (PENTO)

Medication-related osteonecrosis of the jaw (MRONJ) occurs after taking bisphosphonates or targeted therapies. It leads to a significant decrease in quality of life with pain, eating and chewing disorders, and malnutrition. Current treatments are only partially effective. PENTO (pentoxifylline and tocopherol) has been shown to be effective in maxillary osteoradionecrosis. The objective of this study is to evaluate the proportion of bone recovery in patients receiving PENTO in MRONJ at 12 months.

Study Overview

• Status: Recruiting
• Conditions: Medication-related Osteonecrosis of the Jaw (MRONJ)
• Intervention / Treatment: Drug: Pentoxifylline+Tocopherol

Detailed Description

MRONJ is defined as intraoral bone exposure persisting for more than 8 weeks after taking an anti-resorptive agent (per os or IV bisphosphonates, targeted therapies) and without history of maxilla radiotherapy or metastasis. It leads to a significant decrease in quality of life with significant pain at rest and during mastication, and compromised nutrition, sometimes resulting in severe undernutrition in patients already weakened by a history of cancer. Current treatments (prolonged antibiotic therapy, repeated bone curettage) have shown partial effectiveness. PENTO (combination of pentoxifylline, a vasodilator, and tocopherol, vitamin E) has been shown to significantly reduce intraoral exposed bone surface area and pain in maxilla osteoradionecrosis. All studies conducted so far on PENTO in MRONJ are retrospective or involve small samples. Therefore, our idea is to perform a well-conducted prospective phase IIa study to prove the efficacy of PENTO, with a larger sample size and identical follow-up periods. The investigators will study patients with AAOMS stage 2 MRONJ (exposed bone in symptomatic patients, without pathologic fracture).

Treatment will consist of pentoxifylline LP 400 mg morning and evening, combined with tocopherol 500 mg morning and evening. Antibiotic therapy with Augmentin (or clindamycin) will be added for the first month and then punctually if signs of local infection appear.

The primary and secondary endpoints will be assessed at inclusion and at 1, 3, 6 and 12 months.

• Study Type: Interventional
• Enrollment (Estimated): 17
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Julie USSEGLIO, Dr; Phone Number: +33 (0) 555 056 120; Email: julie.usseglio@chu-limoges.fr

Study Locations

• France
  • Limoges, France, 87042
    • Recruiting
    • Limoges University Hospital
    • Contact: Julie USSEGLIO, MD; Email: julie.usseglio@chu-limoges.fr
    • Principal Investigator: Julie USSEGLIO, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Age greater than or equal to 18 years
• Current or past treatment with bisphosphonates (oral or IV) and/or targeted therapies (denosumab, bevacizumab)
• Signs and symptoms for more than 8S with confirmation that the signs and symptoms are not of dental origin
• AAOMS Stage 2 MRONJ
• For patients of childbearing age, effective contraception is required

Exclusion Criteria:

• History of head or neck radiotherapy or maxilla metastases
• Patients who have received treatment in the past (PENTO or PENTOCLO protocol)
• Patients who have undergone surgery for their MRONJ within the last 3 months
• Pregnant or wishing to be pregnant, breastfeeding
• Patient under palliative care
• Patient with hypersensitivity to pentoxifylline or tocopherol or to an excipient
• History of hypersensitivity reaction to penicillins, cephalosporins, or other beta-lactams (and clindamycin or lincomycin if applicable) or excipient of amoxicillin-a. clavulanic or clindamycin
• History of jaundice/hepatic injury related to amoxicillin/clavulanic acid
• Patient taking oral anticoagulants, or with a history of major bleeding or bleeding disorders
• Patient taking platelet aggregation inhibitor, theophylline or aminophylline
• Patient taking methotrexate, probenecid, mycophenolate mofetil, myorelaxant drugs, macrolide or streptogramin antibiotics
• Patients with hepatic failure or renal failure (Cl < 30 mL/min),
• Patient with hypotension (SBP < 90 mmHg)
• Refusal to participate in the study
• Patient participating in other interventional research that may interfere with the conduct of this research
• Patient unable to understand the protocol
• Patient under curatorship or guardianship

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Pentoxifylline; Treatment will consist of pentoxifylline LP 400 mg morning and evening, combined with tocopherol 500 mg morning and evening	Drug: Pentoxifylline+Tocopherol; Treatment will consist of pentoxifylline LP 400 mg morning and evening, combined with tocopherol 500 mg morning and evening

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Exposure bone area (EBA)	exposure bone area (EBA) less than 5 mm at 12 months. It will be expressed as the percentage of patients who achieved healing (EBA < 5 mm) at 12 months.	Month 12

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
SOMA score	describe the evolution of the modified SOMA score (pain, chewing, bone exposure size, trismus, radiological appearance)	Month 1, Month 3, Month 6, Month 12
Nutritional parameters evolution (albuminemia)	describe the nutritional parameters evolution albuminemia	Month 1, Month 3, Month 6, Month 12
Nutritional parameters evolution (pre-albuminemia)	describe the nutritional parameters evolution pre-albuminemia	Month 1, Month 3, Month 6, Month 12
Nutritional parameters evolution (weight)	describe the nutritional parameters evolution weight	Month 1, Month 3, Month 6, Month 12
Nutritional parameters evolution (BMI)	describe the nutritional parameters evolution BMI	Month 1, Month 3, Month 6, Month 12
Exposure bone area (EBA)	describe the evolution of the exposure bone area (EBA)	Month 1, Month 3, Month 6, Month 12
Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability])	description of adverse events	Month 1, Month 3, Month 6, Month 12

Collaborators and Investigators

• Sponsor: University Hospital, Limoges
• Investigators: Principal Investigator: Julie USSEGLIO, Dr, University Hospital, Limoges

Study record dates

Study Major Dates

• Study Start (Actual): February 29, 2024
• Primary Completion (Estimated): April 7, 2025
• Study Completion (Estimated): April 7, 2025

Study Registration Dates

• First Submitted: December 14, 2022
• First Submitted That Met QC Criteria: March 20, 2023
• First Posted (Actual): April 3, 2023

Study Record Updates

• Last Update Posted (Actual): March 12, 2024
• Last Update Submitted That Met QC Criteria: March 11, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: pentoxifylline; MRONJ; tocophérol; bone exposure; renutrition
• Additional Relevant MeSH Terms: Pathologic Processes; Necrosis; Musculoskeletal Diseases; Bone Diseases; Osteonecrosis; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Enzyme Inhibitors; Platelet Aggregation Inhibitors; Protective Agents; Micronutrients; Vitamins; Antioxidants; Phosphodiesterase Inhibitors; Free Radical Scavengers; Radiation-Protective Agents; Vitamin E; Tocopherols; alpha-Tocopherol; Tocotrienols; Pentoxifylline
• Other Study ID Numbers: 87RI21_0052 (PENTO)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No