Pentoxifylline and Tocopherol (PENTO) in the Treatment of Medication-related Osteonecrosis of the Jaw (MRONJ)

NCT03040778 | Active Not Recruiting Phase 3 DMC FDA Drug

• 1 other identifier: STUDY00004779
• Study Type: interventional
• Target: 100
• Locations: 1 country
• Sites: 4

Brief Summary

The overall purpose of this project is to answer the following clinical question: Among Medication-Related Osteonecrosis of the Jaw (MRONJ) patients, do those who are treated with the Pentoxifylline and Tocopherol (PENTO) regimen and standard of care, when compared to those treated with standard of care alone, have decreased areas of exposed bone after one year of treatment?

Conditions

Medication-related Osteonecrosis of the Jaw; Bisphosphonate-related Osteonecrosis of the Jaw; Avascular Necrosis

Keywords

MRONJ; BRONJ

Outcome Measures

Primary Outcomes (1)

• Change in Bone exposure area (mm^2)

  The primary lesion's area of exposed bone will be estimated by measuring the greatest anterior-posterior and superior-inferior dimensions in millimeters (mm) of the site with the largest area of exposed bone present at the time of study enrollment. If there are multiple areas of exposed bone in a single patient, the site with the largest sum of linear anterior-posterior and superior-inferior dimensions will be included in the study.

  0 months, 1 month, 3 months, 6 months, 9 months, 12 months

Secondary Outcomes (5)

• Change in MRONJ Stage

  0 months, 1 month, 3 months, 6 months, 9 months, 12 months

• Change in Pain

  0 months, 1 month, 3 months, 6 months, 9 months, 12 months

• Change in osseous anterior-posterior linear dimension on orthopantomogram

  0 months, 1 month, 3 months, 6 months, 9 months, 12 months

• Change in osseous superior-inferior linear dimension on orthopantomogram

  0 months, 1 month, 3 months, 6 months, 9 months, 12 months

• Change in osseous area on orthopantomogram

  0 months, 1 month, 3 months, 6 months, 9 months, 12 months

Study Arms (2)

Standard of Care + PENTO

EXPERIMENTAL

The current standard of care for MRONJ as outlined by the American Association of Oral and Maxillofacial Surgeons position paper based on stage of disease (Ruggiero 2014) AND PENTO regimen consisting of 400mg pentoxifylline (PTX) and 400IU tocopherol twice-daily PO for a total of 800mg/day PTX and 800 IU/day tocopherol

Drug: Pentoxifylline; Drug: Tocopherol

Standard of Care

PLACEBO COMPARATOR

The current standard of care for MRONJ as outlined by the American Association of Oral and Maxillofacial Surgeons position paper based on stage of disease (Ruggiero 2014). Placebo drugs to be taken in the control group 2 pills BID.

Drug: Placebo

Interventions

Pentoxifylline DRUG

Pentoxifylline is a commonly used medication for muscle pain associated with peripheral artery disease. It is a methylated xanthine derivative that improves peripheral blood flow, flexibility of red blood cell membranes, microcirculation, and tissue oxygenation and reduces viscosity of blood.

Also known as: Pentoxifylline SR, Trental, Oxpentifylline

Standard of Care + PENTO

Placebo DRUG

Placebo tablets

Standard of Care

Tocopherol DRUG

Tocopherol (vitamin E) impairs tissue fibrosis and is a potent oxygen radical scavenger that may reduce damage caused by free radicals impacting necrosis.

Also known as: Vitamin E

Standard of Care + PENTO

Eligibility Criteria

• Age: 18 Years - 90 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Stage 1, 2, or 3 MRONJ as defined by the AAOMS Position Paper on Medication-Related Osteonecrosis of the Jaw-2014 Update (Ruggiero 2014).
• History of exposure to antiresorptive medications such as bisphosphonates or RANK-L inhibitors
• Absence of tumor in the jaw at the time of recruitment
• Patients with the capacity to give informed consent

You may not qualify if:

• Patients with history of external radiation therapy to the jaws
• Patients who underwent any surgical intervention for MRONJ in the past 4 months
• Patients with past microvascular reconstruction of the head and neck
• Patients with an expected survival less than 1 year
• Patients with allergy or hypersensitivity to pentoxifylline, xanthines, or tocopherol
• Patients with planned invasive dental procedure in the next year
• Patients taking oral anticoagulants
• Patients with known hemorrhagic and coagulation disorder
• Patients with a vitamin K deficiency due to any cause
• Female patients who are pregnant or lactating
• Patients with history of serious bleeding or extensive retinal hemorrhage
• Patients with ischemic heart diseases, including, but not limiting, recent myocardial infarction
• Patients with serious cardiac arrhythmia
• Patients with severe liver disease
• Patients with severe renal failure (Creatinine clearance \<30 mL/min)

Sponsors & Collaborators

• University of Washington: lead
• University of Alabama at Birmingham: collaborator
• New York Center for Orthognathic and Maxillofacial Surgery: collaborator
• University of Michigan: collaborator

Study Sites (4)

University of Alabama at Birmingham

Birmingham, Alabama, 35242, United States

Location

University of Michigan

Ann Arbor, Michigan, 48109-0018, United States

Location

New York Center for Orthognathic and Maxillofacial Surgery

Lake Success, New York, 11042, United States

Location

University of Washington

Seattle, Washington, 98195, United States

Location

Related Publications (9)

• Delanian S, Chatel C, Porcher R, Depondt J, Lefaix JL. Complete restoration of refractory mandibular osteoradionecrosis by prolonged treatment with a pentoxifylline-tocopherol-clodronate combination (PENTOCLO): a phase II trial. Int J Radiat Oncol Biol Phys. 2011 Jul 1;80(3):832-9. doi: 10.1016/j.ijrobp.2010.03.029. Epub 2010 Jul 16.

  PMID: 20638190 BACKGROUND

• Delanian S, Depondt J, Lefaix JL. Major healing of refractory mandible osteoradionecrosis after treatment combining pentoxifylline and tocopherol: a phase II trial. Head Neck. 2005 Feb;27(2):114-23. doi: 10.1002/hed.20121.

  PMID: 15641107 BACKGROUND

• Epstein MS, Wicknick FW, Epstein JB, Berenson JR, Gorsky M. Management of bisphosphonate-associated osteonecrosis: pentoxifylline and tocopherol in addition to antimicrobial therapy. An initial case series. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2010 Nov;110(5):593-6. doi: 10.1016/j.tripleo.2010.05.067.

  PMID: 20955948 BACKGROUND

• Magremanne M, Reychler H. Pentoxifylline and tocopherol in the treatment of yearly zoledronic acid-related osteonecrosis of the jaw in a corticosteroid-induced osteoporosis. J Oral Maxillofac Surg. 2014 Feb;72(2):334-7. doi: 10.1016/j.joms.2013.06.188. Epub 2013 Jul 25.

  PMID: 23891014 BACKGROUND

• McLeod NM, Pratt CA, Mellor TK, Brennan PA. Pentoxifylline and tocopherol in the management of patients with osteoradionecrosis, the Portsmouth experience. Br J Oral Maxillofac Surg. 2012 Jan;50(1):41-4. doi: 10.1016/j.bjoms.2010.11.017. Epub 2011 Jan 19.

  PMID: 21247671 BACKGROUND

• Ruggiero SL, Dodson TB, Fantasia J, Goodday R, Aghaloo T, Mehrotra B, O'Ryan F; American Association of Oral and Maxillofacial Surgeons. American Association of Oral and Maxillofacial Surgeons position paper on medication-related osteonecrosis of the jaw--2014 update. J Oral Maxillofac Surg. 2014 Oct;72(10):1938-56. doi: 10.1016/j.joms.2014.04.031. Epub 2014 May 5.

  PMID: 25234529 BACKGROUND

• Delanian S, Lefaix JL, Maisonobe T, Salachas F, Pradat PF. Significant clinical improvement in radiation-induced lumbosacral polyradiculopathy by a treatment combining pentoxifylline, tocopherol, and clodronate (Pentoclo). J Neurol Sci. 2008 Dec 15;275(1-2):164-6. doi: 10.1016/j.jns.2008.08.004. Epub 2008 Sep 19.

  PMID: 18804790 BACKGROUND

• Delanian S, Porcher R, Rudant J, Lefaix JL. Kinetics of response to long-term treatment combining pentoxifylline and tocopherol in patients with superficial radiation-induced fibrosis. J Clin Oncol. 2005 Dec 1;23(34):8570-9. doi: 10.1200/JCO.2005.02.4729. Epub 2005 Oct 31.

  PMID: 16260695 BACKGROUND

• Beth-Tasdogan NH, Mayer B, Hussein H, Zolk O, Peter JU. Interventions for managing medication-related osteonecrosis of the jaw. Cochrane Database Syst Rev. 2022 Jul 12;7(7):CD012432. doi: 10.1002/14651858.CD012432.pub3.

  PMID: 35866376 DERIVED

MeSH Terms

Conditions

Bisphosphonate-Associated Osteonecrosis of the Jaw; Osteonecrosis

Interventions

Pentoxifylline; Tocopherols; Vitamin E

Condition Hierarchy (Ancestors)

Bone Diseases; Musculoskeletal Diseases; Jaw Diseases; Stomatognathic Diseases; Necrosis; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Theobromine; Xanthines; Purinones; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Benzopyrans; Pyrans; Heterocyclic Compounds, 1-Ring

Study Officials

• Jasjit Dillon, DDS, MBBS

  University of Washington

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor & Chief, Program Director, Oral & Maxillofacial Surgery

Study Record Dates

• First Submitted: January 30, 2017
• First Posted: February 2, 2017
• Study Start: April 1, 2018
• Primary Completion: May 1, 2026
• Study Completion (Estimated): June 30, 2026
• Last Updated: April 29, 2026

Record last verified: 2026-04

Data Sharing

• IPD Sharing: Will not share

Locations

US (4)