Pentoxifylline + Tocopherol for Osteonecrosis of the Jaw

Enrolling by invitation at 3 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: University of Washington

Must be taking: Antiresorptives

Must not be taking: Oral anticoagulants, CYP1A2 inhibitors

Disqualifiers: Radiation therapy, Cardiac arrhythmia, Renal failure, others

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 12 months

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a combination of two drugs, Pentoxifylline (also known as Trental, which improves blood flow) and Tocopherol (a form of Vitamin E), to determine if they can better treat Medication-Related Osteonecrosis of the Jaw (MRONJ) compared to the usual treatment alone. MRONJ is a painful condition where the jawbone becomes exposed. The researchers aim to find out if this new treatment can reduce the exposed bone area after a year. Individuals with MRONJ who have taken medications like bisphosphonates or RANK-L inhibitors, and who do not have a tumor in the jaw, might be suitable for this trial. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants a chance to contribute to potentially groundbreaking treatment advancements.

Will I have to stop taking my current medications?

The trial requires that you stop taking additional vitamin E if you decide to enroll. If you are taking oral anticoagulants, you cannot participate. You should also discuss with the study team if you are taking aspirin or other medications that affect blood clotting to see if the study is a good fit for you.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that using pentoxifylline and tocopherol together is generally safe for people. Studies have found that patients with medication-related osteonecrosis of the jaw (MRONJ) tolerate this treatment well.

For instance, one study found that patients taking this combination did not experience significant side effects. Another study reported that the treatment was both safe and effective in managing MRONJ.

Overall, evidence suggests that the pentoxifylline-tocopherol treatment does not pose major safety concerns for those considering joining the clinical trial. ^{1 2 3 4 5}

Why are researchers excited about this study treatment for osteonecrosis of the jaw?

Researchers are excited about the combination of pentoxifylline and tocopherol (often referred to as the PENTO regimen) for treating osteonecrosis of the jaw because it introduces a novel approach by using both an anti-inflammatory agent and a potent antioxidant. Unlike the standard care, which primarily focuses on surgical and conservative management depending on the disease stage, the PENTO regimen aims to enhance healing by improving blood flow and reducing inflammation in the affected jaw bone. This dual-action approach could potentially offer a more effective means of reducing symptoms and promoting recovery in patients with this challenging condition.

What evidence suggests that the PENTO regimen could be an effective treatment for osteonecrosis of the jaw?

Research has shown that using pentoxifylline and tocopherol together holds promise for treating medication-related osteonecrosis of the jaw (MRONJ). In this trial, participants in one arm will receive the PENTO regimen, which includes pentoxifylline and tocopherol, alongside the standard of care. Studies have found that this combination can help reduce or even eliminate exposed bone. A review found that this treatment can manage MRONJ without requiring surgery. It has also benefited patients taking osteoporosis medications. Overall, the pentoxifylline-tocopherol treatment is considered a hopeful option for MRONJ patients. ^{1 2 6 7 8}

Who Is on the Research Team?

Jasjit Dillon, DDS, MBBS

Principal Investigator

University of Washington

Are You a Good Fit for This Trial?

This trial is for individuals with Medication-related Osteonecrosis of the Jaw (MRONJ) who have been treated with antiresorptive medications. They must not have tumors in the jaw, severe heart or kidney issues, bleeding disorders, or be pregnant. Participants should not be on certain drugs like CYP1A2 inhibitors and must agree to avoid vitamin E supplements during the study.

Inclusion Criteria

I have stage 1, 2, or 3 jawbone damage related to medication use.

I do not have a tumor in my jaw.

I understand the details of the clinical trial and can agree to participate.

Exclusion Criteria

My kidneys are not working well (severe renal failure).

I am currently taking medication that affects my liver enzyme CYP1A2.

I have a heart condition related to poor blood flow.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive the PENTO regimen or standard of care for 12 months

12 months

Monthly visits for monitoring and assessment

Interim Analysis

Interim analyses are performed at 3 and 6 months to assess safety and efficacy

6 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

3 months

What Are the Treatments Tested in This Trial?

Interventions

• Pentoxifylline
• Placebo
• Tocopherol

Trial Overview The trial tests if adding Pentoxifylline and Tocopherol (PENTO) to standard care is more effective than standard care alone in reducing exposed bone areas in MRONJ patients after one year. Patients are randomly assigned to receive either PENTO plus standard care or a placebo with standard care.

How Is the Trial Designed?

Group I: Standard of Care + PENTO Experimental Treatment 2 Interventions

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

Group II: Standard of Care Placebo Group 1 Intervention

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.

Pentoxifylline is already approved in United States, Canada, European Union for the following indications:

Approved in United States as Trental for:

• Intermittent claudication

Approved in Canada as Trental for:

• Intermittent claudication

Approved in European Union as Trental for:

• Intermittent claudication

Who Is Running the Clinical Trial?

University of Washington

Lead Sponsor

Trials

1,858

Recruited

2,023,000+

University of Alabama at Birmingham

Collaborator

Trials

1,677

Recruited

2,458,000+

New York Center for Orthognathic and Maxillofacial Surgery

Collaborator

Trials

1

Recruited

100+

University of Michigan

Collaborator

Trials

1,891

Recruited

6,458,000+

Published Research Related to This Trial

In a case series of six patients with bisphosphonate-associated osteonecrosis (BON), treatment with pentoxifylline and α-tocopherol, alongside antimicrobial therapy, resulted in a significant 74% reduction in bony exposure and improved symptom control over an average follow-up of 10 months.

The findings suggest that pentoxifylline and α-tocopherol could be an effective management strategy for BON, indicating the need for further controlled trials to validate these results.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Management of bisphosphonate-associated osteonecrosis: pentoxifylline and tocopherol in addition to antimicrobial therapy. An initial case series. Epstein, MS., Wicknick, FW., Epstein, JB., et al.[2013]

In a case series of seven patients with refractory medication-related osteonecrosis of the jaw (MRONJ), treatment with pentoxifylline and tocopherol (PENT-E) over an average of 16.8 months resulted in symptom relief and radiographic evidence of new bone formation in all patients.

PENT-E was well tolerated, suggesting it may be a safe and effective adjunct treatment for managing MRONJ in patients with metastatic bone disease or multiple myeloma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pentoxifylline and tocopherol in the management of cancer patients with medication-related osteonecrosis of the jaw: an observational retrospective study of initial case series. Owosho, AA., Estilo, CL., Huryn, JM., et al.[2018]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10380687/

A Randomized Study on 202 Osteoporosis Patients - PMC As a conclusion, pentoxifylline and tocopherol protocol seems to be beneficial in the management of MRONJ patients. Keywords: osteonecrosis, ...

2. sciencedirect.com sciencedirect.com/science/article/abs/pii/S2468785524002052

Is the use of Pentoxifylline and Tocopherol effective in ... The treatment of ORN and MRONJ with pentoxifylline and tocopherol has shown good results in the studies presented, with a partial or total reduction in bone ...

3. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/31488389/

Systematic review of the use of pentoxifylline and ... Pentoxifylline and tocopherol has been demonstrated to be effective for managing MRONJ nonsurgically, and, thus, this treatment modality holds promise.

4. clinicaltrials.gov clinicaltrials.gov/study/NCT05795647

The PENTO Protocol in Medication-related Osteonecrosis ... PENTO (pentoxifylline and tocopherol) has been shown to be effective in maxillary osteoradionecrosis. The objective of this study is to evaluate the proportion ...

5. mdpi.com mdpi.com/2077-0383/14/3/974

Pharmacological Treatment of Medication-Related ... Pentoxifylline and tocopherol therapy in MRONJ was effective in patients taking oral and intravenous bisphosphonates, in patients with osteoporosis, and ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC5454806/

Pentoxifylline and Tocopherol in the Management of ... Pentoxifylline and tocopherol were found to be safe and effective in the management of medication-related osteonecrosis of the jaw. Acknowledgments. This ...

7. clinicaltrials.gov clinicaltrials.gov/study/NCT06409546

Impact of Topical Pentoxifylline and Tocopherol in ... Impact of Topical Pentoxifylline and Tocopherol in Treatment and Prevention of Medically-related Osteonecrosis of the Jaws. ClinicalTrials ...

8. sciencedirect.com sciencedirect.com/science/article/abs/pii/S000399692200053X

Effect of pentoxifylline and α-tocopherol on medication- ... Evaluate the effect of pentoxifylline and α-tocopherol administration in the prevention or treatment of medication-related jaw osteonecrosis (MRONJ).