Phase IIa Evaluation of Pentoxifylline, Retinol Acetate, and DL-Alpha Tocopherol Acetate in Medication-Related Osteonecrosis of the Jaw (MRONJ)

The primary objective of this study is to assess the proportion of healing in patients with **medication-related osteonecrosis of the jaw** (MRONJ) receiving the PENTO protocol. Healing is defined as achieving a bone exposure area (EBA) of less than 5 mm at 12 months. This is clinically relevant as it aims to evaluate the effectiveness of the PENTO treatment in reducing bone exposure, which is a critical factor in the management and prognosis of MRONJ.

Secondary objectives include:

• Describing the evolution of the modified SOMA score over 12 months, focusing on parameters such as pain, chewing, bone exposure size, trismus, and radiological appearance.
• Describing the evolution of nutritional parameters over 12 months, including albuminemia, pre-albuminemia, weight, and BMI.
• Following the evolution of EBA over 12 months.
• Evaluating the tolerance of the treatment by collecting adverse events over 12 months.

The clinical trial involves participants diagnosed with **medication-related osteonecrosis of the jaw**. The study population includes both male and female subjects, aged 18 years and older. Participants are required to have a history of current or past treatment with bisphosphonates, either orally or intravenously, and/or targeted therapies such as denosumab or bevacizumab. The trial does not include a vulnerable population. Participants must exhibit signs and symptoms for more than 8 weeks, with confirmation that these are not of dental origin, and must be classified as AAOMS Stage 2 MRONJ. For individuals of childbearing potential, effective contraception is mandatory. The sponsor has not provided information regarding the total number of participants in the trial.

The clinical trial is designed to evaluate the efficacy of **pentoxifylline** in the treatment of medication-related osteonecrosis of the jaw (MRONJ). This is a single-center, phase IIa trial with a randomized, double-blind, controlled design. The trial is expected to commence on February 29, 2024, and conclude by February 28, 2027. The primary objective is to assess the proportion of healing, defined as a bone exposure area (EBA) of less than 5 mm, in patients receiving the treatment over a 12-month period. The trial will involve multiple study visits, including an initial screening visit, followed by follow-up visits at 1, 3, 6, and 12 months, and an end-of-study visit at 12 months.

Participants will be involved in the study for a total duration of 12 months. The inclusion criteria require participants to be 18 years or older, have a history of treatment with bisphosphonates or targeted therapies, and present with AAOMS Stage 2 MRONJ. Effective contraception is required for participants of childbearing age. The primary endpoint is the percentage of patients achieving healing at 12 months, while secondary endpoints include the progression of the modified SOMA score, nutritional parameters, and changes in EBA dimensions. Adverse events will be monitored throughout the study, with data collected on their nature, severity, and causality.

Participants may be terminated early from the study if they experience severe adverse events or if they do not adhere to the study protocol. The trial will utilize oral administration of the investigational product, with a maximum daily dose of 800 mg for **pentoxifylline**. The study will also involve auxiliary products such as **retinol acetate** and **dl-alpha tocopherol acetate**, administered orally. The trial is not classified as a low-intervention study and is categorized under phase 2a, focusing on the therapeutic potential of the investigational product in a specific patient population.

The clinical trial involves the administration of **pentoxifylline**, a chemical-origin medication, as the primary experimental treatment. Pentoxifylline is provided in an oral pharmaceutical form, identified by the code PHF00230MIG. The maximum daily dose is 800 mg, with a total maximum dose of 292 g over a treatment period of up to 12 months. The medication is administered orally, and participant compliance is monitored throughout the trial to ensure adherence to the dosing schedule.

In addition to pentoxifylline, the trial includes the administration of **retinol acetate** and **dl-alpha tocopherol acetate** as auxiliary treatments. These substances are also of chemical origin and are provided in an oral pharmaceutical form, coded as PHF00007MIG. The maximum daily dose for these substances is 1000 mg, with a total maximum dose of 365 g over a 12-month period. The administration route is oral, and compliance is similarly monitored to maintain consistency in dosing.

The trial also incorporates **amoxicillin sodium** and **clavulanic acid** as comparator treatments. These substances are administered in an oral pharmaceutical form, identified by the code PHF00231MIG. The maximum daily dose is 3 g, with a total maximum dose of 93 g over a treatment period of up to 1 month. The administration is oral, and participant adherence to the dosing regimen is closely monitored.

Lastly, **clindamycin hydrochloride** is used as an auxiliary treatment in the trial. This chemical-origin medication is provided in an oral pharmaceutical form, coded as PHF00006MIG. The maximum daily dose is 1.2 g, with a total maximum dose of 37.2 g over a 1-month period. The route of administration is oral, and compliance monitoring is implemented to ensure proper dosing throughout the trial.

Efficacy in the clinical trial titled "The PENTO protocol in Medication-Related Osteonecrosis of the Jaw (MRONJ): a single-center phase IIa trial" will be assessed using both primary and secondary endpoints. The primary endpoint is the proportion of healing, defined as a bone exposure area (EBA) of less than 5 mm, in patients receiving PENTO for MRONJ at 12 months. This will be expressed as the percentage of patients who achieve healing at the 12-month mark.

Secondary endpoints include the progression of the modified SOMA score over 12 months, which will be evaluated at patient inclusion and during follow-up visits at 1, 3, 6, and 12 months. Additionally, the progression of nutritional parameters such as weight, BMI, albuminemia, and pre-albuminemia will be assessed at the same timepoints. Another secondary endpoint is the 12-month change in EBA dimension, quantitatively measured by the major axis of mucosal loss. This will also be assessed at patient inclusion and follow-up visits at 1, 3, 6, and 12 months. The evolution of EBA will be calculated as the relative regression of the dimension (D) defined by the formula (D at x months - D at inclusion)/D at inclusion.

Furthermore, all adverse events will be collected through questioning and blood pressure measurement at each follow-up visit, occurring at 1, 3, 6, and 12 months. Data on adverse events will include their nature, severity (mild, moderate, severe), and causality. These comprehensive assessments will provide a detailed evaluation of the efficacy of the PENTO protocol in treating MRONJ.