Efficacy of Denosumab in Treating Acute Charcot Neuroarthropathy in Diabetic Patients: A Multicenter, Double-Blind, Randomized, Placebo-Controlled Trial

The primary objective of the DENOCHARCOT trial is to evaluate the **efficacy** of treatment with **denosumab** (Prolia®) in patients with **diabetic acute Charcot foot** (Charcot neuroarthropathy). This study is designed as a multicenter, double-blind, randomized, placebo-controlled trial. The clinical relevance of this objective lies in determining whether denosumab can effectively improve clinical outcomes in this patient population, potentially offering a new therapeutic option for managing this debilitating condition.

The clinical trial involves participants diagnosed with **diabetic acute Charcot foot**. The study population includes both male and female subjects, aged between 18 and 80 years, who have been diagnosed with either type 1 or type 2 diabetes for more than three months. Participants must have a unilateral red, swollen, and warm foot, with a skin temperature difference of more than 2 °C compared to the unaffected foot, and signs of Charcot on imaging studies such as x-rays, MRI, bone scintigram, or PET/CT. Additionally, participants must have peripheral neuropathy, either previously diagnosed or confirmed by biothesiometry readings greater than 25 V or a lack of sensation of a 10-gram monofilament on the first toe of the affected foot. The trial does not involve a vulnerable population. The sponsor has not provided information regarding the total number of participants or specific lifestyle considerations such as diet or physical activity.

The clinical trial is designed to evaluate the efficacy of **denosumab** in treating diabetic acute Charcot foot, also known as Charcot neuroarthropathy. This study is a multicenter, double-blind, randomized, placebo-controlled trial. Participants will be randomly assigned to receive either the active treatment, Prolia 60 mg solution for injection in a pre-filled syringe, or a placebo, which is 1 ml saline, sodium chloride 9 mg/ml for subcutaneous injection. The trial is expected to run from December 2020 to December 2027, with the primary objective being the assessment of the time to clinical remission of the acute Charcot foot.

Participants will be involved in the study for a maximum treatment period of 12 months. The study will include several key visits: an initial screening visit to confirm eligibility, regular follow-up visits to monitor progress, and an end-of-study visit to assess the final outcomes. The inclusion criteria require participants to be aged 18-80 years, have type 1 or type 2 diabetes for more than three months, and be diagnosed with acute Charcot foot characterized by a unilateral red, swollen, and warm foot with a temperature difference of more than 2°C compared to the unaffected foot. Peripheral neuropathy must also be present.

The primary endpoint is the time from the first injection until the acute Charcot foot is clinically healed, defined by a temperature difference of less than 2 degrees Celsius compared to the contralateral foot, with subsided edema and redness at two subsequent visits four weeks apart. Secondary endpoints include the fraction of clinically healed participants at each visit, healing observed on imaging modalities, and the number of relapses requiring off-loading with a cast. Participants may be withdrawn from the study if they experience adverse events, fail to comply with the study protocol, or withdraw consent. The trial aims to provide valuable insights into the treatment of diabetic acute Charcot foot with denosumab.

The clinical trial involves the administration of **Prolia**, a pharmaceutical product containing the active substance **denosumab**. Prolia is provided as a **solution for injection** in a pre-filled syringe, with a concentration of 60 mg per syringe. The medication is administered via **subcutaneous injection**. The dosing schedule for Prolia in this trial is a maximum of 60 mg per day, with a total maximum dose of 120 mg over the treatment period. The treatment duration is set for a maximum of 12 months. The active substance, denosumab, is a protein of other origin, and the product is manufactured by Amgen Europe B.V. Compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the protocol.

The trial also includes a **placebo** control, which consists of 1 ml saline, sodium chloride 9 mg/ml, provided by Fresenius Kabi. This placebo is intended for subcutaneous injection, mirroring the administration route of the experimental treatment. The placebo serves as a comparator to evaluate the efficacy of Prolia in the treatment of acute Charcot foot in patients with diabetes. The use of a placebo control is integral to maintaining the double-blind nature of the trial, ensuring that neither the participants nor the investigators are aware of the treatment assignments, thereby reducing bias in the assessment of outcomes.

The efficacy of the treatment in the clinical trial titled "The DENOCHARCOT trial" will be assessed through both primary and secondary endpoints. The primary endpoint is defined as the time from the first injection of the investigational product until the acute **Charcot foot** is clinically healed or in remission. This is determined by a temperature difference of less than 2 degrees Celsius at the site of maximum temperature on the affected Charcot foot compared to the similar site on the contralateral foot. This measurement will be conducted using an infrared thermometer, and the remission is confirmed when edema and redness of the skin have subsided at two subsequent visits, each 4 weeks apart.

Secondary endpoints include the fraction of clinically healed participants at each study visit, the fraction of healing observed on X-rays and MRI (or PET/CT or Scintigram) at the time of clinical healing and at the end of the trial, and the number of relapses, which are defined as the need for or prescription of off-loading with a cast of the Charcot foot again. These assessments will provide a comprehensive evaluation of the treatment's efficacy in managing acute Charcot foot in patients with diabetes.