Evaluation of Denosumab in the Management of Fibrous Dysplasia/McCune-Albright Syndrome in Adults: A Randomized, Double-Blind, Placebo-Controlled Trial

The primary objective of this study is to evaluate the effect of **Denosumab** on pain in patients with **Fibrous dysplasia/McCune-Albright syndrome**. This is assessed by measuring the difference in maximum pain scores after a 6-month period, during which two injections are administered. This objective is clinically relevant as it aims to determine the efficacy of Denosumab in managing pain, a significant symptom impacting the quality of life in affected individuals.

Secondary objectives include:

• Evaluation of Denosumab's effect on quality of life and physical activity.
• Assessment of a possible neuropathic component in the reported pain.
• Evaluation of analgesics use.
• Assessment of changes in mobility.
• Evaluation of Denosumab's effect on fibrous dysplasia lesion size and activity.
• Assessment of Denosumab's effect on bone density.

These secondary objectives aim to provide a comprehensive understanding of Denosumab's impact on various clinical aspects of the disease, potentially guiding future therapeutic strategies.

The clinical trial involves participants diagnosed with **fibrous dysplasia/McCune-Albright syndrome**. The study population includes both male and female subjects, with an age range of 18 years and older, as indicated by the requirement for closed growth plates. Participants are selected based on symptomatic presentation and specific pain criteria, including a pain score of 4 or higher on the Visual Analogue Scale (VAS) for fibrous dysplasia lesions. The trial does not involve a vulnerable population. Participants must have normal levels of calcium, parathyroid hormone, and vitamin D, with supplementation allowed, and must have treated hypophosphatemia. Good dental health is also a requirement, with a dental check-up within the last 12 months. The sponsor has not provided information regarding the total number of participants in the trial.

The clinical trial is designed to evaluate the effect of **Denosumab** on pain in patients with **Fibrous Dysplasia/McCune-Albright Syndrome**. This study is a randomized, double-blind, placebo-controlled trial, ensuring that neither the participants nor the researchers know who is receiving the treatment or placebo, thus minimizing bias. The trial is expected to last until June 30, 2025, with recruitment having started on June 13, 2023. Participants will be involved for a maximum of 12 months, with the possibility of early termination if they experience adverse effects or fail to comply with the study protocol.

The sequence of study visits begins with an inclusion (screening) visit, where eligibility is confirmed based on criteria such as being symptomatic with an established diagnosis of **Fibrous Dysplasia/McCune-Albright Syndrome**, having a pain score of 4 or higher on the Visual Analogue Scale (VAS), and maintaining normal levels of calcium, parathyroid hormone, and vitamin D. Follow-up visits are scheduled at 3, 6, 9, and 12 months to assess the primary endpoint, which is the effect of **Denosumab** on maximum pain scores after 6 months, as well as secondary endpoints including average pain scores, quality of life, and disease activity. The end-of-study visit will evaluate the overall impact of the treatment and any potential side effects, such as atypical femoral fractures.

Participants will receive **Denosumab** via subcutaneous injection, with a maximum daily dose of 120 mg and a total dose of 480 mg over the treatment period. The study also involves the use of **Sodium Chloride** and **Sodium Fluoride (18F)** as auxiliary products. Conditions that may lead to early termination include significant adverse reactions, non-compliance with the study protocol, or withdrawal of consent by the participant. The trial aims to provide valuable insights into the management of pain and quality of life in patients with this rare disease.

The clinical trial involves the administration of **DENOSUMAB**, a therapeutic agent used as the experimental medication. Denosumab is provided in the form of a **solution for injection** and is administered via **subcutaneous injection**. The dosage is set at a maximum of 120 mg per day, with a total maximum dose of 480 mg over the treatment period. The treatment duration is specified as 12 months. Denosumab is a protein-based substance, specifically categorized under "Protein - Other," and is not a pediatric formulation. The primary objective of the trial is to evaluate the effect of Denosumab on pain in adults with Fibrous Dysplasia/McCune-Albright Syndrome.

As part of the trial, **Sodium Chloride Fresenius Kabi Italia 0.9% Solution for infusion** is used as a non-experimental treatment. This solution is administered via **subcutaneous injection** and serves as a placebo in the study. The pharmaceutical form is a **solution for infusion**, and it is chemically derived. The maximum daily dose is 120 mg, with a total maximum dose of 480 mg over a 12-month period. Sodium Chloride is not a pediatric formulation and is provided by Fresenius Kabi Italia S.R.L.

Additionally, **Sodium Fluoride (18F) Life Radiopharma 0.1 - 4 GBq/ml solution injectable** is utilized as an auxiliary treatment. This substance is administered through **intravenous injection** and is presented as a **solution for injection**. The maximum daily dose is 370 MBq/kg, with a total maximum dose of 370 MBq/kg over a 3-month period. Sodium Fluoride (18F) is chemically derived and is not intended for pediatric use. The product is supplied by Life Radiopharma Berlin GmbH.

Efficacy in the clinical trial titled "Denosumab for the treatment of Fibrous Dysplasia/McCune-Albright Syndrome in adults (DeFiD): a randomized double-blind placebo-controlled trial" will be assessed primarily by evaluating the effect of **Denosumab** on pain. The primary endpoint is the difference in maximum pain score after 6 months, measured using the Brief Pain Inventory (BPI) following two injections. Secondary endpoints include the evaluation of average pain scores at 3 and 6 months, and in the case of open-label treatment, at 9 and 12 months. Additionally, the number of patients achieving a 50% reduction in maximal pain, assessed by BPI, will be evaluated at these timepoints.

Further assessments will include the impact of **Denosumab** on quality of life using the SF-36 questionnaire, average weekly pain through a pain diary with VAS score, and physical activity using the Health Assessment Questionnaire – Disability Index and pedometer data. The prevalence of neuropathic pain components will be evaluated using the Pain Detect questionnaire. The trial will also investigate the use and dosage of analgesics, disease activity through laboratory measurements of bone markers, and lesions activity and size via bone scans. Bone density and vertebral fractures will be assessed using Dual-energy X-ray absorptiometry (DXA) and Vertebral Fractures Assessment (VFA) at baseline and after 12 months. Potential side effects, such as atypical femoral fractures, will be monitored with extended DXA after 12 months. These assessments will be conducted at baseline, 3 months, 6 months, and in the case of open-label treatment, at 9 and 12 months.