DEnosumab for the Treatment of FIbrous Dysplasia/McCune-Albright Syndrome in Adults (DeFiD)

Study Overview
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Brief Summary
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Fibrous Dysplasia/McCune-Albright syndrome (FD/MAS) is a rare disease, consisting of the replacement of normal bone tissue with fibrous tissue. FD lesions may be isolated in one or more bones or may be associated with endocrinopathies in McCune-Albright syndrome. Bone lesions constitute of weak bone tissue, leading to higher risk of fractures, pain and decreased quality of life. There is no cure for FD lesions and current therapies failed to soothe patients' complaints or to display any effect on progression of the lesions on imaging. However, the RANKL-inhibitor Denosumab demonstrated encouraging results in mouse models and in off-label clinical use, leading to clinical, biochemical and radiographical improvements. Study's aim is to investigate whether 3-monthly Denosumab will improve the clinical, radiological and biochemical manifestations of FD bone lesions.

Detailed Description
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Eligible patients will be randomized to treatment with either subcutaneous Dmab 120mg or placebo at baseline and 3 months in a blinded fashion. At 6 months, after 2 injections, patients with pain score <4 will exit the study to discontinue study medication and proceed in usual care, while patients with pain score ≥4 or lesional growth will be offered Dmab 120 mg at 6 and 9 months in an open-label design.

Official Title
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DEnosumab for the Treatment of FIbrous Dysplasia/McCune-Albright Syndrome in Adults (DeFiD): a Randomized Double-blind Placebo-controlled Trial

Conditions
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Fibrous Dysplasia, McCune Albright Syndrome

Intervention / Treatment
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* Drug: Denosumab 120 Mg/1.7 Ml Inj
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Symptomatic patients with established diagnosis of FD/MAS and closed growth plates(>18 years) Pain in the region of an FD localization, not responding to adequate pain treatment and without mechanical component e.g. impending fracture Pain score from FD lesion for maximum or average pain on VAS ≥ 4 Increased lesional activity defined as increased bone turnover markers (ALP, P1NP or CTX) or increased activity on Na[18F]-PET/CT or bone scintigraphy in at least one lesion Normal levels of calcium, parathyroid hormone and vitamin D (supplementation is allowed) Treated hypophosphatemia (defined as >0.7 at two separate measures) good dental health (last check within the last 12 months) Exclusion Criteria: Active pregnancy wish, pregnancy or nursing Pain not related to FD Uncontrolled endocrine disease Untreated vitamin D deficiency, hypocalcemia or hypophosphatemia Previous use of bisphosphonates or Dmab < 6 months before inclusion ('6 months wash out') Previously reported severe side effects on Dmab Inability to fulfil study requirements Poor untreated dental health without intention to get treatment Treatment with other bone influencing drugs, such as high doses corticosteroids

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Denosumab<br>Denosumab randomized at baseline and 3 months in a double-blinded fashion and in case of open label at 6 and 9 months | Drug: Denosumab 120 Mg/1.7 Ml Inj<br>* Denosumab randomized at baseline and after 3 months at 6 and 9 months in case of open label<br>* Other names: Xgeva;|
| Placebo Comparator: Placebo<br>Placebo randomized at baseline and 3 months in a double-blinded fashion. | Drug: Placebo<br>* placebo randomized at baseline and after 3 months<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Denosumab effect on maximal pain score | Evaluation of maximal pain score changes after treatment, assessed by Brief Pain Inventory (scale 0 to 10; 0-no pain, 10 worst pain) | at baseline, 3 months and after 6 months and in case of open label treatment after 9 and 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Denosumab effect on average pain scores | Evaluation of average pain score changes after treatment, assessed by Brief Pain Inventory (scale 0 to 10; 0-no pain,10 worst pain) | at baseline, 3 months and after 6 months and in case of open label treatment after 9 and 12 months | 
| To evaluate the number of patients with 50% reduction of maximal pain (BPI) | Evaluation of the number of patients with 50% reduction of maximal pain score changes after treatment, asseses by Brief Pain Inventory (scale 0 to 10; 0-no pain, 10 worst pain) | at baseline, 3 months and after 6 months and in case of open label treatment after 9 and 12 months | 
| Denosumab effect on quality of life | Evaluation of Denosumab effect on quality of life, assessed with validated questionnaire SF-36 (scale 0-100, higher scores indicate better health status) | at baseline, 3 months and after 6 months and in case of open label treatment after 9 and 12 months | 
| Denosumab effect on average weekly pain score | Evaluation of Denosumab effect on average weekly pain score assessed through a pain diary with VAS score (scale 0 to 10) | every week from baseline, through study completion, an average of 1 year | 
| Denosumab effect on Physical activity assessment assessed through Health Assessment Questionnaire - Disability Index | Evaluation of Denosumab effect on on Physical activity assessment (Health Assessment Questionnaire - Disability Index: Health state index scores generally range from less than 0 (where 0 is a health state equivalent to death; negative values are valued as worse than death) to 1 (perfect health), with higher scores indicating higher health utility, though health state preferences can differ between countries. | baseline, 3 months and 6 months, and in case of open label treatment after 9 and 12 months | 
| Denosumab effect on Physical activity assessment assessed through screenshot of pedometer | Evaluation of Denosumab effect on on Physical activity assessment ( screenshot of pedometer of activity during the last week on smartphone, unit measure: number of steps during the last week) | baseline, 3 months and 6 months, and in case of open label treatment after 9 and 12 months | 
| Evaluation of prevalence of possible neuropathic component of the reported pain | to evaluate the prevalence of possible neuropathic component of the reported pain through Pain Detect questionnaire (It is scored from 0 to 38, with total scores of less than 12 considered to represent nociceptive pain, 13-18 possible NeP, and >19 representing >90% likelihood of Neuropathic pain) | baseline, 3 months and 6 months and in case of open label treatment after 9 and 12 months | 
| To investigate the number of analgesics used for pain | number of used analgesics for pain : unit of measure: number | baseline, 3 months and 6 months and in case of open label treatment after 9 and 12 months | 
| To investigate the frequency use of analgesics for pain | the frequency use of analgesics for pain (daily, multiple times per day, multiple times per week, monthly, when necessary) | baseline, 3 months and 6 months and in case of open label treatment after 9 and 12 months | 
| To investigate the dosage of analgesics used for pain | dosage of analgesics used for pain (unit of measure: mg) | baseline, 3 months and 6 months and in case of open label treatment after 9 and 12 months | 
| Denosumab effect on serum bone markers | effect of denosumab on bone serum markers (alkaline phosphatase (measure unit: U/L), P1NP -Procollagen-1-propeptide (measure unit: ng/ml), Beta-crosslaps (measure unit: ug/L) | baseline, 3 months and 6 months and in case of open label treatment after 9 and 12 months | 
| Denosumab effect on serum markers | effect of Denosumab on serum calcium(mmol/L), fosfate (mmol/L), PTH (pmol/L) | baseline, 3 months and 6 months and in case of open label treatment after 9 and 12 months | 
| Denosumab effect on lesion size | Na18F-PET/CT scan- measurement of lesion size | baseline and after 6 months, and in the case of open label treatment after 12 months | 
| Denosumab effect on lesion activity | Na18F-PET/CT scan- ,measurement of Na18F uptake | baseline and after 6 months, and in the case of open label treatment after 12 months | 
| disease quantification (Skeletal Burden Score (SBS) | nuclear imaging ((Skeletal Burden Score (SBS): scale 0 to 75, higher scores meaning increased disease activity | at baseline, 6 months and after 12 months | 
| Denosumab effect on bone density | Dual-energy X-ray absorptiometry (DXA) - bone density measurement ( T-score of -1.0 or above = normal bone density T-score between -1.0 and -2.5 = low bone density, or osteopenia; T-score of -2.5 or lower = osteoporosis) | baseline and after 12 months | 
| Denosumab effect on vertebral fractures | Dual-energy X-ray absorptiometry (DXA) - assement of presence of Vertebral Fractures through Vertebral Fractures Assessment (VFA) and changes from baseline until 12 months after | baseline and after 12 months | 
| To assess potential side effects in the form of Atypical femoral fractures | Dual-energy X-ray absorptiometry (DXA) femur extended | after 12 months |