Clinical trial NCT05966064: DEnosumab for the Treatment of FIbrous Dysplasia/McCune-Albright Syndrome in Adults (DeFiD)
Official title: DEnosumab for the Treatment of FIbrous Dysplasia/McCune-Albright Syndrome in Adults (DeFiD): a Randomized Double-blind Placebo-controlled Trial
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE4
Conditions: Fibrous Dysplasia
McCune Albright Syndrome
Lead sponsor: Leiden University Medical Center
Sponsor class: OTHER
First posted: 2023-07-28
Enrollment: 82
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Denosumab effect on maximal pain score
timeFrame: at baseline, 3 months and after 6 months and in case of open label treatment after 9 and 12 months
Secondary outcomes:
measure: Denosumab effect on average pain scores
timeFrame: at baseline, 3 months and after 6 months and in case of open label treatment after 9 and 12 months
measure: To evaluate the number of patients with 50% reduction of maximal pain (BPI)
timeFrame: at baseline, 3 months and after 6 months and in case of open label treatment after 9 and 12 months
measure: Denosumab effect on quality of life
timeFrame: at baseline, 3 months and after 6 months and in case of open label treatment after 9 and 12 months
measure: Denosumab effect on average weekly pain score
timeFrame: every week from baseline, through study completion, an average of 1 year
measure: Denosumab effect on Physical activity assessment assessed through Health Assessment Questionnaire - Disability Index
timeFrame: baseline, 3 months and 6 months, and in case of open label treatment after 9 and 12 months
measure: Denosumab effect on Physical activity assessment assessed through screenshot of pedometer
timeFrame: baseline, 3 months and 6 months, and in case of open label treatment after 9 and 12 months
measure: Evaluation of prevalence of possible neuropathic component of the reported pain
timeFrame: baseline, 3 months and 6 months and in case of open label treatment after 9 and 12 months
measure: To investigate the number of analgesics used for pain
timeFrame: baseline, 3 months and 6 months and in case of open label treatment after 9 and 12 months
measure: To investigate the frequency use of analgesics for pain
timeFrame: baseline, 3 months and 6 months and in case of open label treatment after 9 and 12 months
measure: To investigate the dosage of analgesics used for pain
timeFrame: baseline, 3 months and 6 months and in case of open label treatment after 9 and 12 months
measure: Denosumab effect on serum bone markers
timeFrame: baseline, 3 months and 6 months and in case of open label treatment after 9 and 12 months
measure: Denosumab effect on serum markers
timeFrame: baseline, 3 months and 6 months and in case of open label treatment after 9 and 12 months
measure: Denosumab effect on lesion size
timeFrame: baseline and after 6 months, and in the case of open label treatment after 12 months
measure: Denosumab effect on lesion activity
timeFrame: baseline and after 6 months, and in the case of open label treatment after 12 months
measure: disease quantification (Skeletal Burden Score (SBS)
timeFrame: at baseline, 6 months and after 12 months
measure: Denosumab effect on bone density
timeFrame: baseline and after 12 months
measure: Denosumab effect on vertebral fractures
timeFrame: baseline and after 12 months
measure: To assess potential side effects in the form of Atypical femoral fractures
timeFrame: after 12 months
Other outcomes:
Locations:
city: Leiden
country: Netherlands
facility: Leiden University Medical Center
Study officials:
affiliation: Leiden University Medical Center
name: Natasha Appelman-Dijsktra, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: