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

Overview

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.

Interventions

• Drug Denosumab 120 Mg/1.7 Ml Inj
  Denosumab randomized at baseline and after 3 months at 6 and 9 months in case of open label
• Drug Placebo
  placebo randomized at baseline and after 3 months

Primary outcome measures

• Denosumab effect on maximal pain score [Time frame: at baseline, 3 months and after 6 months and in case of open label treatment after 9 and 12 months]

Secondary outcome measures (12)

• Denosumab effect on average pain scores [Time frame: 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) [Time frame: 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 [Time frame: 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 [Time frame: 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 [Time frame: 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 [Time frame: 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 [Time frame: 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 [Time frame: 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 [Time frame: 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 [Time frame: baseline, 3 months and 6 months and in case of open label treatment after 9 and 12 months]
• Denosumab effect on serum bone markers [Time frame: baseline, 3 months and 6 months and in case of open label treatment after 9 and 12 months]
• Denosumab effect on serum markers [Time frame: baseline, 3 months and 6 months and in case of open label treatment after 9 and 12 months]

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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Triple blind

Primary purpose

Treatment

Study locations

Netherlands · 1 center

• Leiden University Medical Center — Leiden

Identifiers

NCT: NCT05966064 · 2022-501705-12-00

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗