DEnosumab for the treatment of FIbrous Dysplasia/McCune-Albright Syndrome in adults (DeFiD): a randomized double-blind placebo-controlled trial

Fibrous dysplasia (FD) is a rare genetic disorder, caused by a post-zygotic
mutation of the GNAS-gene, characterized by local replacement of bone by
fibrous tissue in one (monostotic) or several bones (polyostotic). FD lesions
can be associated with endocrinopathies or café au lait patches in the
McCune-Albright syndrome (MAS), therefore the disease is termed FD/MAS. Bone
lesions can lead to pain and low quality of life (QoL) and higher disease
burden is correlated with more pain and worse QoL. There is no cure for FD/MAS
and while several treatments attempt to alleviate pain, current therapies
failed to demonstrate any effect on pain, functional parameters, imaging aspect
or disease progression. However, the RANKL-inhibitor Denosumab (Dmab) has
emerged as a possible treatment, showing promising result in mouse models and
in observational studies on the off label use in patients. As a clinical,
biochemical and radiological response to Dmab has been observed in
observational, non-randomized and non-controlled studies, the next step is to
conduct a randomized, double-blind, controlled trial (RCT) comparing the
effects of Dmab treatment with placebo in adult symptomatic patients with
FD/MAS.

This study has been transitioned to CTIS with ID 2024-511090-30-00 check the CTIS register for the current data.

To investigate whether 3 monthly Dmab will improve the clinical, radiological
and biochemical manifestations of FD bone lesions.

double-blind placebo controlled 6 months intervention study followed by a 6
months open-label study

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.

The patient burden will be minimal, consisting of completing the study
procedures at established time points and participating in a placebo controlled
study. The collection of blood samples, physical examination and the completion
of questionnaires requires engagement, however these procedures are already
incorporated in standard care at our center, and a combined Na18F-PET-CT-scan
will also be performed at baseline, at 6 months and at the end of study. Risks
for AEs and for a rebound phenomenon after withdrawal from Dmab exist, although
risks are minimalized by dental screening and close observation during the
study phase and the current standard of care after discontinuing Dmab.