NCT05662111 Treatment of Ectopic Calcification in Fahr's Disease or Syndrome

Eligibility & Interventions

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What to Expect as a Participant

You will actively receive the study intervention — which may be a drug, biologic, device, or procedure.

In Phase 2, researchers evaluate early signs of effectiveness. You may be randomized to receive the active treatment or a comparator. Monitoring continues closely.

This trial targets 98 participants in total. It began in 2023-04-03 with a primary completion date of 2027-12.

Brief Summary

Fahr's disease or syndrome are neurodegenerative diseases in which patients present with bilateral vessel associated calcifications in the basal ganglia. The clinical penetration of Fahr's disease or syndrome is incomplete and heterogeneous comprising of neuropsychiatric signs, cognitive decline, movement disorders, and various other signs (migraine, speech disorders, pain, seizures). The symptoms start between 30 and 50 years and are (slowly) progressive. Symptomatic patients have an increased risk for dependence in activities of daily living and impaired quality of life. Currently, disease-modifying therapies are not available for patients with Fahr's disease or syndrome. However, in a small case series it was shown that alendronate was effective in the clinical treatment of several patients with Fahr's disease or syndrome. Now the time has come to investigate the effectiveness of treatment with bisphosphonates in patients with Fahr's disease or syndrome in a randomized controlled trial.

Eligibility Criteria

Inclusion criteria are: 1. Age of 18 years or over, 2. Clinical diagnosis of Fahr's disease or syndrome. No international accepted diagnostic criteria for Fahr's disease or syndrome exist yet. It is diagnosed mostly based on the clinical presentation. For the present study the following criteria are used: 1. Clinical symptoms consistent with a clinical diagnosis of Fahr's disease or syndrome. 2. Bilateral calcifications of the basal ganglia as seen on the computed tomography (CT) scan of the head. To rule out basal ganglia calcifications due to aging, a CT based calcification score will be used as proposed by Nicolas et al. Calcification is graded from 0 (no calcification) to 5 (serious and confluent) in specific locations of the brain; lenticular, caudate, thalamus nuclei, subcortical white matter, cortex, cerebellar hemispheres, vermis, midbrain, pons, and medulla. The total calcification score (ranging from 0 to 80) is obtained by adding all location-specific points, where a score higher than the age-specific threshold points at Fahr's disease or syndrome. Furthermore, the next criteria are supportive for the clinical diagnosis of PFBC: 3. Frequently, the family history is consistent with autosomal dominant inheritance. A positive family history with at least one relative in the first or second degree with symptoms of PFBC is supportive for the clinical diagnosis of PFBC. 4. The presence of a (likely) pathogenic mutation in one of the PFBC-related genes is supportive for the clinical diagnosis of PFBC. Mutations in up to now 4 known genes are associated with an autosomal dominant pattern of inheritance: solute carrier family 20 member 2 (SLC20A2) (OMIM#213600), xenotropic and polytropic retrovirus receptor 1 (XPR1) (OMIM#616413), platelet-derived growth factor b (PDGFB) (OMIM#615483), and platelet-derived growth factor receptor b (PDGFRB) (OMIM#615007). Autosomal recessively inherited PFBC is associated with mutations in two genes: myogenesis-regulating glycosidase (MYORG) (OMIM#618317) and junctional adhesion molecule 2 (JAM2) (OMIM#618824). Exclusion criteria are: 1. unable or unwilling to sign an informed consent, 2. severe renal impairment (estimated glomerular filtration rate (eGFR) of \<30 ml/min/1.73m2 calculated using CKD-EPI equation), 3. contraindication to receiving oral medication (for example severe dysphagia), 4. known abnormality of the oesophagus that would interfere with the passage of the drug (for example oesophageal strictures or achalasia), 5. known sensitivity to etidronate, 6. pregnancy, women with an active pregnancy wish \<1 year, or women who are breastfeeding at the time of inclusion, 7. inability to undergo a Dutch neuropsychological assessment (for example, non-fluent Dutch speakers or severe visual, hearing or motor impairment), 8. any other medical or social condition that puts the subject at risk of harm during the study or might adversely affect the interpretation of the study data, 9. use of bisphosphonates during the last 5 years, 10. hypocalcaemia (calcium \<2.20 mmol/L), 11. 25-OH vitamin D deficiency \<35 nmol/L. After correction of hypocalcaemia or vitamin D deficiency, a participant is again suitable for participation.

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