Treatment of Ectopic Calcification in Fahr's Disease or Syndrome

NCT05662111 | Recruiting Phase 2 DMC

• 3 other identifiers: NL 83131.041.222022-003299-17DR-2021-00387
• Study Type: interventional
• Target: 98
• Locations: 2 countries
• Sites: 2

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.

Conditions

Fahr Disease; Fahr Syndrome; Primary Familial Brain Calcification

Outcome Measures

Primary Outcomes (5)

• Overall cognitive functioning

  Montreal Cognitive Assessment (MoCA; range 0-30, higher scores mean better outcome)

  12 months

• Memory

  Composite z-score of Rivermead Behavioral Memory Test (RBMT) Stories immediate and delayed recall, Rey complex figure test immediate and delayed recall

  12 months

• Attention and speed of information processing

  Composite z-score of Wechsler Adult Intelligence Scale third edition (WAIS-III) Digit Span Forward, Trail Making Test A (TMT-A), Stroop I and II

  12 months

• Executive functioning

  Composite z-score of Wechsler Adult Intelligence Scale third edition (WAIS-III) Digit Span Backward, Trail Making Test B (TMT-B), Stroop III, semantic and letter fluency

  12 months

• Social cognition

  Facial Expressions of Emotion - Stimuli and Tests (FEEST; scored based on normative data)

  12 months

Secondary Outcomes (6)

• Mobility

  12 months

• Mobility

  12 months

• Neuropsychiatric symptoms

  12 months

• Activities of daily living

  12 months

• Quality of life questionnaire

  12 months

Study Arms (2)

Etidronate

ACTIVE COMPARATOR

Etidronate 20 mg/kg for two weeks on and ten weeks off during 12 months

Drug: Etidronate

Placebo

PLACEBO COMPARATOR

Placebo for two weeks on and ten weeks off during 12 months

Drug: Placebo

Interventions

Etidronate DRUG

The dosage of etidronate is 20 mg/kg for twee weeks and ten weeks off. Etidronate is given in capsules of 200 mg. Etidronate capsules are administered orally. During the study, participants will receive etidronate in four periods of two weeks during the twelve months of follow-up.

Also known as: Etidronate disodium

Etidronate

Placebo DRUG

Placebo is given in capsules and are administered orally. During the study, participants will receive placebo in four periods of two weeks during the twelve months of follow-up.

Also known as: Etidronate disodium

Placebo

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age of 18 years or over,
• 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:
• Clinical symptoms consistent with a clinical diagnosis of Fahr's disease or syndrome.
• 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:
• 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.
• 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).

You may not qualify if:

• unable or unwilling to sign an informed consent,
• severe renal impairment (estimated glomerular filtration rate (eGFR) of \<30 ml/min/1.73m2 calculated using CKD-EPI equation),
• contraindication to receiving oral medication (for example severe dysphagia),
• known abnormality of the oesophagus that would interfere with the passage of the drug (for example oesophageal strictures or achalasia),
• known sensitivity to etidronate,
• inability to undergo a Dutch neuropsychological assessment (for example, non-fluent Dutch speakers or severe visual, hearing or motor impairment),
• 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,
• use of bisphosphonates during the last 5 years,
• hypocalcaemia (calcium \<2.20 mmol/L),
• OH vitamin D deficiency \<35 nmol/L. After correction of hypocalcaemia or vitamin D deficiency, a participant is again suitable for participation.

Sponsors & Collaborators

• UMC Utrecht: lead
• Netherlands Brain Foundation: collaborator

Study Sites (2)

University Medical Center Utrecht

Utrecht, Utrecht, 3584 CX, Netherlands

RECRUITING

University College London Hospital

London, United Kingdom

NOT YET RECRUITING

Related Publications (1)

• Snijders BM, Mathijssen G, Peters MJ, Emmelot-Vonk MH, de Jong PA, Bakker S, Crommelin HA, Ruigrok YM, Brilstra EH, Schepers VP, Spiering W, van Valen E, Koek HL. The effects of etidronate on brain calcifications in Fahr's disease or syndrome: rationale and design of the randomised, placebo-controlled, double-blind CALCIFADE trial. Orphanet J Rare Dis. 2024 Feb 7;19(1):49. doi: 10.1186/s13023-024-03039-7.

  PMID: 38326858 DERIVED

MeSH Terms

Conditions

Fahr's disease

Interventions

Etidronic Acid

Intervention Hierarchy (Ancestors)

Diphosphonates; Organophosphonates; Organophosphorus Compounds; Organic Chemicals

Study Officials

• Huiberdina L Koek, MD, PhD

  UMC Utrecht

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Huiberdina L Koek, MD PhD

CONTACT

0031 88 75 55555; h.l.koek@umcutrecht.nl

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Model Details: A randomized placebo-controlled double blind trial using etidronate versus placebo

Study Record Dates

• First Submitted: November 16, 2022
• First Posted: December 22, 2022
• Study Start: April 3, 2023
• Primary Completion (Estimated): December 1, 2027
• Study Completion (Estimated): December 1, 2027
• Last Updated: March 2, 2026

Record last verified: 2026-02

Data Sharing

• IPD Sharing: Will not share

Locations

NL (1); GB (1)