Treatment of Ectopic Calcification in Fahr's Disease or Syndrome (CALCIFADE)

December 14, 2022 updated by: H.L. Koek, MD, PhD, UMC Utrecht

A Randomized, Placebo-controlled, Double Blind Trial to Study the Effects of Etidronate on Ectopic CALCIfication in FAhr's Disease or Syndrome

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.

Study Overview

Status

Not yet recruiting

Intervention / Treatment

Detailed Description

Fahr's disease, scientifically known as primary familial brain calcification (PFBC), is a neurodegenerative disease in which all patients present with bilateral vessel associated calcifications in the basal ganglia in the absence of other secondary causes of brain calcifications. When a secondary cause is identified, the term Fahr's syndrome is often used. Dominantly-inherited PFBC is associated with mutations in four genes; solute carrier family 20 member 2 (SLC20A2), xenotropic and polytropic retrovirus receptor 1 (XPR1), platelet-derived growth factor b (PDGFB) and platelet-derived growth factor receptor b (PDGFRB). Recessively inherited PFBC is associated with mutations in two genes; myogenesis-regulating glycosidase (MYORG) and junctional adhesion molecule 2 (JAM2). Mutations in the known genes account for half of patients, suggesting genetic heterogeneity, with new genes yet to be discovered. The estimated minimal prevalence in studies with PFBC diagnosed with genetic and imaging studies is 2.1 to 6.6 per 1,000 suggesting that PFBC is actually not a rare disorder and is underdiagnosed. The clinical penetration of Fahr's disease or syndrome is incomplete and heterogeneous comprising of neuropsychiatric signs (depression, anxiety, psychosis), cognitive decline, movement disorders (ataxia, dystonia, Parkinsonism) 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.

Histology shows small vessel and capillary calcifications, vascular insufficiency and blood-brain barrier damage. Neural pathology has been described and there are indications that calcifications could interfere with neural circuitry. It is not known how mutations in different genes lead to a common pathology. Yet PFBC belongs to a group of genetic diseases that due to different types of faulty phosphor metabolism leads to a shortage of inorganic pyrophosphate (PPi). PPi is the strongest inhibitor of ectopic calcification in the body. PPi can be replaced by etidronate, a stable molecular homologue of PPi and a well known bisphosphonate that has been used widely. Presently, the rare genetic diseases Pseudoxanthoma Elasticum (PXE), Generalized Arterial Calcification of Infancy (GACI) and Arterial Calcification due to Cluster of Designation 73 (CD73) deficiency (ACDC) are successfully treated with this medication. In PFBC, it was shown that due to mutations in the SLC20A2 gene the Pi Transporter 2 (PiT2) is compromised. The PiT2 transporter plays an important role in the maintenance of Pi homeostasis which is essential for adenosine triphosphate synthesis. Another mutation, XPR1 is responsible for phosphate efflux and mutations here lead to calcium deposition in endothelial cells. Recently, it was shown that mutations in the PDGFB and PDGFRB genes cause osteoblast like cells to mediate in the calcification process, as was also shown in PXE, GACI and ACDC patients.

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.

Study Type

Interventional

Enrollment (Anticipated)

96

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

  • Name: Birgitta MG Snijders, MD
  • Phone Number: 0031 88 75 583 78
  • Email: [email protected]

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

17 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  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.46

      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:

  1. Unable or unwilling to sign an informed consent.
  2. Severe renal impairment (estimated creatinine clearance/estimated glomerular filtration rate of < 30 ml/min/1.73m2 calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation).
  3. Contraindication to receiving oral medication.
  4. Known abnormality of the esophagus that would interfere with the passage of the drug.
  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. Any other medical or social condition that, in the opinion of the Principal Investigator, might put the subject at risk of harm during the study or might adversely affect the interpretation of the study data.
  8. Use of bisphosphonate during last 5 years.
  9. Hypocalcemia (calcium <2,20 mmol/L)*.
  10. 25-hydroxy (25-OH) vitamin D deficiency <35 nmol/L)*.

    • After correcting the hypocalcemia or vitamin D deficiency, a participant is again suitable for participation in the CALCIFADE trial, as long as the participant meets the inclusion criteria.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Quadruple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: Etidronate
Etidronate 20 mg/kg for two weeks on and ten weeks off during 12 months
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.
Other Names:
  • Etidronate disodium
Placebo Comparator: Placebo
Placebo for two weeks on and ten weeks off during 12 months
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.
Other Names:
  • Etidronate disodium

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Overall cognitive functioning
Time Frame: 12 months
Montreal Cognitive Assessment (MoCA; range 0-30, higher scores mean better outcome)
12 months
Memory
Time Frame: 12 months
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
Time Frame: 12 months
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
Time Frame: 12 months
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
Time Frame: 12 months
Facial Expressions of Emotion - Stimuli and Tests (FEEST; scored based on normative data)
12 months

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Mobility
Time Frame: 12 months
Condensed version of the Balance Evaluation Systems Test (Mini-BESTest), which is a composite test of gait and balance (range 0-28, higher scores mean better outcome)
12 months
Mobility
Time Frame: 12 months
Unified Parkinson's Disease Rating Scale, part III (UPDRS; range 0-56, higher scores mean worse outcome)
12 months
Neuropsychiatric symptoms
Time Frame: 12 months
Neuropsychiatric Inventory (NPI; range 0-144, higher scores mean worse outcome)
12 months
Activities of daily living
Time Frame: 12 months
Katz-15 scale (range 0-15, higher scores mean worse outcome)
12 months
Quality of life questionnaire
Time Frame: 12 months
36-item Short Form Health Survey (SF-36; range 0-100, higher scores mean better outcome)
12 months
Brain calcification volume
Time Frame: 12 months
Volume of calcification quantified in computed tomography scan (milliliters)
12 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Investigators

  • Principal Investigator: Huiberdina L Koek, MD, PhD, UMC Utrecht

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Anticipated)

February 1, 2023

Primary Completion (Anticipated)

September 1, 2025

Study Completion (Anticipated)

September 1, 2025

Study Registration Dates

First Submitted

November 16, 2022

First Submitted That Met QC Criteria

December 14, 2022

First Posted (Estimate)

December 22, 2022

Study Record Updates

Last Update Posted (Estimate)

December 22, 2022

Last Update Submitted That Met QC Criteria

December 14, 2022

Last Verified

December 1, 2022

More Information

Terms related to this study

Other Study ID Numbers

  • NL 83131.041.22
  • 2022-003299-17 (EudraCT Number)
  • DR-2021-00387 (Other Grant/Funding Number: Hersenstichting)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

IPD Plan Description

Data can be shared with other researchers upon request. Due to the fact that Fahr's disease or syndrome is rare, not all data will be published openly, since this data might be traceable to an individual person.

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact [email protected]. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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