- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT05662111
Treatment of Ectopic Calcification in Fahr's Disease or Syndrome (CALCIFADE)
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
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
Enrollment (Anticipated)
Phase
- Phase 2
Contacts and Locations
Study Contact
- Name: Birgitta MG Snijders, MD
- Phone Number: 0031 88 75 583 78
- Email: b.m.g.snijders@umcutrecht.nl
Study Locations
-
-
-
Utrecht, Netherlands, 3584 CX
- Recruiting
- University Medical Center Utrecht
-
Contact:
- Birgitta MG Snijders, MD
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Description
Inclusion criteria are:
- 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).
Exclusion criteria are:
- 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,
- pregnancy, women with an active pregnancy wish <1 year, or women who are breastfeeding at the time of inclusion,
- 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),
- 25-OH vitamin D deficiency <35 nmol/L. After correction of hypocalcaemia or vitamin D deficiency, a participant is again suitable for participation.
Study Plan
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:
|
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:
|
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
Sponsor
Collaborators
Investigators
- Principal Investigator: Huiberdina L Koek, MD, PhD, UMC Utrecht
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Anticipated)
Study Completion (Anticipated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
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)?
IPD Plan Description
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
product manufactured in and exported from the U.S.
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 register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
Clinical Trials on Fahr Disease
-
ProgenaBiomeRecruitingAlzheimer Disease | Alzheimer Disease, Early Onset | Alzheimer Disease, Late Onset | Alzheimer Disease 1 | Alzheimer Disease 2 | Alzheimer Disease 3 | Alzheimer Disease 4 | Alzheimer Disease 7 | Alzheimer Disease 17 | Alzheimer Disease 5 | Alzheimer Disease 6 | Alzheimer Disease 8 | Alzheimer Disease 10 | Alzheimer... and other conditionsUnited States
-
Cognito Therapeutics, Inc.RecruitingCognitive Impairment | Dementia | Alzheimer Disease | Mild Cognitive Impairment | Cognitive Decline | Alzheimer Disease, Early Onset | Alzheimer Disease, Late Onset | MCI | Dementia Alzheimers | Mild Dementia | Dementia of Alzheimer Type | Cognitive Impairment, Mild | Alzheimer Disease 1 | Dementia, Mild | Alzheimer... and other conditionsUnited States
-
Academisch Medisch Centrum - Universiteit van Amsterdam...CelltrionRecruitingBowel Disease | Inflammatory Disease | Disease CrohnNetherlands
-
Abbott Medical DevicesCompletedCoronary Artery Disease | Coronary Heart Disease | Peripheral Vascular Disease | Peripheral Artery Disease | Arterial Occlusive DiseaseUnited States
-
National Taipei University of Nursing and Health...TerminatedChronic Pulmonary Disease | Chronic Obstructive Pulmonary Disease Exacerbation | Chronic Obstructive Pulmonary Disease With ExacerbationTaiwan
-
Aveiro UniversityPrograma Operacional Inclusão Social e Emprego (POISE); Programa Operacional... and other collaboratorsCompletedLung Diseases | Chronic Obstructive Pulmonary Disease | Pulmonary Disease | Interstitial Lung Disease | Chronic Respiratory DiseasePortugal
-
Eye Hospital Pristina KosovoEnrolling by invitationProgressive Disease of CorneaeKosovo
-
McGill University Health Centre/Research Institute...CompletedChronic Obstructive Pulmonary Disease | Chronic Obstructive Pulmonary Disease ExacerbationCanada
-
Helix, IncMedical University of South Carolina; HealthPartners Institute; WellSpan Health; St. Luke's Hospital and Health Network, Pennsylvania and other collaboratorsRecruiting
-
Universitätsklinikum Hamburg-EppendorfRecruitingBatten Disease | Neuronal Ceroid Lipofuscinosis | CLN1 Disease | CLN2 Disease | CLN3 Disease | CLN4 Disease | CLN5 Disease | CLN6 Disease | CLN7 Disease | CLN8 Disease | CLN10 Disease | CLN11 Disease | CLN12 Disease | CLN13 Disease | CLN14 DiseaseGermany
Clinical Trials on Etidronate
-
National Heart, Lung, and Blood Institute (NHLBI)CompletedArterial Calcification | CD73 DeficiencyUnited States
-
UMC UtrechtRecruitingPseudoxanthoma ElasticumNetherlands
-
British Thoracic SocietyCompletedOsteoporosisUnited Kingdom
-
Cairo UniversityUnknown
-
Washington University School of MedicineCompletedOsteoporosis | Atypical Femoral Fractures | Bisphosphonate Therapy
-
Amsterdam UMC, location VUmcActive, not recruitingProstate Cancer Metastatic to BoneNetherlands
-
Organon and CoWorld Health Information Science Consultants, LLCCompletedAdenocarcinoma | Esophageal Cancer | Squamous Cell Carcinoma