This study has been transitioned to CTIS with ID 2024-512300-19-00 check the CTIS register for the current data. The objective is to determine whether etidronate can halt or attenuate disease progression in patients with Fahr*s disease or syndrome…
ID
Source
Brief title
Condition
- Central nervous system vascular disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary outcome: change in cognitive functioning of patients with Fahr*s
disease or syndrome treated with etidronate or placebo between baseline and 12
months after baseline.
Secondary outcome
Secondary outcomes: change in mobility, psychiatric symptoms, daily
functioning, quality of life, and calcification in the brain of patients with
Fahr*s disease or syndrome treated with etidronate or placebo between baseline
and 12 months after baseline.
Background summary
Fahr*s disease, also known as primary familial brain calcification, is a rare,
monogenetic disease in which 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 (e.g. parathyroid
disease), the term Fahr*s syndrome is used. The calcifications are visible on a
computed tomography scan. Dominantly-inherited Fahr*s disease is associated
with mutations in four genes; SLC20A2, XPR1, PDGFB and PDGFRB. Recessively
inherited Fahr*s disease is associated with mutations in MYORG and JAM2.
Mutations in the known genes account for half of patients, suggesting genetic
heterogeneity, with new genes yet to be discovered. The clinical presentation
of Fahr*s disease or syndrome is heterogeneous comprising of neuropsychiatric
signs (e.g. depression, anxiety), cognitive decline, mobility disorders (e.g.
Parkinsonism) and various other signs (e.g. migraine, pain). The symptoms start
at an age 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.
Mutations in several genes linked to Fahr*s disease are related to the
calcium/phosphate homeostasis. Similar monogenetic, rare calcifying diseases of
arteries in other parts of the body are also caused by a disturbance in the
calcium/phosphate homeostasis. Lack of inorganic pyrophosphate (PPi) is the
central problem. PPi is the strongest inhibitor of ectopic calcification in the
body. These diseases are successfully treated with etidronate, a stable analog
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 CD73
deficiency (ACDC) are successfully treated with this medication.
Currently, disease-modifying therapies are not available for patients with
Fahr*s disease or syndrome. Now the time has come to investigate the
effectiveness of treatment with etidronate in patients with Fahr*s disease or
syndrome in a randomized controlled trial.
Study objective
This study has been transitioned to CTIS with ID 2024-512300-19-00 check the CTIS register for the current data.
The objective is to determine whether etidronate can halt or attenuate disease
progression in patients with Fahr*s disease or syndrome.
Study design
Randomized, placebo controlled, double blind trial.
Intervention
Treatment with etidronate during one year (cyclical 20 mg/kg for 2 weeks on and
10 weeks off) or placebo.
Study burden and risks
Each patient will visit the UMCU three times during the 13 month duration of
the study. At baseline (two times) and after 12 months of follow-up, visits are
planned for laboratory tests, neuropsychological assessment, and tests for
mobility, neuropsychiatric functioning, daily functioning, and quality of life.
At baseline and at 12 months a CT scan of the brain will be made. For the
entire study protocol, the effective dosage is approximately 4 mSv. This
radiation theoretically could marginally increase the lifetime risk of
developing cancer. At three and six months, patients will be scheduled for
telephone consultation for evaluation of treatment compliance and side effects.
The study drug is a known and safe drug, generally well tolerated and side
effects are mostly mild. The most commonly reported side effects are transient
musculoskeletal pain and gastrointestinal side effects like dyspepsia. A rare
side effect is osteonecrosis of the jaw. Patients who have dental disease or
use certain drugs (chemotherapeutic or anti-inflammatory drugs) have a higher
risk for this side effect. To reduce this risk, the physician at the expert
center will perform a medication review and check the dental status before
starting treatment. Though treatment with etidronate in patients with Fahr*s
disease or syndrome is promising, until effectiveness of this treatment is
proven in this trial we can not assume that research participants gain
individual benefit from their participation in the study. However, the study is
expected to open up a new promising treatment for patients with Fahr*s disease
or syndrome, a disease for which at the moment no effective therapy exists,
using a well-known drug with good safety profile.
Heidelberglaan 100
Utrecht 3584 CX
NL
Heidelberglaan 100
Utrecht 3584 CX
NL
Listed location countries
Age
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:
a. Clinical symptoms consistent with a clinical diagnosis of Fahr*s disease or
syndrome.
b. Bilateral calcifications of the basal ganglia as seen on the 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
Fahr's disease:
c. 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 Fahr*s disease is supportive for the clinical
diagnosis of Fahr*s disease.
d. The presence of a (likely) pathogenic mutation in one of the Fahr*s
disease-related genes is supportive for the clinical diagnosis of Fahr*s
disease. Mutations in up to now four known genes are associated with an
autosomal dominant pattern of inheritance: SLC20A2 (OMIM#213600), XPR1
(OMIM#616413), PDGFB (OMIM#615483), and PDGFRB (OMIM#615007). Autosomal
recessively inherited PFBC is associated with mutations in two genes: MYORG
(OMIM#618317) and JAM2 (OMIM#618824).
Exclusion criteria
1. Unable or unwilling to sign an informed consent.
2. Severe renal impairment (estimated creatinine clearance/eGFR of <30
ml/min/1.73m2 calculated using 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 the last 5 years.
9. Hypocalcemia (calcium <2.20 mmol/L)*.
10. 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.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EU-CTR | CTIS2024-512300-19-00 |
| EudraCT | EUCTR2022-003299-17-NL |
| CCMO | NL83131.041.22 |