E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Fahr’s disease or sondrome 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. The clinical penetration of Fahr's disease or syndrome is incomplete and heterogeneous comprising of neuropsychiatric signs, cognitive decline, and movement disorders. The symptoms start between 30 and 50 years and are (slowly) progressive. |
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E.1.1.1 | Medical condition in easily understood language |
Patients with Fahr's disease or syndrome have calcifications in specific areas in the brain. This results in mobility problems, disturbed mental functions and/or psychiatric problems. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10059626 |
E.1.2 | Term | Fahr's disease |
E.1.2 | System Organ Class | 100000004850 |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
1. To determine whether etidronate can halt or attenuate deterioration of cognitive functioning in patients with Fahr's disease or syndrome compared to placebo between baseline and 12 months after baseline. |
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E.2.2 | Secondary objectives of the trial |
To determine whether etidronate can halt or attenuate deterioration of mobility, neuropsychiatric symptoms, dependence in activities of daily living, quality of life, and calcifications in the brain in patients with Fahr's disease or syndrome compared to placebo between baseline and 12 months after baseline. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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 Fahr’s 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 PFBC.46
Furthermore, the next criteria are supportive for the clinical diagnosis of PFBC: 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 PFBC is supportive for the clinical diagnosis of PFBC. d. 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: 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). |
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E.4 | Principal 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 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. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint is the change in cognitive functioning in patients with Fahr's disease or syndrome treated with etidronate 20mg/kg compared to placebo between baseline and 12 months after baseline. Cognitive functioning is measured by means of a standardized neuropsychological test battery of global cognitive functioning and three cognitive domains; memory, attention and speed of information processing, and executive functioning. Overall cognitive functioning is assessed with the Montreal Cognitive Assessment (MoCA). Memory with the Rivermead Behavioral Memory Test Stories immediate and delayed recall, and with the Rey Complex Figure test immediate and delayed recall. Attention and speed of information processing with the third edition of the Wechsler Adult Intelligence Scale (WAIS-III) Digit Span Forward, Trail Making Test A, and Stroop I and II. Executive functioning with the WAIS-III Digit Span Backward, Trail Making Test B and Stroop III, semantic and letter fluency and social cognition with the FEEST. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
The secondary endpoints are: 1. To determine the change in mobility in patients with Fahr's disease or syndrome treated with etidronate 20 mg/kg compared to placebo between baseline and 12 months after baseline. The mobility symptoms are assessed with the condensed version of the Balance Evaluation Systems Test (Mini-BESTest), which is a composite test of gait and balance. 2. To determine the change in neuropsychiatric symptoms in patients with Fahr's disease or syndrome treated with etidronate 20 mg/kg compared to placebo between baseline and 12 months after baseline. Neuropsychiatric symptoms are assessed with the Neuropsychiatric Inventory. 3. To determine the change in dependence in activities of daily living in patients with Fahr's disease or syndrome treated with etidronate 20 mg/kg compared to placebo between baseline and 12 months after baseline. Daily functioning is assessed with the Katz-15 scale. 4. To determine the change in quality of life in patients with Fahr's disease or syndrome treated with etidronate 20 mg/kg compared to placebo between baseline and 12 months after baseline. Quality of life is assessed with the 36-item Short Form Health Survey (SF-36). 5. To determine the change in brain calcification volume compared in patients with Fahr's disease or syndrome treated with etidronate 20mg/kg compared to placebo as quantified in CT-scan between baseline and 12 months after baseline. Participants will be scanned on the IQon CT or CT7500 (Philips Healthcare) from skull base to vertex. Tube voltage will be 120kVp and the tube current will range depending on patient size. Only non-contrast CT will be used to slice thickness < 1 mm. Images will be visually assessed in bone setting (center: 300 Hounsfield Units – width: 1600 Hounsfield Units). Volume of the calcifications in the brain will be measured with standard software (Philips Intellispace Portal v11). Calcifications are defined as hyperdens lesions with a density above 130 Hounsfield Units. Care will be taken that all patients are scanned on the same scanner before and after treatment for all their investigations so that interscan differences can be avoided. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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The end of the trial is the day of the last visit of the last subject undergoing the trial. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 4 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |