E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Not possible to specify |
MedDRA Classification |
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 |
To determine if 24 months of treatment with etidronate halts the progression of arterial calcification in the legs and carotid siphons. |
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E.2.2 | Secondary objectives of the trial |
To determine if 24 months of treatment with etidronate , compared with placebo, affects functional ophthalmological measurements, such as visual acuity and contrast sensitivity. the progression of normalized reflectivity in Bruch’s membrane as measured with SD-optical coherence tomography,. structural ophthalmological measurements, on fundus photography, (infrared (IR) and autofluorescence (FAF)) and OCT-angiography (OCTA). the intracranial velocity pulsatility index as measured with MRI. the progression of elastin degradation and of calcification in skin biopsies inorganic pyrophosphate an desmosine. vascular measurements (carotid intima-media thickness, pulse wave velocity on ultrasound, ankle brachial index, 6 minue walking test and WELCH questionnaire) occurrence of major adverse cardiovascular events. Changes in cognitive functioning. reported quality of life. safety measures: changes in plasma calcium, phosphate and number of anti-VEGF injections used. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
In order to be eligible to participate in this study, a subject must meet all of the following criteria: - Be between 18 years and 50 years. - Have a definitive diagnosis of PXE according to the Plomp criteria, which confirm a diagnosis of PXE when at least two (or more) criteria not belonging to the same category (skin, eye, genetic) are met: 1. Skin a. Yellowish papules and/or plaques on the lateral side of the neck and/or flexural areas of the body or b. Increase of morphologically altered elastin with fragmentation, clumping and calcification of elastic fibers in a skin biopsy taken. 2. Eye a. Peau d'orange of the retina or b. One or more angioid streaks (AS), each at least as long as one disk diameter. When in doubt, fluorescein or indocyanine green angiography of the fundus is needed for confirmation. 3. Genetics a. A pathogenic mutation of both alleles of the ABCC6 gene or b. A first-degree relative (parent, sibling or child) who meets independently the diagnostic criteria for definitive PXE
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E.4 | Principal exclusion criteria |
A potential subject who meets any of the following criteria will be excluded from participation in this study: 1. Patients that are unable or unwilling to sign for informed consent. 2. Pregnant, lactating, or fertile women who might wish to become pregnant within three years. 3. Patients with an estimated glomerular filtration rate below 30 ml/min/1.73m2 according to the CKD-EPI equation.30 4. Patients with a known abnormality of the oesophagus that would interfere with passage of the drug (e.g. oesophagus stenosis). 5. Patients with chronic diarrhoea (> 1 month). 6. Patients with osteomalacia. 7. Patients with hypocalcaemia (calcium <2.20 mmol/L corrected for albumin)* 8. Patients with a vitamin D deficiency (<30 nmol/L)* 9. Patients that used a bisphosphonate in the last 5 years 10. Patients with known sensitivity to etidronate. 11. Any other medical or social condition that, at the discretion 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. * After correction a patient is again suitable for participation, as long as inclusion criteria are met.
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E.5 End points |
E.5.1 | Primary end point(s) |
Total calcification score measured on low dose CT in the legs and carotid siphons. |
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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) |
1. changes in functional ophthalmological measurements, such as visual acuity . 2. normalized reflectivity in Bruch’s membrane as measured with SD-optical coherence tomography. 3. structural ophthalmological measurements on fundus photography (infrared, autofluorescence and OCT-angiography). 4. increased pulsatility index of the intracranial carotid arteries and middle cerebral arteries on 7T MRI 5. elastin degradation and of calcification in the skin in skin biopsies 6. levels of plasma levels of inorganic pyrophosphate compared to placebo. 7. progression of systemic elastin degradation products, as measured via plasma levels of desmosin, compared to placebo. 8. arterial calcification in legs and siphons, as measured with computed tomography, compared to placebo. 9. increased carotid intima media thickness, as measured with ultrasound with a linear array transducer 10. arterial stiffness, as measured by pulse wave analysis and velocity using a Doppler-ultrasound, compared to placebo. 11. peripheral artery disease measured by the ankle brachial index, the WELCH questionnaire and the six-minute walking test. 12. occurrence of major cardiovascular events (stroke, TIA, myocardial infarction or cardiovascular death) events compared to placebo. 13. improved reported quality of life, as measured with the EQ-5D compared to placebo. 14. differences in safety measures: changes in plasma calcium, phosphate, ASAT, ALAT, eGFR measured via laboratory assessment, and number of anti-VEGF injections used. 15. Difference in functioning on cognitive testing compared to placebo after 24 months.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
All secondary endpoints have a timepoint of 24 months, except for the reflectivity of Bruchs membrane on SD-OCT, this will be measured after 12 months as well as after 24 months. |
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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 | No |
E.6.5 | Efficacy | No |
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) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
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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End of the trial is after the last visit of the last subject. |
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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 | 2 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | |