ETIDRONATE DISODIUM for Pseudoxanthoma elasticum

Inclusion criteria

• {"criterion_text":"- Be between 18 years and 55 years\n- Have a definitive diagnosis of PXE according to the Plomp criteria27, 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\n- Fertile women must take adequate anticonception."}

Exclusion criteria

• {"criterion_text":"- Patients that are unable or unwilling to sign for informed consent.\n- Patients with known sensitivity to etidronate.\n- 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.\n- Pregnant, lactating, or fertile women who might wish to become pregnant within three years.\n- Patients with an estimated glomerular filtration rate below 30 ml/min/1.73m2 according to the CKD-EPI equation\n- Patients with a known abnormality of the oesophagus that would interfere with passage of the drug (e.g. oesophagus stenosis).\n- Patients with chronic diarrhoea (> 1 month).\n- Patients with known osteomalacia;\n- Patients with hypocalcaemia (calcium <2.20 mmol/L corrected for albumin)*. *After correction a patient is again suitable for participation, as long as inclusion criteria are met\n- Patients with a vitamin D deficiency (<35 nmol/L)*. *After correction a patient is again suitable for participation, as long as inclusion criteria are met\n- Patients that used a bisphosphonate in the last 5 years."}

Primary endpoints

• {"endpoint_text":"- The main study endpoint will be the percentage change in arterial calcification in carotid siphon and legs measured with low-dose CT scan after 24 months of treatment with etidronate compared with placebo.","definition_or_measurement_approach":"Percentage change in arterial calcification in carotid siphon and legs measured with low-dose CT scan after 24 months of treatment; comparison of etidronate versus placebo."}

Secondary endpoints

• {"endpoint_text":"- To determine the effect of 24 months of treatment with etidronate on functional ophthalmological measurements, such as visual compared to placebo.","definition_or_measurement_approach":"Functional ophthalmological measurements (e.g., visual acuity and contrast sensitivity) after 24 months compared to placebo."}
• {"endpoint_text":"- To determine if 24 months of treatment with etidronate halts the progression of normalized reflectivity in Bruch’s membrane as measured with SD-optical coherence tomography, compared to placebo.","definition_or_measurement_approach":"Normalized reflectivity in Bruch's membrane measured with spectral-domain optical coherence tomography (SD-OCT) after 24 months versus placebo."}
• {"endpoint_text":"- To determine the effect of 24 months of treatment with etidronate on structural ophthalmological measurements on fundus photography (infrared and autofluorescence and OCT-angiography).","definition_or_measurement_approach":"Structural ophthalmological measurements via fundus photography (infrared and autofluorescence) and OCT-angiography after 24 months compared to placebo."}
• {"endpoint_text":"- 7T Magnetic resonance imaging will be used to determine if treatment with etidronate halts the progression of increased pulsatility index of the intracranial carotid arteries and middle cerebral arteries.","definition_or_measurement_approach":"Pulsatility index of intracranial carotid and middle cerebral arteries measured by 7T MRI."}
• {"endpoint_text":"- To determine if treatment with etidronate halts the progression of elastin degradation and of calcification in the skin in skin biopsies, compared to placebo.","definition_or_measurement_approach":"Histological assessment of elastin degradation and calcification in skin biopsies compared after 24 months versus placebo."}
• {"endpoint_text":"- To determine if treatment with etidronate leads to increased levels of plasma levels of inorganic pyrophosphate compared to placebo.","definition_or_measurement_approach":"Plasma inorganic pyrophosphate levels measured and compared to placebo."}
• {"endpoint_text":"- To determine if treatment with etidronate halts the progression of systemic elastin degradation products, as measured via plasma levels of desmosin, compared to placebo.","definition_or_measurement_approach":"Plasma desmosine (desmosin) levels measured and compared to placebo."}
• {"endpoint_text":"- To determine if treatment with etidronate halts the progression of arterial calcification in legs and siphons, as measured with computed tomography, compared to placebo.","definition_or_measurement_approach":"Arterial calcification in legs and carotid siphons measured by low-dose CT and compared to placebo."}
• {"endpoint_text":"- To determine if treatment with etidronate halts the progression of increased carotid intima media thickness, as measured with ultrasound with a linear array transducer, compared to placebo.","definition_or_measurement_approach":"Carotid intima-media thickness measured by ultrasound with linear array transducer and compared to placebo."}
• {"endpoint_text":"- To determine if treatment with etidronate halts the progression of arterial stiffness, as measured by pulse wave analysis and velocity using a Doppler-ultrasound, compared to placebo.","definition_or_measurement_approach":"Arterial stiffness measured by pulse wave analysis and pulse wave velocity using Doppler ultrasound compared to placebo."}
• {"endpoint_text":"- To determine if treatment with etidronate halts progression of peripheral artery disease measured by the ankle brachial index, the WELCH questionnaire and the six-minute walking test.","definition_or_measurement_approach":"Peripheral artery disease assessed by ankle-brachial index, WELCH questionnaire, and six-minute walking test compared to placebo."}
• {"endpoint_text":"- To determine if treatment with etidronate leads to decreased occurrence of major cardiovascular events (stroke, TIA, myocardial infarction or cardiovascular death) events compared to placebo.","definition_or_measurement_approach":"Occurrence of major adverse cardiovascular events (stroke, TIA, MI, cardiovascular death) tracked and compared to placebo."}
• {"endpoint_text":"- To determine if treatment with etidronate leads to improved reported quality of life and self reported health, as measured with the EQ-5D, PROMIS 10, PROMIS PF, USER P compared to placebo.","definition_or_measurement_approach":"Patient-reported outcomes measured by EQ-5D, PROMIS-10, PROMIS PF, USER P compared to placebo."}
• {"endpoint_text":"- To determine if 24 months of treatment with etidronate leads to better results on cognitive outcomes, compared with placebo","definition_or_measurement_approach":"Cognitive outcome measures after 24 months compared to placebo (specific cognitive instruments not detailed)."}
• {"endpoint_text":"- To determine if treatment with etidronate leads to observed differences in safety measures: changes in plasma calcium, phosphate, ASAT, ALAT, eGFR measured via laboratory assessment, and number of anti-VEGF injections used","definition_or_measurement_approach":"Safety laboratory measures (plasma calcium, phosphate, ASAT, ALAT, eGFR) and count of anti-VEGF injections compared between arms."}

Netherlands

Earliest CTIS Part Ii Submission Date

14-10-2024

Latest Decision Or Authorization Date

28-10-2024

Processing Time Days

14

Number Of Sites

1

Number Of Participants

76

Primary sponsor

Full Name

Universitair Medisch Centrum Utrecht

Organisation Type

Hospital/Clinic/Other health care facility

Country Of Registered Address

Netherlands