The Prevention of Systemic Ectopic Mineralization in Pseudoxanthoma Elasticum
试验速览
- 阶段
- 3 期
- 状态
- 招募中
- 发起方
- UMC Utrecht
- 入组人数
- 76
- 试验地点
- 1
- 主要终点
- Arterial calcification
研究概览
简要总结
The goal of this randomized clinical trial is to assess the effect of etidronate on ectopic calcification in relatively young patients with Pseudoxanthoma elasticum. The main question it aims to answer are:
What is the difference in the arterial calcification scores in the legs and the carotid syphon measured on low-dose CT scan after 24 months of treatment compared to baseline between etidronate and placebo.
Participants will be asked to do take etidronate or placebo for 24 months.
详细描述
SUMMARY Rationale: Pseudoxanthoma elasticum is a monogenic disease caused by mutations in the ABCC6 gene. These mutations result in reduced levels of inorganic pyrophosphate, a strong inhibitor of ectopic calcification. This loss of inorganic pyrophosphate leads to a typical pattern of progressive degradation and calcification of elastin fibers in the skin, the medial layer of small- and medium sized arteries and the Bruch's membrane of the retina. This results clinically in skin disorders (pseudoxanthoma's), peripheral arterial disease, gastric bleeding and stroke. The progressive calcification of the Bruch's membrane in the retina results in peau d' orange, angioid streaks, choroidal neovascularizations (CNV's) and macular atrophy. Due to this eye pathology, PXE results in visual impairment and legal blindness at a young age.
The bisphosphonate etidronate is a molecular homologue of pyrophosphate, which therefore has the potential to substitute the loss of pyrophosphate that is seen in PXE. It has been on the market for over 40 years and has a well-established safety profile. Based upon positive results from animal studies, studies in related genetic disorders, and trials in patients with renal disease, recently a double blind, randomized, placebo-controlled clinical trial (RCT) in PXE patients was conducted. This Treatment of Ectopic Mineralization in PXE (TEMP)-trial (protocol ID: NL47602.041.15) showed that one year of treatment with etidronate was safe, and reduced calcifications of the leg arteries and of other vascular beds compared to placebo in PXE patients with arterial calcifications. As no other systemic treatment for PXE exists, this established etidronate as a very promising therapeutic option. The TEMP trial focused on reduction of complications in symptomatic patients with arterial calcifications (mean age 57). Since arterial calcification are so common in PXE patients, the vascular diseases associated with them are as well much more prevalent in the PXE population compared to the general population.
The aim of the TEMP-PREVENT is to include younger patients who developed no or only little vascular calcifications. The investigators suspect that the formation of calcium deposits can be halted in the intima for a large part, if not all together. If so, PXE patients would have the same vascular risk profiles as their peers.
Objective: Primary aim:
To investigate the effect of etidronate on arterial calcification, and therefore vascular health.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 50 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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:
- •Yellowish papules and/or plaques on the lateral side of the neck and/or flexural areas of the body or
- •Increase of morphologically altered elastin with fragmentation, clumping and calcification of elastic fibers in a skin biopsy taken.
- •Peau d'orange of the retina or
- •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.
- •A pathogenic mutation of both alleles of the ABCC6 gene or
- •A first-degree relative (parent, sibling or child) who meets independently the diagnostic criteria for definitive PXE
- •Fertile women must take adequate anticonception.
排除标准
- •A potential subject who meets any of the following criteria will be excluded from participation in this study:
- •Patients that are unable or unwilling to sign for informed consent.
- •Pregnant, lactating, or fertile women who might wish to become pregnant within three years.**
- •Patients with an estimated glomerular filtration rate below 30 ml/min/1.73m2 according to the CKD-EPI equation.31
- •Patients with a known abnormality of the oesophagus that would interfere with passage of the drug (e.g. oesophagus stenosis).
- •Patients with chronic diarrhoea (> 1 month).
- •Patients with known osteomalacia;
- •Patients with hypocalcaemia (calcium <2.20 mmol/L corrected for albumin)*.
- •Patients with a vitamin D deficiency (<35 nmol/L)*.
- •Patients that used a bisphosphonate in the last 5 years.
- •Patients with known sensitivity to etidronate.
- •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 (more information in paragraph 7.3.3).
- •Subjects that become pregnant during the trial will be excluded from further participation.
研究组 & 干预措施
Etidronate
Daily dosis of 20mg/kg of etidronate in a cyclical regimen of 2 weeks on and 10 weeks off, for a total of 24 months.
干预措施: Etidronate (Drug)
Placebo
Daily dosis of placebo in a cyclical regimen of 2 weeks on and 10 weeks off, for a total of 24 months.
干预措施: Placebo (Drug)
结局指标
主要结局
Arterial calcification
时间窗: 24 months.
The difference in arterial calcification volume measured (uL) on CT-scans between the etidronate and placebo group 24 months.
次要结局
- Ophtalmology: Visual acuity(24 months.)
- Ophtalmology: Contrast sensitivity.(24 months.)
- Ophtalmology: Reflectivity of Bruch's membrane(24 months.)
- Ophtalmology: Length of angioid streaks.(24 months.)
- Ophtalmology: Area of angioid streaks.(24 months.)
- Ophtalmology: Area of atrophy(24 months.)
- Intra cranial velocity pulsatility index on MRI(24 months.)
- Elastin degradation of the skin(24 months.)
- Calcification of the skin(24 months.)
- Cognitive Function STROOP(24 months.)
- Cognitive functioning Trailmaking test(24 months.)
- Ankle Brachial index(24 months)
- Pulse wave velocity (m/s)(24 months.)
- carotid intima media thickness(24 months.)
- inorganic pyrophosphate(24 months.)
- EQ-5D(24 months.)
- Cognitive Function 15 Words test(24 months.)
- Safety: Plasma calcium(24 months.)
- serum desmosine(24 months.)
- Cognitive functioning Brixton test(24 months.)
- Cognitive Function semantic fluency(24 months.)
- Incidence of MACE(24 months.)
- PROMIS 10(24 months)
- PROMIS Physical Funtioning short form(24 months)
- WELCH questionnaire(24 months)
- Safety: Anti VGEF use(24 months.)
- Safety: plasma phosphate(24 months.)
- Utrecht Scale for Evaluation of Rehabilitation(24 months)
- 6 minute walking test(24 months.)