This study has been transitioned to CTIS with ID 2024-512133-33-00 check the CTIS register for the current data. Primary Objective To determine if 24 months of treatment with etidronate halts the progression of arterial calcification in the legs and…
ID
Source
Brief title
Condition
- Retina, choroid and vitreous haemorrhages and vascular disorders
- Epidermal and dermal conditions
- Arteriosclerosis, stenosis, vascular insufficiency and necrosis
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Arterial calcification in the legs and carotid syphons measured on low dose Ct
scan.
Secondary outcome
1. To determine the effect of 24 months of treatment with etidronate on
functional ophthalmological measurements, such as visual acuity and contrast
sensitivity compared to placebo.
2. 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.
3. To determine the effect of 24 months of treatment with etidronate on
structural ophthalmological measurements, on fundus photography, (infrared (IR)
and autofluorescence (FAF)) and OCT-angiography (OCTA).
4. To determine if 24 months of treatment with etidronate affects the
intracranial velocity pulsatility index as measured with MRI.
5. To determine if 24 months of treatment with etidronate halts the progression
of elastin degradation and of calcification in the skin in dermatological
observation of skin biopsies, compared to placebo.
6. To determine the effect of 24 months of treatment with etidronate on
inorganic pyrophosphate an desmosine compared to placebo.
7. To determine if 24 months of treatment with etidronate halts leads to
changes in vascular measurements (carotid intima-media thickness, pulse wave
velocity on ultrasound, ankle brachial index, 6 minute walking test and WELCH
questionnaire) compared to placebo.
8. To determine if 24 months of treatment with etidronate leads to decreased
occurrence of major adverse cardiovascular events (stroke, TIA, myocardial
infarction or cardiovascular death) compared to placebo.
9. To determine if 24 months of treatment with etidronate leads to improved
reported quality of life amd physical functioning, as measured with the EQ-5D,
PROMIS 10, PROMIS PF and USER P compared to placebo.
10. To determine if 24 months of treatment with etidronate leads to better
results on cognitive tests compared to placebo.
11. To determine if 24 months of treatment with etidronate leads to observed
differences in safety measures: changes in plasma calcium, phosphate measured
via laboratory assessment, and number of anti-VEGF injections used.
Background summary
Pseudoxanthoma elasticum is a genetic disease caused by mutations in the ABCC6
gene. These mutations result in reduced levels of inorganic pyrophosphate, a
strong inhibitor of ectopic calcification. PXE is characterized by 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 results in peau d*
orange, angioid streaks, choroidal neovascularizations (CNV*s) and macular
atrophy.
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, we recently conducted a double blind, randomized,
placebo-controlled clinical trial (RCT) in PXE patients. 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 progression of clinical manifestations
in patients with already manifest arterial calcifications. However, if
etidronate is effective in young patients with little to no arterial
calcification to prevent calcification from arising is not yet systematically
assessed.
Therefore, the TEMP-prevent trial aims to investigate the effect of etidronate
on the progression of arterial calcification in the legs and the carotid
artery.
Study objective
This study has been transitioned to CTIS with ID 2024-512133-33-00 check the CTIS register for the current data.
Primary Objective
To determine if 24 months of treatment with etidronate halts the progression of
arterial calcification in the legs and carotid siphons.
Secondary Objectives
1. To determine the effect of 24 months of treatment with etidronate on
functional ophthalmological measurements, such as visual acuity and contrast
sensitivity compared to placebo.
2. 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.
3. To determine the effect of 24 months of treatment with etidronate on
structural ophthalmological measurements, on fundus photography, (infrared (IR)
and autofluorescence (FAF)) and OCT-angiography (OCTA).
4. To determine if 24 months of treatment with etidronate affects the
intracranial velocity pulsatility index as measured with MRI.
5. To determine if 24 months of treatment with etidronate halts the progression
of elastin degradation and of calcification in the skin in dermatological
observation of skin biopsies, compared to placebo.
6. To determine the effect of 24 months of treatment with etidronate on
inorganic pyrophosphate an desmosine compared to placebo.
7. To determine if 24 months of treatment with etidronate halts leads to
changes in vascular measurements (carotid intima-media thickness, pulse wave
velocity on ultrasound, ankle brachial index, 6 minute walking test and WELCH
questionnaire) compared to placebo.
8. To determine if 24 months of treatment with etidronate leads to decreased
occurrence of major adverse cardiovascular events (stroke, TIA, myocardial
infarction or cardiovascular death) compared to placebo.
9. To determine if 24 months of treatment with etidronate leads to improved
reported quality of life amd physical functioning, as measured with the EQ-5D,
PROMIS 10, PROMIS PF and USER P compared to placebo.
10. To determine if 24 months of treatment with etidronate leads to better
results on cognitive tests compared to placebo.
11. To determine if 24 months of treatment with etidronate leads to observed
differences in safety measures: changes in plasma calcium, phosphate measured
via laboratory assessment, and number of anti-VEGF injections used.
Study design
Randomised, double blind, placebo controlled clinical trial.
Intervention
Etidronate versus placebo
Study burden and risks
Every participant will visit the UMC Utrecht 3 times during this study
(screening and M0, M12, M24). A low-dose CT scan of the neck and the legs will
be performed two times (M0 + M24). The effective dose of radiation is 2.84 mSV
pro person. In theory the additional radiation increases the risk on malignancy
in the future. Dermatological measurements are performed by a punch biopsy.
Laboratorial results are measured by venipuncture. Apart from the usual risk
(hematoma, pain and swelling, bleeding, vagal reaction, infection or allergic
reaction to local anesthesia), there is no additional risk in these research
operations. The 7Tesla MRI-scanner that is used in this study is not CE-marked,
and is only used for research. In previous studies with this MRI-scanner there
were no problems regarding subject safety.
Because of the know safety of etidronate and the long term experience with this
pharmaceutical, the overall risk of the TEMP-prevent is deemed low.
Heidelberglaan 100
Utrecht 3584 CX
NL
Heidelberglaan 100
Utrecht 3584 CX
NL
Listed location countries
Age
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 55 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
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.
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 (<35 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.
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 | CTIS2024-512133-33-00 |
| EudraCT | EUCTR2021-000434-34-NL |
| CCMO | NL75350.041.21 |