The main objective is to determine if bisphosphonate therapy with etidronate leads to stabilization or attenuation of ongoing calcification in the leg arteries as quantified by 18F-sodium fluoride(18F-NaF) PET-CT imaging in patients with PXE.…
ID
Source
Brief title
Condition
- Cardiac and vascular disorders congenital
- Retina, choroid and vitreous haemorrhages and vascular disorders
- Vascular disorders NEC
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary endpoint is the percentage change in 18F-NaF-uptake after 12 months
treatment with etidronate 20 mg/kg compared with placebo.
Secondary outcome
Secondary endpoints are the percentage change in 18F-NaF-uptake in other
arteries than the femoral artery, ophthalmological changes , changes in
vascular stiffness, changes in bone mineral density, dermatological changes,
changes in quality of life and changes in serum calcium and phosphate, changes
in MRI brain lesions, vascular brain flow, pulsatility and brain tissue
perfusion, changes in cognitive function.
Background summary
Pseudoxanthoma elasticum (PXE) is a rare autosomal recessive disorder affecting
primarily the skin, the eyes and the vascular system with a considerable
morbidity and occasional mortality. PXE is caused by mutations in the ABCC6
gene leading to mineralization of elastic fibers in the skin, the Bruch*s
membrane of the retina and the vasculature. Decreased pyrophosphate levels has
been shown to be related both to ABCC6 mutations and the occurrence of ectopic
mineralization. In animal models treatment with pyrophosphate and pyrophosphate
analogues such as bisphosphonates has been proven to inhibit mineralization.
Studies in generalized arterial calcification of infancy (GACI), a
mineralization disorder genetically and phenotypically similar to PXE, suggest
that treatment with bisphosphonates is very effective on resolution of
calcification of blood vessels and is associated with improved survival. Also
in patients without PXE bisphosphonates have been shown to be able to stabilize
vascular calcifications. Also, in age-related macular degeneration
bisphosphonates can reduce the choroidal neovascularization. Based on these
positive findings, a clinical trial is now evaluating the effectiveness on
arterial calcification and safety of the bisphosphonate etidronate in patients
with Arterial Calcifications due to Deficiency in SD73 (ACDC), another genetic
disease in which vascular calcifications of the tunica media develop. Like in
GACI, treatment with bisphosphonates is a potentially effective treatment in
PXE. After the effectiveness of treatment with bisphosphonates in PXE in animal
models has been established and promising results has been found in studies in
patients with GACI, a disease from the same clinical spectrum as PXE, now the
time has come to investigate the effectiveness of treatment with
bisphosphonates in patients with PXE in a randomized controlled trial.
Study objective
The main objective is to determine if bisphosphonate therapy with etidronate
leads to stabilization or attenuation of ongoing calcification in the leg
arteries as quantified by 18F-sodium fluoride(18F-NaF) PET-CT imaging in
patients with PXE. Secondary objectives are to determine if bisphosphonate
therapy with etidronate leads to changes in calcium scores of the peripheral
arteries, attenuation of ongoing calcification in other arteries than the leg
arteries, ophthalmological changes, dermatological changes, changes in vascular
stiffness, changes in bone mineral density, changes in quality of life, changes
in serum calcium and phosphate and changes in pyrophosphate, changes in MRI
brain laesions, vascular brain flow, pulsatility and brain tissue perfusion,
changes in cognitive function.
Study design
Randomized placebo-controlled trial
Intervention
Subjects will be randomized to either treatment with etidronate during one year
(cyclical 20 mg/kg for 2 weeks on and 10 weeks of) or placebo.
Study burden and risks
Each patient will visit the UMC Utrecht six times for the 12 month duration of
the study. At baseline and after 12 months a *whole-body* 18F-NaF PET-CT scan
will be made. After 6 months of follow-up a conventional CT-scan will be
performed. For the entire study protocol, the effective dosage is approximately
13.6 mSv. This radiation theoretically could marginally increase the lifetime
risk of developing cancer. During the study follow-up visits are planned each 3
months for ophthalmological evaluation (M0, M3, M6, M9, M12), non-invasive
evaluation of vascular stiffness (M0, M12), laboratory evaluations (M0, M3, M6,
M9, M12), and quality of life questionnaire (M0, M12). Additionaly participants
will undergo cognitive testing and MRI brain imaging with contrast at M0 and
M12. Twelve months etidronate use carries a potential health risk (estimated as
medium risk). Though treatment with etidronate in PXE patients is promising,
until effectiveness of this treatment is proven in this trial we can not assume
that research participants gain individual benefit from their participation in
the study. However, the study is expected to open up a new promising treatment
in patients with PXE, a disease for which at the moment no therapy exists,
using a well known drug with good safety profile.
Heidelberglaan 100
Utrecht 3584 CX
NL
Heidelberglaan 100
Utrecht 3584 CX
NL
Listed location countries
Age
Inclusion criteria
1. All patients should be at least 18 years old.
2. A participant must meet the revised diagnostic criteria of Plomp et al. for the diagnosis of PXE
3. In all patients evidence of arterial calcification should be available.
Exclusion criteria
1. Subjects who are 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. Known abnormality of the esophagus that would interfere with the passage of the drug, such as a oesophagus stenosis.
4. Patients with osteomalacy
5. Patients with chronic diarrhea (>1 month)
6. Known sensitivity to etidronate.;7. Pregnant, lactating or fertile women who might wish to become pregnant within three years.
8. 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.
9. Use of bisphosphonate during last 5 years.
10. Hypocalcemia (calcium <2,20 mmol/L and ionised calcium < 1.15)*.
11. Vitamin D deficiency <35 nmol/L*.
*After correcting the hypocalcemia or vitamin D deficiency a participant is again suitable for participation in the TEMP trial, as long as the participant meets the inclusion criteria.
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
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2013-005620-41-NL |
| CCMO | NL47602.041.15 |
| OMON | NL-OMON27089 |