TEMP trial

SUMMARY



Rationale: Pseudoxanthoma elasticum (PXE) is a rare autosomal recessive disorder affecting primarily the skin, the eyes and the vascular system (tunica media calcifications) with a considerable morbidity and possibly premature 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. A decreased inorganic pyrophosphate level has been shown to be related both to ABCC6 mutations and the occurrence of ectopic mineralization. In PXE animal models treatment with inorganic pyrophosphate and inorganic 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. 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 CD73 (ACDC), another genetic disease in which vascular calcifications of the tunica media develop. Like in GACI and ACDC, 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 have been found in studies in patients with GACI now the time has come to investigate the effectiveness of treatment with bisphosphonates in patients with PXE in a randomized controlled trial.



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 inorganic pyrophosphate.



Study design: Randomized placebo-controlled trial.



Study population: 74 PXE patients >18 years with evidence of arterial calcification.



Intervention: Subjects will be randomized to either treatment with etidronate during one year (cyclical 20 mg/kg for 2 weeks on and 10 weeks off) or placebo.



Main study parameters/endpoints: Primary endpoint: the percentage change in 18F-NaF uptake in the leg arteries after 12 months of treatment with etidronate 20 mg/kg compared with placebo.

Secondary endpoints: the percentage change in 18F-NaF uptake after 12 months treatment in other arteries than the leg arteries, ophthalmological changes after 12 months, changes in vascular stiffness after 12 months, changes in bone mineral density after 12 months, changes in quality of life and changes in serum calcium and phosphate.

Nature and extent of the burden and risks associated with participation, benefit and group relatedness: Each patient will visit the UMC Utrecht six times during 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). 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 for patients with PXE, a disease for which at the moment no effective therapy exists, using a well-known drug with good safety profile.

Pseudoxanthoma elasticum (PXE) is a rare autosomal recessive disorder affecting primarily the skin, the eyes and the vascular system (tunica media calcifications) with a considerable morbidity and possibly premature 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. A decreased inorganic pyrophosphate level has been shown to be related both to ABCC6 mutations and the occurrence of ectopic mineralization. In PXE animal models treatment with inorganic pyrophosphate and inorganic 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. 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 CD73 (ACDC), another genetic disease in which vascular calcifications of the tunica media develop. Like in GACI and ACDC, 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 have been found in studies in patients with GACI now the time has come to investigate the effectiveness of treatment with bisphosphonates in patients with PXE in a randomized controlled trial.

3 months, 6 months, 9 months and 12 months

Etidronate 20 mg/kg