PyROphosPHate Supplementation to Fight ECtopIc Calcification in PseudoXanthoma Elasticum

• Status: Not yet recruiting
• Trial end date: 2024-09-01
• Target enrollment: 0
• Participant gender: All

Summary

Pseudoxanthoma elasticum (PXE) is a rare inherited metabolic disorder (OMIM 264800, frequency 1/25000) characterized by progressive ectopic calcification of connective tissues.

PXE mainly affects the skin (unsighting skin folds and papules), the retina (central blindness), the vasculature (peripheral arterial occlusive disease and stroke) and the renal system (renal lithiasis) in adulthood. Although rarely, early lethal forms have been reported.

This chronic and highly disabling condition results from a loss of function of the gene encoding for the ABCC6 membrane transporter primarily expressed in the hepatocytes and renal tubular cells. Recently, it has been reported that PXE was characterized by a 50-60% decrease in the plasma level of inorganic pyrophosphate (PPi), a major physiological anti-calcifying factor. PXE is an incurable disease although encouraging advances with animals PXE models and human patients were obtained with the use of etidronate (Eti), a stable, non-hydrolysable analog of PPi.

However, this proof-of-concept study was statistically underpowered, mitigating the overall results, notably with respect to the effect on vascular calcification and ocular lesions. Renal lithiasis was also not investigated in the study.

Furthermore, the long term use of Eti maybe a concern because of its side-effects (spontaneous fracture and mandibular necrosis) and the fact that non-hydrolysable bisphosphonate lead to stable and irreversible calcification.

Recent studies in animals and healthy volunteers have shown that, contrary to what was initially reported and thought, the oral administration of PPi salts resulted in increased PPi plasma levels, opening up new therapeutic perspectives in PXE by using PPi in place of Eti.

Therefore,the investigators propose to perform the first Phase II randomized controlled trial (RCT) to evaluate the safety and efficacy of a daily and oral administration of PPi salts against safety and efficacy of treatment with Eti (reference treatment) in PXE patients.

• Phase: Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Centre Hospitalier Universitaire de Nice

Criteria

Inclusion Criteria:

Patients (>18 years and <65 years), men and women, presenting a clinically and biologically authenticated PXE (genotype + phenotype) according to the international diagnostic criteria (25).

• Efficient contraceptive method in woman of childbearing age at inclusion and during the overall study

• Patient affiliated to a social security insurance

• Signed informed consent

• Patient without acute complication linked or not to the pathology at the time of the study

NON-INCLUSION CRITERIA

• Renal insufficiency (i.e. defined by a renal clearance <30ml / min / 1.73 m²)

• Known abnormality of the esophagus that would interfere with the passage of the drug, (e.g. esophagus stenosis).

• Patients with osteomalacia

• Patients with chronic diarrhea (> 1 month)

• Known sensitivity to Etidronate or its derivatives

• Pregnancy, lactating or fertile women who may wish to become pregnant within three years.

• Any other medical condition that may be considered in the opinion of the Principal Investigator.

• Use of bisphosphonate during last 5 years.

• Hypocalcemia (calcium <2.20 mmol/L and ionized calcium <1.15 mmol/L) *.

• Vitamin D deficiency <35 nmol/L *

• Enrollment in another inteventional clinical trial which could interfere with the present study

• After correcting the hypocalcemia and/or vitamin D deficiency, a participant is again suitable for participation in the trial, as long as the participant meets the inclusion criteria.