PyROphosPHate Supplementation to Fight ECtopIc Calcification in PseudoXanthoma Elasticum

PyROphosPHate Supplementation to Fight ECtopIc Calcification in PseudoXanthoma Elasticum: PROPHECI Study

Sponsors

Lead Sponsor: Centre Hospitalier Universitaire de Nice

Source Centre Hospitalier Universitaire de Nice
Brief 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.

Overall Status Not yet recruiting
Start Date 2021-05-01
Completion Date 2024-05-01
Primary Completion Date 2022-05-01
Phase Phase 2
Study Type Interventional
Primary Outcome
Measure Time Frame
Arterial calcification score 12 months
Secondary Outcome
Measure Time Frame
clinical observation of dermatological changes 12 months
clinical observation of ophtalmologic changes 12 Montths
vascular changes 12 months
Enrollment 99
Condition
Intervention

Intervention Type: Drug

Intervention Name: study treatment PPI

Description: patient take PPI every day and Etidronate placebo only 2 weeks every 12 weeks

Arm Group Label: PPI+Eti placebo

Intervention Type: Drug

Intervention Name: Study comparator ETI

Description: patient take PPI placebo every day ans Etidronate only 2 weeks every 12 weeks

Arm Group Label: PPI placebo+Eti

Eligibility

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.

Gender:

All

Minimum Age:

18 Years

Maximum Age:

65 Years

Healthy Volunteers:

No

Overall Contact

Last Name: Georges LEFTHERIOTIS, PUPH

Phone: 33 4 92 03 29 41

Email: [email protected]

Location
Facility: Contact: Investigator:
Angers Hospital | Angers, 49000, France ludovic Martin, PHD 33 2 41 35 34 19 [email protected] ludovic Martin Principal Investigator Emmanuel Letavernier Sub-Investigator Samir Henni Sub-Investigator
Nice Hospital | Nice, 06000, France Georges leftheriotis 04 92 03 29 41 [email protected] georges Leftheriotis Principal Investigator
Location Countries

France

Verification Date

2021-03-01

Responsible Party

Type: Sponsor

Has Expanded Access No
Condition Browse
Number Of Arms 2
Arm Group

Label: PPI+Eti placebo

Type: Experimental

Description: the patient take PPI caps and Etidronate placebo caps

Label: PPI placebo+Eti

Type: Active Comparator

Description: The patient take PPI placebo caps and Etidrontate caps

Acronym PROPHECI
Patient Data No
Study Design Info

Allocation: Randomized

Intervention Model: Parallel Assignment

Primary Purpose: Treatment

Masking: Double (Participant, Investigator)

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