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Trial record 3 of 11 for:    apn01

PyROphosPHate Supplementation to Fight ECtopIc Calcification in PseudoXanthoma Elasticum (PROPHECI)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT04868578
Recruitment Status : Not yet recruiting
First Posted : May 3, 2021
Last Update Posted : May 5, 2021
Information provided by (Responsible Party):
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.

Condition or disease Intervention/treatment Phase
Pseudoxanthoma Elasticum Drug: study treatment PPI Drug: Study comparator ETI Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 99 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: PyROphosPHate Supplementation to Fight ECtopIc Calcification in PseudoXanthoma Elasticum: PROPHECI Study
Estimated Study Start Date : May 1, 2021
Estimated Primary Completion Date : May 1, 2022
Estimated Study Completion Date : May 1, 2024

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Minerals

Arm Intervention/treatment
Experimental: PPI+Eti placebo
the patient take PPI caps and Etidronate placebo caps
Drug: study treatment PPI
patient take PPI every day and Etidronate placebo only 2 weeks every 12 weeks

Active Comparator: PPI placebo+Eti
The patient take PPI placebo caps and Etidrontate caps
Drug: Study comparator ETI
patient take PPI placebo every day ans Etidronate only 2 weeks every 12 weeks

Primary Outcome Measures :
  1. Arterial calcification score [ Time Frame: 12 months ]
    Using manufacturer dedicated software, the investigator, will determine the calcification score from CT images according to the validated Agatston score method. A threshold of 130 Hounsfield Units for calcium detection will be used for the study. Voxels above this threshold representing arterial wall calcifications will be manually identified and selected by the observer on the CT image. Calcifications mass in the studied arterial segments will be analyzed and quantified. The length and antero-posterior mean diameter of each arterial segment will be determined for further normalization of the calcification score to the arterial wall surface (data expressed as HU/mm2 of arterial surface). The intraclass correlation and Bland-Altman coefficient for inter-observer reliability of the total peripheral artery calcium mass measurement will be determined by scoring 10 random scans by two independent investigators.

Secondary Outcome Measures :
  1. clinical observation of dermatological changes [ Time Frame: 12 months ]

    number of patient with dematological changes. Dermatological changes will be monitored by a dermatoscopic study of the skin according to the following protocol: Images will be acquired from commonly affected areas (neck, axilla, antecubital fossae, armpits and periumbilical area) by a contact dermatoscope (SD) with non-polarized light and recorded, as previously described .

    The investigators will ensure that the very same areas are imaged at baseline and at the end of the study. The surface of SD elementary changes featuring yellow papulae (presenting as "dots" or "reticular networks") on digitized images will be compared using an open image processing software (ImageJ, NIH).

  2. clinical observation of ophtalmologic changes [ Time Frame: 12 Montths ]
    Number of patietns with ophtalmologic changes. These changes will be monitored (blinded to treatment) by the occurrence of subretinal neovascularization events, the frequency of anti-VEGF administration and the best-corrected visual acuity (BCVA). A sub-retinal neovascularization event will be defined as any of the following that provide an indication to start or intensify anti-VEGF injections to prevent (further) visual impairment: 1) retinal bleeding suspected to be caused by sub-retinal neovascularization (if needed confirmed by fluorescein angiography); 2) a significant increase in sub retinal or intraretinal fluid; and/or 3) growth of a sub retinal neovascular complex. These events will be scored by the trained ophthalmologist of the PXE reference center (Dr Th Bresson) who will be blinded for the treatment.

  3. vascular changes [ Time Frame: 12 months ]

    Ankle Brachial Index (ABI) at rest: Systolic arterial blood pressure will be recorded using a pneumatic cuff wrapped around the ankle. An ultrasound probe allows recording the blood flow in the left and right ankle arteries (namely posterior and anterior tibial arteries) and brachial arteries supine at rest. The ABI is determined by the ratio between the lowest ankle artery pressure and the highest brachial artery blood pressure.

    A peripheral arterial occlusive disease (PAOD) is defined according to the actual recommendations: an ABI <0.90) and an incompressible arterial wall reflecting mediacalcosis defined by ABI>1.40.

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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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


  • 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT04868578

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Contact: Georges LEFTHERIOTIS, PUPH 33 4 92 03 29 41
Contact: Sophie Bonnet

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Angers Hospital
Angers, France, 49000
Contact: ludovic Martin, PHD    33 2 41 35 34 19   
Principal Investigator: ludovic Martin         
Sub-Investigator: Emmanuel Letavernier         
Sub-Investigator: Samir Henni         
Nice Hospital
Nice, France, 06000
Contact: Georges leftheriotis    04 92 03 29 41    leftheriotis.g@chu-nice.Fr   
Principal Investigator: georges Leftheriotis         
Sponsors and Collaborators
Centre Hospitalier Universitaire de Nice
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Responsible Party: Centre Hospitalier Universitaire de Nice Identifier: NCT04868578    
Other Study ID Numbers: 19-APN-01
First Posted: May 3, 2021    Key Record Dates
Last Update Posted: May 5, 2021
Last Verified: March 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Pseudoxanthoma Elasticum
Cardiovascular Diseases
Hemostatic Disorders
Vascular Diseases
Hemorrhagic Disorders
Hematologic Diseases
Skin Abnormalities
Congenital Abnormalities
Skin Diseases, Genetic
Genetic Diseases, Inborn
Connective Tissue Diseases
Skin Diseases