Clinical trial NCT01585402: Etidronate for Arterial Calcifications Due to Deficiency in CD73 (ACDC)
Official title: An Open-label, Non-Randomized, Single-Arm Pilot Study to Evaluate the Effectiveness of Etidronate Treatment for Arterial Calcifications Due to Deficiency in CD73 (ACDC)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Arterial Calcification
CD73 Deficiency
Keywords: NT5E
Bisphosphonates
Vascular Calcifications
Joint Capsule Calcifications
Inherited Disease
Lead sponsor: National Institutes of Health Clinical Center (CC)
Sponsor class: NIH
First posted: 2012-04-25
Enrollment: 7
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: Background:

* Arterial Calcifications due to Deficiency in CD73 (ACDC) is a rare genetic disease. People with ACDC develop calcification in the arteries of the lower extremities as well as calcium deposit in the joints of the fingers, wrists, ankles and feet. The lower extremities calcification causes claudication because of severe ischemia requiring at time revascularization procedures. the calcium deposits in the joints causes severe debilitating pain in the hands and feet. Currently, there are no standard treatments for ACDC.
* Etidronate is a bisphosphonate that interferes with bone metabolism. It is approved to treat Paget's disease, a condition in which the bones are soft and weak and may be deformed, painful, or easily broken. It is also used to treat high blood calcium levels. Researchers want to see if it can be used to treat the calcifications of ACDC and improve pain and blood flow in the lower extremities and arthritic pain of the hands and feet.

Objectives:

- To see if etidronate is a safe and effective treatment for ACDC.

Eligibility:

- People between 18 and 80 years of age who have been diagnosed with ACDC.

Design:

* Participants will be screened with a physical exam and medical history. They will also have imaging studies, including CT scan of the lower extremities, x-rays and DEXA bone scans, before starting treatment. Blood and urine samples will be collected. An exercise tolerance test will also be given and ABI (ankle brachial index will be measured.
* Participants will take etidronate by mouth once a day for 14 days every 3 months. They will be assigned an individualized 6- month drug schedule to follow.
* Participants will have regular study visits throughout the treatment period. These visits will involve imaging studies, full dental exams, and blood and urine tests. Participants will also have exercise tolerance tests and ABIs measured.
* Participants may also provide tissue samples for further study.
* Treatment will continue for up to 3 years as long as the side effects are not severe and the condition does not become worse. Participants will have a final follow-up visit after stopping treatment.

Detailed description: We have recently identified a novel genetic disease affecting nine known adults in whom de novo vascular calcifications develop in the lower extremity arteries and juxta-articular joint capsules of the fingers, wrists, ankles and feet. This rare disease results from bi-allelic mutations in the gene ecto-5-prime-nucleotidase (NT5E), encoding the CD73 protein. CD73, an enzyme involved in the extracellular ATP metabolic pathway, converts extracellular AMP to adenosine and inorganic phosphate. The clinical symptoms of this rare disease, termed ACDC (Arterial Calcifications due to Deficiency in CD73), include claudication of the calves, thighs, and buttocks, chronic ischemic pain of the feet at rest with threat of potential limb loss, and debilitating rheumatoid pain in the wrists and hands. Radiological and histological evaluations do not resemble classic atherosclerotic vascular calcification, since the calcification and dysplasia in ACDC occur in the medial portion of the arterial blood vessel wall. Data from patient-specific cell lines indicate increased activity of tissue non-specific alkaline phosphatase (TNAP), a key mediator of pathological ectopic tissue calcification, and thus reveals a potential therapeutic target.

To date, no effective therapy exists for ACDC patients. However, since bisphosphonates are potent competitive inhibitors of TNAP activity and are widely used to modulate bone metabolism, they may beneficially alter vascular calcification. In addition, our preliminary in vitro studies demonstrate the effectiveness of etidronate, a nitrogen-containing bisphosphonate, in lowering TNAP activity in cells isolated from ACDC patients. Etidronate, and bisphosphonates in general, have proven safe and are well tolerated by most patients.

This protocol provides for the administration of etidronate to ACDC patients, for whom no alternative treatment is available. Patients will be examined at the NIH Clinical Center bi-annually for 3 years. The primary objective of this clinical study is to test the effectiveness of etidronate in attenuating the progression of lower extremity arterial calcification and vascular blood flow based on CT calcium score and Ankle Brachial Index (ABI).

Eligibility criteria: * INCLUSION CRITERIA

Inclusion and exclusion criteria are to be assessed at Screening and Baseline prior to starting study drug. Each subject must meet the following criteria to be enrolled in this study:

* Subjects must be diagnosed with ACDC based on genetic tests confirming mutation(s) in NT5E and evidence of lower extremity arterial calcifications.
* Either gender and any ethnic background or race
* Age 18-80 years
* Willingness and legal ability to give and sign informed study consent
* Willingness to travel to NIH and local sites for scheduled protocol studies and treatment

EXCLUSION CRITERIA

Subjects who meet any of the following criteria will be excluded from the study:

* Subjects not diagnosed with ACDC
* Subjects \<18 or \>80 years of age
* Subjects who are unable or unwilling to sign an informed consent
* Severe renal impairment (estimated creatinine clearance/eGFR of \< 30ml/min calculated using CKD-EPI equation)
* Longstanding diabetes mellitus (more than 10 years)
* Known abnormality of the esophagus that would interfere with the passage of the drug
* Known sensitivity to etidronate
* Pregnancy
* 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.

Primary outcomes:
measure: Ankle-brachial Index at Rest at Pre-treatment, On-treatment and Post-treatment of Etidronate in Participants Diagnosed With ACDC
timeFrame: Up to 2 years (pre-treatment), 3 years (on-treatment) and up to 1 year (post-treatment)
measure: Ankle-brachial Index After Exercise at Pre-treatment, On-treatment and Post-treatment of Etidronate in Participants Diagnosed With ACDC
timeFrame: Up to 2 years (pre-treatment), 3 years (on-treatment) and up to 1 year (post-treatment)
measure: Computed Tomography Calcium Score of Lower Extremities at Pre-treatment, On-treatment and Post-treatment of Etidronate in Participants Diagnosed With ACDC
timeFrame: Up to 2 years (pre-treatment), 3 years (on-treatment) and up to 1 year (post-treatment)
Secondary outcomes:
measure: Changes in Hand Joint Calcification Based on Hand X-ray Before and During Etidronate in Participants Diagnosed With ACDC
timeFrame: Up to 2 years (pre-treatment), 3 years (on-treatment)
measure: Simple Disease Activity Index Score at Pre-treatment, On-treatment and Post-treatment of Etidronate in Participants Diagnosed With ACDC
timeFrame: Up to 2 years (pre-treatment), 3 years (on-treatment) and up to 1 year (post-treatment)
measure: Duke Activity Status Index Score at Pre-treatment, On-treatment and Post-treatment of Etidronate in Participants Diagnosed With ACDC
timeFrame: Up to 2 years (pre-treatment), 3 years (on-treatment) and up to 1 year (post-treatment)
measure: Peak Metabolic Equivalents (METS) During Treadmill Test at Pre-treatment, On-treatment and Post- Treatment of Etidronate in Participants Diagnosed With ACDC
timeFrame: Up to 2 years (pre-treatment), 3 years (on-treatment) and up to 1 year (post-treatment)
Other outcomes:
Locations:
city: Bethesda
country: United States
facility: National Institutes of Health Clinical Center, 9000 Rockville Pike
state: Maryland
Study officials:
affiliation: National Heart, Lung, and Blood Institute (NHLBI)
name: Alessandra Brofferio, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: St Hilaire C, Ziegler SG, Markello TC, Brusco A, Groden C, Gill F, Carlson-Donohoe H, Lederman RJ, Chen MY, Yang D, Siegenthaler MP, Arduino C, Mancini C, Freudenthal B, Stanescu HC, Zdebik AA, Chaganti RK, Nussbaum RL, Kleta R, Gahl WA, Boehm M. NT5E mutations and arterial calcifications. N Engl J Med. 2011 Feb 3;364(5):432-42. doi: 10.1056/NEJMoa0912923.
citation: Fleisch H. Bisphosphonates: mechanisms of action. Endocr Rev. 1998 Feb;19(1):80-100. doi: 10.1210/edrv.19.1.0325. No abstract available.
citation: Russell RG. Bisphosphonates: mode of action and pharmacology. Pediatrics. 2007 Mar;119 Suppl 2:S150-62. doi: 10.1542/peds.2006-2023H.