Etidronate for Arterial Calcifications Due to Deficiency in CD73 (ACDC)
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|ClinicalTrials.gov Identifier: NCT01585402|
Recruitment Status : Active, not recruiting
First Posted : April 25, 2012
Last Update Posted : November 27, 2020
- Arterial Calcifications due to Deficiency in CD73 (ACDC) is a rare genetic disease. People with ACDC develop calcium deposits in the arteries and joints of the fingers, wrists, ankles and feet. These deposits cause severe pain in the hands and feet, even when the person is at rest, and may lead to loss of the affected hand or foot. Currently, there are no standard treatments for ACDC.
- Etidronate is a drug that helps to slow or stop the natural process that dissolves bone tissue. 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 symptoms of ACDC and improve pain and blood flow in the hands and feet.
- To see if etridronate is a safe and effective treatment for ACDC.
- People between 18 and 80 years of age who have been diagnosed with ACDC.
- Participants will be screened with a physical exam and medical history. They will also have imaging studies, including x-rays and DEXA bone scans, before starting treatment. Blood and urine samples will be collected. An exercise tolerance test will also be given.
- Participants will take etridronate by mouth once a day for 14 days every 3 months. They will be assigned an individualized 6-month drug schedule to follow. Participants should not eat foods that are high in calcium for at least 2 hours after taking the study drug.
- 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 arm and leg blood pressure tests to measure pain and blood flow.
- 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.
|Condition or disease||Intervention/treatment||Phase|
|Arterial Calcification CD73 Deficiency||Drug: Etidronate Device: MRI Scan||Phase 2|
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 bisphophonates in general, have proven safe and 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).
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||7 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|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)|
|Actual Study Start Date :||August 20, 2012|
|Estimated Primary Completion Date :||August 31, 2021|
|Estimated Study Completion Date :||August 31, 2021|
20 mg/kg oral 14 days on / 10 weeks off study drug
Didronel (etidronate disodium)- Didronel tablets contain either 200 mg or 400 mg of etidronate disodium, the disodium salt of (1-hydroxyethylidene) diphosphonic acid, for oral administration. This compound, also known as EHDP. regulates bone metabolism. It is a white powder, highly soluble in water. The 400 mg tablets are white capsule-shaped tablets with ED 400 on one side and G on the other side.
Device: MRI Scan
Visit on day 0 and visit at 36 month - Exploratory MRI studies may be employed to evaluate the lumen of the artery and degree of collateral vessels, given that the highh degree of calcification is precluding that evaluation by CT.
- effectiveness etidronate in attenuating the progression of lower extremity arterial calcification and improved vascular blood flow [ Time Frame: 3 years ]This trial is designed to evaluate the effectiveness of etidronate in subjects diagnosed with ACDC. The primary endpoints will be CT calcium score and Ankle- brachial Index (ABI). The planned analyses will include descriptive statistics and longitudinal trends in the CT calcium score and ABI. Percentage changes in CT calcium score and ABI will be compared between the pre-treatment phase baseline and treatment phase. The significance of the changes will be reported with the use of t-test or rank-based test as appropriate.
- Changes in hand joint calcification based on hand x-ray [ Time Frame: 3 years ]At each study visit participants will complete a Rheumatoid Arthritis questionnaire (Appendix 1) to assess hand pain
- Decrease in hand pain based on Rheumatoid Arthritis assessment tool [ Time Frame: 3 years ]At each study visit participants will complete the Duke Activity Index (Appendix 2)to measure functional capacity.
- Functional improvement in treadmill test results [ Time Frame: 3 years ]A symptom-limited treadmill progressive test (Gardner Protocol) with gradual increase in grade will be performed in accordance with standard practice to evaluation exercise capacity and pain on exertion in subjects with decreased peripheral arterial perfusion. Briefly, the test will use a constant speed of 2 mph and gradual increase in grade of 2% every 2 minutes beginning at 0% grade. Distance to onset of pain and to maximal pain will be recorded. Lower extremity arterial Doppler pressure will be measured immediately post exercise.
- Analysis of the composition of collected surgical tissue with calcification/inflammation [ Time Frame: 3 years ]Composition of collected surgical tissue with calcification/inflammation will be analyzed to identify markers of inflammation and types of minerals in the calcium deposits
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 ClinicalTrials.gov identifier (NCT number): NCT01585402
|United States, Maryland|
|National Institutes of Health Clinical Center, 9000 Rockville Pike|
|Bethesda, Maryland, United States, 20892|
|Principal Investigator:||Alessandra Brofferio, M.D.||National Heart, Lung, and Blood Institute (NHLBI)|