Etidronate for Arterial Calcifications Due to Deficiency in CD73 (ACDC)

NCT01585402 | Completed Phase 2 Results FDA Drug FDA Device

• 2 other identifiers: 12011012-H-0110
• Study Type: interventional
• Target: 7
• Locations: 1 country
• Sites: 1

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.

Conditions

Arterial Calcification; CD73 Deficiency

Keywords

NT5E; Bisphosphonates; Vascular Calcifications; Joint Capsule Calcifications; Inherited Disease

Outcome Measures

Primary Outcomes (3)

• Ankle-brachial Index at Rest at Pre-treatment, On-treatment and Post-treatment of Etidronate in Participants Diagnosed With ACDC

  Ankle-brachial Index (ABI) at rest at pre-treatment, on-treatment and post-treatment of etidronate in participants diagnosed with ACDC. ABI is the ratio of the blood pressure in the lower and upper extremities obtained by dividing the blood pressure in an artery of the ankle by the blood pressure in an artery of the arm. Interpreting ABI values indicate the amount of arterial disease. Interpretation is as follows: \> or equal to 1.3 is noncompressible vessel, \> or equal to 1.0 is normal, 0.9 to 0.99 is borderline or equivocal, 0.7 to 0.89 is mild arterial disease, 0.5 to 0.69 is moderate arterial disease, and \<0.5 is severe arterial disease.

  Up to 2 years (pre-treatment), 3 years (on-treatment) and up to 1 year (post-treatment)

• Ankle-brachial Index After Exercise at Pre-treatment, On-treatment and Post-treatment of Etidronate in Participants Diagnosed With ACDC

  Ankle-brachial Index (ABI) after exercise at pre-treatment, on-treatment and post-treatment of etidronate in participants diagnosed with ACDC. ABI is the ratio of the blood pressure in the lower and upper extremities obtained by dividing the blood pressure in an artery of the ankle by the blood pressure in an artery of the arm. Interpreting ABI values indicate the amount of arterial disease. Interpretation is as follows: \> or equal to 1.3 is noncompressible vessel, \> or equal to 1.0 is normal, 0.9 to 0.99 is borderline or equivocal, 0.7 to 0.89 is mild arterial disease, 0.5 to 0.69 is moderate arterial disease, and \<0.5 is severe arterial disease.

  Up to 2 years (pre-treatment), 3 years (on-treatment) and up to 1 year (post-treatment)

• Computed Tomography Calcium Score of Lower Extremities at Pre-treatment, On-treatment and Post-treatment of Etidronate in Participants Diagnosed With ACDC

  Computed tomography (CT) Calcium Score of lower extremities at pre-treatment, on-treatment and post-treatment of etidronate in participants diagnosed with ACDC. According to Cleveland Clinic, a calcium score uses CT to detect calcium deposits in the coronary arteries of the heart. A higher coronary calcium score indicates a higher chance of significant narrowing in the coronary arteries and a higher risk of future heart attack. The Calcium Score range is as follows: zero is no evidence of Coronary Artery Disease (CAD), 1-10 is minimal evidence of CAD, 11-100 is mild evidence of CAD, 101-400 is moderate evidence of CAD and over 400 is extensive evidence of CAD. We applied the same concept to the arteries of the lower extremities. ACDC participants have an overwhelming amount of calcification in the lower extremity vasculature therefore their Calcium Scores are all out of range at baseline and during the study period.

  Up to 2 years (pre-treatment), 3 years (on-treatment) and up to 1 year (post-treatment)

Secondary Outcomes (4)

• Changes in Hand Joint Calcification Based on Hand X-ray Before and During Etidronate in Participants Diagnosed With ACDC

  Up to 2 years (pre-treatment), 3 years (on-treatment)

• Simple Disease Activity Index Score at Pre-treatment, On-treatment and Post-treatment of Etidronate in Participants Diagnosed With ACDC

  Up to 2 years (pre-treatment), 3 years (on-treatment) and up to 1 year (post-treatment)

• Duke Activity Status Index Score at Pre-treatment, On-treatment and Post-treatment of Etidronate in Participants Diagnosed With ACDC

  Up to 2 years (pre-treatment), 3 years (on-treatment) and up to 1 year (post-treatment)

• Peak Metabolic Equivalents (METS) During Treadmill Test at Pre-treatment, On-treatment and Post- Treatment of Etidronate in Participants Diagnosed With ACDC

  Up to 2 years (pre-treatment), 3 years (on-treatment) and up to 1 year (post-treatment)

Study Arms (1)

Etidronate Treatment for Arterial Calcifications due to Deficiency in CD73 (ACDC)

EXPERIMENTAL

Participants diagnosed with Arterial Calcifications due to Deficiency in CD73 (ACDC) will receive Etidronate. Etidronate will be administered orally at total dose of 20mg/kg daily x 14 days, followed by 10 weeks off study drug (12 weeks = one cycle). Participants may receive up to 12 cycles of etidronate.

Drug: Etidronate; Device: MRI Scan

Interventions

Etidronate 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.

Also known as: Etidronate disodium, Didronel

Etidronate Treatment for Arterial Calcifications due to Deficiency in CD73 (ACDC)

MRI Scan DEVICE

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 high degree of calcification is precluding that evaluation by CT.

Etidronate Treatment for Arterial Calcifications due to Deficiency in CD73 (ACDC)

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may not qualify if:

• 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
• 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.

Sponsors & Collaborators

• National Heart, Lung, and Blood Institute (NHLBI): lead

Study Sites (1)

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892, United States

Location

Related Publications (5)

• 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.

  PMID: 21288095 BACKGROUND

• Fleisch H. Bisphosphonates: mechanisms of action. Endocr Rev. 1998 Feb;19(1):80-100. doi: 10.1210/edrv.19.1.0325. No abstract available.

  PMID: 9494781 BACKGROUND

• Russell RG. Bisphosphonates: mode of action and pharmacology. Pediatrics. 2007 Mar;119 Suppl 2:S150-62. doi: 10.1542/peds.2006-2023H.

  PMID: 17332236 BACKGROUND

• Ferrante EA, Cudrici CD, Rashidi M, Fu YP, Huffstutler R, Carney K, Chen MY, St Hilaire C, Smith K, Bagheri H, Katz JD, Ferreira CR, Gahl WA, Boehm M, Brofferio A. Pilot study to evaluate the safety and effectiveness of etidronate treatment for arterial calcification due to deficiency of CD73 (ACDC). Vasc Med. 2024 Jun;29(3):245-255. doi: 10.1177/1358863X241235669. Epub 2024 Apr 3.

  PMID: 38568107 DERIVED

• Snijders BM, Mathijssen G, Peters MJ, Emmelot-Vonk MH, de Jong PA, Bakker S, Crommelin HA, Ruigrok YM, Brilstra EH, Schepers VP, Spiering W, van Valen E, Koek HL. The effects of etidronate on brain calcifications in Fahr's disease or syndrome: rationale and design of the randomised, placebo-controlled, double-blind CALCIFADE trial. Orphanet J Rare Dis. 2024 Feb 7;19(1):49. doi: 10.1186/s13023-024-03039-7.

  PMID: 38326858 DERIVED

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Vascular Calcification; Genetic Diseases, Inborn

Interventions

Etidronic Acid; Magnetic Resonance Imaging

Condition Hierarchy (Ancestors)

Calcinosis; Calcium Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Intervention Hierarchy (Ancestors)

Diphosphonates; Organophosphonates; Organophosphorus Compounds; Organic Chemicals; Tomography; Diagnostic Imaging; Diagnostic Techniques and Procedures; Diagnosis

Results Point of Contact

• Title: Alessandra Brofferio, M.D.
• Organization: National Heart, Lung, and Blood Institute (NHLBI)

alessandra.brofferio@nih.gov

301.496.2634

Study Officials

• Alessandra Brofferio, M.D.

  National Heart, Lung, and Blood Institute (NHLBI)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 24, 2012
• First Posted: April 25, 2012
• Study Start: August 20, 2012
• Primary Completion: August 6, 2021
• Study Completion: August 6, 2021
• Last Updated: October 4, 2022
• Results First Posted: October 4, 2022

Record last verified: 2021-08

Locations

US (1)