Arterial CalcificationPhase 2NCT01585402
Etidronate for Arterial Calcifications Due to Deficiency in CD73 (ACDC)
A Phase 2 study testing Etidronate and MRI Scan in people with Arterial Calcification and CD73 Deficiency, run by National Heart, Lung, and Blood Institute (NHLBI) at 1 site in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 80 years
- Conditions the study is for
- Arterial Calcification, CD73 Deficiency
- What is being tested?
- Etidronate and MRI Scan
- Type of treatment
- Pill or oral medicine, Medical device
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 7 participants
- Where
- 1 siteUnited States
- Study dates
- 20 Aug 2012to 6 Aug 2021
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 80 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Who cannot join
- 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)
Show all 10Show fewer
- 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.
Trial locations and contacts
1 site in 1 country.
United States1 site
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, 20892
About this study
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)
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.
Read more
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.
Read the 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).
- Conditions
- Arterial Calcification, CD73 Deficiency
- Being tested
- Etidronate, MRI Scan
- Keywords
- NT5E, Bisphosphonates, Vascular Calcifications, Joint Capsule Calcifications, Inherited Disease
- Medical subject headings
- Vascular Calcification, Genetic Diseases, Inborn
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
EtidronateDrug
Also called Etidronate disodium, Didronel
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.
MRI ScanDevice
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.
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: Drug: Etidronate; Device: MRI Scan |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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.
Measured: 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.
Measured: 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
Changes in hand joint calcification are based on bilateral hand x-ray before and during Etidronate in participants diagnosed with ACDC as a composite score provided by a radiologist measuring calcium deposit volume (mm^3), calcium deposit density and number of calcifications observed in each finger joint. This is a new scoring system created by our team for the research study, so it has never been used before and healthy volunteer data is not available. However, healthy volunteers would be expected to have no joint calcifications in their hands, in sharp contrast with what we observe in ACDC patients. Density is subjectively defined as 0 equals no calcification, 1 equals barely visible, 2 equals visible with faint margins, 3 equals moderately dense and 4 equals fully dense. The range for the hand X-ray calcification score in this cohort was 288 (minimum) to 863 (maximum).
Measured: 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
Simple Disease Activity Index (SDAI) score at pre-treatment, on-treatment and post-treatment of Etidronate in Participants Diagnosed With ACDC.
The SDAI is a standard rheumatoid arthritis scores that provide treatment outcome measures on patient joint swelling and pain as well as participants ability to perform daily activity tasks. The SDAI is the sum of five parameters: tender and swollen joint count (based on a 28-joint assessment), patient and physician global assessment of disease activity and level of C-Reactive Protein (mg/dl, normal <1 mg/dl). Total score is defined as: remission as less than 3, low disease activity is between 3 to 11, moderate disease activity is between 11 to 26 and high disease activity is greater than 26. Maximum score possible score is 86 with high disease activity.
Measured: 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
Duke Activity Status Index (DASI) score at pre-treatment, on-treatment and post-treatment of Etidronate in Participants Diagnosed With ACDC.
The DASI is an assessment tool used to evaluate the functional capacity of patients with cardiovascular disease (CVD), such as coronary artery disease, myocardial infarction, and heart failure. Positive responses are summed up to get a total score, which ranges from 0 to 58.2. Higher scores would indicate a higher functional capacity.
Measured: 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
Peak Metabolic Equivalents (METS) During Treadmill Test at Pre-treatment, On-treatment and Post- treatment of Etidronate in Participants Diagnosed With ACDC
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. This test will use a constant speed of 2 mph and gradual increase in grade of 2% every 2 minutes beginning at 0% grade.
METS is a measure of how able a person is to tolerate exercise. No scales exists. METS is calculated by = METs x 3.5 x (your body weight in kilograms) / 200 = calories burned per minute.
Measured: Up to 2 years (pre-treatment), 3 years (on-treatment) and up to 1 year (post-treatment)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted25 Apr 2012 (estimated)
- Study start20 Aug 2012
- Primary completion6 Aug 2021
- Study completion6 Aug 2021
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (5)Papers the sponsor has linked to this study.
- Other trials for Arterial CalcificationStudies of the same condition, open and under way.
- More trials run by National Heart, Lung, and Blood Institute (NHLBI)The sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 7 participants (actual)
Sponsor and investigators
- Sponsor type
- US National Institutes of Health
- Responsible party
- Sponsor
- Investigators
- Alessandra Brofferio, M.D., Principal investigator, National Heart, Lung, and Blood Institute (NHLBI)
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01585402
- Sponsor's protocol ID
- 120110
- Other IDs
- 12-H-0110
- Status last verified
- Aug 2021
- First submitted
- 24 Apr 2012
- Last updated
- 4 Oct 2022
- Results posted
- Yes, on ClinicalTrials.gov
- FDA-regulated drug
- Yes
- FDA-regulated device
- Yes
Publications
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.
PubMed 21288095Fleisch H. Bisphosphonates: mechanisms of action. Endocr Rev. 1998 Feb;19(1):80-100. doi: 10.1210/edrv.19.1.0325. No abstract available.
PubMed 9494781Russell RG. Bisphosphonates: mode of action and pharmacology. Pediatrics. 2007 Mar;119 Suppl 2:S150-62. doi: 10.1542/peds.2006-2023H.
PubMed 17332236Ferrante 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.
PubMed 38568107Snijders 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.
PubMed 38326858
Study at a glance
From the registry record, last updated by the sponsor on 4 Oct 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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)
- ClinicalTrials.gov ID
- NCT01585402
- Acronym / sponsor ID
- 120110
- Conditions
- Arterial Calcification, CD73 Deficiency
- Keywords
- NT5E, Bisphosphonates, Vascular Calcifications, Joint Capsule Calcifications, Inherited Disease
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 7 participants (actual)
- Lead sponsor
- National Heart, Lung, and Blood Institute (NHLBI)US National Institutes of Health
- Study start
- 20 Aug 2012 (actual)
- Primary completion
- 6 Aug 2021 (actual)
- Study completion
- 6 Aug 2021 (actual)
- First posted
- 25 Apr 2012 (estimated)
- Results
- Posted 4 Oct 2022
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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).
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Etidronate Treatment for Arterial Calcifications due to Deficiency in CD73 (ACDC) | Experimental | Drug: Etidronate, Device: MRI ScanParticipants 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. |
Who may qualify
- Ages
- 18 to 80 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (6 listed)
- 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
Key exclusion criteria (10 listed)
- 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)
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| EtidronateAlso: Etidronate disodium, DidronelDidronel (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. | Drug | Etidronate Treatment for Arterial Calcifications due to Deficiency in CD73 (ACDC) |
| MRI ScanVisit 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. | Device | Etidronate Treatment for Arterial Calcifications due to Deficiency in CD73 (ACDC) |
Primary outcome
Ankle-brachial Index at Rest at Pre-treatment, On-treatment and Post-treatment of Etidronate in Participants Diagnosed With ACDC
Time frame: Up to 2 years (pre-treatment), 3 years (on-treatment) and up to 1 year (post-treatment)
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.
Ankle-brachial Index After Exercise at Pre-treatment, On-treatment and Post-treatment of Etidronate in Participants Diagnosed With ACDC
Time frame: Up to 2 years (pre-treatment), 3 years (on-treatment) and up to 1 year (post-treatment)
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.
Computed Tomography Calcium Score of Lower Extremities at Pre-treatment, On-treatment and Post-treatment of Etidronate in Participants Diagnosed With ACDC
Time frame: Up to 2 years (pre-treatment), 3 years (on-treatment) and up to 1 year (post-treatment)
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.
4 secondary outcomes
Changes in Hand Joint Calcification Based on Hand X-ray Before and During Etidronate in Participants Diagnosed With ACDC
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: Up to 2 years (pre-treatment), 3 years (on-treatment) and up to 1 year (post-treatment)
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 4 Oct 2022.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Background: PubMed 21288095St 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.
- Background: PubMed 9494781Fleisch H. Bisphosphonates: mechanisms of action. Endocr Rev. 1998 Feb;19(1):80-100. doi: 10.1210/edrv.19.1.0325. No abstract available.
- Background: PubMed 17332236Russell RG. Bisphosphonates: mode of action and pharmacology. Pediatrics. 2007 Mar;119 Suppl 2:S150-62. doi: 10.1542/peds.2006-2023H.
- Derived from this study: PubMed 38568107Ferrante 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.
- Derived from this study: PubMed 38326858Snijders 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.
- NIH Clinical Center Detailed Web PageLink provided by the sponsor.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Alessandra Brofferio, M.D. principal investigator
National Heart, Lung, and Blood Institute (NHLBI)
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Etidronate and MRI Scan in people with Arterial Calcification and CD73 Deficiency, run by National Heart, Lung, and Blood Institute (NHLBI) at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 6 inclusion and 10 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 4 Oct 2022. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 4 Oct 2022). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Ankle-brachial Index at Rest at Pre-treatment, On-treatment and Post-treatment of Etidronate in Participants Diagnosed With ACDC (time frame: Up to 2 years (pre-treatment), 3 years (on-treatment) and up to 1 year (post-treatment)). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01585402, which also lists 5 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 4 Oct 2022.