A Phase 2 interventional study of Etidronate and MRI Scan in Arterial Calcification and CD73 Deficiency, sponsored by National Heart, Lung, and Blood Institute (NHLBI). Completed at 1 site in United States. Open to participants aged 18 Years to 80 Years. Per ClinicalTrials.gov, last updated 2022-10-04.
Sponsored by National Heart, Lung, and Blood Institute (NHLBI) · Phase 2, Interventional, and Treatment
Background:
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:
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).
83 studies on the registry are indexed under Vascular Calcification; 17 are open to participants now.
This study's enrollment of 7 is below the median of 60 across 55 interventional studies indexed under Vascular Calcification.
Browse Vascular Calcification studies →National Heart, Lung, and Blood Institute (NHLBI) is the lead sponsor of 1,143 studies on the registry; 72 are open to participants now.
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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:
EXCLUSION CRITERIA
Subjects who meet any of the following criteria will be excluded from the study:
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
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
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.
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.
Time frame: 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.
Time frame: 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.
Time frame: Up to 2 years (pre-treatment), 3 years (on-treatment) and up to 1 year (post-treatment)
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).
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
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.
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
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.
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
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.
Time frame: Up to 2 years (pre-treatment), 3 years (on-treatment) and up to 1 year (post-treatment)
Participants were recruited at the National Institutes of Health Clinical Care Center at Bethesda, Maryland from August 2012 to August 2021.
| Milestone | Etidronate Treatment for Arterial Calcifications Due to Deficiency in CD73 (ACDC) |
|---|---|
| Started | 7 |
| Completed | 7 |
| Not completed | 0 |
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.
| score on a scale | Etidronate Treatment for Arterial Calcifications Due to Deficiency in CD73 (ACDC) |
|---|---|
| Left Side Pre-Treatment at Rest | 0.5741 (0.4801 to 0.6681) |
| Left Side On-Treatment at Rest | 0.5411 (0.4479 to 0.6342) |
| Left Side Post-Treatment at Rest | 0.5222 (0.4254 to 0.6190) |
| Right Side Pre-Treatment at Rest | 0.5266 (0.3746 to 0.6785) |
| Right Side On-Treatment at Rest | 0.5322 (0.3827 to 0.6817) |
| Right Side Post-Treatment at Rest | 0.5771 (0.4122 to 0.7420) |
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.
| score on a scale | Etidronate Treatment for Arterial Calcifications Due to Deficiency in CD73 (ACDC) |
|---|---|
| Left Side Pre-Treatment after Exercise | 0.5658 (0.4651 to 0.6664) |
| Left Side On-Treatment after Exercise | 0.5310 (0.4320 to 0.6300) |
| Left Side Post-Treatment after Exercise | 0.5031 (0.3989 to 0.6073) |
| Right Side Pre-Treatment after Exercise | 0.6056 (0.3927 to 0.8184) |
| Right Side On-Treatment after Exercise | 0.5664 (0.3483 to 0.7844) |
| Right Side Post-Treatment after Exercise | 0.4077 (0.1878 to 0.6275) |
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.
| score on a scale | Etidronate Treatment for Arterial Calcifications Due to Deficiency in CD73 (ACDC) |
|---|---|
| Left Lower Extremity Pre-Treatment | 88817 (20615 to 157019) |
| Left Lower Extremity On-Treatment | 91454 (23243 to 159664) |
| Left Lower Extremity Post-Treatment | 94358 (26166 to 162551) |
| Right Lower Extremity Pre-Treatment | 80289 (12355 to 148222) |
| Right Lower Extremity On-Treatment | 81641 (13689 to 149592) |
| Right Lower Extremity Post-Treatment | 83950 (16206 to 151694) |
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).
| score on a scale | Etidronate Treatment for Arterial Calcifications Due to Deficiency in CD73 (ACDC) |
|---|---|
| Left Hand Pre-Treatment | 241.16 (148.45 to 333.87) |
| Left Hand On Treatment | 275.15 (173.43 to 376.88) |
| Right Hand Pre Treatment | 255.77 (119.40 to 392.13) |
| Right Hand On Treatment | 360.20 (209.41 to 510.98) |
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.
| score on a scale | Etidronate Treatment for Arterial Calcifications Due to Deficiency in CD73 (ACDC) |
|---|---|
| Pre-Treatment | 18.5919 (14.5739 to 22.6099) |
| On-treatment | 8.2987 (5.1215 to 11.4759) |
| Post-treatment | 5.0098 (1.1502 to 8.8693) |
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.
| score on a scale | Etidronate Treatment for Arterial Calcifications Due to Deficiency in CD73 (ACDC) |
|---|---|
| Pre-Treatment | 47.2282 (41.0117 to 53.4447) |
| On-treatment | 46.6314 (41.8702 to 51.3926) |
| Post-treatment | 50.8242 (44.6566 to 56.9917) |
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.
| Metabolic Equivalents | Etidronate Treatment for Arterial Calcifications Due to Deficiency in CD73 (ACDC) |
|---|---|
| Left Lower Extremity Pre-Treatment | 6.2514 (5.4057 to 7.0971) |
| Left Lower Extremity On-Treatment | 6.2577 (5.4467 to 7.0687) |
| Left Lower Extremity Post-Treatment | 6.2888 (5.4060 to 7.1717) |
| Right Lower Extremity Pre-Treatment | 6.2514 (5.4057 to 7.0971) |
| Right Lower Extremity On-Treatment | 6.2577 (5.4467 to 7.0687) |
| Right Lower Extremity Post-Treatment | 6.2888 (5.4060 to 7.1717) |
Collected over 37 months. Non-serious events are listed at a 0% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Etidronate Treatment for Arterial Calcifications Due to Deficiency in CD73 (ACDC) | 0/7 (0%) | 4/7 (57.1%) | 7/7 (100%) |
| Event | Etidronate Treatment for Arterial Calcifications Due to Deficiency in CD73 (ACDC) |
|---|---|
| Skin infectionInfections and infestations | 2/7 |
| StrokeNervous system disorders | 1/7 |
| Abdominal painGastrointestinal disorders | 1/7 |
| ConstipationGastrointestinal disorders | 1/7 |
| Lower gastrointestinal hemorrhageGastrointestinal disorders | 1/7 |
| Lung infectionInfections and infestations | 1/7 |
| Urinary tract infectionInfections and infestations | 1/7 |
| External iliac artery stenosisVascular disorders | 1/7 |
| Jump graft on the bypass area declining function of previous graftVascular disorders | 1/7 |
| Event | Etidronate Treatment for Arterial Calcifications Due to Deficiency in CD73 (ACDC) |
|---|---|
| DiarrheaGastrointestinal disorders | 7/7 |
| NauseaGastrointestinal disorders | 5/7 |
| ArthralgiaMusculoskeletal and connective tissue disorders | 5/7 |
| MyalgiaMusculoskeletal and connective tissue disorders | 5/7 |
| FatigueGeneral disorders | 5/7 |
| VomitingGastrointestinal disorders | 4/7 |
| HypernatremiaMetabolism and nutrition disorders | 4/7 |
| HypertriglyceridemiaMetabolism and nutrition disorders | 3/7 |
| PalpitationsCardiac disorders | 3/7 |
| Sinus bradycardiaCardiac disorders | 3/7 |
| Age, Categorical(Participants) | Etidronate Treatment for Arterial Calcifications Due to Deficiency in CD73 (ACDC) |
|---|---|
| <=18 years | 0 |
| Between 18 and 65 years | 7 |
| >=65 years | 0 |
| Sex: Female, Male(Participants) | Etidronate Treatment for Arterial Calcifications Due to Deficiency in CD73 (ACDC) |
|---|---|
| Female | 4 |
| Male | 3 |
| Ethnicity (NIH/OMB)(Participants) | Etidronate Treatment for Arterial Calcifications Due to Deficiency in CD73 (ACDC) |
|---|---|
| Hispanic or Latino | 0 |
| Not Hispanic or Latino | 7 |
| Unknown or Not Reported | 0 |
| Race (NIH/OMB)(Participants) | Etidronate Treatment for Arterial Calcifications Due to Deficiency in CD73 (ACDC) |
|---|---|
| American Indian or Alaska Native | 0 |
| Asian | 1 |
| Native Hawaiian or Other Pacific Islander | 0 |
| Black or African American | 0 |
| White | 6 |
| More than one race | 0 |
| Unknown or Not Reported | 0 |
| Region of Enrollment(participants) | Etidronate Treatment for Arterial Calcifications Due to Deficiency in CD73 (ACDC) |
|---|---|
| United States | 7 |
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