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NCT01585402

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

Completed Phase 2 Results posted Last updated 4 October 2022
What this trial tests

Phase 2 trial testing Etidronate in Arterial Calcification in 7 participants. Completed in 6 August 2021.

Timeline
20 August 2012
Primary endpoint
6 August 2021
6 August 2021

Quick facts

Lead sponsorNational Heart, Lung, and Blood Institute (NHLBI)
PhasePhase 2
StatusCompleted
Study typeINTERVENTIONAL
Allocationna
Designsingle group
Maskingnone
Primary purposetreatment
Enrollment7
Start date20 August 2012
Primary completion6 August 2021
Estimated completion6 August 2021
Sites1 location across United States

Drugs / interventions tested

Conditions studied

Sponsor

National Heart, Lung, and Blood Institute (NHLBI)

Who can join

Adults 18 to 80, any sex, with Arterial Calcification or CD73 Deficiency. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

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

Left Side Pre-Treatment at Rest
GroupValue95% CI
Etidronate Treatment for Arterial Calcifications Due to Deficiency in CD73 (ACDC)0.57410.4801 – 0.6681
Left Side On-Treatment at Rest
GroupValue95% CI
Etidronate Treatment for Arterial Calcifications Due to Deficiency in CD73 (ACDC)0.54110.4479 – 0.6342
Left Side Post-Treatment at Rest
GroupValue95% CI
Etidronate Treatment for Arterial Calcifications Due to Deficiency in CD73 (ACDC)0.52220.4254 – 0.6190
Right Side Pre-Treatment at Rest
GroupValue95% CI
Etidronate Treatment for Arterial Calcifications Due to Deficiency in CD73 (ACDC)0.52660.3746 – 0.6785
Right Side On-Treatment at Rest
GroupValue95% CI
Etidronate Treatment for Arterial Calcifications Due to Deficiency in CD73 (ACDC)0.53220.3827 – 0.6817
Right Side Post-Treatment at Rest
GroupValue95% CI
Etidronate Treatment for Arterial Calcifications Due to Deficiency in CD73 (ACDC)0.57710.4122 – 0.7420
Ankle-brachial Index After Exercise at Pre-treatment, On-treatment and Post-treatment of Etidronate in Participants Diagnosed With ACDC Primary · 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 moder

Left Side Pre-Treatment after Exercise
GroupValue95% CI
Etidronate Treatment for Arterial Calcifications Due to Deficiency in CD73 (ACDC)0.56580.4651 – 0.6664
Left Side On-Treatment after Exercise
GroupValue95% CI
Etidronate Treatment for Arterial Calcifications Due to Deficiency in CD73 (ACDC)0.53100.4320 – 0.6300
Left Side Post-Treatment after Exercise
GroupValue95% CI
Etidronate Treatment for Arterial Calcifications Due to Deficiency in CD73 (ACDC)0.50310.3989 – 0.6073
Right Side Pre-Treatment after Exercise
GroupValue95% CI
Etidronate Treatment for Arterial Calcifications Due to Deficiency in CD73 (ACDC)0.60560.3927 – 0.8184
Right Side On-Treatment after Exercise
GroupValue95% CI
Etidronate Treatment for Arterial Calcifications Due to Deficiency in CD73 (ACDC)0.56640.3483 – 0.7844
Right Side Post-Treatment after Exercise
GroupValue95% CI
Etidronate Treatment for Arterial Calcifications Due to Deficiency in CD73 (ACDC)0.40770.1878 – 0.6275
Computed Tomography Calcium Score of Lower Extremities at Pre-treatment, On-treatment and Post-treatment of Etidronate in Participants Diagnosed With ACDC Primary · 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 i

Left Lower Extremity Pre-Treatment
GroupValue95% CI
Etidronate Treatment for Arterial Calcifications Due to Deficiency in CD73 (ACDC)8881720615 – 157019
Left Lower Extremity On-Treatment
GroupValue95% CI
Etidronate Treatment for Arterial Calcifications Due to Deficiency in CD73 (ACDC)9145423243 – 159664
Left Lower Extremity Post-Treatment
GroupValue95% CI
Etidronate Treatment for Arterial Calcifications Due to Deficiency in CD73 (ACDC)9435826166 – 162551
Right Lower Extremity Pre-Treatment
GroupValue95% CI
Etidronate Treatment for Arterial Calcifications Due to Deficiency in CD73 (ACDC)8028912355 – 148222
Right Lower Extremity On-Treatment
GroupValue95% CI
Etidronate Treatment for Arterial Calcifications Due to Deficiency in CD73 (ACDC)8164113689 – 149592
Right Lower Extremity Post-Treatment
GroupValue95% CI
Etidronate Treatment for Arterial Calcifications Due to Deficiency in CD73 (ACDC)8395016206 – 151694
Changes in Hand Joint Calcification Based on Hand X-ray Before and During Etidronate in Participants Diagnosed With ACDC Secondary · Up to 2 years (pre-treatment), 3 years (on-treatment)

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

Left Hand Pre-Treatment
GroupValue95% CI
Etidronate Treatment for Arterial Calcifications Due to Deficiency in CD73 (ACDC)241.16148.45 – 333.87
Left Hand On Treatment
GroupValue95% CI
Etidronate Treatment for Arterial Calcifications Due to Deficiency in CD73 (ACDC)275.15173.43 – 376.88
Right Hand Pre Treatment
GroupValue95% CI
Etidronate Treatment for Arterial Calcifications Due to Deficiency in CD73 (ACDC)255.77119.40 – 392.13
Right Hand On Treatment
GroupValue95% CI
Etidronate Treatment for Arterial Calcifications Due to Deficiency in CD73 (ACDC)360.20209.41 – 510.98
Simple Disease Activity Index Score at Pre-treatment, On-treatment and Post-treatment of Etidronate in Participants Diagnosed With ACDC Secondary · Up to 2 years (pre-treatment), 3 years (on-treatment) and up to 1 year (post-treatment)

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

Pre-Treatment
GroupValue95% CI
Etidronate Treatment for Arterial Calcifications Due to Deficiency in CD73 (ACDC)18.591914.5739 – 22.6099
On-treatment
GroupValue95% CI
Etidronate Treatment for Arterial Calcifications Due to Deficiency in CD73 (ACDC)8.29875.1215 – 11.4759
Post-treatment
GroupValue95% CI
Etidronate Treatment for Arterial Calcifications Due to Deficiency in CD73 (ACDC)5.00981.1502 – 8.8693
Duke Activity Status Index Score at Pre-treatment, On-treatment and Post-treatment of Etidronate in Participants Diagnosed With ACDC Secondary · Up to 2 years (pre-treatment), 3 years (on-treatment) and up to 1 year (post-treatment)

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.

Pre-Treatment
GroupValue95% CI
Etidronate Treatment for Arterial Calcifications Due to Deficiency in CD73 (ACDC)47.228241.0117 – 53.4447
On-treatment
GroupValue95% CI
Etidronate Treatment for Arterial Calcifications Due to Deficiency in CD73 (ACDC)46.631441.8702 – 51.3926
Post-treatment
GroupValue95% CI
Etidronate Treatment for Arterial Calcifications Due to Deficiency in CD73 (ACDC)50.824244.6566 – 56.9917
Peak Metabolic Equivalents (METS) During Treadmill Test at Pre-treatment, On-treatment and Post- Treatment of Etidronate in Participants Diagnosed With ACDC Secondary · 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 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 exerci

Left Lower Extremity Pre-Treatment
GroupValue95% CI
Etidronate Treatment for Arterial Calcifications Due to Deficiency in CD73 (ACDC)6.25145.4057 – 7.0971
Left Lower Extremity On-Treatment
GroupValue95% CI
Etidronate Treatment for Arterial Calcifications Due to Deficiency in CD73 (ACDC)6.25775.4467 – 7.0687
Left Lower Extremity Post-Treatment
GroupValue95% CI
Etidronate Treatment for Arterial Calcifications Due to Deficiency in CD73 (ACDC)6.28885.4060 – 7.1717
Right Lower Extremity Pre-Treatment
GroupValue95% CI
Etidronate Treatment for Arterial Calcifications Due to Deficiency in CD73 (ACDC)6.25145.4057 – 7.0971
Right Lower Extremity On-Treatment
GroupValue95% CI
Etidronate Treatment for Arterial Calcifications Due to Deficiency in CD73 (ACDC)6.25775.4467 – 7.0687
Right Lower Extremity Post-Treatment
GroupValue95% CI
Etidronate Treatment for Arterial Calcifications Due to Deficiency in CD73 (ACDC)6.28885.4060 – 7.1717

Adverse events — posted to ClinicalTrials.gov

Time frame: 37 months. Reporting threshold: 0%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Etidronate Treatment for Arterial Calcifications Due to Deficiency in CD73 (ACDC)
Serious: 4/7 (57%)
Deaths: 0/7

Serious adverse events (9 terms)

ReactionSystemEtidronate Treatment for A…
Skin infectionInfections and infestations
StrokeNervous system disorders
Abdominal painGastrointestinal disorders
ConstipationGastrointestinal disorders
Lower gastrointestinal hemorrhageGastrointestinal disorders
Lung infectionInfections and infestations
Urinary tract infectionInfections and infestations
External iliac artery stenosisVascular disorders
Jump graft on the bypass area declining function of previous graftVascular disorders
Other adverse events (101 terms — click to expand)

ReactionSystemEtidronate Treatment for A…
DiarrheaGastrointestinal disorders
NauseaGastrointestinal disorders
ArthralgiaMusculoskeletal and connective tissue disorders
MyalgiaMusculoskeletal and connective tissue disorders
FatigueGeneral disorders
VomitingGastrointestinal disorders
HypernatremiaMetabolism and nutrition disorders
HypertriglyceridemiaMetabolism and nutrition disorders
PalpitationsCardiac disorders
Sinus bradycardiaCardiac disorders
Back painMusculoskeletal and connective tissue disorders
DizzinessNervous system disorders
DysgeusiaNervous system disorders
HeadacheNervous system disorders
AnemiaBlood and lymphatic system disorders
Flu like symptomsGeneral disorders
Abdominal painGastrointestinal disorders
BloatingGastrointestinal disorders
ConstipationGastrointestinal disorders
Dental cariesGastrointestinal disorders
DyspepsiaGastrointestinal disorders
Gastroesophageal reflux diseaseGastrointestinal disorders
AnorexiaMetabolism and nutrition disorders
Cholesterol highMetabolism and nutrition disorders
AnxietyPsychiatric disorders
Alanine aminotransferase increasedInvestigations
Cholesterol highInvestigations
Weight gainInvestigations
Weight lossInvestigations
Bone painMusculoskeletal and connective tissue disorders
Skin infectionInfections and infestations
Upper respiratory infectionInfections and infestations
Neck painMusculoskeletal and connective tissue disorders
ParesthesiaNervous system disorders
HematuriaRenal and urinary disorders
Rash maculo-papularSkin and subcutaneous tissue disorders
HypertensionVascular disorders
Dry mouthGastrointestinal disorders
DysphagiaGastrointestinal disorders
EsophagitisGastrointestinal disorders

Most-reported serious reactions: Skin infection, Stroke, Abdominal pain, Constipation, Lower gastrointestinal hemorrhage, Lung infection, Urinary tract infection, External iliac artery stenosis.

Data from ClinicalTrials.gov NCT01585402 adverse events section.

Sponsor's own description

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.

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

  1. Ectopic calcification in pseudoxanthoma elasticum responds to inhibition of tissue-nonspecific alkaline phosphatase.
    Ziegler SG, Ferreira CR, MacFarlane EG, Riddle RC, et al · · 2017 · cited 98× · PMID 28592560 · DOI 10.1126/scitranslmed.aal1669
  2. Increased activity of TNAP compensates for reduced adenosine production and promotes ectopic calcification in the genetic disease ACDC.
    Jin H, St Hilaire C, Huang Y, Yang D, et al · · 2016 · cited 74× · PMID 27965423 · DOI 10.1126/scisignal.aaf9109
  3. CD73 (Cluster of Differentiation 73) and the Differences Between Mice and Humans.
    Joolharzadeh P, St Hilaire C. · · 2019 · cited 42× · PMID 30676071 · DOI 10.1161/atvbaha.118.311579
  4. Inorganic Pyrophosphate Deficiency Syndromes and Potential Treatments for Pathologic Tissue Calcification.
    Ralph D, van de Wetering K, Uitto J, Li Q. · · 2022 · cited 37× · PMID 35182493 · DOI 10.1016/j.ajpath.2022.01.012
  5. Etidronate prevents, but does not reverse, ectopic mineralization in a mouse model of pseudoxanthoma elasticum (<i>Abcc6<sup>-/-</sup></i> ).
    Li Q, Kingman J, Sundberg JP, Levine MA, et al · · 2018 · cited 32× · PMID 30112102 · DOI 10.18632/oncotarget.10738
  6. Mechanisms of calcification in Fahr disease and exposure of potential therapeutic targets.
    Peters MEM, de Brouwer EJM, Bartstra JW, Mali WPTM, et al · · 2020 · cited 27× · PMID 33299674 · DOI 10.1212/cpj.0000000000000782
  7. Therapeutics Development for Pseudoxanthoma Elasticum and Related Ectopic Mineralization Disorders: Update 2020.
    Luo H, Li Q, Cao Y, Uitto J. · · 2020 · cited 24× · PMID 33396306 · DOI 10.3390/jcm10010114
  8. Vascular calcification: from the perspective of crosstalk.
    Yang S, Zeng Z, Yuan Q, Chen Q, et al · · 2023 · cited 13× · PMID 37851172 · DOI 10.1186/s43556-023-00146-y

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