Etidronate for Arterial Calcifications Due to Deficiency in CD73 (ACDC)
| Status: | Recruiting |
|---|---|
| Healthy: | No |
| Age Range: | 18 - 80 |
| Updated: | 3/20/2019 |
| Start Date: | August 20, 2012 |
| End Date: | March 1, 2020 |
| Contact: | Katherine Carney |
| Email: | katherine.carney@nih.gov |
| Phone: | (301) 402-9841 |
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 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.
Objectives:
- To see if etridronate 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 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.
- 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.
Objectives:
- To see if etridronate 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 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.
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).
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).
- INCLUSION CRITERIA
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
EXCLUSION CRITERIA
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.
We found this trial at
1
site
9000 Rockville Pike
Bethesda, Maryland 20892
Bethesda, Maryland 20892
Phone: 800-411-1222
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