Hydroxyurea in Pulmonary Arterial Hypertension
| Status: | Completed |
|---|---|
| Conditions: | High Blood Pressure (Hypertension), High Blood Pressure (Hypertension) |
| Therapuetic Areas: | Cardiology / Vascular Diseases |
| Healthy: | No |
| Age Range: | 18 - Any |
| Updated: | 11/8/2014 |
| Start Date: | September 2013 |
| End Date: | June 2015 |
| Contact: | Marlene Peters-Lawrence, R.N. |
| Email: | mpeters@nhlbi.nih.gov |
| Phone: | (301) 443-6144 |
Pulmonary arterial hypertension (PAH) is a serious and eventually fatal disease damaging the
lungs and the heart. It results from narrowing and eventual blockage of small blood vessels
in the lung, due to abnormal proliferation of cells in the blood vessel (arterial). Patients
with PAH suffer from fatigue, shortness of breath, low oxygen levels, blood clots and heart
failure. No therapies reverse the disease process in the lung arteries, however there are
three approved drugs that can temporarily dilate the vessels and improve symptoms. However,
all three drugs have significant side effects and toxicities, they do not work effectively
in many patients, survival remains on average only 2 to 3 years once symptoms begin, and
none of these drugs prevent the underlying disease process in the small arteries of the
lung.
PAH is known to develop in patients with a pre-existing class of bone marrow diseases called
myeloproliferative disorders (MPDs). We and others have recently shown that patients
with PAH have bone marrow changes similar to those seen in patients with MPDs, even without
other signs and symptoms of those bone marrow diseases such as anemia or high platelet and
white blood cell counts. Compared to healthy volunteers, patients with PAH have a higher
frequency of immature stem and progenitor cells able to produce blood cells and vascular
wall cells in their bone marrow. They also have higher circulating numbers of these cells
in the blood, and increased localization of these cells in the lung blood vessels. When
immature bone marrow cells from PAH patients and normal volunteers were infused into mice,
the mice receiving PAH marrow cells developed similar lung and heart problems to PAH
patients, suggesting that the bone marrow problem is a primary cause of the lung problems,
and that the increased numbers of immature bone marrow cells in the bone marrow and blood of
PAH patients causes the lung blood vessel disease.
The drug hydroxyurea is used to inhibit the abnormally high level of bone marrow cell
proliferation in patients with MPDs. It has been shown to reduce the numbers of circulating
immature bone marrow cells in patients with MPDs. Hydroxyurea has been available for almost
fifty years, and has been used to treat patients with MPDs, sickle cell anemia, and
congenital heart disease for very prolonged periods of time, up to twenty or more years in
individual patients. It has an excellent long-term safety profile and few side effects and
is generally well tolerated. It does not appear to result in an increased rate of leukemia
even with many years of treatment.
In the current protocol, we hypothesize that treating patients with PAH with hydroxyurea
will decrease the level of circulating immature bone marrow cells and interrupt the abnormal
narrowing and occlusion of lung arteries. We will treat patients with moderately severe
primary (no known underlying cause) PAH with 6 months of hydroxyurea, carefully
monitoring side effects and adjusting dosage as necessary, and measure the effect on
circulating immature cells, lung blood vessel pressures, other blood markers of active PAH,
and exercise tolerance.
lungs and the heart. It results from narrowing and eventual blockage of small blood vessels
in the lung, due to abnormal proliferation of cells in the blood vessel (arterial). Patients
with PAH suffer from fatigue, shortness of breath, low oxygen levels, blood clots and heart
failure. No therapies reverse the disease process in the lung arteries, however there are
three approved drugs that can temporarily dilate the vessels and improve symptoms. However,
all three drugs have significant side effects and toxicities, they do not work effectively
in many patients, survival remains on average only 2 to 3 years once symptoms begin, and
none of these drugs prevent the underlying disease process in the small arteries of the
lung.
PAH is known to develop in patients with a pre-existing class of bone marrow diseases called
myeloproliferative disorders (MPDs). We and others have recently shown that patients
with PAH have bone marrow changes similar to those seen in patients with MPDs, even without
other signs and symptoms of those bone marrow diseases such as anemia or high platelet and
white blood cell counts. Compared to healthy volunteers, patients with PAH have a higher
frequency of immature stem and progenitor cells able to produce blood cells and vascular
wall cells in their bone marrow. They also have higher circulating numbers of these cells
in the blood, and increased localization of these cells in the lung blood vessels. When
immature bone marrow cells from PAH patients and normal volunteers were infused into mice,
the mice receiving PAH marrow cells developed similar lung and heart problems to PAH
patients, suggesting that the bone marrow problem is a primary cause of the lung problems,
and that the increased numbers of immature bone marrow cells in the bone marrow and blood of
PAH patients causes the lung blood vessel disease.
The drug hydroxyurea is used to inhibit the abnormally high level of bone marrow cell
proliferation in patients with MPDs. It has been shown to reduce the numbers of circulating
immature bone marrow cells in patients with MPDs. Hydroxyurea has been available for almost
fifty years, and has been used to treat patients with MPDs, sickle cell anemia, and
congenital heart disease for very prolonged periods of time, up to twenty or more years in
individual patients. It has an excellent long-term safety profile and few side effects and
is generally well tolerated. It does not appear to result in an increased rate of leukemia
even with many years of treatment.
In the current protocol, we hypothesize that treating patients with PAH with hydroxyurea
will decrease the level of circulating immature bone marrow cells and interrupt the abnormal
narrowing and occlusion of lung arteries. We will treat patients with moderately severe
primary (no known underlying cause) PAH with 6 months of hydroxyurea, carefully
monitoring side effects and adjusting dosage as necessary, and measure the effect on
circulating immature cells, lung blood vessel pressures, other blood markers of active PAH,
and exercise tolerance.
Pulmonary arterial hypertension (PAH) is a serious and eventually fatal disease damaging the
lungs and the heart. It results from narrowing and eventual blockage of small blood vessels
in the lung, due to abnormal proliferation of cells in the blood vessel (arterial). Patients
with PAH suffer from fatigue, shortness of breath, low oxygen levels, blood clots and heart
failure. No therapies reverse the disease process in the lung arteries, however there are
three approved drugs that can temporarily dilate the vessels and improve symptoms. However,
all three drugs have significant side effects and toxicities, they do not work effectively
in many patients, survival remains on average only 2 to 3 years once symptoms begin, and
none of these drugs prevent the underlying disease process in the small arteries of the
lung.
PAH is known to develop in patients with a pre-existing class of bone marrow diseases called
myeloproliferative disorders (MPDs). We and others have recently shown that patients
with PAH have bone marrow changes similar to those seen in patients with MPDs, even without
other signs and symptoms of those bone marrow diseases such as anemia or high platelet and
white blood cell counts. Compared to healthy volunteers, patients with PAH have a higher
frequency of immature stem and progenitor cells able to produce blood cells and vascular
wall cells in their bone marrow. They also have higher circulating numbers of these cells
in the blood, and increased localization of these cells in the lung blood vessels. When
immature bone marrow cells from PAH patients and normal volunteers were infused into mice,
the mice receiving PAH marrow cells developed similar lung and heart problems to PAH
patients, suggesting that the bone marrow problem is a primary cause of the lung problems,
and that the increased numbers of immature bone marrow cells in the bone marrow and blood of
PAH patients causes the lung blood vessel disease.
The drug hydroxyurea is used to inhibit the abnormally high level of bone marrow cell
proliferation in patients with MPDs. It has been shown to reduce the numbers of circulating
immature bone marrow cells in patients with MPDs. Hydroxyurea has been available for almost
fifty years, and has been used to treat patients with MPDs, sickle cell anemia, and
congenital heart disease for very prolonged periods of time, up to twenty or more years in
individual patients. It has an excellent long-term safety profile and few side effects and
is generally well tolerated. It does not appear to result in an increased rate of leukemia
even with many years of treatment.
In the current protocol, we hypothesize that treating patients with PAH with hydroxyurea
will decrease the level of circulating immature bone marrow cells and interrupt the abnormal
narrowing and occlusion of lung arteries. We will treat patients with moderately severe
primary (no known underlying cause) PAH with 6 months of hydroxyurea, carefully
monitoring side effects and adjusting dosage as necessary, and measure the effect on
circulating immature cells, lung blood vessel pressures, other blood markers of active PAH,
and exercise tolerance.
lungs and the heart. It results from narrowing and eventual blockage of small blood vessels
in the lung, due to abnormal proliferation of cells in the blood vessel (arterial). Patients
with PAH suffer from fatigue, shortness of breath, low oxygen levels, blood clots and heart
failure. No therapies reverse the disease process in the lung arteries, however there are
three approved drugs that can temporarily dilate the vessels and improve symptoms. However,
all three drugs have significant side effects and toxicities, they do not work effectively
in many patients, survival remains on average only 2 to 3 years once symptoms begin, and
none of these drugs prevent the underlying disease process in the small arteries of the
lung.
PAH is known to develop in patients with a pre-existing class of bone marrow diseases called
myeloproliferative disorders (MPDs). We and others have recently shown that patients
with PAH have bone marrow changes similar to those seen in patients with MPDs, even without
other signs and symptoms of those bone marrow diseases such as anemia or high platelet and
white blood cell counts. Compared to healthy volunteers, patients with PAH have a higher
frequency of immature stem and progenitor cells able to produce blood cells and vascular
wall cells in their bone marrow. They also have higher circulating numbers of these cells
in the blood, and increased localization of these cells in the lung blood vessels. When
immature bone marrow cells from PAH patients and normal volunteers were infused into mice,
the mice receiving PAH marrow cells developed similar lung and heart problems to PAH
patients, suggesting that the bone marrow problem is a primary cause of the lung problems,
and that the increased numbers of immature bone marrow cells in the bone marrow and blood of
PAH patients causes the lung blood vessel disease.
The drug hydroxyurea is used to inhibit the abnormally high level of bone marrow cell
proliferation in patients with MPDs. It has been shown to reduce the numbers of circulating
immature bone marrow cells in patients with MPDs. Hydroxyurea has been available for almost
fifty years, and has been used to treat patients with MPDs, sickle cell anemia, and
congenital heart disease for very prolonged periods of time, up to twenty or more years in
individual patients. It has an excellent long-term safety profile and few side effects and
is generally well tolerated. It does not appear to result in an increased rate of leukemia
even with many years of treatment.
In the current protocol, we hypothesize that treating patients with PAH with hydroxyurea
will decrease the level of circulating immature bone marrow cells and interrupt the abnormal
narrowing and occlusion of lung arteries. We will treat patients with moderately severe
primary (no known underlying cause) PAH with 6 months of hydroxyurea, carefully
monitoring side effects and adjusting dosage as necessary, and measure the effect on
circulating immature cells, lung blood vessel pressures, other blood markers of active PAH,
and exercise tolerance.
- INCLUSION CRITERIA:
- Age greater than or equal to 18 years old
- Patients with idiopathic or familial PAH with WHO II-III performance status
- On PAH medications that have not changed and are stable for the past two months
- Seronegative for HIV antibody, hepatitis B antigen, and hepatitis C antibody.
EXCLUSION CRITERIA:
- Thrombocytopenia with platelets less than 100,000/mm3, anemia with hemoglobin less
than 10.5g/dL or neutropenia with ANC less than 1500/mm3
- Creatinine > 2.0mg/dL
- Hepatic insufficiency (transaminase levels > 4 fold the upper limit of normal or
bilirubin > 2 fold the upper limit of normal)
- Severe arterial hypertension (systolic blood pressure > 200mmHg or diastolic >
120mmHg)
- Female subjects who are nursing or pregnant or are unwilling to take oral
contraceptives or refrain from pregnancy if of childbearing potential
- Participation in any other investigative treatment studies at the time of enrollment
- Unable to understand the investigational nature of the study or give informed consent
(i.e. decisionally impaired)< TAB>
- Evidence of major bleeding or active infection
- Known allergy to the study drug or drugs similar to the study drug
- Subjects with known liver cirrhosis or chronic active hepatitis.
- HIV positivity
- Moribund status or concurrent hepatic, renal, cardiac, neurologic, pulmonary,
infectious, or metabolic disease of such severity that it would preclude the patient
s ability to tolerate protocol therapy, or that death within 30 days is likely
- Presence of 9;22 BCR/ABL translocation as detected by conventional bone marrow
cytogenetics or PCR for BCR/ABL transcript, or presence of JAK2 V617F mutation in
bone marrow or peripheral blood cells.
- On beta-blocker therapy requiring dose adjustment.
We found this trial at
1
site
9000 Rockville Pike
Bethesda, Maryland 20892
Bethesda, Maryland 20892
301-496-4000
National Institutes of Health Clinical Center The National Institutes of Health (NIH) Clinical Center in...
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