Hydroxyurea in Pulmonary Arterial Hypertension

Pulmonary Hypertension Clinical Trial

Official title: Hydroxyurea in Pulmonary Arterial Hypertension

Status Withdrawn

Clinical Trial Summary

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.

Clinical Trial Description

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. ;

Related Conditions & MeSH terms

• Familial Primary Pulmonary Hypertension
• Hypertension
• Hypertension, Pulmonary
• Pulmonary Hypertension

• NCT number: NCT01950585
• Study type: Interventional
• Source: National Institutes of Health Clinical Center (CC)
• Status: Withdrawn
• Phase: Early Phase 1
• Start date: September 6, 2013
• Completion date: October 23, 2014