Protocol Number: 06-H-0054

Title:

Evaluation of Synergy of Combining Hydroxyurea with Recombinant Human Erythropoietin Glycoform Alpha (rhu Erythropoietin-alpha) on Fetal Hemoglobin Synthesis in Patients with Sickle Cell Anemia

Number:

06-H-0054

Summary:

This study will examine the use of hydroxyurea and erythropoietin for treating sickle cell disease in patients who also have kidney disease or pulmonary hypertension (high blood pressure in the lungs). Hydroxyurea increases production of fetal hemoglobin in the red blood cells of patients with sickle cell disease, reducing the amount of sickle cells that cause pain and other complications requiring hospitalizations. However, hydroxyurea treatment has limitations: patients with sickle cell disease who have developed kidney disease may not be able to get the full benefit of the medicine, and hydroxyurea alone may not be able to treat life-threatening complications such as pulmonary hypertension or stroke. This study will determine which of two dosing schedules of hydroxyurea and erythropoietin is more effective for treating patients with sickle cell disease who also have kidney disease or pulmonary hypertension, and will examine whether the two drugs can lower blood pressure in the lungs.

Patients 18 years of age and older with sickle cell anemia and kidney disease or pulmonary hypertension, or both, may be eligible for this study. Candidates are screened with a medical history, physical examination, blood tests, a 6-minute walk test (test to see how far the subject can walk in 6 minutes), and echocardiogram (ultrasound of the heart to measure blood pressure in the lungs).

Participants undergo the following tests and procedures:

Stabilization Phase: Patients take 2 hydroxyurea tablets a day until their fetal hemoglobin levels stabilize, usually over 2 to 4 months. They have blood tests every 2 weeks to monitor hemoglobin and fetal hemoglobin levels. At some time during this period, they undergo a test to measure kidney function, in which they are injected with an iodine-containing dye and wear a small pump for 1 day that injects a small amount of dye under the skin over 24 hours. They come to the clinic for 2 or 3 blood tests collected over 4 hours.

Sequence I (Standard): When the fetal hemoglobin levels have been stable for 2 months, patients have a repeat echocardiogram and 6-minute walk test. Erythropoietin is then added to the hydroxyurea regimen. It is given 3 days a week, as an injection under the skin, along with iron supplements. Patients have blood tests and blood pressure measurements every week or every other week. Patients with pulmonary hypertension have another echocardiogram and 6-minute walk test once the hemoglobin level is stable.

Sequence II (Cycled): When hemoglobin levels have stabilized with hydroxyurea once a day and erythropoietin 3 times a week, the hydroxyurea is adjusted so that the amount taken in 7 days is "cycled" over 4 days, and the erythropoietin is cycled over 3 days, with the dose increased twice, every 3 to 4 weeks. Blood pressure and hemoglobin are monitored once or twice a month. Patients with pulmonary hypertension have another echocardiogram and 6-minute walk test once the hemoglobin level is stable.

Patients who develop complications while taking the drugs have their treatment regimens adjusted as needed.

Sponsoring Institute:

National Heart, Lung and Blood Institute (NHLBI)

Recruitment Detail

Type: Participants currently recruited/enrolled

Gender: Male & Female

Referral Letter Required: No

Population Exclusion(s): Children

Eligibility Criteria:

INCLUSION CRITERIA:

Patients with homozygous SCD or other sickling disorders (e.g., B(0) Thalassemia/Sickle) who are 18 years of age or greater will be eligible for treatment. Patients currently being followed on an NIH study or at Howard University on stable doses of hydroxyurea are also eligible. A totalof 60 patients will be recruited to the study, with the recognition from our earlier studies of a failure-to-complete rate approaching 50%.

Patients must have documented hemoglobin S-only or S-beta(0)-thalassemia.

Patients must have relatively well preserved hepatic function (less than 3 X upper limits of normal ALT).

Patients must be able to provide informed consent.

Patients must have:

-an eGFR of 15 to 60 ml/min per 1.73 m(2) BSA,

or

an eGFR of 61 - 90 ml/min per 1.73 m(2) BSA and greater than 16.9 mg of albumin/g creatinine (greater than 0.017 ratio g/g),

and/or

a trans-thoracic echocardiographic measurements of pulmonary artery pressure (PAP), as estimated by tricuspid regurgitant velocity, of greater than 2.5 m sec(-1) monthly at baseline times two.

EXCLUSION CRITERIA:

Patients who are doubly heterozygous for hemoglobin-S and fully or partially expressed hemoglobin-A or any other non-S beta-type globin chain, or hemoglobin A-only (non-sickle cell).

Patients who are on a chronic transfusion program, defined as regular transfusions every 2-8 weeks.

Patients who are pregnant or breast-feeding.

Patients who have a history of a documented cerebrovascular accident or venous thrombosis within one year of study entry.

Patients with active proliferative retinopathy within 1 year of study entry

Patients with eGFR less than or equal to 14 ml/min per 1.73 M(2) BSA.

Patients with a total Hgb at entry that is 10.5 g/dl or greater

Patients with a known allergy to Albumin or cell-derived products

Patients with uncontrolled hypertension, defined as a systolic blood pressure greater than 170 mmHg and diastolic blood pressure greater than 110 mm Hg that is sustained and unresponsive over 1 week to conventional anti-hypertensive therapy .

Special Instructions:

Currently Not Provided

Keywords:

Erythropoietin Therapy

Fetal Hemoglobin Induction

Sickle Cell Disease

Pulmonary Hypertension

Chronic Kidney Disease

Recruitment Keyword(s):

Sickle Cell Disease

SCD

Condition(s):

Sickle Cell Disease

Chronic Kidney Disease

Pulmonary Hypertension

Investigational Drug(s):

Erythropoietin and Hydroxyurea

Investigational Device(s):

None

Intervention(s):

Drug: Erythropoietin and Hydroxyurea

Supporting Site:

National Heart, Lung and Blood Institute

Contact(s):

Patient Recruitment and Public Liaison Office
Building 61
10 Cloister Court
Bethesda, Maryland 20892-4754
Toll Free: 1-800-411-1222
TTY: 301-594-9774 (local),1-866-411-1010 (toll free)
Fax: 301-480-9793

Electronic Mail:prpl@mail.cc.nih.gov

Citation(s):

Platt OS, Thorington BD, Brambilla DJ, Milner PF, Rosse WF, Vichinsky E, Kinney TR. Pain in sickle cell disease. Rates and risk factors. N Engl J Med. 1991 Jul 4;325(1):11-6

Platt OS, Brambilla DJ, Rosse WF, Milner PF, Castro O, Steinberg MH, Klug PP. Mortality in sickle cell disease. Life expectancy and risk factors for early death. N Engl J Med. 1994 Jun 9;330(23):1639-44.

McKerrell TD, Cohen HW, Billett HH. The older sickle cell patient. Am J Hematol. 2004 Jun;76(2):101-6.

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