Ignite Creation Date:
2024-05-05 @ 11:29 AM
Last Modification Date:
2024-10-26 @ 9:08 AM
Study NCT ID:
NCT00056433
Status:
COMPLETED
Last Update Posted:
2019-11-22
First Post:
2003-03-12
Brief Title:
Evaluation of Hydroxyurea Plus L-arginine or Sildenafil to Treat Sickle Cell Anemia
Sponsor:
National Institutes of Health Clinical Center CC
Organization:
National Institutes of Health Clinical Center CC
Study Overview
Official Title:
Evaluation of Potential Synergy of Combining Hydroxyurea With Nitric Oxide Donors on Fetal Hemoglobin Synthesis in Patients With Sickle Cell Anemia
Status:
COMPLETED
Status Verified Date:
2015-12-07
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
Patients with sickle cell disease have abnormal hemoglobin the protein in red blood cells that carries oxygen to the body This abnormality causes red blood cells to take on a sickle shape producing disease symptoms Fetal hemoglobin a type of hemoglobin present in fetuses and babies can prevent red cells from sickling The drug hydroxyurea increases fetal hemoglobin production in patients with sickle cell disease by making a molecule called nitric oxide The drugs L-arginine and Sildenafil Viagra increase the amount or the effect of nitric oxide This study will evaluate
The safety of giving L-arginine or Sildenafil together with hydroxyurea in patients with sickle cell disease
The effectiveness of L-arginine plus hydroxyurea or Sildenafil plus hydroxyurea in increasing fetal hemoglobin in patients with sickle cell disease and
The effectiveness of L-arginine plus hydroxyurea or Sildenafil and hydroxyurea in lowering blood pressure in the lungs of patients with sickle cell disease Pulmonary blood pressure is elevated in about one-third of patients with sickle cell disease and this condition increases the risk of dying from the disease
Patients with hemoglobin S-only S-beta-thalassemia or other sickle cell disease genotype may be eligible for this study
Before starting treatment patients will have a complete medical history and physical examination All patients will take hydroxyurea once a day every day by mouth for at least 2 months They will be admitted to the NIH Clinical Center to take their first dose of hydroxyurea and will have blood drawn through a catheter plastic tube placed in a vein every hour for 6 hours for tests to determine nitric oxide levels After discharge they will return to the clinic once every 2 weeks to check for treatment side effects and for blood tests to monitor hemoglobin and fetal hemoglobin levels After fetal hemoglobin levels have been stable for 2 months patients will be admitted to the Clinical Center for their first dose of L-arginine for men or Sildenafil for women Again blood samples will be collected through a catheter once an hour for 6 hours If there are no complications patients will be discharged and will continue taking hydroxyurea once a day and L-arginine or Sildenafil three times a day for at least 3 months until fetal hemoglobin levels have been stable for at least 2 months Patients will return to the clinic for blood tests every week for 2 weeks and then every 2 weeks to monitor hemoglobin and fetal hemoglobin levels and to check for treatment side effects
Patients will have eye examinations before and during treatment Some patients with sickle cell disease develop abnormalities in the blood vessels of the eye Also Sildenafil can cause temporary changes in color vision Rarely more serious eye problems can occur such as bleeding from the eye blood vessels or damage to the retina a layer of tissue that lines the back of the eye Patients will also have an echocardiogram ultrasound of the heart before beginning treatment after hydroxyurea treatment and after 1 and 3 months of combined treatment with hydroxyurea and L-arginine or Sildenafil to help measure blood pressure in the lungs
Patients who develop complications from L-arginine or Sildenafil may continue in the study on hydroxyurea alone Patients whose fetal hemoglobin levels increase with the combination therapy of hydroxyurea and L-arginine or Sildenafil may continue to take them
The safety of giving L-arginine or Sildenafil together with hydroxyurea in patients with sickle cell disease
The effectiveness of L-arginine plus hydroxyurea or Sildenafil plus hydroxyurea in increasing fetal hemoglobin in patients with sickle cell disease and
The effectiveness of L-arginine plus hydroxyurea or Sildenafil and hydroxyurea in lowering blood pressure in the lungs of patients with sickle cell disease Pulmonary blood pressure is elevated in about one-third of patients with sickle cell disease and this condition increases the risk of dying from the disease
Patients with hemoglobin S-only S-beta-thalassemia or other sickle cell disease genotype may be eligible for this study
Before starting treatment patients will have a complete medical history and physical examination All patients will take hydroxyurea once a day every day by mouth for at least 2 months They will be admitted to the NIH Clinical Center to take their first dose of hydroxyurea and will have blood drawn through a catheter plastic tube placed in a vein every hour for 6 hours for tests to determine nitric oxide levels After discharge they will return to the clinic once every 2 weeks to check for treatment side effects and for blood tests to monitor hemoglobin and fetal hemoglobin levels After fetal hemoglobin levels have been stable for 2 months patients will be admitted to the Clinical Center for their first dose of L-arginine for men or Sildenafil for women Again blood samples will be collected through a catheter once an hour for 6 hours If there are no complications patients will be discharged and will continue taking hydroxyurea once a day and L-arginine or Sildenafil three times a day for at least 3 months until fetal hemoglobin levels have been stable for at least 2 months Patients will return to the clinic for blood tests every week for 2 weeks and then every 2 weeks to monitor hemoglobin and fetal hemoglobin levels and to check for treatment side effects
Patients will have eye examinations before and during treatment Some patients with sickle cell disease develop abnormalities in the blood vessels of the eye Also Sildenafil can cause temporary changes in color vision Rarely more serious eye problems can occur such as bleeding from the eye blood vessels or damage to the retina a layer of tissue that lines the back of the eye Patients will also have an echocardiogram ultrasound of the heart before beginning treatment after hydroxyurea treatment and after 1 and 3 months of combined treatment with hydroxyurea and L-arginine or Sildenafil to help measure blood pressure in the lungs
Patients who develop complications from L-arginine or Sildenafil may continue in the study on hydroxyurea alone Patients whose fetal hemoglobin levels increase with the combination therapy of hydroxyurea and L-arginine or Sildenafil may continue to take them
Detailed Description:
Hydroxyurea is a cell-cycle specific agent that blocks DNA synthesis by inhibiting ribonucleotide reductase the enzyme that converts ribonucleotides to deoxyribonucleotides Hydroxyurea has been shown to induce the production of fetal hemoglobin HbF initially in non-human primates and now in patients with sickle cell anemia The majority of patients with sickle cell disease respond to the drug with a more than two-fold increase in HbF levels in some patients the percent of HbF exceeds 10 or 15 percent It is estimated that levels of 20 percent are required to substantially reduce the sickling propensity of red cells and to modulate disease severity We have recently found that hydroxyurea therapy is associated with the intravascular and intraerythrocytic generation of nitric oxide NO and that NO accounts for HbF induction via the guanylyl cyclasecGMP dependent pathways In fact NO donors such as S-nitroso-cysteine and NONOates similarly induce HbF expression in human erythropoietin treated human CD 34 stem cells Possible synergy between NO donor therapy and classic cytostatic and differentiating medications should be explored We propose to treat several patients chronically with hydroxyurea to determine hematological changes Iongitudinally Once a maximal Hb-F raising effect of hydroxyurea has been established oral L-arginine the substrate for NO synthase and sildenafil Viagra a phosphodiesterase inhibitor that potentates cGMP dependent signaling will be added to determine the ability of other agents to enhance HbF synthesis especially in hydroxyurea non-responders or partial-responders Additionally we have found that up to 33 of patients with sickle cell disease also have secondary pulmonary hypertension measured by echocardiogram A secondary endpoint of this study will be to evaluate if chronic hydroxyurea therapy and the addition of L-arginine or sildenafil will improve the pulmonary hypertension in this subgroup
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| 03-CC-0127 | None | None | None |