Assessment of Algorithm-Based Hydroxyurea Dosing on Fetal Hemoglobin Response, Acute Complications, and Organ Function in People With Sickle Cell Disease
Condition: Sickle Cell Disease
MeSH terms: Anemia, Sickle Cell
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      Background:

      - Sickle cell disease (SCD) is a blood disease. The drug hydroxyurea (HU) is approved to
      prevent pain crises in people with SCD. Researchers want to see how higher doses of HU affect
      the blood. This will help them learn about the right dosage of HU to give to people with SCD.

      Objective:

      - To improve hydroxyurea dosing in people with SCD.

      Eligibility:

      - People age 15 or older with homozygous SCD (HbSS).

      Design:

        -  Participants will be screened with medical history, physical exam, medication review,
           and blood and urine tests.

        -  Participants will be in the study for about 15 months.

        -  First 3 months: monthly study visits with blood and urine tests.

        -  After 3 months: participants will take HU as a capsule by mouth. If you are already
           taking HU, your dose will be increased.

        -  Within a month of starting or increasing HU: participants will keep a daily pain diary
           for 2 weeks. They will have an echocardiogram (ultrasound) of the heart, a 6-minute walk
           test. They will complete a quality-of-life questionnaire.

        -  Participants will visit every month until they reach their highest tolerated dose of HU.
           They may need to come as often as every week sometimes to closely monitor their blood
           counts. Then they will alternate a phone call one month and a visit the next. At the
           visits, participants will bring their pill bottle, answer questions about side effects,
           and have blood tests.

        -  Every 2 months, participants will have a medical history, physical exam, and blood
           tests.

        -  Every 4 months, participants will have blood and urine tests. They will also complete
           another 2-week pain diary and quality-of-life questionnaire.

        -  About 12 months after starting or increasing HU, participants will have blood tests, an
           echocardiogram, and a 6-minute walk test.
    

Detailed description: 
      Sickle cell disease (SCD) is associated with significant morbidity and early mortality.
      Despite the discovery of the disease more than 100 years ago, only one drug, hydroxyurea
      (HU), has been FDA-approved. Hydroxyurea exerts its beneficial effects largely by inducing
      fetal hemoglobin (HbF) and thereby inhibiting red blood cell sickling. Hydroxyurea has been
      shown to decrease the frequency of acute complications such as painful crises and acute chest
      syndrome. However, previous studies are conflicting regarding whether HU improves survival; 2
      long-term studies where HU was titrated to the maximum tolerated dose show that HU improves
      survival. However, multiple studies performed in the era post-FDA approval of HU show no
      change in median survival. We and others have found that patients with SCD who die
      prematurely have more evidence of renal, hepatic, and cardiopulmonary damage. Our work also
      suggests that HU treatment per se is not sufficient to improve survival and decrease organ
      damage in patients with homozygous SCD (HbSS). Instead, patients treated with the highest HU
      doses and who had the highest HbF levels appeared more likely to survive and had less
      evidence of organ damage over time. Hydroxyurea management can be intimidating; therefore,
      many adults with HbSS are either not treated with HU or are treated with doses below that
      which are FDA-approved. A HU dosing algorithm may simplify dosing such that not only are more
      patients treated with HU, but more may be titrated to the maximal tolerated dose which may be
      necessary to prevent organ damage and prolong survival. Further, myelosuppression beyond what
      has traditionally been recommended may further maximize HbF response. This protocol is a
      prospective pilot study which follows a 2 month run-in period. Hydroxyurea dosing will be
      based on a written algorithm which will be derived manually, and by a computer program which
      was developed at the NIH Clinical Center. Clinical, laboratory, and echocardiographic
      parameters will be monitored at baseline and after treatment to further study the effect of
      maximum HbF response on acute complications associated with HbSS and organ function.
    

Intervention name(s): Hydroxyurea
Intervention type(s): Drug
Intervention description(s): The precise mechanism by which hydroxyurea produces its cytotoxic and cytoreductive effects is not known. However, various studies support the hypothesis that hydroxyurea causes an immediate inhibition of DNA synthesis by acting as a ribonucleotide reductase inhibitor, without interfering with the synthesis of ribonucleic acid or of protein.
The mechanisms by which DROXIA produces its beneficial effects in patients with sickle cell anemia (SCA) are uncertain. Known pharmacologic effects of DROXIA that may contribute to its beneficial effects include increasing hemoglobin F levels in RBCs, decreasing neutrophils, increasing the water content of RBCs, increasing deformability of sickled cells, and altering the adhesion of RBCs to endothelium.
Intervention MeSH terms: Hydroxyurea
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Hydroxyurea; Sickle Cell Disease; Fetal Hemoglobin Induction