Multicenter Study of Hydroxyurea in Patients With Sickle Cell Anemia (MSH)
Condition: Anemia, Sickle Cell; Hematologic Diseases; Hemoglobinopathies
MeSH terms: Anemia; Anemia, Sickle Cell; Hematologic Diseases; Hemoglobinopathies
Study type: Interventional
Phase: Phase 3

Summary: 
      To assess the efficacy and safety of orally administered hydroxyurea in the treatment of
      painful crises in patients with sickle cell anemia.
    

Detailed description: 
      BACKGROUND:

      In spite of the fact that advances have been made in the management or prevention of some of
      the complications of sickle cell disease, the management of the most common complication--the
      painful crisis--is still unsatisfactory, and appropriate methods for its prevention are
      unknown. The morbidity associated with a painful crisis is much more than the suffering from
      pain alone. The interference with a normal lifestyle, the resulting obstacles to obtaining an
      education and holding a job, the risk of narcotics addiction, the cost of multiple
      hospitalizations, and the financial impact on the family and the individual must all be
      considered.

      Evidence from the Cooperative Study of Sickle Cell Disease (CSSCD) study showed that there is
      an association between multiple pain events and early death in young adults. If this
      association is true, then MSH has the potential to not only reduce morbidity but mortality as
      well. The CSSCD study has shown that over 50 percent of patients with sickle cell disease
      have at least one crisis per year, and a considerable number have more. These episodes are
      believed to occur as a result of hemoglobin S within the red cells leading to rigid,
      non-deformable cells which can no longer traverse the microvasculature and as a result
      produce obstruction with consequent pain, ischemia, and tissue necrosis.

      Previous approaches to the therapy of this group of disorders have included: attempts to
      modify the hemoglobin molecule so as to prevent polymerization; the use of vasoreactive
      drugs; and increasing red cell volume. All of these attempts have been abandoned either
      because of their inefficacy, toxicity, or impracticality. Chronic exchange transfusion
      programs have been of limited usefulness because of high rates of isoimmunization, iron
      overload, and risk of transmission of hepatitis and retroviral disease.

      The rationale for the present study draws its substance from the observation that patients
      with higher levels of fetal hemoglobin (Hb F) (particularly the Saudi Arabian group), and
      infants who also have high Hb F levels have fewer crises. Several myelosuppressive drugs,
      such as 5-azacytidine and hydroxyurea, have been shown to increase Hb F production. The work
      with 5-azacytidine has had to be abandoned because of the known risk of malignancy.

      Preliminary studies by the investigators and others have shown convincingly that Hb F levels
      can be increased by administering hydroxyurea to patients over a several month period without
      producing dangerous levels of myelosuppression. The patients have also had a rise in their
      red cell life span and hematocrit. Further, it has been reported that these patients had a
      dramatic decrease in crisis frequency. This agent is readily available to all physicians, and
      there is evidence that it is being used without adequate justification and, possibly, without
      adequate monitoring. The timing of this study is therefore critical to ensure that an
      adequate answer to the question of efficacy is obtained and the risk of inappropriate use
      minimized.

      DESIGN NARRATIVE:

      Phase I has concluded. Phase II, also concluded, was a randomized, double-blind,
      placebo-controlled trial. Patients in the Phase II trial were recruited from 21 clinics and
      randomized to receive hydroxyurea or placebo. The hydroxyurea was gradually increased from an
      initial dose of 15 mg/kg to the maximal level tolerated by each patient in order to maximize
      red blood cell hemoglobin F(Hb F) content without undue marrow suppression. Changes in Hb F
      production were monitored in each of the two groups by a variety of laboratory tests. The
      primary endpoint was a comparison of crisis rates in the treated and control groups. Painful
      crises were defined as pain lasting longer than four hours, requiring parenteral narcotics
      for relief, including chest syndrome but excluding ankle ulcer pain. Secondary endpoints
      included changes in pain severity and duration, psychosocial status, complications of the
      disease, and reasons for non-compliance with either regimen. Patients were followed for two
      to three years depending on when they entered the study. Because of the mutagenic nature of
      hydroxyurea, the use of contraception was a requirement of admission to the study.

      The trial was stopped early, on January 14, 1995, instead of in May 1995. The Data and Safety
      Monitoring Board determined that daily doses of hydroxyurea reduced the frequency of painful
      episodes and hospital admissions for those crises by about 50 percent.

      Beginning in 1996, a five year follow-up of the adult patients in MSH was initiated. The
      purpose was to ascertain the long-term effects of hydroxyurea in this patient population.
      Patients were followed annually to determine health status, quality of life, incidence of
      malignancies, and birth defects in their offspring. In addition, mortality rates were
      determined so that a comparison could be made between this cohort and the mortality data from
      the Cooperative Study of Sickle Cell Disease (CSSCD) adult cohort and the normal
      African-American population mortality data. The follow-up was conducted in three phases.
      Phase I or the Planning Phase in which the final protocol was developed, lasted three months.
      Phase II, patient entry between March 1996 and June 1996 and patient follow-up, extended from
      the fourth to the 48th month. Phase III, patient exit and data analysis, were carried out
      during the final nine months of the study.

      The DSMB stopped MSH Phase III early because the study showed that hydroxyurea substantially
      reduced the frequency of vaso-occlusive (painful) crises.
    

Intervention name(s): hydroxyurea
Intervention type(s): Drug
Intervention MeSH terms: Hydroxyurea
Allocation: Randomized
Masking: Double
Primary purpose: Treatment