Objectives

The primary objective of MSH was to determine whether or not treatment with hydroxyurea titrated to maximum tolerated doses would reduce the frequency of vaso-occlusive (painful) crises by at least 50%. The principal end point was the occurrence of a vaso-occlusive (painful) crisis, defined as pain not due to another cause, lasting at least four hours and requiring parenteral (or equivalent doses of oral narcotics)) narcotics or non-steroidal anti-inflammatory drugs for relief. Occurrences of chest syndrome were counted as crises. Pain due to chronic conditions such as ankle ulcers, osteomyelitis or aseptic necrosis of bone was not counted as crises. The secondary objectives investigated the correlations of fetal hemoglobin (HbF) levels and other patient or treatment characteristics with the occurrence of vaso-occlusive (painful) crises, and the effect of treatment on the quality of life.

Background

Sickle cell anemia affects nearly one in every five hundred African-American newborns in the United States. As of the early 1990’s there was no available effective treatment for patients with sickle cell anemia for the prevention or reduction of recurrent, vaso-occlusive (painful) crises. There are an estimated 80,000 to 100,000 people in the United States with sickle cell anemia. At least 10% (8,000 to 10,000) of adults with sickle cell disease have more than three crises per year, based on projections from the Study of the Cooperative Study of Sickle Cell Disease (CSSCD)., In 1948, Janet Watson observed that children with sickle cell anemia did not begin to develop symptoms until HbF levels had dropped to those seen in adults (at approximately 6 months of age). This was the first indication that HbF may interfere with HbS formation within the red cells. Supportive evidence was provided some years later by clinical descriptions of the asymptomatic compound heterozygous condition sickle cell/hereditary persistence of fetal hemoglobin and observations that patients with relatively mild sickle cell anemia in eastern Saudi Arabia and India tended to have higher HbF concentrations. Data from 3,578 American patients studied by the CSSCD show that HbF level is a significant predictor of pain rate, over the entire range of values encountered, without a threshold, leading to the hypothesis that increases in HbF would have beneficial clinical effects.

Participants

The original MSH study cohort included 299 men and women between 18 and 50 years old with a diagnosis of sickle cell anemia by gel electrophoresis conducted by a Core Laboratory. Subjects were also required to have had at least 3 vaso-occlusive crises in the 12 months prior to enrollment, and were required to successfully complete a 2 week “run-in” period comprised of two visits with baseline blood sample collections, completion of a two week diary and daily ingestion of a folic acid tablet. 238 subjects from the original cohort were enrolled in the first 5 year observational study.

Design

The MSH study was a randomized, double-blind, placebo-controlled clinical trial in men and women with sickle cell anemia, aged 18 and over. All subjects randomized to the hydroxyrea arm began with an initial dose of 15 mg/kg which was incremented by 5 mg/kg every twelve weeks but never to a daily dose of greater than 35 mg/kg. Blood specimens were obtained from each subject every two weeks during the trial from which clinical data is available.

The MSH conducted two consecutive 5 year observational follow up studies for long-term morbidity and mortality in association with long-term hydroxyurea usage. Reportable events included stroke, renal failure, hepatic failure, cancer, and sepsis. Fatal events and serious illnesses were documented from medical records. In the follow-up study, patients were free to continue, start, or stop treatment with hydroxyurea after consultation with their physicians. Subjects were evaluated annually in the follow-up studies. Serum samples were obtained at these visits and were submitted to the repository.

Conclusions

This controlled trial made hydroxyurea the first drug of proven benefit in the prevention of vaso-occlusive pain crisis and acute chest syndrome caused by sickle cell disease. No significant side-effects of hydroxyurea therapy were noted.

The study found that adult patients taking hydroxyurea for frequent painful sickle cell episodes appear to have reduced mortality after 9 of years follow-up. Survival was related to HbF levels and frequency of vaso-occlusive events.

Specimen Notes

Specimens are available only from the PFU and EXT annual follow-up visits, not the original clinical trial.

Publications

Charache S, Terrin ML, Moore RD, Dover GJ, Barton FB, Eckert SV, McMahon RP, Bonds DR. Mortality in sickle cell disease. Effect of Hydroxyurea on the Frequency of Painful Crises in Sickle Cell Anemia. N Engl J Med. 1995; 332(20):1317-22.

Charache S, Dover GJ, Moore RD, Eckert S, Ballas SK, Koshy M, Milner PF, Orringer EP, Phillips G Jr, Platt OS, et al. Hydroxyurea: effects on hemoglobin F production in patients with sickle cell anemia. Blood. 1992;79(10):2555-65.

Charache S, Terrin ML, Moore RD, Dover GJ, McMahon RP, Barton FB, Waclawiw M, Eckert SV. Design of the multicenter study of hydroxyurea in sickle cell anemia. Investigators of the Multicenter Study of Hydroxyurea. Control Clin Trials. 1995;16(6):432-46.

Charache S, Barton FB, Moore RD, Terrin ML, Steinberg MH, Dover GJ, Ballas SK, McMahon RP, Castro O, Orringer EP. Hydroxyurea and sickle cell anemia. Clinical utility of a myelosuppressive "switching" agent. The Multicenter Study of Hydroxyurea in Sickle Cell Anemia. Medicine (Baltimore). 1996; 75(6):300-26.

Steinberg MH, Lu ZH, Barton FB, Terrin ML, Charache S, Dover GJ. Fetal hemoglobin in sickle cell anemia: determinants of response to hydroxyurea. Multicenter Study of Hydroxyurea. Blood. 1997; 89(3):1078-88.

Steinberg MH, Barton F, Castro O, Pegelow CH, Ballas SK, Kutlar A, Orringer E, Bellevue R, Olivieri N, Eckman J, Varma M, Ramirez G, Adler B, Smith W, Carlos T, Ataga K, DeCastro L, Bigelow C, Saunthararajah Y, Telfer M, Vichinsky E, Claster S, Shurin S, Bridges K, Waclawiw M, Bonds D, Terrin M. Effect of hydroxyurea on mortality and morbidity in adult sickle cell anemia: risks and benefits up to 9 years of treatment. JAMA. 2003; 289(13):1645-51.

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