Objectives

The purpose of this study was to evaluate the safety and effectiveness of hydroxyurea and magnesium, alone and combined, at reducing red blood cell density and the frequency of sickle cell crises in people with Hemoglobin Sickle Cell Disease (HbSC).

Background

Sickle Cell Disease (SCD) is an inherited blood disorder. Symptoms include anemia, infections, organ damage, and intense episodes of pain, which are called "sickle cell crises." SCD is caused by an abnormal type of hemoglobin, which is a protein inside red blood cells that carries oxygen. There are two main forms of SCD: HbSC and HbSS.

HbSC is a form of SCD that is characterized by the presence of dense red blood cells. People with HbSC usually develop less severe SCD symptoms when compared to subjects with HbSS. The medication hydroxyurea is currently used in patients with HbSS to prevent sickle cell crises and to decrease the need for blood transfusions. The evaluation of hydroxyurea use in HbSC disease has been limited.

A hallmark of HbSC disease is severe erythrocyte, or red blood cell, dehydration due to increased potassium-chloride (K-Cl) co-transport. Previous studies on magnesium suggest it may interfere with cation transport and therefore result in reduction of cell dehydration.

Participants

Eligible participants included children and adults, aged ≥ 5 years, with HbSC. Additional enrollment criteria included: hemoglobin level between 8 and 12.5 g/dL and at least one vaso-occlusive event in the 12 months prior to study entry but not within 4 weeks prior to enrollment.

Participants were excluded for: a previous transfusion with remaining hemoglobin A ≥10%, previous treatment with either study drug within the past 3 months, liver or kidney dysfunction, daily narcotic use, investigational drug use in past 3 months, and positive HIV test or other chronic diseases affecting performance in the study.

Original sample size calculations were based on randomization of 188 subjects. Final numbers for the study consisted of 64 subjects enrolled with 44 randomized subjects. Of the 44 subjects randomized, 36 completed the primary endpoint evaluation and 22 completed the full 44-week study timeline.

Design

The CHAMPS study was a phase-II, double blind, factorial trail. Subjects were randomized to one of four treatment arms: hydroxyurea + magnesium, hydroxyurea + placebo, magnesium + placebo, and placebo + placebo, stratified within site and age group (5–15 vs. >15 years).

Two pre-randomization visits were performed to evaluate eligibility and obtain baseline laboratory measurements. Subjects were evaluated every 2 weeks for the first 8 weeks after randomization (primary endpoint) and every 4 weeks thereafter for a total of 44 weeks. At each visit, a physical exam and standard blood counts were performed. Evaluations at baseline and weeks 8, 16, 24, and 44 included measures of erythrocyte density, cation content, K-Cl co-transport, Gardos channel activity, sodium/magnesium (Na/Mg) exchange, endothelial adhesion, hemoglobin type F (HbF)levels, and plasma Mg. Selected visits also included urine collection and a pregnancy test for female participants. Throughout the study, participants recorded their study medication use in a daily diary.

The primary endpoint was the proportion of hyperdense red blood cells (cell density >410 g/l) after 8 weeks.

Conclusions

The study was terminated early due to limited enrollment.

The two hydroxyurea treatment arms (hydroxyurea + magnesium, hydroxyurea + placebo) showed significant increases in mean cell volume (MCV) and hemoglobin type F (HbF); however, there were no differences in hyperdense red blood cells. Children experienced greater increases when compared to adults. Magnesium had no treatment effect.

Wang W, Brugnara C, Snyder C, et al. The effects of hydroxycarbamide and magnesium on haemoglobin SC disease: results of the multi-centre CHAMPS trial. Br J Haematol. 2011;152(6):771-776. doi:10.1111/j.1365-2141.2010.08523.x

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