Anemia is a common clinical condition in which the volume of peripheral erythrocytes decreases below the lower limit of normal range. Because of the complexity of erythrocyte volumetric measurement, hemoglobin (Hb) concentration is often used as medical index at diagnosis. According to the diagnostic criteria formulated by WHO in 1972, anemia was diagnosed when Hb was lower than the following levels, 110 g/L for children aged 6 months to 6 years, 120 g/L for children aged 6 to 14 years, 130 g/L for adult males, 120 g/L for adult females, and 110 g/L for pregnant women. Clinically, the pathogenesis and etiology of anemia are usually classified as iron-deficiency anemia and thalassemia. The symptoms of anemia include dizziness, weakness, sleepiness, lack of concentration and angina, and heart failure in some patients with severe anemia.
Studies have shown that the lactoferrin extracted from cow's milk can effectively improve the symptoms of iron-deficiency anemia. Continuous use of lactoferrin for 1 month can significantly increase the number of erythrocyte, the serum ferritin and hemoglobin. Thalassemia is an inherited hemoglobin disorder, and long-term blood transfusion and iron removal therapy are the most effective but costly methods to treat thalassemia.
Case Study
Patient enrollment is a key challenge in most clinical trials. This clinical trial of a drug for treating anemia has many requirements for the patients involved. For example, to enter the study, patients have to report more than 3 vaso-occlusive crises in the year before entry into the study and/or have a previous history of stroke, acute chest syndrome, recurrent crises without free interval, or splenic sequestration. Transfusion therapy is clearly recommended in preventing recurrent stroke. Patients and/or parents or tutors were made aware of the potential risk of teratogenesis and mutagenesis associated with chronic exposure to hydroxyurea (HU), which could enhance the synthesis of fetal hemoglobin (HbF) and can improve the clinical course of some adult patients with sickle cell anemia (SCA). Teenage and adult patients were counselled regarding contraception and pregnancy.
Another challenge is statistical analysis. The paired Student's t-test was used to determine the level of significance of differences between biologic parameters before and after HU treatment. Correlations were computed using the Pearson's correlation test. The standard analysis of the 2-treatment 2-period cross-over trial was adopted. The Wilcoxon rank-sum test was used to assess the significance of the effects of treatment, period, and carry-over. Two-tailed P values less than 0.05 were considered to be statistically significant.
By drawing consecutive sealed envelopes, patients were randomly allocated to one of the following treatment sequences: either HU first for a period of 6 months, followed by placebo for 6 months, or placebo first, followed by HU for an additional 6 months. The study was run single-blind (the patient was unaware of the treatment received, but the physician had knowledge of the treatment). The drug or the placebo was provided monthly for each patient by the hospital pharmacy. Both were indistinguishable. The trial was run single-blind rather than double-blind because of the logistic difficulty of blinding the attending physician to the treatment received. Indeed, for the blinding to be effective, the attending physician had been denied access to the pharmacy records and to the laboratory results in the hospital database.
Design:
A randomized, placebo-controlled, single-blind and parallel group trial, including complete eligibility criteria, data collection schedule and detailed statistical analysis.
Participants:
We selected twenty-five children and young adults who were severely affected by SCA to receive HU. There were 13 girls and 12 boys. Ages ranged from 2 to 22 years, with an average age of 9 years. They all originate from Central African countries (24 from Zaire and 1 from Cameroun). All recruited patients had to meet the requirements as followed.
- Patients had homozygous SCA.
- Patients with a-gene deletion were included, with sickle cell thalassemia were excluded.
- They had more than 3 vaso-occlusive crises in the year before entry into the study and/or have a previous history of stroke, acute chest syndrome, recurrent crises without free interval, or splenic sequestration.
Length of Enrollment Period:
12 months.
Interventions:
By drawing consecutive sealed envelopes, patients were randomly allocated to one of the following treatment sequences: either HU first for a period of 6 months, followed by placebo for 6 months, or placebo first, followed by HU for an additional 6 months. HU was administered at an initial dosage of 20 mg/L every day. If no change in reactivation of HbF level had occurred after 2 months (increase<2%), the doses of HU were increased up to 25 mg/kg/d. In case of bone marrow toxicity defined by a white blood cell count (WBC) less than 3*109/L and/or a platelet count less than 80*109/L, the initial dosage was reduced by 50%. All patients received I mg of folic acid each day. Children under 6 years of age also receive oral penicillin. All patients were seen monthly in the outpatient clinic. By screening patients who met the requirements and using this statistical strategy, we recruited a number of suitable patients and analyzed the results of hydroxycarbamide treatment for severe sickle cell anemia.
Main Outcomes:
- Mean hematologic values before and after 6 Months of treatment with HU;
- Correlation between the increase of HbF and that of MCV(mean corpuscular volume);
- P values of the statistical tests performed on the number of hospitalizations and the number of days in hospital;
- Number of Hospitalizations and number of days in hospital by treatment (both periods combined);
- Mean number of days in hospital by time period and treatment.
Results:
In the randomized cross-over trial, treatment with HU resulted in a clear clinical benefit, with a significant reduction in the number of hospitalizations and hospitalization days. What’s more, no clinically relevant toxicity was associated with HU therapy. The data supported the use of HU therapy for children and young adults severely affected by SCA.
After 6 months of HU treatment, the mean Hb of these patients increased to 8.5 g/dL (range, 7.2 to 10 g/dL). An increase of more than 1 g/dL was observed in 9 of 22 evaluable patients. The difference was not significant (P=0.068). The mean initial MCV increased to 95.5 fL (range 68 to 112 fL).This change was highly significant (P<0.001). The mean corpuscular hemoglobin concentration (MCHC) did not change significantly (P=0.069). The mean initial HbF value increased up to 15%, and the change was highly significant (P< 0.001). The increase of HbF correlated significantly with the increase of MCV (Table 1).
Table 1. Mean hematologic values before and after 6 months of treatment with HU
Besides, the number of hospitalizations was reduced when patients were on HU therapy as compared with placebo (Figure 1). The statistical tests indicated a very significant effect of treatment.
Figure 1. Mean number of days in hospital by time period and treatment.
If you are looking for any specific service, please feel free to contact us.
References:
1. Ferster A, Vermylen C, Cornu G, et al. (1996) ‘Hydroxyurea for treatment of severe sickle cell anemia: a pediatric clinical trial’, Molecular Medicine Today, 2(11):450-451.
2. Parfrey P S, Foley R N, Wittreich B H, et al. (2005) ‘Double-Blind Comparison of Full and Partial Anemia Correction in Incident Hemodialysis Patients without Symptomatic Heart Disease’, Journal of the American Society of Nephrology Jasn, 16(7):2180.
3. Jane Hankins MD MS, Pamela Hinds PhD RN FAAN, Sara Day RN MSN, et al. (2010) ‘Therapy preference and decision‐making among patients with severe sickle cell anemia and their families’, Pediatric Blood & Cancer, 48(7):705-710.