Efficacy and Safety of Oral Hydroxyurea in Patients with Transfusion Dependent β Thalassaemia: a Randomized Double-Blind Placebo-Controlled Clinical Trial

Abstract

INTRODUCTION AND OBJECTIVES: Patients with β- thalassaemia require blood transfusions and iron chelation for life. Hydroxyurea is a licenced medication for sickle cell disease but its usefulness in transfusion dependent β-thalassaemia is unclear. Here, we aim to assess the efficacy and safety of oral hydroxyurea in patients with transfusion dependent β-thalassaemia. METHODS: A phase III randomized double-blind placebo-controlled clinical trial was conducted at Thalassaemia Unit of Colombo North Teaching Hospital in 2019. Forty-one patients with transfusion dependent β-thalassaemia were randomized into hydroxyurea (10-20mg/kg/day) or placebo (pharmaceutically inert capsule identical to hydroxyurea) groups. Transfused blood volume, pre-transfusion haemoglobin, haemoglobin F level and side effects were monitored monthly during 6- month treatment and 6-month follow-up periods. Adverse events were assessed by trained medical officers. The study was approved by ethics committee of University of Kelaniya and registered in Sri Lanka Clinical Trials Registry (SLCTR/ 2018/024). RESULTS: Of the 41 (hydroxyurea-20; placebo-21) patients, three discontinued treatment due to thrombocytopenia (hydroxyurea-2) and rash (placebo-1). Baseline characteristics of two groups were similar. Mean pre-transfusion haemoglobin (8.52+0.57 vs 8.38+0.55, p=0.45) and haemoglobin F levels (4.3+7.1% vs 3.1+1.9%, p=0.48) were higher in hydroxyurea group compared to placebo. Also, transfused blood volume was lower in hydroxyurea group (102+24ml/kg vs 111+27ml/kg, p=0.3). However, none were statistically significant. Based on elevation of haemoglobin F (>1.5% from baseline), we identified 6/18 patients as hydroxyurea responders. Hydroxyurea responders required significantly lower blood volume (87+13ml/kg) compared to non-responders (110+25ml/kg, p=0.05) and placebo group (111+27ml/kg, p<0.05) while maintaining higher pre-transfusion haemoglobin level (8.6+0.5 vs 8.4+0.5 and 8.3+0.5). No serious side effects were reported. CONCLUSIONS: One-third of patients with transfusion dependent β-thalassaemia responded to hydroxyurea treatment requiring 20% less blood compared to controls. No serious side effects were reported following hydroxyurea treatment.