Efficacy/Safety Study of Deferiprone Compared to Deferasirox in Paediatric Patients

Haemoglobinopathies are a group of inherited disorders characterized by structural variations of the haemoglobin molecule. Most of the patients affected require for survival chronic red blood cells transfusions to overcome ineffective erythropoiesis. Unfortunately, all chronically transfused patients become clinically iron overloaded as there is no physiological mechanism for the removal of iron from the body. The pathologic changes and clinical manifestations associated to chronic iron overload are common among all transfusional iron-overload patients, albeit best documented in patients with beta-thalassemia major. The recommended treatment consists in regular blood transfusions combined with chelating therapy to remove the harmful iron accumulation in the body.

Currently, in the clinical practice particularly in children and adolescents, the criteria leading to the choice of the chelating agent include also the adherence to therapy, thus favouring the use of oral chelators (Ceci A et al., 2011) DFP (Deferiprone) was the first oral chelator authorised in Europe in 1999 as second line treatment for the treatment of iron overload in patients with thalassaemia major when DFO (Deferoxamine) is contraindicated or inadequate. However, despite a wide experience of DFP with iron overloaded (specifically thalassaemic )patients, limited data are available for younger children. For this reason the need for additional data in younger children is expressively included in the 2009 PDCO (Paediatric Committee) Priority List.

The purpose of this study is to assess the non-inferiority of DFP compared to DFX (deferasirox)in paediatric patients affected by hereditary haemoglobinopathies requiring chronic transfusions and chelation. Non inferiority will be established in terms of percentage of patients successfully chelated, as assessed by serum ferritin levels (in all patients) and cardiac MRI T2* (in patients above 10 years of age able to have an MRI scan without sedation).

Inclusion criteria

• Patients of both genders aged from 1 month up to less than 18 years at the time of enrolment
• Patients affected by any hereditary haemoglobinopathy requiring chronic transfusion therapy and chelation, including but not limited to thalassemia syndromes and sickle cell disease
• Patients on current treatment with deferoxamine (DFO) or DFX or DFP in a chronic transfusion program receiving at least 150 mL/kg/year of packed red blood cells (corresponding approximately to 12 transfusions);
• For patients naïve to chelation treatment: patients that have received at least 150 mL/kg of packed red blood cells (corresponding to approximately 12 transfusions) in a chronic transfusion program and with serum ferritin levels ≥ 800 ng/mL;
• Until availability of results from the PK Study (Study DEEP-1, EudraCT n. 2012-000658-67) for patients aged from 1 month to less than 6 years: known intolerance or contraindication to DFO;
• Written informed consent and patient's informed assent, relating to his/her comprehension abilities and level of maturity

Exclusion criteria

• Patients with intolerance or known contraindication to either DFP or DFX
• Patients receiving DFX at a dose > 40 mg/kg/day or DFP at a dose > 100 mg/kg/day at screening
• Platelet count <100.000/mm3 during the run-in phase
• Absolute neutrophils count <1.500/mm3 during the run-in phase
• Hb levels lower than 8g/dL during the run-in phase
• Evidence of abnormal liver function
• Iron overload from causes other than transfusional haemosiderosis
• Severe heart dysfunction secondary to iron overload
• Serum creatinine level > ULN (Upper Limit of Normal) for age during the run-in phase
• History of significant medical or psychiatric disorder
• The patient has received another investigational drug within 30 days prior to this clinical trial
• Fever and other signs/symptoms of infection in the 10 days before baseline assessment
• Concomitant use of trivalent cation-dependent medicinal products such as aluminium-based antacids
• Positive test for β-HCG (Human chorionic gonadotropin) and lactating female patients