Pharmacokinetic Study of Deferiprone in Paediatric Patients
Condition: Chronic Iron Overload
MeSH terms: Hemoglobinopathies; Iron Overload
Intervention: Deferiprone, dose level 1; Deferiprone, dose level 2; Deferiprone, dose level 3
Intervention description: a solution at 80 mg/mL will be administered orally; a solution at 80 mg/mL will be administered orally; a solution at 80 mg/mL will be administered orally
Intervention MeSH terms: Deferiprone
Phase: Phase 2
Study type: Interventional
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single (Investigator)
Enrollment: 23.0
Sex: All
Minimum age: 1 Month
Maximum age: 6 Years
Healthy volunteers: No
Keywords: chronic iron overload; hereditary haemoglobinopathy; beta thalassaemia major

Summary:

      Deferiprone (DFP) is the most extensively studied oral iron chelator to date. It has been
      authorised in Europe in 1999 for the treatment of iron overload in patients with
      beta-thalassaemia major when DFO is contraindicated or inadequate. Despite a wide experience
      of DFP there are limited experimental data available on DFP in children and no
      pharmacokinetic data in children under 6 years of age. On the basis of the existing data in
      adults and adolescent, in the DEEP-1 trial a pharmacokinetic bridging model was developed to
      support the dose selection in children aged less than 6 years affected by transfusion
      dependent haemoglobinopathies. The study consisted of two phases, namely an experimental
      phase, during which patients received a single dose and a modeling phase, during which PK
      data obtained after single dose in patients < 6 years of age were analysed in conjunction
      with historical PK data in adults and older children and adolescents. The model-based
      analysis of the data obtained after single dose enabled the assessment of the dosing regimen
      required for the purpose of accurate pharmacokinetic bridging. The ratio between the
      predicted systemic exposure parameters (AUC and Cmax) in the target population and reference
      group were used as basis for recommendation of the dose in the target population.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Patients in a chronic transfusional program who have received at least 150 ml/kg/year
             of packed red blood cells (corresponding approximately to 12 transfusions) and on
             current treatment with DFO, DFX, DFP; aged from 1 month to less than 6 years; or

          -  Patients naïve to any chelation treatment who have received not less than 150 ml/kg of
             packed red blood cells (corresponding to approximately 12 transfusions) and have
             ferritin levels > 800 ng/mL, aged from 1 month to less than 6 years; or

          -  Patients who meet the transfusion criteria (150 ml/kg/year corresponding approximately
             to 12 transfusions) and have known intolerance or contraindication to DFO

        And if all of the following criteria apply:

          -  Patients affected by any hereditary haemoglobinopathies requiring chronic transfusion
             therapy including but not limited to thalassaemia and sickle cell disease

          -  Written informed consent obtained from their legal guardian on the patient's behalf in
             accordance with the national legislations. According to his/her capability, patient's
             informed assent will be collected

        Exclusion Criteria:

          -  Patient with known intolerance or contraindication to the trial treatment

          -  Patient with Hb levels less than 8g/dl (entry may be delayed until values return to
             normal)

          -  Patient with platelet count <100.000/mm3 or absolute neutrophil count <1.500/mm3
             (entry may be delayed until values return to normal)

          -  Patient with evidence of abnormal liver function (ALT level >5 times the upper normal
             limit during six months preceding enrolment; entry may be delayed until values return
             to normal)

          -  iron overload from causes other than transfusional haemosiderosis

          -  severe heart dysfunction secondary to iron overload defined as the occurrence of heart
             failure or severe arrhythmia or as indicated by cardiac T2* lower than 10 ms, if
             recent MRI data is available,

          -  Patient with serum creatinine level above the upper normal limit at screening; entry
             may be delayed until values return to normal.

          -  Serological evidence of chronic hepatitis B (presence of HBe Ag, HBsAg, HBcAb-IgM, in
             the absence of HBsAb).

          -  History of significant medical or psychiatric disorder that may impair compliance with
             the requirements of the protocol.

          -  The patient has received another investigational drug within 30 days prior to this
             study.

          -  Patient with a pre-existing condition or any other surgical or medical condition which
             might significantly interfere with normal gastrointestinal and hepatic function that
             could alter the absorption, metabolism, and/or excretion of the study drug.

          -  Patient with a known history of HIV seropositivity.

          -  Fever and other signs/symptoms of infection in the 10 days before drug
             administration(treatment day)

          -  Concomitant use of other iron chelators or trivalent cation-dependent medicinal
             products such as aluminium-based antacids.

          -  Patient with a chronic condition that does not allow suspension of related treatment
             from starting of washout until drug is administered.