The purpose of this protocol amendment is 1) to introduce a fixed starting dose of 20 mg/kg for all patients 2) to implement a dose adjustment schedule based on serial serum ferritin measurements 3) to provide further details on the assessment of further potential surrogate markers and the necessity of increasing blood sample volume 4) to introduce safety measures to be taken in case of increased liver parameters 5) to update the liver biopsy laboratory procedures 6) to clarify some protocol discrepancies.

This amendment extends study CICL670A2402 by means of a separate extension protocol CICL670A2402E1 provided as Post-text supplement 9 to the original protocol. In this extension study, liver MRI will be the reference technique for determination of liver iron concentration (LIC) in all patients. Only in patients in whom liver MRI is not practicable, liver biopsy (the technique used for LIC determination in the core study) will be used.

The purpose of this protocol amendment is 1) to simplify the dosing and assessment procedures in the core and extension protocol based upon the emerging safety and efficacy profile that has been observed in the clinical development program, 2) to extend the duration of the extension study for another year to give study patients access to the study drug until it will be commercially available, and 3) to correct protocol inconsistencies.

This amendment is to update the dosing, dose adjustment and assessment procedures in the extension protocol based upon the update of the global periodic safety review (the monitoring of serum creatinine and the dose reduction criteria for increased serum creatinine levels will be updated; dose modification criteria for hypersensitivity reactions, cytopenias and for increased urinary protein/creatinine ratio will be newly introduced), to further clarify dose adjustments due to changes in serum ferritin and due to increased transaminases levels, and skin rash in the extension study. It will allow harmonization of dosing adjustments across multiple clinical studies with ICL670 and to further clarify definition of study population for statistical analysis in the extension study. The changes introduced by amendment 4 will only apply for the extension. Based on the global periodic safety review of the clinical and post-marketing data, the global label for ICL670 has been updated and the following dose adjustments/procedures in ongoing studies have been added/modified. • Monitoring of the serum creatinine has been incorporated for patients with preexisting renal conditions and for patients who are receiving medicinal products that depress renal function. • The dose modification procedure, for adult and pediatric patients has been adjusted: for pediatric patients with increased serum creatinine levels above the age-appropriate ULN and for adult patients with non-progressive increases by >33% above average of pretreatment measures at 2 consecutive visits. • Monthly tests for proteinuria have been added to the visit schedule to monitor the renal safety for all patients. • Cases of serious hypersensitivity reactions, have been reported in patients receiving ICL670, the onset of the reaction occurring in the majority of cases within the first month of treatment. If reactions are severe, ICL670 should be discontinued and appropriate medical intervention instituted.