Efficacy and Safety of Ferriprox® in Patients With Sickle Cell Disease or Other Anemias (FIRST)

The Efficacy and Safety of Ferriprox® for the Treatment of Transfusional Iron Overload in Patients With Sickle Cell Disease or Other Anemias

Difficulties with additional recruitment as pool of potential patients was exhausted, and sufficient information for determination of study outcome measure was already obtained

This research is being done so that we can look at the safety and efficacy of deferiprone in people with sickle cell disease or other anemias. Deferiprone is a drug that removes iron from the body. We will be comparing deferiprone with deferoxamine, another drug that removes iron from the body.

Deferiprone (brand name Ferriprox®) is an iron chelator that is approved in the United States and over 60 other countries for the treatment of iron overload in patients with thalassemia, when other treatments are inadequate. This study has been designed to evaluate the efficacy, safety, and tolerability of deferiprone vs. deferoxamine in patients who have SCD or other anemias, and who require chelation because of the extra iron they are taking in through blood transfusions. About 300 people from North America, South America, Europe, and the Middle East will take part in this study. Participants will be randomized in a 2:1 ratio to receive therapy for 52 weeks with either deferiprone or deferoxamine, another type of iron chelator. Patients who are randomized to the deferiprone group can choose to get the drug as either tablets or liquid, and must take it three times daily. Patients who are randomized to the deferoxamine group will receive it as a subcutaneous infusion that lasts from 8 to 12 hours and is given 5 to 7 days per week. For both drugs, the starting dosage is based on how much extra iron they have taken in through transfusions in the last 3 months and on the severity of iron load, as measured by serum ferritin levels in the blood and by the amount of iron in the liver and the heart. For deferiprone, the starting dosage will be increased each week over the first 3 weeks; and for both drugs, the dosage may be adjusted up or down during the study based on the level of iron overload and on safety considerations. Patients will need to have their blood count checked every week for the first 26 weeks, then every other week for the remaining 26 weeks; they will also have to give a blood sample for more detailed safety testing every month; and to give a blood sample for the measurement of serum ferritin every 3 months. Every six months, they will undergo an ECG and an MRI scan, and will be asked to complete a quality of life survey. At the end of the 52 weeks, participants will be invited to enter a 2-year study in which all patients will receive deferiprone, including those who were randomized to receive deferoxamine in the first year.

Patients randomized to the deferiprone arm will be prescribed either tablets or liquid medication. Deferiprone is taken orally, at a dosage that is calculated in terms of milligrams per kilogram of body weight (mg/kg) and is divided into 3 equal doses taken approximately 8 hours apart. The daily dosage is 75 mg/kg (25 mg/kg per dose) for patients with less severe iron load, and 99 mg/kg (33 mg/kg per dose) for those with more severe iron load.

Patients randomized to the deferoxamine arm will be prescribed the drug as per the approved US prescribing information. Deferoxamine is administered as a subcutaneous infusion over 8-12 hours, 5 to 7 days a week. The dosage is 20 mg/kg (children) or 40 mg/kg (adults) in patients with less severe iron load, and up to 40 mg/kg (children) or 50 mg/kg (adults) in those with more severe iron load.

Cardiac iron is measured by MRI in milliseconds (ms). A score of less than 20 ms is indicative of cardiac iron overload.

Serum ferritin provides a measure of iron level in the blood. Normal levels of serum ferritin are under 300 µg/L for females and 400 µg/L for males.

Change in Patient-reported Quality of Life, as Measured by the Short Form Health Survey (SF-36) or the Child Health Questionnaire (CHQ-PF50).

Adult patients completed the SF-36 questionnaire and minors completed the CHQ-PF50. These questionnaires yield a profile of functional health and well-being, based on 8 scales of physical and mental health measures: Physical Functioning, Role Limitations due to Physical Health, Bodily Pain, General Health Perceptions, Vitality, Social Functioning, Role Limitations due to Emotional Problems, and Mental Health (MH), and summary scores are produced for physical well-being and mental well-being. The summaries are scored from 0-100, with higher scores reflecting better outcomes.

Inclusion Criteria: Male or female ≥ 2 years of age; Have sickle cell disease (confirmed by Hb electrophoresis or more specific tests) or other conditions with iron overload from repeated blood transfusions (see exclusion criteria for exceptions); Baseline LIC >7 mg/g dw (measured by MRI); Patients who have received no less than 20 transfusions of RBCs; Patients who have received at least 1 transfusion per year in the last 2 years and who are expected to have a continuing requirement (based on Investigator's judgement) during the duration of the trial Exclusion Criteria: Thalassemia syndromes; Myelodysplastic syndrome (MDS) or myelofibrosis; Diamond Blackfan anemia; Primary bone marrow failure; Baseline LIC >30 mg/g dw (measured by MRI); Unable or unwilling to undergo a 7 day washout period if currently being treated with deferiprone or deferoxamine or deferasirox; Previous discontinuation of treatment with deferiprone or deferoxamine due to adverse events; History or presence of hypersensitivity or idiosyncratic reaction to deferiprone or deferoxamine; Treated with hydroxyurea within 30 days; History of malignancy; Evidence of abnormal liver function (serum ALT level(s) > 5 times upper limit of normal at screening or creatinine levels >2 times upper limit of normal at screening); A serious, unstable illness, as judged by the Investigator, during the past 3 months before screening/baseline visit including but not limited to: hepatic, renal, gastro-enterologic, respiratory, cardiovascular, endocrinologic, neurologic or immunologic disease; Clinically significant abnormal 12-lead ECG findings; Cardiac MRI T2* <10ms; Myocardial infarction, cardiac arrest or cardiac failure within 1 year before screening/baseline visit; Unable to undergo MRI Presence of metallic objects such as artificial joints, inner ear (cochlear) implants, brain aneurysm clips, pacemakers, and metallic foreign bodies in the eye or other body areas that would prevent use of MRI imaging

Kwiatkowski JL, Hamdy M, El-Beshlawy A, Ebeid FSE, Badr M, Alshehri A, Kanter J, Inusa B, Adly AAM, Williams S, Kilinc Y, Lee D, Tricta F, Elalfy MS. Deferiprone vs deferoxamine for transfusional iron overload in SCD and other anemias: a randomized, open-label noninferiority study. Blood Adv. 2022 Feb 22;6(4):1243-1254. doi: 10.1182/bloodadvances.2021004938. Erratum In: Blood Adv. 2023 Jun 27;7(12):2925.