Aurelio Maggio1, Antonis Kattamis2, Mariagrazia Felisi3, Giorgio Reggiardo4, Amal El-Beshlawy5, Mohamed Bejaoui6, Laila Sherief7, Soteroula Christou8, Carlo Cosmi9, Oscar Della Pasqua10, Giovanni Carlo Del Vecchio11, Aldo Filosa12, Liana Cuccia13, Hoda Hassab14, Manika Kreka15, Raffaella Origa16, Maria Caterina Putti17, Michael Spino18, Paul Telfer19, Bianca Tempesta3, Angela Vitrano20, Yu Chung Tsang18, Ariana Zaka21, Fernando Tricta18, Donato Bonifazi3, Adriana Ceci22. 1. Department of Hematology and Rare Diseases, V Cervello, Azienda Ospedaliera Ospedali Riuniti Villa Sofia-Cervello, Palermo, Italy. Electronic address: aurelio.maggio@villasofia.it. 2. First Department of Pediatrics, National and Kapodistriam University of Athens, Athens, Greece. 3. Consorzio per Valutazioni Biologiche e Farmacologiche, Bari-Pavia, Italy. 4. Biostatistics and Data Management Unit, Medi Service, Genoa, Italy. 5. Pediatric Hospital, Cairo University, Cairo, Egypt. 6. Pediatrics and Bone Marrow Transplantation Centre, Tunis, Tunisia. 7. Pediatrics Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt. 8. Thalassaemia Center, Hospital Archbishop Makarios III, Nicosia, Cyprus. 9. Clinica Pediatrica, Azienda Ospedaliero Universitaria (AOU) Sassari, Sassari, Italy. 10. Clinical Pharmacology and Therapeutics Group, University College London, London, UK. 11. UO Pediatrica B Trambusti, AOU Consorziale Policlinico-Giovanni XXIII, Bari, Italy. 12. UOSD Malattie rare del globulo rosso, AORN A Cardarelli, Napoli, Italy. 13. UOC Ematologia con Talassemia, Dipartimento di Medicina, AO Civico Di Cristina-Benfratelli, Palermo, Italy. 14. Department of Pediatrics and Clinical Research Center, Faculty of Medicine, Alexandria University, Alexandria, Egypt. 15. Pediatrics Department, University Hospital Center Mother Teresa, Tirana, Albania. 16. DH Talassemia, Ospedale Pediatrico Microcitemico A CAO, AO G Brotzu, Cagliari, Italy. 17. Department of Women's and Child's Health (DSDB), University Hospital, Padova, Italy. 18. ApoPharma, Toronto, ON, Canada. 19. Centre for Genomics and Child Health, Blizard Institute, Queen Mary University of London, London, UK. 20. Department of Hematology and Rare Diseases, V Cervello, Azienda Ospedaliera Ospedali Riuniti Villa Sofia-Cervello, Palermo, Italy. 21. Center of Thalassemia, Hospital Ihsan Cabej, Lushnje, Albania. 22. Fondazione per la Ricerca Farmacologica Gianni Benzi Onlus, Valenzano, Italy.
Abstract
BACKGROUND:Transfusion-dependent haemoglobinopathies require lifelong iron chelation therapy with one of the three iron chelators (deferiprone, deferasirox, or deferoxamine). Deferasirox and deferiprone are the only two oral chelators used in adult patients with transfusion-dependent haemoglobinopathies. To our knowledge, there are no randomised clinical trials comparing deferiprone, a less expensive iron chelator, with deferasirox in paediatric patients. We aimed to show the non-inferiority of deferiprone versus deferasirox. METHODS: DEEP-2 was a phase 3, multicentre, randomised trial in paediatric patients (aged 1 month to 18 years) with transfusion-dependent haemoglobinopathies. The study was done in 21 research hospitals and universities in Italy, Egypt, Greece, Albania, Cyprus, Tunisia, and the UK. Participants were receiving at least 150 mL/kg per year of red blood cells for the past 2 years at the time of enrolment, and were receiving deferoxamine (<100 mg/kg per day) or deferasirox (<40 mg/kg per day; deferasirox is not registered for use in children aged <2years so only deferoxamine was being used in these patients). Any previous chelation treatment was permitted with a 7-day washout period. Patients were randomly assigned 1:1 to receive orally administered daily deferiprone (75-100 mg/kg per day) or daily deferasirox (20-40 mg/kg per day) administered as dispersible tablets, both with dose adjustment for 12 months, stratified by age (<10 years and ≥10 years) and balanced by country. The primary efficacy endpoint was based on predefined success criteria for changes in serum ferritin concentration (all patients) and cardiac MRI T2-star (T2*; patients aged >10 years) to show non-inferiority of deferiprone versus deferasirox in the per-protocol population, defined as all randomly assigned patients who received the study drugs and had available data for both variables at baseline and after 1 year of treatment, without major protocol violations. Non-inferiority was based on the two-sided 95% CI of the difference in the proportion of patients with treatment success between the two groups and was shown if the lower limit of the two-sided 95% CI was greater than -12·5%. Safety was assessed in all patients who received at least one dose of study drug. This study is registered with EudraCT, 2012-000353-31, and ClinicalTrials.gov, NCT01825512. FINDINGS:435 patients were enrolled between March 17, 2014, and June 16, 2016, 393 of whom were randomly assigned to a treatment group (194 to the deferiprone group; 199 to the deferasirox group). 352 (90%) of 390 patients had β-thalassaemia major, 27 (7%) had sickle cell disease, five (1%) had thalassodrepanocytosis, and six (2%) had other haemoglobinopathies. Median follow-up was 379 days (IQR 294-392) for deferiprone and 381 days (350-392) for deferasirox. Non-inferiority of deferiprone versus deferasirox was established (treatment success in 69 [55·2%] of 125 patients assigned deferiprone with primary composite efficacy endpoint data available at baseline and 1 year vs 80 [54·8%] of 146 assigned deferasirox, difference 0·4%; 95% CI -11·9 to 12·6). No significant difference between the groups was shown in the occurrence of serious and drug-related adverse events. Three (2%) cases of reversible agranulocytosis occurred in the 193 patients in the safety analysis in the deferiprone group and two (1%) cases of reversible renal and urinary disorders (one case of each) occurred in the 197 patients in the deferasirox group. Compliance was similar between treatment groups: 183 (95%) of 193 patients in the deferiprone group versus 192 (97%) of 197 patients in the deferisirox group. INTERPRETATION: In paediatric patients with transfusion-dependenthaemoglobinopathies, deferiprone was effective and safe in inducing control of iron overload during 12 months of treatment. Considering the need for availability of more chelation treatments in paediatric populations, deferiprone offers a valuable treatment option for this age group. FUNDING: EU Seventh Framework Programme.
RCT Entities:
BACKGROUND: Transfusion-dependent haemoglobinopathies require lifelong iron chelation therapy with one of the three iron chelators (deferiprone, deferasirox, or deferoxamine). Deferasirox and deferiprone are the only two oral chelators used in adult patients with transfusion-dependent haemoglobinopathies. To our knowledge, there are no randomised clinical trials comparing deferiprone, a less expensive iron chelator, with deferasirox in paediatric patients. We aimed to show the non-inferiority of deferiprone versus deferasirox. METHODS: DEEP-2 was a phase 3, multicentre, randomised trial in paediatric patients (aged 1 month to 18 years) with transfusion-dependent haemoglobinopathies. The study was done in 21 research hospitals and universities in Italy, Egypt, Greece, Albania, Cyprus, Tunisia, and the UK. Participants were receiving at least 150 mL/kg per year of red blood cells for the past 2 years at the time of enrolment, and were receiving deferoxamine (<100 mg/kg per day) or deferasirox (<40 mg/kg per day; deferasirox is not registered for use in children aged <2 years so only deferoxamine was being used in these patients). Any previous chelation treatment was permitted with a 7-day washout period. Patients were randomly assigned 1:1 to receive orally administered daily deferiprone (75-100 mg/kg per day) or daily deferasirox (20-40 mg/kg per day) administered as dispersible tablets, both with dose adjustment for 12 months, stratified by age (<10 years and ≥10 years) and balanced by country. The primary efficacy endpoint was based on predefined success criteria for changes in serum ferritin concentration (all patients) and cardiac MRI T2-star (T2*; patients aged >10 years) to show non-inferiority of deferiprone versus deferasirox in the per-protocol population, defined as all randomly assigned patients who received the study drugs and had available data for both variables at baseline and after 1 year of treatment, without major protocol violations. Non-inferiority was based on the two-sided 95% CI of the difference in the proportion of patients with treatment success between the two groups and was shown if the lower limit of the two-sided 95% CI was greater than -12·5%. Safety was assessed in all patients who received at least one dose of study drug. This study is registered with EudraCT, 2012-000353-31, and ClinicalTrials.gov, NCT01825512. FINDINGS: 435 patients were enrolled between March 17, 2014, and June 16, 2016, 393 of whom were randomly assigned to a treatment group (194 to the deferiprone group; 199 to the deferasirox group). 352 (90%) of 390 patients had β-thalassaemia major, 27 (7%) had sickle cell disease, five (1%) had thalassodrepanocytosis, and six (2%) had other haemoglobinopathies. Median follow-up was 379 days (IQR 294-392) for deferiprone and 381 days (350-392) for deferasirox. Non-inferiority of deferiprone versus deferasirox was established (treatment success in 69 [55·2%] of 125 patients assigned deferiprone with primary composite efficacy endpoint data available at baseline and 1 year vs 80 [54·8%] of 146 assigned deferasirox, difference 0·4%; 95% CI -11·9 to 12·6). No significant difference between the groups was shown in the occurrence of serious and drug-related adverse events. Three (2%) cases of reversible agranulocytosis occurred in the 193 patients in the safety analysis in the deferiprone group and two (1%) cases of reversible renal and urinary disorders (one case of each) occurred in the 197 patients in the deferasirox group. Compliance was similar between treatment groups: 183 (95%) of 193 patients in the deferiprone group versus 192 (97%) of 197 patients in the deferisirox group. INTERPRETATION: In paediatric patients with transfusion-dependent haemoglobinopathies, deferiprone was effective and safe in inducing control of iron overload during 12 months of treatment. Considering the need for availability of more chelation treatments in paediatric populations, deferiprone offers a valuable treatment option for this age group. FUNDING: EU Seventh Framework Programme.
Authors: Janet L Kwiatkowski; Mona Hamdy; Amal El-Beshlawy; Fatma S E Ebeid; Mohammed Badr; Abdulrahman Alshehri; Julie Kanter; Baba Inusa; Amira A M Adly; Suzan Williams; Yurdanur Kilinc; David Lee; Fernando Tricta; Mohsen S Elalfy Journal: Blood Adv Date: 2022-02-22
Authors: Martin Scoglio; Maria Domenica Cappellini; Emanuela D'Angelo; Mario G Bianchetti; Sebastiano A G Lava; Carlo Agostoni; Gregorio P Milani Journal: Children (Basel) Date: 2021-12-01