A MULTICENTRE, RANDOMIZED, NON-INFERIORITY TRIAL COMPARING THE EFFICACY OF DEFERIPRONE VERSUS DEFERASIROX IN PEDIATRIC PATIENTS AFFECTED BY TRANSFUSION-DEPENDENT HEMOGLOBINOPATHIES (DEEP-2 TRIAL)
Author(s): ,
Antonis Kattamis
Affiliations:
First Department of Pediatrics,National and Kapodistriam University of Athens,Athens,Greece
,
Mariagrazia Felisi
Affiliations:
Consorzio per Valutazioni Biologiche e Farmacologiche,Pavia,Italy
,
Giorgio Reggiardo
Affiliations:
Biostatistics and Data Management Unit,Medi Service,Genoa,Italy
,
Amal El-Beshlawy
Affiliations:
Pediatric Hospital,Cairo University,Cairo,Egypt
,
Mohamed Bejaoui
Affiliations:
Pediatrics,Bone Marrow Transplantation Centre,Tunis,Tunisia
,
Laila Sherief
Affiliations:
Pediatric,Faculty of Medicine, Zagazig Univeristy,Zagazig,Egypt
,
Soteroula Christou
Affiliations:
Thalassaemia Center,Hospital Archibishop Makarios III,Nicosia,Cyprus
,
Carlo Cosmi
Affiliations:
Clinica Pediatrica,AOU Sassari,Sassari,Italy
,
Oscar Della Pasqua
Affiliations:
Clinical Pharmacology & Therapeutics Group,University College London,London,United Kingdom
,
Giovanni Carlo Del Vecchio
Affiliations:
U.O. Pediatrica “B. Trambusti”,A.O.U. Consorziale Policlinico-Giovanni XXIII,Bari,Italy
,
Aldo Filosa
Affiliations:
UOSD Malattie rare del globulo rosso,AORN “A. Cardarelli”,Napoli,Italy
,
Hoda Hassab
Affiliations:
Department of Pediatrics & Clinical Research Center,Faculty of Medicine, Alexandria University,Alexandria,Egypt
,
Manika Kreka
Affiliations:
Pediatrics,University Hospital Center 'Mother Teresa',Tirana,Albania
,
Raffaella Origa
Affiliations:
DH Talassemia,Ospedale Pediatrico Microcitemico 'A.CAO, A.O. 'G.Brotzu',Cagliari,Italy
,
Maria Caterina Putti
Affiliations:
Department of Woman’s and Child’s Health (DSDB),University Hospital,Padova,Italy
,
Michael Spino
Affiliations:
ApoPharma Inc.,Toronto,Canada
,
Paul Telfer
Affiliations:
Genomics and Child Health,Blizard Institute, Queen Mary University of London,London,United Kingdom
,
Bianca Tempesta
Affiliations:
Consorzio per Valutazioni Biologiche e Farmacologiche,Bari,Italy
,
Yu Chung Tsang
Affiliations:
Medical Affairs,ApoPharma Inc.,Toronto,Canada
,
Ariana Zaka
Affiliations:
Center of Thalassemia,Hospital”Ihsan Cabej',Lushnje,Albania
,
Fernando Tricta
Affiliations:
Medical Affairs,ApoPharma Inc.,Toronto,Canada
,
Donato Bonifazi
Affiliations:
Consorzio per Valutazioni Biologiche e Farmacologiche,Bari,Italy
,
Adriana Ceci
Affiliations:
Fondazione per la Ricerca Farmacologica Gianni Benzi Onlus,Valenzano,Italy
Aurelio Maggio
Affiliations:
Department of Hematology and Rare Diseases of P.O. “V. Cervello”,Azienda Ospedaliera Ospedali Riuniti “Villa Sofia-Cervello”,Palermo,Italy
EHA Library. KATTAMIS A. 06/14/19; 267345; S144
Prof. Antonis KATTAMIS
Prof. Antonis KATTAMIS
Contributions
Abstract

Abstract: S144

Type: Oral Presentation

Presentation during EHA24: On Friday, June 14, 2019 from 12:30 - 12:45

Location: Hall E106

Background
While the efficacy and safety of deferiprone (DFP) in adult patients with transfusion-dependent hemoglobinopathies (TDH) has been extensively studied, data in children are sparse.

Aims
We report results of DEferiprone Evaluation in Pediatrics-2 (DEEP-2), (EudraCT Number 2012-000353-31), a Phase III multicentre, randomized, open label study funded by the EU FP7 Research Program, to compare the efficacy of DFP liquid formulation versus deferasirox dispersible tablets (DFX).

Methods
DEEP-2 was a non-inferiority, 12-months, active-controlled trial that included TDH patients, including sickle cell disease (SCD), of 1 month to <18 years of age. The primary composite efficacy endpoint was treatment success rate based on changes in serum ferritin (SF) levels (all patients) and cardiac iron concentration (MRI-T2*) (patients >10 years able to undergo MRI). Predefined criteria (Figure) were used to determine treatment success for the per protocol (PP) population. The secondary endpoints were changes in SF level, cardiac MRI-T2*, liver iron concentration-R2 (LIC-R2) and safety profile. Non-inferiority (NI) was based on the 2-sided 95% confidence interval (CIL, CIU) of the difference in the success rate between the two arms and was established if CIL was greater than -0.125. In the intention-to-treat (ITT) analysis, treatment failure was strictly assigned to patients who withdrew from the study, irrespective of the ferritin response observed at the time of the study suspension.

Results
21 sites from 7 countries participated in the trial between 3/2014 and 9/2017. 393 patients were randomized (1:1 DFP vs. DFX) and included 117 patients < 6 years of age (30%), 38 with non β-thalassemia TDH (mainly SCD) and 54 chelation-naïve. DFP was non-inferior to DFX based on the PP population (n=271) while the NI criterion was not met for the ITT population (n=390) due mainly to more patient withdrawals in the DFP arm, which were not mandated by the protocol (Figure). After 1year treatment (PP population) SF changed from 2468 to 2120 ng/ml in DFP arm and from 2822 to 2328 ng/ml in the DFX arm. Cardiac MRI T2* values changed from 31.3 to 32.4ms and from 30.8 to 32.0ms in DFP and DFX arm, respectively. Statistical analysis of the change in SF at the end of treatment also showed NI of DFP for the PP population (δ = -20, CIU = 317 ng/ml; NI criterion: <400 ng/ml), but not for the ITT population when missing SF levels were not analyzed. No significant differences were seen between treatment arms for changes in MRI-T2* and LIC. Overall, there were no statistically significant differences between the two arms in serious adverse events (SAEs) and drug-related SAEs. 18 (9.3%) DFP and 11 (5.5%) DFX-treated patients were reported with neutropenia, 3 reversible cases of agranulocytosis were detected in DFP arm, and 2 reversible renal failures in DFX arm.

Conclusion
This FP7-sponsored trial on chelation therapy in pediatric patients with TDH is the largest in this age group and the only one comparing the two oral chelating agents. The results of the study show that 1) oral iron chelation treatment is effective even in very young ages, 2) treatment with DFP was not inferior to DFX in patients who received 12 months treatment, 3) NI was not shown in the ITT analysis partially due to a different rate of withdrawal not necessarily mandated by the protocol, 4) the overall safety profile of both DFP and DFX was acceptable. The results of the DEEP-2 trial provide evidence to support the use of DFP in pediatric patients.

Session topic: 27. Thalassemias

Keyword(s): Iron chelation, Sickle cell disease, Thalassemia

Abstract: S144

Type: Oral Presentation

Presentation during EHA24: On Friday, June 14, 2019 from 12:30 - 12:45

Location: Hall E106

Background
While the efficacy and safety of deferiprone (DFP) in adult patients with transfusion-dependent hemoglobinopathies (TDH) has been extensively studied, data in children are sparse.

Aims
We report results of DEferiprone Evaluation in Pediatrics-2 (DEEP-2), (EudraCT Number 2012-000353-31), a Phase III multicentre, randomized, open label study funded by the EU FP7 Research Program, to compare the efficacy of DFP liquid formulation versus deferasirox dispersible tablets (DFX).

Methods
DEEP-2 was a non-inferiority, 12-months, active-controlled trial that included TDH patients, including sickle cell disease (SCD), of 1 month to <18 years of age. The primary composite efficacy endpoint was treatment success rate based on changes in serum ferritin (SF) levels (all patients) and cardiac iron concentration (MRI-T2*) (patients >10 years able to undergo MRI). Predefined criteria (Figure) were used to determine treatment success for the per protocol (PP) population. The secondary endpoints were changes in SF level, cardiac MRI-T2*, liver iron concentration-R2 (LIC-R2) and safety profile. Non-inferiority (NI) was based on the 2-sided 95% confidence interval (CIL, CIU) of the difference in the success rate between the two arms and was established if CIL was greater than -0.125. In the intention-to-treat (ITT) analysis, treatment failure was strictly assigned to patients who withdrew from the study, irrespective of the ferritin response observed at the time of the study suspension.

Results
21 sites from 7 countries participated in the trial between 3/2014 and 9/2017. 393 patients were randomized (1:1 DFP vs. DFX) and included 117 patients < 6 years of age (30%), 38 with non β-thalassemia TDH (mainly SCD) and 54 chelation-naïve. DFP was non-inferior to DFX based on the PP population (n=271) while the NI criterion was not met for the ITT population (n=390) due mainly to more patient withdrawals in the DFP arm, which were not mandated by the protocol (Figure). After 1year treatment (PP population) SF changed from 2468 to 2120 ng/ml in DFP arm and from 2822 to 2328 ng/ml in the DFX arm. Cardiac MRI T2* values changed from 31.3 to 32.4ms and from 30.8 to 32.0ms in DFP and DFX arm, respectively. Statistical analysis of the change in SF at the end of treatment also showed NI of DFP for the PP population (δ = -20, CIU = 317 ng/ml; NI criterion: <400 ng/ml), but not for the ITT population when missing SF levels were not analyzed. No significant differences were seen between treatment arms for changes in MRI-T2* and LIC. Overall, there were no statistically significant differences between the two arms in serious adverse events (SAEs) and drug-related SAEs. 18 (9.3%) DFP and 11 (5.5%) DFX-treated patients were reported with neutropenia, 3 reversible cases of agranulocytosis were detected in DFP arm, and 2 reversible renal failures in DFX arm.

Conclusion
This FP7-sponsored trial on chelation therapy in pediatric patients with TDH is the largest in this age group and the only one comparing the two oral chelating agents. The results of the study show that 1) oral iron chelation treatment is effective even in very young ages, 2) treatment with DFP was not inferior to DFX in patients who received 12 months treatment, 3) NI was not shown in the ITT analysis partially due to a different rate of withdrawal not necessarily mandated by the protocol, 4) the overall safety profile of both DFP and DFX was acceptable. The results of the DEEP-2 trial provide evidence to support the use of DFP in pediatric patients.

Session topic: 27. Thalassemias

Keyword(s): Iron chelation, Sickle cell disease, Thalassemia

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