Efficacy/Safety Study of Deferiprone Compared to Deferasirox in Paediatric Patients

Multicentre, Randomised, Open Label, Non-inferiority Trial to Evaluate the Efficacy and Safety of Deferiprone Compared to Deferasirox in Patients Aged From 1 Month to Less Than 18 Years Affected by Transfusion Dependent Haemoglobinopathies

Multicentre, randomised, open label, non-inferiority active-controlled trial to evaluate efficacy and safety of a 12-months treatment with deferiprone (DFP) at dose of 75-100 mg/kg/day versus deferasirox (DFX) at dose of 20-40 mg/kg/day in paediatric patients (1 month < 18 years old) affected by hereditary haemoglobinopathies and requiring frequent transfusions and chelation.

Study Overview

• Status: Completed
• Conditions: Chronic Iron Overload
• Intervention / Treatment: Drug: Deferiprone; Drug: Deferasirox

Detailed Description

Haemoglobinopathies are a group of inherited disorders characterized by structural variations of the haemoglobin molecule. Most of the patients affected require for survival chronic red blood cells transfusions to overcome ineffective erythropoiesis. Unfortunately, all chronically transfused patients become clinically iron overloaded as there is no physiological mechanism for the removal of iron from the body. The pathologic changes and clinical manifestations associated to chronic iron overload are common among all transfusional iron-overload patients, albeit best documented in patients with beta-thalassemia major. The recommended treatment consists in regular blood transfusions combined with chelating therapy to remove the harmful iron accumulation in the body.

Currently, in the clinical practice particularly in children and adolescents, the criteria leading to the choice of the chelating agent include also the adherence to therapy, thus favouring the use of oral chelators (Ceci A et al., 2011) DFP (Deferiprone) was the first oral chelator authorised in Europe in 1999 as second line treatment for the treatment of iron overload in patients with thalassaemia major when DFO (Deferoxamine) is contraindicated or inadequate. However, despite a wide experience of DFP with iron overloaded (specifically thalassaemic )patients, limited data are available for younger children. For this reason the need for additional data in younger children is expressively included in the 2009 PDCO (Paediatric Committee) Priority List.

The purpose of this study is to assess the non-inferiority of DFP compared to DFX (deferasirox)in paediatric patients affected by hereditary haemoglobinopathies requiring chronic transfusions and chelation. Non inferiority will be established in terms of percentage of patients successfully chelated, as assessed by serum ferritin levels (in all patients) and cardiac MRI T2* (in patients above 10 years of age able to have an MRI scan without sedation).

• Study Type: Interventional
• Enrollment (Actual): 435
• Phase: Phase 3

Contacts and Locations

Study Locations

• Albania
  • Lushnjë, Albania
    • Hospital 'Ihsan Çabej'
  • Tirana, Albania
    • Qendra Spitalore Universitare "Nene Tereza" Tirane
• Cyprus
  • Nicosia, Cyprus
    • Department of Medical and Public health Services of the Ministry of Health
• Egypt
  • Alexandria, Egypt
    • Alexandria University Hospital - Faculty of Medicine
  • Cairo, Egypt
    • Cairo University Faculty of Medicine
  • Zagazig, Egypt
    • Zagazig University Hospitals
• Greece
  • Athens, Greece
    • National and Kapodistrian University of Athens
• Italy
  • Bari, Italy
    • Università di Bari - Facoltà di Medicina
  • Cagliari, Italy
    • ASL Cagliari Ospedale Regionale per le Microcitemie
  • Catania, Italy
    • Azienda Ospedaliera Di Rilievo Nazionale E Di Alta Specializzazione Garibaldi
  • Cosenza, Italy
    • Presidio Ospedaliero "Annunziata", Centro di Studi della Microcitemia
  • Firenze, Italy
    • A.O.Universitaria Meyer
  • Modena, Italy
    • Clinica Pediatrica Policlinico di Modena
  • Napoli, Italy
    • Azienda Ospedaliera di Rilievo Nazionale "Antonio Cardarelli"
  • Padova, Italy
    • Azienda Ospedaliera di Padova
  • Palermo, Italy
    • Ospedali Riuniti Villa Sofia - Cervello
  • Palermo, Italy
    • U.O.C. Ematologia - Emoglobinopatie, Ospedale G. Di Cristina
  • Sassari, Italy
    • Clinica Pediatrica Università - ASL 1 D.H per Talassemia
  • SR
    • Lentini, SR, Italy
      • Centro di Thalassemia, Ospedale Civile di Lentini
• Tunisia
  • Tunis, Tunisia
    • Centre National de Greffe de Moelle Osseuse Tunis
• United Kingdom
  • London, United Kingdom
    • Barts Health NHS Trust
  • Romford, United Kingdom
    • Queen's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 month to 17 years (CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patients of both genders aged from 1 month up to less than 18 years at the time of enrolment
• Patients affected by any hereditary haemoglobinopathy requiring chronic transfusion therapy and chelation, including but not limited to thalassemia syndromes and sickle cell disease
• Patients on current treatment with deferoxamine (DFO) or DFX or DFP in a chronic transfusion program receiving at least 150 mL/kg/year of packed red blood cells (corresponding approximately to 12 transfusions);
• For patients naïve to chelation treatment: patients that have received at least 150 mL/kg of packed red blood cells (corresponding to approximately 12 transfusions) in a chronic transfusion program and with serum ferritin levels ≥ 800 ng/mL;
• Until availability of results from the PK Study (Study DEEP-1, EudraCT n. 2012-000658-67) for patients aged from 1 month to less than 6 years: known intolerance or contraindication to DFO;
• Written informed consent and patient's informed assent, relating to his/her comprehension abilities and level of maturity

Exclusion Criteria:

• Patients with intolerance or known contraindication to either DFP or DFX
• Patients receiving DFX at a dose > 40 mg/kg/day or DFP at a dose > 100 mg/kg/day at screening
• Platelet count <100.000/mm3 during the run-in phase
• Absolute neutrophils count <1.500/mm3 during the run-in phase
• Hb levels lower than 8g/dL during the run-in phase
• Evidence of abnormal liver function
• Iron overload from causes other than transfusional haemosiderosis
• Severe heart dysfunction secondary to iron overload
• Serum creatinine level > ULN (Upper Limit of Normal) for age during the run-in phase
• History of significant medical or psychiatric disorder
• The patient has received another investigational drug within 30 days prior to this clinical trial
• Fever and other signs/symptoms of infection in the 10 days before baseline assessment
• Concomitant use of trivalent cation-dependent medicinal products such as aluminium-based antacids
• Positive test for β-HCG (Human chorionic gonadotropin) and lactating female patients

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Deferiprone; 75-100 mg/kg/day seven days per week	Drug: Deferiprone; Deferiprone 80 mg/mL oral solution; Other Names: DFP
ACTIVE_COMPARATOR: Deferasirox; 20 to 40 mg/kg/day seven days per week	Drug: Deferasirox; Deferasirox is used at the following dosage strengths: 125 mg, 250 mg and 500 mg; Other Names: DFX; ATC Code:V03AC03

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Successfully Chelated Patients	Percentage of successfully chelated patients is assessed by serum ferritin levels (in all patients) and cardiac MRI T2* (in patients above 10 years of age able to perform an MRI scan without sedation)	at baseline and after 12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Liver MRI	Change in liver iron concentration (measured using liver MRI), assessed as difference between value at 12 months minus value at baseline.	at baseline and after 12 months
Cardiac MRI T2*	Change in cardiac iron concentration (measured using cardiac MRI T2*), assessed as difference between value at 12 months minus value at baseline. MRI T2* is a non-invasive method based on gradient echo (GRE) sequences, where T2* represents the spin-spin relaxation times, measured in milliseconds. The faster the curve decreases (ie, the smaller T2*), the greater amount of iron is in the tissue. Treatment success was assessed as follows: if baseline cardiac T2* was less than 20 ms, an increase of 10% or more after 1 year of treatment was defined as treatment success; if baseline cardiac T2* was more than 20 ms, any increase or a decrease of less than 10% after 1 year of treatment was defined as treatment success.	at baseline and after 12 months
Ferritin Level	Change in serum ferritin level, assessed as difference between value at 12 months minus value at baseline.	at baseline and after 12 months

Collaborators and Investigators

• Sponsor: Consorzio per Valutazioni Biologiche e Farmacologiche
• Collaborators: European Commission
• Investigators: Study Director: Donato Bonifazi, Dr, Consorzio per Valutazioni Biologiche e Farmacologiche; Principal Investigator: Aurelio Maggio, MD, Ospedali Riuniti Villa Sofia-Cervello

Publications and helpful links

General Publications

• Giannuzzi V, Felisi M, Bonifazi D, Devlieger H, Papanikolaou G, Ragab L, Fattoum S, Tempesta B, Reggiardo G, Ceci A. Ethical and procedural issues for applying researcher-driven multi-national paediatric clinical trials in and outside the European Union: the challenging experience of the DEEP project. BMC Med Ethics. 2021 Apr 29;22(1):49. doi: 10.1186/s12910-021-00618-2.
• Maggio A, Kattamis A, Felisi M, Reggiardo G, El-Beshlawy A, Bejaoui M, Sherief L, Christou S, Cosmi C, Della Pasqua O, Del Vecchio GC, Filosa A, Cuccia L, Hassab H, Kreka M, Origa R, Putti MC, Spino M, Telfer P, Tempesta B, Vitrano A, Tsang YC, Zaka A, Tricta F, Bonifazi D, Ceci A. Evaluation of the efficacy and safety of deferiprone compared with deferasirox in paediatric patients with transfusion-dependent haemoglobinopathies (DEEP-2): a multicentre, randomised, open-label, non-inferiority, phase 3 trial. Lancet Haematol. 2020 Jun;7(6):e469-e478. doi: 10.1016/S2352-3026(20)30100-9.

Study record dates

Study Major Dates

• Study Start (ACTUAL): March 17, 2014
• Primary Completion (ACTUAL): September 21, 2017
• Study Completion (ACTUAL): September 21, 2017

Study Registration Dates

• First Submitted: April 3, 2013
• First Submitted That Met QC Criteria: April 3, 2013
• First Posted (ESTIMATE): April 5, 2013

Study Record Updates

• Last Update Posted (ACTUAL): May 4, 2021
• Last Update Submitted That Met QC Criteria: April 8, 2021
• Last Verified: October 1, 2017

More Information

Terms related to this study

• Keywords: children; deferasirox; paediatrics; deferiprone; chronic iron overload; hereditary haemoglobinopathy; beta thalassaemia major; chelating agents
• Additional Relevant MeSH Terms: Metabolic Diseases; Hematologic Diseases; Genetic Diseases, Inborn; Iron Metabolism Disorders; Iron Overload; Hemoglobinopathies; Molecular Mechanisms of Pharmacological Action; Chelating Agents; Sequestering Agents; Iron Chelating Agents; Deferasirox; Deferiprone
• Other Study ID Numbers: DEEP-2

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO