Clinical trial NCT01825512: Efficacy/Safety Study of Deferiprone Compared to Deferasirox in Paediatric Patients
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Chronic Iron Overload
Keywords: chronic iron overload
hereditary haemoglobinopathy
beta thalassaemia major
chelating agents
deferiprone
deferasirox
children
paediatrics
Lead sponsor: Consorzio per Valutazioni Biologiche e Farmacologiche
Sponsor class: OTHER
Collaborators: name: European Commission
First posted: 2013-04-05
Enrollment: 435
Sex: ALL
Minimum age (years): 1
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

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).

Eligibility criteria: 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

Primary outcomes:
measure: Percentage of Successfully Chelated Patients
timeFrame: at baseline and after 12 months
Secondary outcomes:
measure: Liver MRI
timeFrame: at baseline and after 12 months
measure: Cardiac MRI T2*
timeFrame: at baseline and after 12 months
measure: Ferritin Level
timeFrame: at baseline and after 12 months
Other outcomes:
Locations:
city: Lushnjë
country: Albania
facility: Hospital 'Ihsan Çabej'
city: Tirana
country: Albania
facility: Qendra Spitalore Universitare "Nene Tereza" Tirane
city: Nicosia
country: Cyprus
facility: Department of Medical and Public health Services of the Ministry of Health
city: Alexandria
country: Egypt
facility: Alexandria University Hospital - Faculty of Medicine
city: Cairo
country: Egypt
facility: Cairo University Faculty of Medicine
city: Zagazig
country: Egypt
facility: Zagazig University Hospitals
city: Athens
country: Greece
facility: National And Kapodistrian University of Athens
city: Lentini
country: Italy
facility: Centro di Thalassemia, Ospedale Civile di Lentini
state: SR
city: Bari
country: Italy
facility: Università di Bari - Facoltà di Medicina
city: Cagliari
country: Italy
facility: ASL Cagliari Ospedale Regionale per le Microcitemie
city: Catania
country: Italy
facility: Azienda Ospedaliera di Rilievo Nazionale e di Alta Specializzazione Garibaldi
city: Cosenza
country: Italy
facility: Presidio Ospedaliero "Annunziata", Centro di Studi della Microcitemia
city: Firenze
country: Italy
facility: A.O.Universitaria Meyer
city: Modena
country: Italy
facility: Clinica Pediatrica Policlinico di Modena
city: Napoli
country: Italy
facility: Azienda Ospedaliera di Rilievo Nazionale "Antonio Cardarelli"
city: Padova
country: Italy
facility: Azienda Ospedaliera di Padova
city: Palermo
country: Italy
facility: Ospedali Riuniti Villa Sofia - Cervello
city: Palermo
country: Italy
facility: U.O.C. Ematologia - Emoglobinopatie, Ospedale G. Di Cristina
city: Sassari
country: Italy
facility: Clinica Pediatrica Università - ASL 1 D.H per Talassemia
city: Tunis
country: Tunisia
facility: Centre National de Greffe de Moelle Osseuse Tunis
city: London
country: United Kingdom
facility: Barts Health NHS Trust
city: Romford
country: United Kingdom
facility: Queen's Hospital
Study officials:
affiliation: Consorzio per Valutazioni Biologiche e Farmacologiche
name: Donato Bonifazi, Dr
role: STUDY_DIRECTOR
affiliation: Ospedali Riuniti Villa Sofia-Cervello
name: Aurelio Maggio, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.