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

• ClinicalTrials.gov Identifier: NCT01825512
• Recruitment Status: Completed
• First Posted: April 5, 2013
• Results First Posted: April 8, 2021
• Last Update Posted: May 4, 2021
• Sponsor: Consorzio per Valutazioni Biologiche e Farmacologiche
• Collaborator: European Commission
• Information provided by (Responsible Party): Consorzio per Valutazioni Biologiche e Farmacologiche

Tracking Information

• First Submitted Date: April 3, 2013
• First Posted Date: April 5, 2013
• Results First Submitted Date: January 27, 2021
• Results First Posted Date: April 8, 2021
• Last Update Posted Date: May 4, 2021
• Actual Study Start Date: March 17, 2014
• Actual Primary Completion Date: September 21, 2017 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: March 15, 2021)

Percentage of Successfully Chelated Patients [ Time Frame: at baseline and after 12 months ]

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)

Original Primary Outcome Measures (submitted: April 3, 2013)

Percentage of successfully chelated patients [ Time Frame: twelve months ]

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)

Current Secondary Outcome Measures (submitted: April 8, 2021)

• Liver MRI [ Time Frame: at baseline and after 12 months ]
  Change in liver iron concentration (measured using liver MRI), assessed as difference between value at 12 months minus value at baseline.
• Cardiac MRI T2* [ Time Frame: at baseline and after 12 months ]
  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.
• Ferritin Level [ Time Frame: at baseline and after 12 months ]
  Change in serum ferritin level, assessed as difference between value at 12 months minus value at baseline.

Original Secondary Outcome Measures (submitted: April 3, 2013)

• LIC (Liver Iron Concentration) [ Time Frame: twelve months ]
  It is measured by MRI scan and will be assessed in all patients able to undergo MRI scan without sedation
• Safety and tolerability [ Time Frame: monthly ]
  Collection of adverse events (nature, severity, grade, duration), the monitoring of haematology, blood chemistry and urine values
• Health-related quality of life [ Time Frame: twelve months ]
  It is evaluated using the Child Health Questionnaire™ (CHQ) in the subgroup of patients for which the questionnaire is validated (5-18 years)
• Pharmacokinetics (PK) [ Time Frame: twelve months ]
  Assessment of drug concentrations at steady-state conditions. PK data will be analysed to confirm the influence of relevant covariates on the systemic exposure to Deferiprone.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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
• 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).

• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Chronic Iron Overload

Intervention

• Drug: Deferiprone
  Deferiprone 80 mg/mL oral solution
  Other Name: DFP
• Drug: Deferasirox
  Deferasirox is used at the following dosage strengths: 125 mg, 250 mg and 500 mg
  Other Names:

  • DFX
  • ATC Code:V03AC03

Study Arms

• Experimental: Deferiprone
  75-100 mg/kg/day seven days per week
  Intervention: Drug: Deferiprone
• Active Comparator: Deferasirox
  20 to 40 mg/kg/day seven days per week
  Intervention: Drug: Deferasirox

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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: March 15, 2021): 435
• Original Estimated Enrollment (submitted: April 3, 2013): 344
• Actual Study Completion Date: September 21, 2017
• Actual Primary Completion Date: September 21, 2017 (Final data collection date for primary outcome measure)

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 1 Month to 17 Years (Child)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Albania, Cyprus, Egypt, Greece, Italy, Tunisia, United Kingdom

Administrative Information

• NCT Number: NCT01825512
• Other Study ID Numbers: DEEP-2
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Consorzio per Valutazioni Biologiche e Farmacologiche
• Original Responsible Party: Same as current
• Current Study Sponsor: Consorzio per Valutazioni Biologiche e Farmacologiche
• Original Study Sponsor: Same as current
• 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

• PRS Account: Consorzio per Valutazioni Biologiche e Farmacologiche
• Verification Date: October 2017