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

Sponsor
Consorzio per Valutazioni Biologiche e Farmacologiche (Other)
Overall Status
Completed
CT.gov ID
NCT01825512
Collaborator
European Commission (Other)
435
Enrollment
22
Locations
2
Arms
42.2
Actual Duration (Months)
19.8
Patients Per Site
0.5
Patients Per Site Per Month

Study Details

Study Description

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.

Condition or DiseaseIntervention/TreatmentPhase
Phase 3

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 Design

Study Type:
Interventional
Actual Enrollment :
435 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
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
Actual Study Start Date :
Mar 17, 2014
Actual Primary Completion Date :
Sep 21, 2017
Actual Study Completion Date :
Sep 21, 2017

Arms and Interventions

ArmIntervention/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
  • Outcome Measures

    Primary Outcome Measures

    1. Percentage of Successfully Chelated Patients [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)

    Secondary Outcome Measures

    1. Liver MRI [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.

    2. Cardiac MRI T2* [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.

    3. Ferritin Level [at baseline and after 12 months]

      Change in serum ferritin level, assessed as difference between value at 12 months minus value at baseline.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    1 Month to 17 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    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

    Contacts and Locations

    Locations

    SiteCityStateCountryPostal Code
    1Hospital 'Ihsan Çabej'LushnjëAlbania
    2Qendra Spitalore Universitare "Nene Tereza" TiraneTiranaAlbania
    3Department of Medical and Public health Services of the Ministry of HealthNicosiaCyprus
    4Alexandria University Hospital - Faculty of MedicineAlexandriaEgypt
    5Cairo University Faculty of MedicineCairoEgypt
    6Zagazig University HospitalsZagazigEgypt
    7National And Kapodistrian University of AthensAthensGreece
    8Centro di Thalassemia, Ospedale Civile di LentiniLentiniSRItaly
    9Università di Bari - Facoltà di MedicinaBariItaly
    10ASL Cagliari Ospedale Regionale per le MicrocitemieCagliariItaly
    11Azienda Ospedaliera di Rilievo Nazionale e di Alta Specializzazione GaribaldiCataniaItaly
    12Presidio Ospedaliero "Annunziata", Centro di Studi della MicrocitemiaCosenzaItaly
    13A.O.Universitaria MeyerFirenzeItaly
    14Clinica Pediatrica Policlinico di ModenaModenaItaly
    15Azienda Ospedaliera di Rilievo Nazionale "Antonio Cardarelli"NapoliItaly
    16Azienda Ospedaliera di PadovaPadovaItaly
    17Ospedali Riuniti Villa Sofia - CervelloPalermoItaly
    18U.O.C. Ematologia - Emoglobinopatie, Ospedale G. Di CristinaPalermoItaly
    19Clinica Pediatrica Università - ASL 1 D.H per TalassemiaSassariItaly
    20Centre National de Greffe de Moelle Osseuse TunisTunisTunisia
    21Barts Health NHS TrustLondonUnited Kingdom
    22Queen's HospitalRomfordUnited Kingdom

    Sponsors and Collaborators

    • Consorzio per Valutazioni Biologiche e Farmacologiche
    • European Commission

    Investigators

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

    Study Documents (Full-Text)

    More Information

    Publications

    None provided.
    Responsible Party:
    Consorzio per Valutazioni Biologiche e Farmacologiche
    ClinicalTrials.gov Identifier:
    NCT01825512
    Other Study ID Numbers:
    • DEEP-2
    First Posted:
    Apr 5, 2013
    Last Update Posted:
    May 4, 2021
    Last Verified:
    Oct 1, 2017
    Individual Participant Data (IPD) Sharing Statement:
    No
    Plan to Share IPD:
    No
    Keywords provided by Consorzio per Valutazioni Biologiche e Farmacologiche
    Additional relevant MeSH terms:

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment DetailInformed consent was collected for 435 patients that were enrolled in the study, however 42 of them were excluded from the study for the following reasons: 17 did not meet inclusion criteria, 5 withdrew the consent and 20 were lost to follow-up.
    Arm/Group TitleDeferiproneDeferasirox
    Arm/Group Description75-100 mg/kg/day seven days per week Deferiprone: Deferiprone 80 mg/mL oral solution20 to 40 mg/kg/day seven days per week Deferasirox: Deferasirox is used at the following dosage strengths: 125 mg, 250 mg and 500 mg
    Period Title: Baseline
    STARTED194199
    COMPLETED193197
    NOT COMPLETED12
    Period Title: Baseline
    STARTED193197
    COMPLETED140170
    NOT COMPLETED5327

    Baseline Characteristics

    Arm/Group TitleDeferiproneDeferasiroxTotal
    Arm/Group Description75-100 mg/kg/day seven days per week Deferiprone: Deferiprone 80 mg/mL oral solution20 to 40 mg/kg/day seven days per week Deferasirox: Deferasirox is used at the following dosage strengths: 125 mg, 250 mg and 500 mgTotal of all reporting groups
    Overall Participants193197390
    Age, Customized (participants) [Number]
    <6 years
    59
    30.6%
    58
    29.4%
    117
    30%
    > or equal to 6 years and <10 years
    47
    24.4%
    47
    23.9%
    94
    24.1%
    > or equal to 10 years
    87
    45.1%
    92
    46.7%
    179
    45.9%
    Sex: Female, Male (Count of Participants)
    Female
    80
    41.5%
    93
    47.2%
    173
    44.4%
    Male
    113
    58.5%
    104
    52.8%
    217
    55.6%
    Race/Ethnicity, Customized (participants) [Number]
    Europe
    56
    29%
    56
    28.4%
    112
    28.7%
    North Africa
    121
    62.7%
    122
    61.9%
    243
    62.3%
    Rest of Africa
    6
    3.1%
    5
    2.5%
    11
    2.8%
    Asia
    0
    0%
    1
    0.5%
    1
    0.3%
    North America
    0
    0%
    0
    0%
    0
    0%
    Latin America
    0
    0%
    0
    0%
    0
    0%
    Other
    5
    2.6%
    6
    3%
    11
    2.8%
    Missing
    5
    2.6%
    7
    3.6%
    12
    3.1%
    Region of Enrollment (participants) [Number]
    United Kingdom
    11
    5.7%
    12
    6.1%
    23
    5.9%
    Italy
    30
    15.5%
    28
    14.2%
    58
    14.9%
    Tunisia
    28
    14.5%
    28
    14.2%
    56
    14.4%
    Egypt
    96
    49.7%
    99
    50.3%
    197
    50.5%
    Albania
    19
    9.8%
    20
    10.2%
    39
    10%
    Greece
    5
    2.6%
    6
    3%
    11
    2.8%
    Cyprus
    4
    2.1%
    4
    2%
    8
    2.1%
    Ferritin level (ng/ml) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [ng/ml]
    2756
    (2175)
    2989
    (2409)
    2876
    (2298)

    Outcome Measures

    1. Primary Outcome
    TitlePercentage of Successfully Chelated Patients
    DescriptionPercentage 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)
    Time Frameat baseline and after 12 months

    Outcome Measure Data

    Analysis Population Description
    Per-protocol population 1 (PP1): number of patients for whom the primary composite efficacy endpoint data were available at baseline and after 1 year of treatment (271 subjects)
    Arm/Group TitleDeferiproneDeferasirox
    Arm/Group Description75-100 mg/kg/day seven days per week Deferiprone: Deferiprone 80 mg/mL oral solution20 to 40 mg/kg/day seven days per week Deferasirox: Deferasirox is used at the following dosage strengths: 125 mg, 250 mg and 500 mg
    Measure Participants125146
    Count of Participants [Participants]
    69
    35.8%
    80
    40.6%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Deferiprone, Deferasirox
    Comments
    Type of Statistical Test Non-Inferiority
    Comments Deferiprone was declared non inferior to Deferasirox if the lower limit of the 95% confidence interval for the difference in the proportion of successful chelation in the two groups is above -12.5%.
    Statistical Test of Hypothesisp-Value
    Comments
    Method
    Comments
    Method of EstimationEstimation ParameterTreatment success rate
    Estimated Value-12.5
    Confidence Interval (1-Sided) 95%
    -12.5 to
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    2. Secondary Outcome
    TitleLiver MRI
    DescriptionChange in liver iron concentration (measured using liver MRI), assessed as difference between value at 12 months minus value at baseline.
    Time Frameat baseline and after 12 months

    Outcome Measure Data

    Analysis Population Description
    Per-protocol population 3 (PP3): number of patients for whom liver iron concentration were available at baseline and after 1 year of treatment (106 subjects)
    Arm/Group TitleDeferiproneDeferasirox
    Arm/Group Description75-100 mg/kg/day seven days per week Deferiprone: Deferiprone 80 mg/mL oral solution20 to 40 mg/kg/day seven days per week Deferasirox: Deferasirox is used at the following dosage strengths: 125 mg, 250 mg and 500 mg
    Measure Participants4660
    Mean (Standard Error) [mg/g]
    -0.848
    (0.887)
    -2.975
    (0.776)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Deferiprone, Deferasirox
    Comments
    Type of Statistical Test Other
    Comments GLM model
    Statistical Test of Hypothesisp-Value0.074
    Comments
    MethodANCOVA
    Comments
    Method of EstimationEstimation ParameterMean Difference (Final Values)
    Estimated Value2.128
    Confidence Interval (2-Sided) 95%
    -0.213 to 4.468
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 1.18
    Estimation Comments
    3. Secondary Outcome
    TitleCardiac MRI T2*
    DescriptionChange 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.
    Time Frameat baseline and after 12 months

    Outcome Measure Data

    Analysis Population Description
    Per-protocol population 3 (PP3): number of patients for whom cardiac T2* concentration were available at baseline and after 1 year of treatment (108 subjects)
    Arm/Group TitleDeferiproneDeferasirox
    Arm/Group Description75-100 mg/kg/day seven days per week Deferiprone: Deferiprone 80 mg/mL oral solution20 to 40 mg/kg/day seven days per week Deferasirox: Deferasirox is used at the following dosage strengths: 125 mg, 250 mg and 500 mg
    Measure Participants4959
    Mean (Standard Error) [milliseconds (ms)]
    0.488
    (1.284)
    1.121
    (1.169)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Deferiprone, Deferasirox
    Comments
    Type of Statistical Test Other
    Comments GLM Analysis
    Statistical Test of Hypothesisp-Value0.717
    Comments
    MethodANCOVA
    Comments
    Method of EstimationEstimation ParameterMean Difference (Final Values)
    Estimated Value-0.633
    Confidence Interval (2-Sided) 95%
    -4.085 to 2.819
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 1.741
    Estimation Comments
    4. Secondary Outcome
    TitleFerritin Level
    DescriptionChange in serum ferritin level, assessed as difference between value at 12 months minus value at baseline.
    Time Frameat baseline and after 12 months

    Outcome Measure Data

    Analysis Population Description
    Per-protocol population 2 (PP2): number of patients for whom the per-protocol centralised serum ferritin concentration data were available at baseline and after 1 year of treatment (303 subjects, this population was larger than PP1 because PP2 included patients who did not have cardiac T2* data)
    Arm/Group TitleDeferiproneDeferasirox
    Arm/Group Description75-100 mg/kg/day seven days per week Deferiprone: Deferiprone 80 mg/mL oral solution20 to 40 mg/kg/day seven days per week Deferasirox: Deferasirox is used at the following dosage strengths: 125 mg, 250 mg and 500 mg
    Measure Participants137166
    Mean (Standard Error) [ng/mL]
    -397.583
    (121.794)
    -398.184
    (110.619)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Deferiprone, Deferasirox
    Comments
    Type of Statistical Test Non-Inferiority
    Comments Non inferiority of Deferiprone to Deferasirox is tested considering a non-inferiority margin of 400 ng/mL.
    Statistical Test of Hypothesisp-Value0.997
    Comments
    MethodGLM
    Comments
    Method of EstimationEstimation ParameterMean Difference (Final Values)
    Estimated Value0.601
    Confidence Interval (2-Sided) 95%
    -323.580 to 324.781
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 164.734
    Estimation Comments

    Adverse Events

    Time Framethrough study completion, an average of 1 year for subject
    Adverse Event Reporting Description
    Arm/Group TitleDeferiproneDeferasirox
    Arm/Group Description75-100 mg/kg/day seven days per week Deferiprone: Deferiprone 80 mg/mL oral solution20 to 40 mg/kg/day seven days per week Deferasirox: Deferasirox is used at the following dosage strengths: 125 mg, 250 mg and 500 mg
    All Cause Mortality
    DeferiproneDeferasirox
    Affected / at Risk (%)# EventsAffected / at Risk (%)# Events
    Total0/193 (0%) 0/197 (0%)
    Serious Adverse Events
    DeferiproneDeferasirox
    Affected / at Risk (%)# EventsAffected / at Risk (%)# Events
    Total13/193 (6.7%) 14/197 (7.1%)
    Blood and lymphatic system disorders
    agranulocytosis3/193 (1.6%) 30/197 (0%) 0
    neutropenia2/193 (1%) 20/197 (0%) 0
    sickle cell anaemia with crisis subjects affected/exposed0/193 (0%) 02/197 (1%) 2
    Gastrointestinal disorders
    diarrhoea0/193 (0%) 01/197 (0.5%) 1
    General disorders
    pyrexia1/193 (0.5%) 11/197 (0.5%) 1
    chest pain0/193 (0%) 02/197 (1%) 2
    gait disturbance0/193 (0%) 01/197 (0.5%) 1
    Hepatobiliary disorders
    hypertransaminasaemia2/193 (1%) 21/197 (0.5%) 1
    Infections and infestations
    gastroenteritis0/193 (0%) 01/197 (0.5%) 1
    meningitis meningococcal0/193 (0%) 01/197 (0.5%) 1
    herpangina0/193 (0%) 01/197 (0.5%) 1
    pneumonia2/193 (1%) 21/197 (0.5%) 1
    subcutaneous abscess0/193 (0%) 01/197 (0.5%) 1
    urinary tract infection1/193 (0.5%) 11/197 (0.5%) 1
    herpes virus infection0/193 (0%) 01/197 (0.5%) 1
    impetigo0/193 (0%) 01/197 (0.5%) 1
    upper respiratory tract infection0/193 (0%) 01/197 (0.5%) 1
    Injury, poisoning and procedural complications
    testicular injury1/193 (0.5%) 10/197 (0%) 0
    Musculoskeletal and connective tissue disorders
    pain in extremity0/193 (0%) 01/197 (0.5%) 1
    Nervous system disorders
    seizure1/193 (0.5%) 10/197 (0%) 0
    Renal and urinary disorders
    acute kidney injury0/193 (0%) 02/197 (1%) 2
    Surgical and medical procedures
    splenectomy1/193 (0.5%) 10/197 (0%) 0
    Other (Not Including Serious) Adverse Events
    DeferiproneDeferasirox
    Affected / at Risk (%)# EventsAffected / at Risk (%)# Events
    Total152/193 (78.8%) 89/197 (45.2%)
    Blood and lymphatic system disorders
    neutropenia18/193 (9.3%) 2611/197 (5.6%) 15
    General disorders
    pyrexia28/193 (14.5%) 4032/197 (16.2%) 56
    abdominal pain20/193 (10.4%) 248/197 (4.1%) 9
    vomiting33/193 (17.1%) 428/197 (4.1%) 10
    Infections and infestations
    pharyngitis15/193 (7.8%) 189/197 (4.6%) 11
    Musculoskeletal and connective tissue disorders
    arthralgia23/193 (11.9%) 285/197 (2.5%) 5
    Respiratory, thoracic and mediastinal disorders
    cough15/193 (7.8%) 2116/197 (8.1%) 25

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.

    Results Point of Contact

    Name/TitleDonato Bonifazi
    OrganizationConsorzio per Valutazioni Biologiche e Farmacologiche
    Phone+393936698076
    Emailceo@cvbf.net
    Responsible Party:
    Consorzio per Valutazioni Biologiche e Farmacologiche
    ClinicalTrials.gov Identifier:
    NCT01825512
    Other Study ID Numbers:
    • DEEP-2
    First Posted:
    Apr 5, 2013
    Last Update Posted:
    May 4, 2021
    Last Verified:
    Oct 1, 2017