Chronic Iron Overload
Conditions
Keywords
chronic iron overload, hereditary haemoglobinopathy, beta thalassaemia major, chelating agents, deferiprone, deferasirox, children, paediatrics
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).
Interventions
DRUGDeferiprone
Deferiprone 80 mg/mL oral solution
DRUGDeferasirox
Deferasirox is used at the following dosage strengths: 125 mg, 250 mg and 500 mg
Sponsors
European Commission
Consorzio per Valutazioni Biologiche e Farmacologiche
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
1 Months to 17 Years
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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. |
Countries
Albania, Cyprus, Egypt, Greece, Italy, Tunisia, United Kingdom
Participant flow
Pre-assignment details
Informed 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.
Participants by arm
| Arm | Count |
|---|---|
| Deferiprone 75-100 mg/kg/day seven days per week
Deferiprone: Deferiprone 80 mg/mL oral solution | 193 |
| Deferasirox 20 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 | 197 |
| Total | 390 |
Baseline characteristics
| Characteristic | Deferiprone | Deferasirox | Total |
|---|---|---|---|
| Age, Customized <6 years | 59 participants | 58 participants | 117 participants |
| Age, Customized > or equal to 10 years | 87 participants | 92 participants | 179 participants |
| Age, Customized > or equal to 6 years and <10 years | 47 participants | 47 participants | 94 participants |
| Ferritin level | 2756 ng/ml STANDARD_DEVIATION 2175 | 2989 ng/ml STANDARD_DEVIATION 2409 | 2876 ng/ml STANDARD_DEVIATION 2298 |
| Race/Ethnicity, Customized Asia | 0 participants | 1 participants | 1 participants |
| Race/Ethnicity, Customized Europe | 56 participants | 56 participants | 112 participants |
| Race/Ethnicity, Customized Latin America | 0 participants | 0 participants | 0 participants |
| Race/Ethnicity, Customized Missing | 5 participants | 7 participants | 12 participants |
| Race/Ethnicity, Customized North Africa | 121 participants | 122 participants | 243 participants |
| Race/Ethnicity, Customized North America | 0 participants | 0 participants | 0 participants |
| Race/Ethnicity, Customized Other | 5 participants | 6 participants | 11 participants |
| Race/Ethnicity, Customized Rest of Africa | 6 participants | 5 participants | 11 participants |
| Region of Enrollment Albania | 19 participants | 20 participants | 39 participants |
| Region of Enrollment Cyprus | 4 participants | 4 participants | 8 participants |
| Region of Enrollment Egypt | 96 participants | 99 participants | 197 participants |
| Region of Enrollment Greece | 5 participants | 6 participants | 11 participants |
| Region of Enrollment Italy | 30 participants | 28 participants | 58 participants |
| Region of Enrollment Tunisia | 28 participants | 28 participants | 56 participants |
| Region of Enrollment United Kingdom | 11 participants | 12 participants | 23 participants |
| Sex: Female, Male Female | 80 Participants | 93 Participants | 173 Participants |
| Sex: Female, Male Male | 113 Participants | 104 Participants | 217 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 193 | 0 / 197 |
| other Total, other adverse events | 152 / 193 | 89 / 197 |
| serious Total, serious adverse events | 13 / 193 | 14 / 197 |
Outcome results
Primary
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)
Time frame: at baseline and after 12 months
Population: 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 | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Deferiprone | Percentage of Successfully Chelated Patients | 69 Participants |
| Deferasirox | Percentage of Successfully Chelated Patients | 80 Participants |
Secondary
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.
Time frame: at baseline and after 12 months
Population: 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 | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Deferiprone | Cardiac MRI T2* | 0.488 milliseconds (ms) | Standard Error 1.284 |
| Deferasirox | Cardiac MRI T2* | 1.121 milliseconds (ms) | Standard Error 1.169 |
p-value: 0.71795% CI: [-4.085, 2.819]ANCOVA
Secondary
Ferritin Level
Change in serum ferritin level, assessed as difference between value at 12 months minus value at baseline.
Time frame: at baseline and after 12 months
Population: 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 | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Deferiprone | Ferritin Level | -397.583 ng/mL | Standard Error 121.794 |
| Deferasirox | Ferritin Level | -398.184 ng/mL | Standard Error 110.619 |
p-value: 0.99795% CI: [-323.58, 324.781]GLM
Secondary
Liver MRI
Change in liver iron concentration (measured using liver MRI), assessed as difference between value at 12 months minus value at baseline.
Time frame: at baseline and after 12 months
Population: 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 | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Deferiprone | Liver MRI | -0.848 mg/g | Standard Error 0.887 |
| Deferasirox | Liver MRI | -2.975 mg/g | Standard Error 0.776 |
p-value: 0.07495% CI: [-0.213, 4.468]ANCOVA