Pediatric Rare Anemia, Transfusional Iron Overload, β-thalassemia Major
Conditions
Keywords
β-thalassemia major, iron overload, deferasirox, pediatric rare anemia
Brief summary
In this 4-year extension study the safety, efficacy and and pharmacokinetics of deferasirox in regularly transfused pediatric patients with β-thalassemia major was assessed. Patients who successfully completed the main 1 year trial (NCT00390858) were eligible to continue in this extension trial and receive chelation therapy with deferasirox for up to 4 years.
Interventions
DRUGDeferasirox
Deferasirox in children from 1 to 18 years old was given orally once daily, 30 minutes prior to breakfast. An initial daily dose of 10 mg/kg was used during the 1-year core study. In this 4-year extension study dose modifications of ± 5 or 10 mg/kg were based on safety parameters and on increasing or decreasing Liver Iron Concentration (LIC), and serum ferritin. Deferasirox was available as 125 mg, 250 mg and 500 mg tablets.
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
1 Years to 18 Years
Healthy volunteers
No
Inclusion criteria
* Completion of the planned 12-month core trial, (NCT00390858). * Female patients who have reached menarche and who were sexually active were to use double-barrier contraception, oral contraceptive plus barrier contraceptive, or must have undergone clinically documented total hysterectomy and/or ovariectomy, or tubal ligation. * Written informed consent obtained from the patient, and/or from the parent or legal guardian in accordance with the national legislation.
Exclusion criteria
* Pregnant or breast feeding patients * Patients with a history of non-compliance to medical regimens and patients who are considered by the investigator as potentially unreliable. Other protocol-defined
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Participants With Adverse Events by Primary System Organ Class (SOC) | 4 year extension + core 1 year | Safety parameters were measured by the number and type of adverse events (AEs). An adverse event is any untoward medical occurence in a patient administered a medicinal product that does not necessarily have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign ( for example, an abnormal laboratory finding), symptom or disease temporally associated with the use of the medicinal product, whether or not this is associated with the use of this medicinal product. |
| Change in Liver Iron Concentration (LIC) | Baseline of Core Study to End of Extension Study, up to 5 years. | Change in Liver Iron Concentration \[LIC\] measured by means of SQUID (Superconducting Quantum Interference Device). LIC is expressed in milligrams of iron per gram of liver dry weight (mg Fe/g dw) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Total Body Iron Elimination (TBIE) Rate (mg/kg/Day) | Baseline of Core Study to End of Extension Study, up to 5 years | Total Iron Body Elimination (TBIE) Rate \[mg/kg/Day\] was calculated for each patient based on SQUID ( Superconducting Quantum Interference Device) results. |
| Relative Change in Serum Ferritin Level | Baseline of Core Study to Extension 18 months, up to 2.5 years. | Serum levels were drawn at the baseline of the Core Study up to 18 months of the Extension Study. Levels were analyzed for serum ferritin measured in micrograms per Liter. Relative change (%) in serum ferritin level was assessed from Baseline to Extension 18 months. Relative Change = 1 - (Change in ferritin level from Baseline/Baseline level) x 100. |
Countries
France, Italy
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Children (<12 Years) Deferasirox was given orally once daily, 30 minutes prior to breakfast. An initial daily dose of 10 mg/kg was used during the 1-year core study. In this 4-year extension study dose modifications of ± 5 or 10 mg/kg were based on safety parameters (e.g. renal and hematology) and whether Liver Iron Concentration (LIC), and serum ferritin were increasing or decreasing | 20 |
| Adolescents ( ≧12 Years) Deferasirox was given orally once daily, 30 minutes prior to breakfast. An initial daily dose of 10 mg/kg was used during the 1-year core study. In this 4-year extension study dose modifications of ± 5 or 10 mg/kg were based on safety parameters (e.g. renal and hematology) and whether Liver Iron Concentration (LIC), and serum ferritin were increasing or decreasing | 20 |
| Total | 40 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 6 | 2 |
| Overall Study | Lack of Efficacy | 0 | 1 |
| Overall Study | Withdrawal by Subject | 3 | 4 |
Baseline characteristics
| Characteristic | Children (<12 Years) | Adolescents ( ≧12 Years) | Total |
|---|---|---|---|
| Age, Continuous | 6.7 years STANDARD_DEVIATION 2.83 | 14.1 years STANDARD_DEVIATION 1.64 | 10.4 years STANDARD_DEVIATION 4.37 |
| Race/Ethnicity, Customized Caucasian | 20 participants | 20 participants | 40 participants |
| Sex: Female, Male Female | 12 Participants | 11 Participants | 23 Participants |
| Sex: Female, Male Male | 8 Participants | 9 Participants | 17 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 20 / 20 | 20 / 20 |
| serious Total, serious adverse events | 4 / 20 | 8 / 20 |
Outcome results
Primary
Change in Liver Iron Concentration (LIC)
Change in Liver Iron Concentration \[LIC\] measured by means of SQUID (Superconducting Quantum Interference Device). LIC is expressed in milligrams of iron per gram of liver dry weight (mg Fe/g dw)
Time frame: Baseline of Core Study to End of Extension Study, up to 5 years.
Population: The safety set was used for all analyses. This comprised of all 40 patients who received at least one dose of deferasirox during the core or extension study.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Children (<12 Years) | Change in Liver Iron Concentration (LIC) | Core Baseline LIC (n = 20, 20) | 6.25 mg Fe/g dw | Standard Deviation 2.507 |
| Children (<12 Years) | Change in Liver Iron Concentration (LIC) | End of Extension LIC (n=19, 20) | 5.46 mg Fe/g dw | Standard Deviation 3.192 |
| Children (<12 Years) | Change in Liver Iron Concentration (LIC) | Change from Baseline LIC (n=19, 20) | -0.9 mg Fe/g dw | Standard Deviation 3.85 |
| Adolescents ( ≧12 Years) | Change in Liver Iron Concentration (LIC) | Core Baseline LIC (n = 20, 20) | 5.73 mg Fe/g dw | Standard Deviation 2.185 |
| Adolescents ( ≧12 Years) | Change in Liver Iron Concentration (LIC) | End of Extension LIC (n=19, 20) | 4.66 mg Fe/g dw | Standard Deviation 3.533 |
| Adolescents ( ≧12 Years) | Change in Liver Iron Concentration (LIC) | Change from Baseline LIC (n=19, 20) | -1.10 mg Fe/g dw | Standard Deviation 3.03 |
Primary
Participants With Adverse Events by Primary System Organ Class (SOC)
Safety parameters were measured by the number and type of adverse events (AEs). An adverse event is any untoward medical occurence in a patient administered a medicinal product that does not necessarily have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign ( for example, an abnormal laboratory finding), symptom or disease temporally associated with the use of the medicinal product, whether or not this is associated with the use of this medicinal product.
Time frame: 4 year extension + core 1 year
Population: The safety set comprising of all the 40 patients who received at least one dose of deferasirox during the core or extension study was used in all analyses.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Children (<12 Years) | Participants With Adverse Events by Primary System Organ Class (SOC) | Investigations | 13 participants |
| Children (<12 Years) | Participants With Adverse Events by Primary System Organ Class (SOC) | Hepatobiliary disorders | 1 participants |
| Children (<12 Years) | Participants With Adverse Events by Primary System Organ Class (SOC) | Reproductive system & breast disorders | 0 participants |
| Children (<12 Years) | Participants With Adverse Events by Primary System Organ Class (SOC) | Nervous system disorders | 9 participants |
| Children (<12 Years) | Participants With Adverse Events by Primary System Organ Class (SOC) | Cardiac disorders | 1 participants |
| Children (<12 Years) | Participants With Adverse Events by Primary System Organ Class (SOC) | Surgical & medical procedures | 0 participants |
| Children (<12 Years) | Participants With Adverse Events by Primary System Organ Class (SOC) | Blood & lymphatic system disorders | 1 participants |
| Children (<12 Years) | Participants With Adverse Events by Primary System Organ Class (SOC) | Injury, poisoning & procedural complications | 11 participants |
| Children (<12 Years) | Participants With Adverse Events by Primary System Organ Class (SOC) | Psychiatric disorders | 2 participants |
| Children (<12 Years) | Participants With Adverse Events by Primary System Organ Class (SOC) | Infections & infestations | 18 participants |
| Children (<12 Years) | Participants With Adverse Events by Primary System Organ Class (SOC) | Immune system disorders | 0 participants |
| Children (<12 Years) | Participants With Adverse Events by Primary System Organ Class (SOC) | Ear & labyrinth disorders | 9 participants |
| Children (<12 Years) | Participants With Adverse Events by Primary System Organ Class (SOC) | Vascular disorders | 0 participants |
| Children (<12 Years) | Participants With Adverse Events by Primary System Organ Class (SOC) | Respiratory, thoracic & mediastinal disorders | 19 participants |
| Children (<12 Years) | Participants With Adverse Events by Primary System Organ Class (SOC) | Gastrointestinal disorders | 18 participants |
| Children (<12 Years) | Participants With Adverse Events by Primary System Organ Class (SOC) | Musculoskeletal & connective tissue disorders | 12 participants |
| Children (<12 Years) | Participants With Adverse Events by Primary System Organ Class (SOC) | Skin & subcutaneous tissue disorders | 12 participants |
| Children (<12 Years) | Participants With Adverse Events by Primary System Organ Class (SOC) | Patients with at least one Adverse Event (AE) | 20 participants |
| Children (<12 Years) | Participants With Adverse Events by Primary System Organ Class (SOC) | Metabolism & nutrition disorders | 6 participants |
| Children (<12 Years) | Participants With Adverse Events by Primary System Organ Class (SOC) | Eye disorders | 6 participants |
| Children (<12 Years) | Participants With Adverse Events by Primary System Organ Class (SOC) | Endocrine disorders | 1 participants |
| Children (<12 Years) | Participants With Adverse Events by Primary System Organ Class (SOC) | General disorders & administration site conditions | 19 participants |
| Children (<12 Years) | Participants With Adverse Events by Primary System Organ Class (SOC) | Renal & urinary disorders | 3 participants |
| Children (<12 Years) | Participants With Adverse Events by Primary System Organ Class (SOC) | Congenital, familial & genetic disorders | 1 participants |
| Adolescents ( ≧12 Years) | Participants With Adverse Events by Primary System Organ Class (SOC) | Skin & subcutaneous tissue disorders | 8 participants |
| Adolescents ( ≧12 Years) | Participants With Adverse Events by Primary System Organ Class (SOC) | Patients with at least one Adverse Event (AE) | 20 participants |
| Adolescents ( ≧12 Years) | Participants With Adverse Events by Primary System Organ Class (SOC) | General disorders & administration site conditions | 20 participants |
| Adolescents ( ≧12 Years) | Participants With Adverse Events by Primary System Organ Class (SOC) | Respiratory, thoracic & mediastinal disorders | 17 participants |
| Adolescents ( ≧12 Years) | Participants With Adverse Events by Primary System Organ Class (SOC) | Gastrointestinal disorders | 17 participants |
| Adolescents ( ≧12 Years) | Participants With Adverse Events by Primary System Organ Class (SOC) | Infections & infestations | 17 participants |
| Adolescents ( ≧12 Years) | Participants With Adverse Events by Primary System Organ Class (SOC) | Musculoskeletal & connective tissue disorders | 15 participants |
| Adolescents ( ≧12 Years) | Participants With Adverse Events by Primary System Organ Class (SOC) | Nervous system disorders | 13 participants |
| Adolescents ( ≧12 Years) | Participants With Adverse Events by Primary System Organ Class (SOC) | Injury, poisoning & procedural complications | 8 participants |
| Adolescents ( ≧12 Years) | Participants With Adverse Events by Primary System Organ Class (SOC) | Ear & labyrinth disorders | 8 participants |
| Adolescents ( ≧12 Years) | Participants With Adverse Events by Primary System Organ Class (SOC) | Metabolism & nutrition disorders | 10 participants |
| Adolescents ( ≧12 Years) | Participants With Adverse Events by Primary System Organ Class (SOC) | Eye disorders | 9 participants |
| Adolescents ( ≧12 Years) | Participants With Adverse Events by Primary System Organ Class (SOC) | Renal & urinary disorders | 6 participants |
| Adolescents ( ≧12 Years) | Participants With Adverse Events by Primary System Organ Class (SOC) | Reproductive system & breast disorders | 8 participants |
| Adolescents ( ≧12 Years) | Participants With Adverse Events by Primary System Organ Class (SOC) | Cardiac disorders | 5 participants |
| Adolescents ( ≧12 Years) | Participants With Adverse Events by Primary System Organ Class (SOC) | Blood & lymphatic system disorders | 5 participants |
| Adolescents ( ≧12 Years) | Participants With Adverse Events by Primary System Organ Class (SOC) | Psychiatric disorders | 4 participants |
| Adolescents ( ≧12 Years) | Participants With Adverse Events by Primary System Organ Class (SOC) | Endocrine disorders | 1 participants |
| Adolescents ( ≧12 Years) | Participants With Adverse Events by Primary System Organ Class (SOC) | Congenital, familial & genetic disorders | 0 participants |
| Adolescents ( ≧12 Years) | Participants With Adverse Events by Primary System Organ Class (SOC) | Investigations | 10 participants |
| Adolescents ( ≧12 Years) | Participants With Adverse Events by Primary System Organ Class (SOC) | Hepatobiliary disorders | 7 participants |
| Adolescents ( ≧12 Years) | Participants With Adverse Events by Primary System Organ Class (SOC) | Immune system disorders | 2 participants |
| Adolescents ( ≧12 Years) | Participants With Adverse Events by Primary System Organ Class (SOC) | Surgical & medical procedures | 3 participants |
| Adolescents ( ≧12 Years) | Participants With Adverse Events by Primary System Organ Class (SOC) | Vascular disorders | 2 participants |
Secondary
Relative Change in Serum Ferritin Level
Serum levels were drawn at the baseline of the Core Study up to 18 months of the Extension Study. Levels were analyzed for serum ferritin measured in micrograms per Liter. Relative change (%) in serum ferritin level was assessed from Baseline to Extension 18 months. Relative Change = 1 - (Change in ferritin level from Baseline/Baseline level) x 100.
Time frame: Baseline of Core Study to Extension 18 months, up to 2.5 years.
Population: The safety set was used for all analyses. This comprised of all 40 patients who received at least one dose of deferasirox during the core or extension study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Children (<12 Years) | Relative Change in Serum Ferritin Level | 62.4 percent change | Standard Deviation 53.47 |
| Adolescents ( ≧12 Years) | Relative Change in Serum Ferritin Level | 54.9 percent change | Standard Deviation 64.64 |
Secondary
Total Body Iron Elimination (TBIE) Rate (mg/kg/Day)
Total Iron Body Elimination (TBIE) Rate \[mg/kg/Day\] was calculated for each patient based on SQUID ( Superconducting Quantum Interference Device) results.
Time frame: Baseline of Core Study to End of Extension Study, up to 5 years
Population: The safety set was used for all analyses. This comprised of all 40 patients who received at least one dose of deferasirox during the core or extension study.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Children (<12 Years) | Total Body Iron Elimination (TBIE) Rate (mg/kg/Day) | Core Baseline TBIE (n=19, 20) | 0.4292 mg/kg/Day | Standard Deviation 0.06454 |
| Children (<12 Years) | Total Body Iron Elimination (TBIE) Rate (mg/kg/Day) | End of Extension TBIE (n=11,14) | 0.4939 mg/kg/Day | Standard Deviation 0.05175 |
| Adolescents ( ≧12 Years) | Total Body Iron Elimination (TBIE) Rate (mg/kg/Day) | Core Baseline TBIE (n=19, 20) | 0.4083 mg/kg/Day | Standard Deviation 0.07158 |
| Adolescents ( ≧12 Years) | Total Body Iron Elimination (TBIE) Rate (mg/kg/Day) | End of Extension TBIE (n=11,14) | 0.4286 mg/kg/Day | Standard Deviation 0.0637 |