Hereditary Hemochromatosis, Iron Overload
Conditions
Keywords
Deferasirox, ICL670A, Iron chelators, Deferiprone, Transfusional Hemochromatosis
Brief summary
Brief Summary: This study was designed to explore a safe dose and characterize the preliminary safety and efficacy of ICL670 in adult patients with previously documented history of homozygous C282Y.
Interventions
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Age 18 years of age or older * Male or female patients homozygous for the C282Y mutation. * Iron overload as documented by serum ferritin and transferrin saturation * No known allergy or contraindication to the administration of deferasirox * Ability to comply with all study-related procedures, medications, and evaluations * Effective use of birth control measures.
Exclusion criteria
* Iron overload not due to hereditary hemochromatosis * Males with hemoglobin \<13 mg/dL, females with hemoglobin \<12 mg/dL * Desferal treatment within 1 month of the screening visit * Patients currently or previously treated with deferiprone or deferasirox * Significant medical condition interfering with the ability to partake in this study * Presence of a surgical or medical condition that might significantly alter the absorption, distribution, metabolism or excretion of any study drug * Clinical evidence of Active Hepatitis B or C * Positive HIV serology * Pregnant or breast feeding patients * Patients treated with systemic investigational drug within 4 weeks prior or with topical investigational drug within 7 days prior to the screening visit Other protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Absolute Change of Serum Ferritin From Baseline to the End of Extension, by Dose Cohort (Extension Per-protocol Population) | 0 to 48 weeks | Mean absolute change in serum ferritin from baseline to the end of the extension study. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Trough Concentrations of Deferasirox (ICL670), by Dose Cohort (Per-protocol Population) | 4, 8, 12, 16, 20, and 24 weeks | A blood sample was collected just prior to administration of the next dose of Deferasirox (pre-dose trough level) or approximately 24 hours after the previous dose at weeks 4, 8, 12, 16, 20 and 24. The mean trough concentration at each time point was calculated. |
Countries
Australia, Canada, France, Germany, Italy, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Deferasirox (ICL670) 5 mg/kg/Day Deferasirox (ICL670) was provided as 125 mg, 250 mg, and 500 mg tablets. Dosage was based on the participant's body weight. ICL670 was administered orally, once a day, 30 minutes prior to breakfast. | 11 |
| Deferasirox (ICL670) 10 mg/kg/Day Deferasirox (ICL670) was provided as 125 mg, 250 mg, and 500 mg tablets. Dosage was based on the participant's body weight. ICL670 was administered orally, once a day, 30 minutes prior to breakfast. | 15 |
| Deferasirox (ICL670) 15 mg/kg/Day Deferasirox (ICL670) was provided as 125 mg, 250 mg, and 500 mg tablets. Dosage was based on the participant's body weight. ICL670 was administered orally, once a day, 30 minutes prior to breakfast. | 23 |
| Total | 49 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Core Study | Abnormal laboratory value(s) | 0 | 0 | 1 |
| Core Study | Adverse Event | 0 | 3 | 4 |
| Core Study | Lost to Follow-up | 0 | 0 | 1 |
| Core Study | Protocol Violation | 1 | 0 | 0 |
| Core Study | Withdrawal by Subject | 0 | 1 | 1 |
| Extension Study | Administrative problems | 0 | 0 | 1 |
| Extension Study | Adverse Event | 0 | 0 | 2 |
Baseline characteristics
| Characteristic | Deferasirox (ICL670) 5 mg/kg/Day | Deferasirox (ICL670) 10 mg/kg/Day | Deferasirox (ICL670) 15 mg/kg/Day | Total |
|---|---|---|---|---|
| Age Continuous Core Study | 55.8 years STANDARD_DEVIATION 12.78 | 47.8 years STANDARD_DEVIATION 10.26 | 49.8 years STANDARD_DEVIATION 16.41 | 50.6 years STANDARD_DEVIATION 14.04 |
| Age Continuous Extension Study (n=9,6,11,26) | 55.7 years STANDARD_DEVIATION 14.23 | 44.8 years STANDARD_DEVIATION 10.61 | 50.1 years STANDARD_DEVIATION 15.88 | 50.8 years STANDARD_DEVIATION 14.34 |
| Sex/Gender, Customized Core Participants not enrolled in the Extension | 2 participants | 9 participants | 12 participants | 23 participants |
| Sex/Gender, Customized Female_Core Study | 2 participants | 4 participants | 10 participants | 16 participants |
| Sex/Gender, Customized Female_Extension Study | 1 participants | 1 participants | 3 participants | 5 participants |
| Sex/Gender, Customized Male_Core Study | 9 participants | 11 participants | 13 participants | 33 participants |
| Sex/Gender, Customized Male_Extension Study | 8 participants | 5 participants | 8 participants | 21 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 10 / 11 | 14 / 15 | 23 / 23 | 9 / 9 | 5 / 6 | 11 / 11 |
| serious Total, serious adverse events | 0 / 11 | 0 / 15 | 0 / 23 | 1 / 9 | 0 / 6 | 0 / 11 |
Outcome results
Primary
Absolute Change of Serum Ferritin From Baseline to the End of Extension, by Dose Cohort (Extension Per-protocol Population)
Mean absolute change in serum ferritin from baseline to the end of the extension study.
Time frame: 0 to 48 weeks
Population: Extension Per-protocol population including all participants of the per protocol population who also were part of the extension safety population.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Deferasirox (ICL670) 5 mg/kg/Day | Absolute Change of Serum Ferritin From Baseline to the End of Extension, by Dose Cohort (Extension Per-protocol Population) | -389.1 µg/L | Standard Deviation 185.35 |
| Deferasirox (ICL670) 10 mg/kg/Day | Absolute Change of Serum Ferritin From Baseline to the End of Extension, by Dose Cohort (Extension Per-protocol Population) | -610.5 µg/L | Standard Deviation 341.84 |
| Deferasirox (ICL670) 15 mg/kg/Day | Absolute Change of Serum Ferritin From Baseline to the End of Extension, by Dose Cohort (Extension Per-protocol Population) | -571.6 µg/L | Standard Deviation 552.81 |
Secondary
Trough Concentrations of Deferasirox (ICL670), by Dose Cohort (Per-protocol Population)
A blood sample was collected just prior to administration of the next dose of Deferasirox (pre-dose trough level) or approximately 24 hours after the previous dose at weeks 4, 8, 12, 16, 20 and 24. The mean trough concentration at each time point was calculated.
Time frame: 4, 8, 12, 16, 20, and 24 weeks
Population: Per-protocol population included all participants of the safety population; who received at least one dose of study drug within the core study and had at least one safety assessment, and who did not have any major protocol deviation. n in each of the Categories is the number of participants in each arm/group who had data for that time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Deferasirox (ICL670) 5 mg/kg/Day | Trough Concentrations of Deferasirox (ICL670), by Dose Cohort (Per-protocol Population) | Week 12 (n=10,12,13) | 10.58 µmol/L | Standard Deviation 11.752 |
| Deferasirox (ICL670) 5 mg/kg/Day | Trough Concentrations of Deferasirox (ICL670), by Dose Cohort (Per-protocol Population) | Week 16 (n=10,11,11) | 12.38 µmol/L | Standard Deviation 11.634 |
| Deferasirox (ICL670) 5 mg/kg/Day | Trough Concentrations of Deferasirox (ICL670), by Dose Cohort (Per-protocol Population) | Week 24 (n=10,9,6) | 14.62 µmol/L | Standard Deviation 12.216 |
| Deferasirox (ICL670) 5 mg/kg/Day | Trough Concentrations of Deferasirox (ICL670), by Dose Cohort (Per-protocol Population) | Week 8 (n=10,12,17) | 8.86 µmol/L | Standard Deviation 5.828 |
| Deferasirox (ICL670) 5 mg/kg/Day | Trough Concentrations of Deferasirox (ICL670), by Dose Cohort (Per-protocol Population) | Week 20 (n=9,10,8) | 11.72 µmol/L | Standard Deviation 10.316 |
| Deferasirox (ICL670) 5 mg/kg/Day | Trough Concentrations of Deferasirox (ICL670), by Dose Cohort (Per-protocol Population) | Week 4 (n=10,14,17) | 9.63 µmol/L | Standard Deviation 8.783 |
| Deferasirox (ICL670) 10 mg/kg/Day | Trough Concentrations of Deferasirox (ICL670), by Dose Cohort (Per-protocol Population) | Week 20 (n=9,10,8) | 26.47 µmol/L | Standard Deviation 17.934 |
| Deferasirox (ICL670) 10 mg/kg/Day | Trough Concentrations of Deferasirox (ICL670), by Dose Cohort (Per-protocol Population) | Week 24 (n=10,9,6) | 21.32 µmol/L | Standard Deviation 21.84 |
| Deferasirox (ICL670) 10 mg/kg/Day | Trough Concentrations of Deferasirox (ICL670), by Dose Cohort (Per-protocol Population) | Week 4 (n=10,14,17) | 19.62 µmol/L | Standard Deviation 9.502 |
| Deferasirox (ICL670) 10 mg/kg/Day | Trough Concentrations of Deferasirox (ICL670), by Dose Cohort (Per-protocol Population) | Week 12 (n=10,12,13) | 28.71 µmol/L | Standard Deviation 23.849 |
| Deferasirox (ICL670) 10 mg/kg/Day | Trough Concentrations of Deferasirox (ICL670), by Dose Cohort (Per-protocol Population) | Week 16 (n=10,11,11) | 21.62 µmol/L | Standard Deviation 16.539 |
| Deferasirox (ICL670) 10 mg/kg/Day | Trough Concentrations of Deferasirox (ICL670), by Dose Cohort (Per-protocol Population) | Week 8 (n=10,12,17) | 23.88 µmol/L | Standard Deviation 22.787 |
| Deferasirox (ICL670) 15 mg/kg/Day | Trough Concentrations of Deferasirox (ICL670), by Dose Cohort (Per-protocol Population) | Week 12 (n=10,12,13) | 23.39 µmol/L | Standard Deviation 11.403 |
| Deferasirox (ICL670) 15 mg/kg/Day | Trough Concentrations of Deferasirox (ICL670), by Dose Cohort (Per-protocol Population) | Week 4 (n=10,14,17) | 30.48 µmol/L | Standard Deviation 20.201 |
| Deferasirox (ICL670) 15 mg/kg/Day | Trough Concentrations of Deferasirox (ICL670), by Dose Cohort (Per-protocol Population) | Week 8 (n=10,12,17) | 27.06 µmol/L | Standard Deviation 21.686 |
| Deferasirox (ICL670) 15 mg/kg/Day | Trough Concentrations of Deferasirox (ICL670), by Dose Cohort (Per-protocol Population) | Week 16 (n=10,11,11) | 21.80 µmol/L | Standard Deviation 18.713 |
| Deferasirox (ICL670) 15 mg/kg/Day | Trough Concentrations of Deferasirox (ICL670), by Dose Cohort (Per-protocol Population) | Week 20 (n=9,10,8) | 27.58 µmol/L | Standard Deviation 25.324 |
| Deferasirox (ICL670) 15 mg/kg/Day | Trough Concentrations of Deferasirox (ICL670), by Dose Cohort (Per-protocol Population) | Week 24 (n=10,9,6) | 26.83 µmol/L | Standard Deviation 11.178 |