Diamond Blackfan Anemia, Myelofibrosis, Sickle Cell Disease, Thalassemia
Conditions
Keywords
Deferasirox, Congenital Anemias, Anemias, Red Blood Cell Disorders, Chronic Iron Overload, Transfusional Iron Overload, Iron Chelators, Oral Iron Chelators, Thalassemia, Sickle Cell Disease, Diamond Blackfan Anemia, Myelofibrosis, ICL670A
Brief summary
This is an open-label, non-randomized, multi-center trial designed to provide expanded access of deferasirox to patients with congenital disorders of red blood cells and chronic iron overload from blood transfusions who cannot adequately be treated with locally approved iron chelators.
Interventions
DRUGDeferasirox
125 mg, 250 mg and 500 mg tablets. Dosage was calculated based on participant's body weight. Tablets were dispersed in water, orange or apple juice and taken orally once a day.
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
2 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Male or female patients greater than or equal to 2 years of age * Documented congenital disorder of red blood cells (e.g., β-thalassemia major, sickle cell anemia, diamond-blackfan anemia) requiring ongoing blood transfusions * Cannot be adequately treated with a locally approved iron chelator due to one of the following reasons: * Documented non-compliance, defined as having taken less than 50% of the prescribed chelation therapy doses in the 12 months prior to study entry * Contraindications, unacceptable toxicities and/or documented poor response to locally approved iron chelators despite proper compliance * History of at least 20 blood transfusions (equivalent to 100 mL/kg of packed red blood cells (PRBC\]) * Serum ferritin value greater than or equal to 1000 µg/L * Ability to comply with all study-related procedures, medications, and evaluations
Exclusion criteria
* Ongoing treatment with another iron chelator (Any other iron chelation therapy must be discontinued at least 24 hours prior to study entry.) * Patients who meet the eligibility criteria for any other ongoing Novartis sponsored clinical study protocol with deferasirox and who have geographic access to these sites * Patients unable to tolerate (or who have unacceptable toxicities to) prior treatment with deferasirox * Serum creatinine above the upper limit of normal at screening. * Patients with ALT ≥ 500 U/L at screening. * Evidence of chelation-related cataracts or hearing loss within 4 weeks prior to baseline * Pregnancy (as indicated by serum β-HCG pregnancy test at screening for all female patients with the potential to become pregnant) and patients who are breastfeeding * Patients treated with systemic investigational drug within 4 weeks prior to or with topical investigational drug within 7 days prior to the baseline visit Other protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Safety Profile of Deferasirox Based Upon Drug Administration and Reporting of Serious Adverse Events | Baseline to end of study (Median exposure time to drug was approximately 30 weeks; Maximum exposure was 104 weeks) | Safety as assessed by the number of participants with death, serious adverse events (SAE), and/or Adverse Events (AEs) leading to study drug interruption or discontinuation. Note: only treatment emergent AEs are summarized. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| The Change in Serum Ferritin Values From Baseline Through Completion of the Study | Baseline to end of study (Median exposure time to drug was approximately 30 weeks; Maximum exposure was 104 weeks) | The number of participants with Improvement, No Change or Worsening in Serum ferritin category levels at the end of the study compared to baseline. Serum ferritin levels in µg/L were divided into to 6 categories: (\<1000), (1000-\<2500), (2500-\<4000), (4000-\<5500), (5500-\<7000) and (\>=7000). Improvement was defined as a shift to a lower category at the end of study compared to the category at baseline. Worsening was defined as a shift to a higher category at the end of the study compared to the category at baseline. No change was no change in category at end of study from baseline. |
Countries
Belgium, Canada, Germany, Greece, Italy, Netherlands, Spain, Taiwan, Thailand, Turkey (Türkiye), United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 2 to < 6 Years Deferasirox was administered orally once a day, 30 minutes prior to breakfast. Dosage was based on participant's body weight. Tablets were dispersed in water, orange or apple juice. | 97 |
| 6 to < 12 Years Deferasirox was administered orally once a day, 30 minutes prior to breakfast. Dosage was based on participant's body weight. Tablets were dispersed in water, orange or apple juice. | 200 |
| 12 to < 16 Years Deferasirox was administered orally once a day, 30 minutes prior to breakfast. Dosage was based on participant's body weight. Tablets were dispersed in water, orange or apple juice. | 172 |
| 16 to < 50 Years Deferasirox was administered orally once a day, 30 minutes prior to breakfast. Dosage was based on participant's body weight. Tablets were dispersed in water, orange or apple juice. | 1,164 |
| 50 to < 65 Years Deferasirox was administered orally once a day, 30 minutes prior to breakfast. Dosage was based on participant's body weight. Tablets were dispersed in water, orange or apple juice. | 43 |
| ≥ 65 Years Deferasirox was administered orally once a day, 30 minutes prior to breakfast. Dosage was based on participant's body weight. Tablets were dispersed in water, orange or apple juice. | 7 |
| Total | 1,683 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Overall Study | Abnormal laboratory value(s) | 3 | 5 | 4 | 27 | 1 | 2 |
| Overall Study | Administrative problems | 0 | 0 | 0 | 1 | 0 | 0 |
| Overall Study | Adverse Event | 4 | 5 | 10 | 72 | 5 | 2 |
| Overall Study | Condition no longer requires treatment | 3 | 0 | 0 | 11 | 1 | 0 |
| Overall Study | Death | 0 | 0 | 1 | 4 | 0 | 0 |
| Overall Study | Lost to Follow-up | 0 | 3 | 3 | 16 | 0 | 0 |
| Overall Study | Protocol deviation | 0 | 0 | 1 | 11 | 0 | 0 |
| Overall Study | Unsatisfactory therapeutic effect | 0 | 2 | 2 | 17 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 2 | 3 | 3 | 61 | 5 | 0 |
Baseline characteristics
| Characteristic | 2 to < 6 Years | Total | ≥ 65 Years | 50 to < 65 Years | 16 to < 50 Years | 12 to < 16 Years | 6 to < 12 Years |
|---|---|---|---|---|---|---|---|
| Age Continuous | 3.48 years STANDARD_DEVIATION 1.13 | 24.27 years STANDARD_DEVIATION 12.63 | 70.14 years STANDARD_DEVIATION 3.98 | 54.58 years STANDARD_DEVIATION 3.92 | 28.91 years STANDARD_DEVIATION 8.06 | 13.48 years STANDARD_DEVIATION 1.2 | 8.52 years STANDARD_DEVIATION 1.64 |
| Baseline Disease Characteristics Beta-Thalassemia Intermedia | 1 participants | 156 participants | 3 participants | 20 participants | 94 participants | 16 participants | 22 participants |
| Baseline Disease Characteristics Beta-Thalassemia Major | 74 participants | 1221 participants | 0 participants | 10 participants | 905 participants | 114 participants | 118 participants |
| Baseline Disease Characteristics Diamond-Blackfan Anemia | 4 participants | 43 participants | 0 participants | 0 participants | 24 participants | 8 participants | 7 participants |
| Baseline Disease Characteristics Other Diseases | 10 participants | 87 participants | 3 participants | 11 participants | 48 participants | 3 participants | 12 participants |
| Baseline Disease Characteristics Sickle Cell Disease | 8 participants | 176 participants | 1 participants | 2 participants | 93 participants | 31 participants | 41 participants |
| Prior Chelation Drug Therapy Deferiprone | 1 participants | 173 participants | 1 participants | 6 participants | 146 participants | 11 participants | 8 participants |
| Prior Chelation Drug Therapy Deferoxamine | 80 participants | 1165 participants | 5 participants | 31 participants | 745 participants | 137 participants | 167 participants |
| Prior Chelation Drug Therapy Deferoxamine and Deferiprone | 2 participants | 314 participants | 0 participants | 6 participants | 269 participants | 21 participants | 16 participants |
| Prior Chelation Drug Therapy Other Chelation Drug | 6 participants | 19 participants | 0 participants | 0 participants | 4 participants | 3 participants | 6 participants |
| Prior Chelation Drug Therapy Prior Chelatation Drug Information Missing | 8 participants | 12 participants | 1 participants | 0 participants | 0 participants | 0 participants | 3 participants |
| Reason for inadequate prior chelation therapy Reason for inadequate therapy information missing | 6 participants | 10 participants | 1 participants | 0 participants | 0 participants | 0 participants | 3 participants |
| Reason for inadequate prior chelation therapy Therapy contraindication | 1 participants | 45 participants | 1 participants | 1 participants | 29 participants | 6 participants | 7 participants |
| Reason for inadequate prior chelation therapy Therapy non-compliance | 57 participants | 974 participants | 2 participants | 25 participants | 659 participants | 106 participants | 125 participants |
| Reason for inadequate prior chelation therapy Therapy poor response | 20 participants | 367 participants | 0 participants | 8 participants | 267 participants | 38 participants | 34 participants |
| Reason for inadequate prior chelation therapy Therapy unacceptable discomfort | 2 participants | 87 participants | 2 participants | 3 participants | 78 participants | 0 participants | 2 participants |
| Reason for inadequate prior chelation therapy Therapy unacceptable toxicity | 11 participants | 200 participants | 1 participants | 6 participants | 131 participants | 22 participants | 29 participants |
| Sex: Female, Male Female | 44 Participants | 896 Participants | 5 Participants | 32 Participants | 633 Participants | 81 Participants | 101 Participants |
| Sex: Female, Male Male | 53 Participants | 787 Participants | 2 Participants | 11 Participants | 531 Participants | 91 Participants | 99 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 85 / 1,683 |
| serious Total, serious adverse events | 194 / 1,683 |
Outcome results
Primary
Safety Profile of Deferasirox Based Upon Drug Administration and Reporting of Serious Adverse Events
Safety as assessed by the number of participants with death, serious adverse events (SAE), and/or Adverse Events (AEs) leading to study drug interruption or discontinuation. Note: only treatment emergent AEs are summarized.
Time frame: Baseline to end of study (Median exposure time to drug was approximately 30 weeks; Maximum exposure was 104 weeks)
Population: The safety population, comprising all participants who received at least one dose of deferasirox during the study, was used in the analyses.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| 2 to < 6 Years | Safety Profile of Deferasirox Based Upon Drug Administration and Reporting of Serious Adverse Events | AEs leading to discontinuation | 4 Participants |
| 2 to < 6 Years | Safety Profile of Deferasirox Based Upon Drug Administration and Reporting of Serious Adverse Events | Non-fatal SAEs | 10 Participants |
| 2 to < 6 Years | Safety Profile of Deferasirox Based Upon Drug Administration and Reporting of Serious Adverse Events | Number of deaths | 0 Participants |
| 2 to < 6 Years | Safety Profile of Deferasirox Based Upon Drug Administration and Reporting of Serious Adverse Events | AEs leading dose adjustment/temporary interruption | 15 Participants |
| 6 to < 12 Years | Safety Profile of Deferasirox Based Upon Drug Administration and Reporting of Serious Adverse Events | AEs leading dose adjustment/temporary interruption | 31 Participants |
| 6 to < 12 Years | Safety Profile of Deferasirox Based Upon Drug Administration and Reporting of Serious Adverse Events | AEs leading to discontinuation | 5 Participants |
| 6 to < 12 Years | Safety Profile of Deferasirox Based Upon Drug Administration and Reporting of Serious Adverse Events | Number of deaths | 0 Participants |
| 6 to < 12 Years | Safety Profile of Deferasirox Based Upon Drug Administration and Reporting of Serious Adverse Events | Non-fatal SAEs | 22 Participants |
| 12 to < 16 Years | Safety Profile of Deferasirox Based Upon Drug Administration and Reporting of Serious Adverse Events | Number of deaths | 1 Participants |
| 12 to < 16 Years | Safety Profile of Deferasirox Based Upon Drug Administration and Reporting of Serious Adverse Events | AEs leading to discontinuation | 10 Participants |
| 12 to < 16 Years | Safety Profile of Deferasirox Based Upon Drug Administration and Reporting of Serious Adverse Events | Non-fatal SAEs | 27 Participants |
| 12 to < 16 Years | Safety Profile of Deferasirox Based Upon Drug Administration and Reporting of Serious Adverse Events | AEs leading dose adjustment/temporary interruption | 28 Participants |
| 16 to < 50 Years | Safety Profile of Deferasirox Based Upon Drug Administration and Reporting of Serious Adverse Events | Number of deaths | 4 Participants |
| 16 to < 50 Years | Safety Profile of Deferasirox Based Upon Drug Administration and Reporting of Serious Adverse Events | Non-fatal SAEs | 129 Participants |
| 16 to < 50 Years | Safety Profile of Deferasirox Based Upon Drug Administration and Reporting of Serious Adverse Events | AEs leading to discontinuation | 75 Participants |
| 16 to < 50 Years | Safety Profile of Deferasirox Based Upon Drug Administration and Reporting of Serious Adverse Events | AEs leading dose adjustment/temporary interruption | 209 Participants |
| 50 to < 65 Years | Safety Profile of Deferasirox Based Upon Drug Administration and Reporting of Serious Adverse Events | AEs leading dose adjustment/temporary interruption | 11 Participants |
| 50 to < 65 Years | Safety Profile of Deferasirox Based Upon Drug Administration and Reporting of Serious Adverse Events | Non-fatal SAEs | 4 Participants |
| 50 to < 65 Years | Safety Profile of Deferasirox Based Upon Drug Administration and Reporting of Serious Adverse Events | Number of deaths | 0 Participants |
| 50 to < 65 Years | Safety Profile of Deferasirox Based Upon Drug Administration and Reporting of Serious Adverse Events | AEs leading to discontinuation | 5 Participants |
| ≥ 65 Years | Safety Profile of Deferasirox Based Upon Drug Administration and Reporting of Serious Adverse Events | Non-fatal SAEs | 2 Participants |
| ≥ 65 Years | Safety Profile of Deferasirox Based Upon Drug Administration and Reporting of Serious Adverse Events | AEs leading to discontinuation | 2 Participants |
| ≥ 65 Years | Safety Profile of Deferasirox Based Upon Drug Administration and Reporting of Serious Adverse Events | AEs leading dose adjustment/temporary interruption | 2 Participants |
| ≥ 65 Years | Safety Profile of Deferasirox Based Upon Drug Administration and Reporting of Serious Adverse Events | Number of deaths | 0 Participants |
Secondary
The Change in Serum Ferritin Values From Baseline Through Completion of the Study
The number of participants with Improvement, No Change or Worsening in Serum ferritin category levels at the end of the study compared to baseline. Serum ferritin levels in µg/L were divided into to 6 categories: (\<1000), (1000-\<2500), (2500-\<4000), (4000-\<5500), (5500-\<7000) and (\>=7000). Improvement was defined as a shift to a lower category at the end of study compared to the category at baseline. Worsening was defined as a shift to a higher category at the end of the study compared to the category at baseline. No change was no change in category at end of study from baseline.
Time frame: Baseline to end of study (Median exposure time to drug was approximately 30 weeks; Maximum exposure was 104 weeks)
Population: Safety population defined as all participants who received at least one dose of study drug. This analysis did not include participants with unknown status at baseline and/or at the end of the study.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| 2 to < 6 Years | The Change in Serum Ferritin Values From Baseline Through Completion of the Study | No Change | 63 Participants |
| 2 to < 6 Years | The Change in Serum Ferritin Values From Baseline Through Completion of the Study | Improvement | 17 Participants |
| 2 to < 6 Years | The Change in Serum Ferritin Values From Baseline Through Completion of the Study | Worsening | 16 Participants |
| 6 to < 12 Years | The Change in Serum Ferritin Values From Baseline Through Completion of the Study | No Change | 106 Participants |
| 6 to < 12 Years | The Change in Serum Ferritin Values From Baseline Through Completion of the Study | Improvement | 27 Participants |
| 6 to < 12 Years | The Change in Serum Ferritin Values From Baseline Through Completion of the Study | Worsening | 63 Participants |
| 12 to < 16 Years | The Change in Serum Ferritin Values From Baseline Through Completion of the Study | No Change | 87 Participants |
| 12 to < 16 Years | The Change in Serum Ferritin Values From Baseline Through Completion of the Study | Improvement | 26 Participants |
| 12 to < 16 Years | The Change in Serum Ferritin Values From Baseline Through Completion of the Study | Worsening | 55 Participants |
| 16 to < 50 Years | The Change in Serum Ferritin Values From Baseline Through Completion of the Study | No Change | 570 Participants |
| 16 to < 50 Years | The Change in Serum Ferritin Values From Baseline Through Completion of the Study | Improvement | 206 Participants |
| 16 to < 50 Years | The Change in Serum Ferritin Values From Baseline Through Completion of the Study | Worsening | 341 Participants |
| 50 to < 65 Years | The Change in Serum Ferritin Values From Baseline Through Completion of the Study | No Change | 31 Participants |
| 50 to < 65 Years | The Change in Serum Ferritin Values From Baseline Through Completion of the Study | Improvement | 4 Participants |
| 50 to < 65 Years | The Change in Serum Ferritin Values From Baseline Through Completion of the Study | Worsening | 7 Participants |
| ≥ 65 Years | The Change in Serum Ferritin Values From Baseline Through Completion of the Study | Improvement | 2 Participants |
| ≥ 65 Years | The Change in Serum Ferritin Values From Baseline Through Completion of the Study | Worsening | 1 Participants |
| ≥ 65 Years | The Change in Serum Ferritin Values From Baseline Through Completion of the Study | No Change | 3 Participants |