Beta-thalassemia Major, Hemosiderosis, Iron Overload, Rare Anemia
Conditions
Keywords
Transfusional hemosiderosis, Beta-thalassemia major, Deferasirox, iron overload, rare anemia, iron overload due to transfusion
Brief summary
To allow patients treated with deferasirox in the core study to continue iron chelation therapy for 2 years or until the drug became locally commercially available. To evaluate the long-term safety and efficacy of deferasirox by measuring treatment success, change in liver iron content (LIC) and change in serum ferritin levels. Safety was mainly assessed by incidence of adverse events (AEs)and clinically significant lab parameters.
Detailed description
Iron accumulation is an inevitable consequence of chronic blood transfusions and results in serious complications in the absence of chelation treatment to remove excess iron. Deferasirox (Exjade, ICL670) is an oral chelator with high iron-binding potency and selectivity. This extension study aimed at collecting efficacy and safety data during 2 years of treatment with deferasirox in the extension study or until deferasirox became commercially available in the countries where the centers were located, whichever came first. The population comprised of β-thalassemia patients with transfusional hemosiderosis who could not be satisfactorily treated with deferoxamine or deferiprone.
Interventions
DRUGDeferasirox
Deferasirox was administered orally once daily. Deferasirox was available as 125 mg, 250 mg, and 500 mg tablets.
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
* Patients completing the planned 12-month core study (NCT00171171) * Female patients who have reached menarche and who are sexually active must use an effective method of contraception, or must have undergone clinically documented total hysterectomy and/or ovariectomy, or tubal ligation * Written informed consent obtained from the patient and/or legal guardian on the patient's behalf in accordance with the national legislation
Exclusion criteria
* Pregnant or breast feeding patients. * Patients being considered by the investigator potentially unreliable and/or not cooperative with regard to the core study protocol, or the planned extension protocol
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Treatment Success From Core Baseline (BL) to Extension End of Study, by Baseline LIC Level and Age | From Core Study Baseline, to Extension End of Study, Up to 3 Years | Success was defined as the percentage of participants with decreased liver iron content (LIC) at the end of extension study compared to core baseline (BL) LIC. Success Criteria: For participants with Baseline LIC from 1 - \<7 mg Fe/g dw, success was achieved if LIC level maintained at 1 - \<7 mg Fe/g dw. For participants with Baseline LIC ≥7 - \<10 mg Fe/g dw, success was achieved if LIC dropped to between 1 and \< 7 mg Fe/g dw. For participants with Baseline LIC ≥10 mg Fe/g dw, success was achieved if LIC dropped by at least 3 mg Fe/g dw. LIC was measured by biopsy or magnetic resonance imaging. |
| Absolute Change in Liver Iron Concentration (LIC)Measured by Liver MRI or Liver Biopsy From Core Study Baseline (BL) to End of Extension Study, by LIC Category | From Baseline of Core Study to End of Extension Study, up to 3 years | Liver MRI or Liver Biopsy was performed at the core study baseline (BL) and then 1 year and 2 years in the core study, baseline of the extension study and time of discontinuation from the extension visit (end of study). Liver iron content (LIC) is reported in milligram Iron per gram dry weight (mg Fe/g dw). Absolute change in LIC from core study baseline to the end of the extension study is presented for participants with the following two core study baseline LIC levels: 1-\<7 mg Fe/g dw and ≥7 mg Fe/g dw. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Absolute Change in Serum Ferritin Level Measured From Core Study Baseline (BL) to End of Extension Study | From Baseline of Core Study to End of Extension Study, up to 3 years | Serum Levels were assessed at core study baseline (BL), 1 year, 2 years in core study, baseline of extension study and time of discontinuation from the extension visit (end of study) in monthly intervals. Serum Ferritin is reported in micrograms per Liter (µg/L). |
| Absolute Change in Serum Ferritin Level for All Participants Measured From Core Study Baseline (BL) to End of Extension Study, by Baseline Liver Iron Content (LIC) | From Baseline of Core Study to End of Extension Study, up to 3 years | Serum Levels were assessed at core study baseline (BL) and then 1 year and 2 years in core study, baseline of extension study and time of discontinuation from the extension visit (end of study). Serum Ferritin is reported in micrograms per Liter. Absolute change in Serum Ferritin from core study baseline to the end of the extension study is presented for participants with the following two core study baseline LIC levels: 1-\<7 mg Fe/g dw and ≥7 mg Fe/g dw. |
Countries
Egypt, Lebanon, Oman, Saudi Arabia, Syria
Participant flow
Recruitment details
This is an Extension to Core Study CICL670A2402 (NCT00171171). 233 participants completed the core study and entered this extension study.
Pre-assignment details
2 participants from the 16 and older group did not receive deferasirox. Thus, the 16 and older group comprises of 69 treated participants.
Participants by arm
| Arm | Count |
|---|---|
| Deferasirox (Between 2 <16 Years ) Participants age 2 years up to 16 years received a daily oral dose of deferasirox. Dose selection was based on the dose last received in the core study. The individual daily doses of deferasirox and the exact amount of tablets (125, 250, or 500 mg) contributing to each dose were calculated by the investigator based on the patient's body weight. | 162 |
| Deferasirox (16 Years or Older) Participants age 16 years or older received a daily oral dose of deferasirox. Dose selection was based on the dose last received in the core study. The individual daily doses of deferasirox and the exact amount of tablets (125, 250, or 500 mg) contributing to each dose were calculated by the investigator based on the patient's body weight. | 71 |
| Total | 233 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 2 |
| Overall Study | Death | 1 | 2 |
| Overall Study | Lost to Follow-up | 6 | 2 |
| Overall Study | Protocol Violation | 0 | 2 |
| Overall Study | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Deferasirox (Between 2 <16 Years ) | Deferasirox (16 Years or Older) | Total |
|---|---|---|---|
| Age Continuous | 9.5 years STANDARD_DEVIATION 3.59 | 21.2 years STANDARD_DEVIATION 5.82 | 13.0 years STANDARD_DEVIATION 6.93 |
| Sex/Gender, Customized Female | 80 participants | 35 participants | 115 participants |
| Sex/Gender, Customized Male | 82 participants | 36 participants | 118 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 54 / 162 | 33 / 69 |
| serious Total, serious adverse events | 5 / 162 | 12 / 69 |
Outcome results
Primary
Absolute Change in Liver Iron Concentration (LIC)Measured by Liver MRI or Liver Biopsy From Core Study Baseline (BL) to End of Extension Study, by LIC Category
Liver MRI or Liver Biopsy was performed at the core study baseline (BL) and then 1 year and 2 years in the core study, baseline of the extension study and time of discontinuation from the extension visit (end of study). Liver iron content (LIC) is reported in milligram Iron per gram dry weight (mg Fe/g dw). Absolute change in LIC from core study baseline to the end of the extension study is presented for participants with the following two core study baseline LIC levels: 1-\<7 mg Fe/g dw and ≥7 mg Fe/g dw.
Time frame: From Baseline of Core Study to End of Extension Study, up to 3 years
Population: Participants from the Intent-to-Treat (ITT) population for whom LIC data was available at Core Study baseline and at the End of Extension Study. n is the number of participants analyzed in each category.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Deferasirox (Between 2 <16 Years) | Absolute Change in Liver Iron Concentration (LIC)Measured by Liver MRI or Liver Biopsy From Core Study Baseline (BL) to End of Extension Study, by LIC Category | Core Baseline LIC 1-<7 mg Fe/g dw (n=12, 0) | -1.32 mg Fe/g dw | Standard Deviation 3.125 |
| Deferasirox (Between 2 <16 Years) | Absolute Change in Liver Iron Concentration (LIC)Measured by Liver MRI or Liver Biopsy From Core Study Baseline (BL) to End of Extension Study, by LIC Category | Core Baseline LIC ≥7 mg Fe/g dw (n=107, 41) | -9.03 mg Fe/g dw | Standard Deviation 9.26 |
| Deferasirox (16 Years or Older) | Absolute Change in Liver Iron Concentration (LIC)Measured by Liver MRI or Liver Biopsy From Core Study Baseline (BL) to End of Extension Study, by LIC Category | Core Baseline LIC 1-<7 mg Fe/g dw (n=12, 0) | NA mg Fe/g dw | — |
| Deferasirox (16 Years or Older) | Absolute Change in Liver Iron Concentration (LIC)Measured by Liver MRI or Liver Biopsy From Core Study Baseline (BL) to End of Extension Study, by LIC Category | Core Baseline LIC ≥7 mg Fe/g dw (n=107, 41) | -8.39 mg Fe/g dw | Standard Deviation 11.312 |
Primary
Percentage of Participants With Treatment Success From Core Baseline (BL) to Extension End of Study, by Baseline LIC Level and Age
Success was defined as the percentage of participants with decreased liver iron content (LIC) at the end of extension study compared to core baseline (BL) LIC. Success Criteria: For participants with Baseline LIC from 1 - \<7 mg Fe/g dw, success was achieved if LIC level maintained at 1 - \<7 mg Fe/g dw. For participants with Baseline LIC ≥7 - \<10 mg Fe/g dw, success was achieved if LIC dropped to between 1 and \< 7 mg Fe/g dw. For participants with Baseline LIC ≥10 mg Fe/g dw, success was achieved if LIC dropped by at least 3 mg Fe/g dw. LIC was measured by biopsy or magnetic resonance imaging.
Time frame: From Core Study Baseline, to Extension End of Study, Up to 3 Years
Population: The primary analysis will be on the intent-to-treat (ITT) population. ITT population includes all participants who performed the core end of study (EOS) visit evaluation and assessments and were included in the extension study. n is the number of participants analyzed in each category.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Deferasirox (Between 2 <16 Years) | Percentage of Participants With Treatment Success From Core Baseline (BL) to Extension End of Study, by Baseline LIC Level and Age | Core Baseline LIC 1-<7 mg Fe/g dw (n=20, 2) | 75.0 percentage of participants |
| Deferasirox (Between 2 <16 Years) | Percentage of Participants With Treatment Success From Core Baseline (BL) to Extension End of Study, by Baseline LIC Level and Age | Core Baseline LIC 7-<10 mg Fe/g dw (n=18, 8) | 72.2 percentage of participants |
| Deferasirox (Between 2 <16 Years) | Percentage of Participants With Treatment Success From Core Baseline (BL) to Extension End of Study, by Baseline LIC Level and Age | Core Baseline LIC ≥10 mg Fe/g dw (n=124, 61) | 76.6 percentage of participants |
| Deferasirox (16 Years or Older) | Percentage of Participants With Treatment Success From Core Baseline (BL) to Extension End of Study, by Baseline LIC Level and Age | Core Baseline LIC 1-<7 mg Fe/g dw (n=20, 2) | 100 percentage of participants |
| Deferasirox (16 Years or Older) | Percentage of Participants With Treatment Success From Core Baseline (BL) to Extension End of Study, by Baseline LIC Level and Age | Core Baseline LIC 7-<10 mg Fe/g dw (n=18, 8) | 50.0 percentage of participants |
| Deferasirox (16 Years or Older) | Percentage of Participants With Treatment Success From Core Baseline (BL) to Extension End of Study, by Baseline LIC Level and Age | Core Baseline LIC ≥10 mg Fe/g dw (n=124, 61) | 73.8 percentage of participants |
Secondary
Absolute Change in Serum Ferritin Level for All Participants Measured From Core Study Baseline (BL) to End of Extension Study, by Baseline Liver Iron Content (LIC)
Serum Levels were assessed at core study baseline (BL) and then 1 year and 2 years in core study, baseline of extension study and time of discontinuation from the extension visit (end of study). Serum Ferritin is reported in micrograms per Liter. Absolute change in Serum Ferritin from core study baseline to the end of the extension study is presented for participants with the following two core study baseline LIC levels: 1-\<7 mg Fe/g dw and ≥7 mg Fe/g dw.
Time frame: From Baseline of Core Study to End of Extension Study, up to 3 years
Population: Participants from the Intent-to-Treat (ITT) population for whom Serum Ferritin data was available at Core Study baseline and at the End of Extension Study. n is the number of participants analyzed in each category.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Deferasirox (Between 2 <16 Years) | Absolute Change in Serum Ferritin Level for All Participants Measured From Core Study Baseline (BL) to End of Extension Study, by Baseline Liver Iron Content (LIC) | Core Baseline LIC 1-<7 mg Fe/g dw (n=12) | -369.83 µg/L | Standard Deviation 1349.57 |
| Deferasirox (Between 2 <16 Years) | Absolute Change in Serum Ferritin Level for All Participants Measured From Core Study Baseline (BL) to End of Extension Study, by Baseline Liver Iron Content (LIC) | Core Baseline LIC ≥ 7 mg Fe/g dw (n=151) | -1619.31 µg/L | Standard Deviation 2217.104 |
Secondary
Absolute Change in Serum Ferritin Level Measured From Core Study Baseline (BL) to End of Extension Study
Serum Levels were assessed at core study baseline (BL), 1 year, 2 years in core study, baseline of extension study and time of discontinuation from the extension visit (end of study) in monthly intervals. Serum Ferritin is reported in micrograms per Liter (µg/L).
Time frame: From Baseline of Core Study to End of Extension Study, up to 3 years
Population: Participants from the Intent-to-Treat (ITT) population for whom Serum Ferritin data was available at Core Study baseline and at the End of Extension Study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Deferasirox (Between 2 <16 Years) | Absolute Change in Serum Ferritin Level Measured From Core Study Baseline (BL) to End of Extension Study | -1432.51 µg/L | Standard Deviation 1969.622 |
| Deferasirox (16 Years or Older) | Absolute Change in Serum Ferritin Level Measured From Core Study Baseline (BL) to End of Extension Study | -1791.91 µg/L | Standard Deviation 2712.334 |