Chronic Anemia, Transfusional Hemosiderosis
Conditions
Keywords
Iron Overload,, Chelation,, MDS,, Chronic Anemia,, Deferasirox,, Transfusional hemosiderosis,
Brief summary
The overall purpose of this trial is to further evaluate the efficacy and safety of deferasirox, dosed initially according to the transfusional iron intake, in patients with transfusion dependant anemia related to disorders other than β-thalassemia and sickle cell disease. During the study, the dose will be adjusted based on serum Ferritin.The overall purpose of the extension is to allow further treatment of patients who have already completed the core study, and to enable collection of long term efficacy and safety data. Patients will continue to receive Deferasirox at the dose they received at the end of the core study.
Interventions
The recommended initial daily dose of Deferasirox is 20 mg/kg body weight.
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
2 Years to No maximum
Healthy volunteers
No
Inclusion criteria
(Core): * Patients with transfusional iron overload due to: * low or intermediate (INT-1) risk Myelodysplastic Syndrome (MDS)determined via International Prognosis Scoring System (IPSS) criteria * other congenital or acquired anemias excluding B-thalassemia and sickle cell disease * Lifetime transfusion history of ≥20 unit (approximately 100 mL/kg) of packed red blood cells or showing evidence of iron overload (serum ferritin \>1000 µg/L). * Able to provide written informed consent * Life expectancy ≥ 12 months If patient was previously treated with deferiprone, a washout period of one month should occur before the first dose of deferasirox Inclusion criteria (Extension): * Patients completing the planned 12-month core study (CICL670A2204). * Written informed consent obtained from the patient and/or legal guardian on the patient's behalf in accordance with national legislation.
Exclusion criteria
(Core and Extension): * Patients with β-thalassemia, sickle cell disease or myelodysplastic syndrome with an IPSS score being Intermediate-2 or High. * Patients with serum creatinine \> ULN * Patients with ALT(SGPT) levels \> 5 x ULN * Significant proteinuria as indicated by a urinary protein/creatinine ratio \>0.5 mg/mg in a non-first void urine sample on two assessments during the screening period. * History of HIV positive test result , or of clinical or laboratory evidence of active Hepatitis B or Hepatitis C (HBsAg in the absence of HBsAb OR HCV Ab positive with HCV RNA positive and ALT above the normal range) * Patients on investigational MDS therapies, including lenalidomide, thalidomide, azacitidine and arsenic trioxide, must have a ≥ 4 week washout period prior to the first dose of study drug. * Patients with systemic uncontrolled hypertension * Patients with unstable cardiac disease not controlled by standard medical therapy * Systemic disease (cardiovascular, renal, hepatic, etc.) which would prevent study treatment * Pregnancy (as documented in required screening laboratory test) or breast feeding. * Patients treated with systemic investigational drug within the past 4 weeks or topical investigational drug within the past 7 days * Other surgical or medical condition which might significantly alter the absorption, distribution, metabolism or excretion of study drug * Patients being considered by the investigator potentially unreliable and/or not cooperative with regard to the study protocol * History of hypersensitivity to any of the study drug or excipients * Sexually active pre-menopausal female patients without adequate contraception. Female patients must use effective contraception or must have undergone clinically documented total hysterectomy and/or oophorectomy, tubal ligation or be postmenopausal defined by amenorrhea for at least 12 months. Other protocol defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Absolute Change From Baseline in Liver Iron Concentration (LIC) to Year 1 | From the Baseline, Year 1 (End of core study) | Liver iron concentration (LIC), a predictor of iron burden, was measured using relaxation rate magnetic resonance imaging (R2-MRI) technique. Relaxation rate was determined as R2 = 1/relaxation time (T2). The baseline value of LIC of participants was categorized as \< 7, ≥ 7 to \< 15, and ≥ 15 milligram of iron/tissue dry weight (mg Fe/g dw). A negative change from baseline favored study treatment in reducing LIC. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Absolute Change From Baseline in Liver Iron Concentration (LIC) in Japanese Subgroup | From the Baseline, End of Year 1 (End of core study), End of Year 2 (End of extension study) | Liver Iron Concentration (LIC), a predictor of iron burden, was measured using R2-MRI technique. Relaxation rate was determined as R2 = 1/T2. The baseline value of LIC was \< 7, ≥ 7 to \< 15, and ≥ 15 mg Fe/g dw. A negative change from baseline favoured study treatment in reducing LIC. |
| Absolute Change From Baseline in Serum Ferritin Levels to Year 2 | From the Baseline up to Year 2 (End of extension study) | Serum ferritin was a marker for the monitoring of chelation therapy. Ferritin protein stores iron and provides overall iron levels, higher ferritin in blood showed more iron content. |
| Absolute Serum Ferritin Levels Over 2 Years | From the Baseline, Year 1 (End of core study), Year 2 (End of extension study) | Serum ferritin was a marker for the monitoring of chelation therapy. Ferritin protein stores iron and provides overall iron levels, higher ferritin in blood showed more iron content. |
| Absolute Change From Baseline in Liver Iron Concentration (LIC) to End of Year 2 | From the Baseline to End of Year 2 (End of extension study) | Liver Iron Concentration (LIC), a predictor of iron burden, was measured using R2-MRI technique. Relaxation rate was determined as R2 = 1/T2. The baseline value of LIC of participants was categorized as \< 7, ≥ 7 to \< 15, and ≥ 15 mg Fe/g dw. A negative change from baseline favoured study treatment in reducing LIC. |
| Correlation of LIC and Serum Ferritin at Core and Extension Study | From the Baseline, Year 1 (End of core study), Year 2 (End of extension study) | LIC, a predictor of iron burden, was measured using R2-MRI technique. Relaxation rate was determined as R2 = 1/T2. The baseline value of LIC was \< 7, ≥ 7 to \< 15, and ≥ 15 mg Fe/g dw. Serum ferritin was a marker for the monitoring of chelation therapy. Ferritin protein stores iron and provides overall iron levels, higher ferritin in blood showed more iron content. The correlation between absolute change in LIC and absolute change in serum ferritin was determined. |
| Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), Adverse Event of Special Interest (AESI), Discontinuation and Interruption | From the Baseline up to Year 2 (End of extension study) | Adverse events (AEs) were defined as any unfavorable and unintended diagnosis, symptom, sign (including an abnormal laboratory finding), syndrome or disease which either occurs during study, having been absent at baseline, or, if present at baseline, appears to worsen. Serious adverse events (SAEs) were defined as any untoward medical occurrences that result in death, are life threatening, require hospitalisation, cause persistent or significant disability/incapacity, result in congenital anomalies or birth defects, or are other conditions which in judgement of investigators represent significant hazards. Death was defined as a fatal event leading to permanent cessation of all vital functions of the body. |
| Number of Participants With Clinically Significant Ophthalmological Abnormalities | At 2 years (End of extension study) | Clinically significant changes in left eye and right eye were assessed by the investigator based on methods like visual acuity, slit lamp examination, tonometry and fundus oculi. |
| Total Body Iron Elimination Rate (TBIE), Iron Intake, Iron Excretion/Iron Intake and Chelation Efficiency After 2 Years | From the Baseline, Year 2 (End of extension study) | Total body iron excretion (TBIE)was used to investigate the chelation efficacy of Deferasirox therapy. TBIE rate was estimated based on the iron influx as determined by the amount of red cells transfused and the change in total body iron (TBI) stores. |
Countries
Japan, Poland, Singapore, Spain, Turkey (Türkiye)
Participant flow
Recruitment details
The study was conducted at 31 centers and five countries.
Pre-assignment details
A total of 144 Participants were screened, of which only 102 Participants enrolled in the study. Remaining 42 Participants were considered as screen failures.
Participants by arm
| Arm | Count |
|---|---|
| Deferasirox Participants received initial dose of 20 mg/kg Deferasirox tablets was administered orally OD based on the participants body weight. The dose of Deferasirox was adjusted to either 10 mg/kg or 30 mg/kg based on the volumes of blood transfusions being administered. | 102 |
| Total | 102 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Number of Participants in Year 1 | Administrative problems | 6 |
| Number of Participants in Year 1 | Adverse Event | 12 |
| Number of Participants in Year 1 | Death | 6 |
| Number of Participants in Year 1 | Lost to Follow-up | 1 |
| Number of Participants in Year 1 | Patient's condition no longer requires study drug | 1 |
| Number of Participants in Year 1 | Withdrawal by Subject | 8 |
| Number of Participants in Year 2 | Abnormal laboratory value | 1 |
| Number of Participants in Year 2 | Adverse Event | 1 |
| Number of Participants in Year 2 | Protocol Violation | 1 |
| Number of Participants in Year 2 | Withdrawal by Subject | 2 |
Baseline characteristics
| Characteristic | Deferasirox |
|---|---|
| Age, Continuous | 47.8 years STANDARD_DEVIATION 25.9 |
| Race/Ethnicity, Customized Asian | 56 Participants |
| Race/Ethnicity, Customized Caucasian | 46 Participants |
| Race/Ethnicity, Customized Chinese | 2 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 4 Participants |
| Race/Ethnicity, Customized Japanese | 53 Participants |
| Race/Ethnicity, Customized Other | 43 Participants |
| Sex: Female, Male Female | 49 Participants |
| Sex: Female, Male Male | 53 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 2 / 42 | 3 / 29 | 1 / 31 |
| other Total, other adverse events | 39 / 42 | 25 / 29 | 25 / 31 |
| serious Total, serious adverse events | 22 / 42 | 14 / 29 | 10 / 31 |
Outcome results
Primary
Absolute Change From Baseline in Liver Iron Concentration (LIC) to Year 1
Liver iron concentration (LIC), a predictor of iron burden, was measured using relaxation rate magnetic resonance imaging (R2-MRI) technique. Relaxation rate was determined as R2 = 1/relaxation time (T2). The baseline value of LIC of participants was categorized as \< 7, ≥ 7 to \< 15, and ≥ 15 milligram of iron/tissue dry weight (mg Fe/g dw). A negative change from baseline favored study treatment in reducing LIC.
Time frame: From the Baseline, Year 1 (End of core study)
Population: The analysis was performed in per-protocol population in core study (PP1 Set), comprising of all enrolled participants who had LIC assessments at baseline and Year 1.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Deferasirox | Absolute Change From Baseline in Liver Iron Concentration (LIC) to Year 1 | -10.9 mg Fe/g dw | Standard Deviation 11.86 |
Secondary
Absolute Change From Baseline in Liver Iron Concentration (LIC) in Japanese Subgroup
Liver Iron Concentration (LIC), a predictor of iron burden, was measured using R2-MRI technique. Relaxation rate was determined as R2 = 1/T2. The baseline value of LIC was \< 7, ≥ 7 to \< 15, and ≥ 15 mg Fe/g dw. A negative change from baseline favoured study treatment in reducing LIC.
Time frame: From the Baseline, End of Year 1 (End of core study), End of Year 2 (End of extension study)
Population: The analysis was performed in PP1 set in Japanese subgroup defined as all participants who were enrolled in Japan for core study (Year 1) and PP2 set in Japanese subgroup for extension study (Year 2). Here, 'n' signifies the participants reviewed for Liver Iron Concentration (LIC) in Japanese subgroup for each group, respectively.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Deferasirox | Absolute Change From Baseline in Liver Iron Concentration (LIC) in Japanese Subgroup | Year 2 | -18.4 mg Fe/g dw | Standard Deviation 12.48 |
| Deferasirox | Absolute Change From Baseline in Liver Iron Concentration (LIC) in Japanese Subgroup | Year 1 | -13.9 mg Fe/g dw | Standard Deviation 10.21 |
Secondary
Absolute Change From Baseline in Liver Iron Concentration (LIC) to End of Year 2
Liver Iron Concentration (LIC), a predictor of iron burden, was measured using R2-MRI technique. Relaxation rate was determined as R2 = 1/T2. The baseline value of LIC of participants was categorized as \< 7, ≥ 7 to \< 15, and ≥ 15 mg Fe/g dw. A negative change from baseline favoured study treatment in reducing LIC.
Time frame: From the Baseline to End of Year 2 (End of extension study)
Population: The analysis was performed in per-protocol population in core study (PP2 Set), comprising of all enrolled participants who had LIC assessments at baseline and at end of the extension phase.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Deferasirox | Absolute Change From Baseline in Liver Iron Concentration (LIC) to End of Year 2 | -13.5 mg Fe/g dw | Standard Deviation 14.1 |
Secondary
Absolute Change From Baseline in Serum Ferritin Levels to Year 2
Serum ferritin was a marker for the monitoring of chelation therapy. Ferritin protein stores iron and provides overall iron levels, higher ferritin in blood showed more iron content.
Time frame: From the Baseline up to Year 2 (End of extension study)
Population: The analysis was performed in PP2 Set population and Japanese subgroup. Here, Number of subjects analyzed signifies the participants assessed for serum ferritin during the study for each arm, respectively.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Deferasirox | Absolute Change From Baseline in Serum Ferritin Levels to Year 2 | -677.9 nanogram(s)/millilitre | Standard Deviation 4462.11 |
| Japanese Participants | Absolute Change From Baseline in Serum Ferritin Levels to Year 2 | -892.8 nanogram(s)/millilitre | Standard Deviation 5724.89 |
Secondary
Absolute Serum Ferritin Levels Over 2 Years
Serum ferritin was a marker for the monitoring of chelation therapy. Ferritin protein stores iron and provides overall iron levels, higher ferritin in blood showed more iron content.
Time frame: From the Baseline, Year 1 (End of core study), Year 2 (End of extension study)
Population: The analysis was performed in PP1 set population for core study (Year 1) and PP2 set population for extension study (Year 2) and Japanese subgroup. Here, Number of participants analysed signifies the subjects assessed for serum ferritin during the study for each arm, respectively.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Deferasirox | Absolute Serum Ferritin Levels Over 2 Years | Year 1 | 2653.3 nanogram(s)/millilitre | Standard Deviation 2952.07 |
| Deferasirox | Absolute Serum Ferritin Levels Over 2 Years | Year 2 | 2092.4 nanogram(s)/millilitre | Standard Deviation 2287.11 |
| Japanese Participants | Absolute Serum Ferritin Levels Over 2 Years | Year 1 | 2903.5 nanogram(s)/millilitre | Standard Deviation 3376 |
| Japanese Participants | Absolute Serum Ferritin Levels Over 2 Years | Year 2 | 2114.8 nanogram(s)/millilitre | Standard Deviation 2391.31 |
Secondary
Correlation of LIC and Serum Ferritin at Core and Extension Study
LIC, a predictor of iron burden, was measured using R2-MRI technique. Relaxation rate was determined as R2 = 1/T2. The baseline value of LIC was \< 7, ≥ 7 to \< 15, and ≥ 15 mg Fe/g dw. Serum ferritin was a marker for the monitoring of chelation therapy. Ferritin protein stores iron and provides overall iron levels, higher ferritin in blood showed more iron content. The correlation between absolute change in LIC and absolute change in serum ferritin was determined.
Time frame: From the Baseline, Year 1 (End of core study), Year 2 (End of extension study)
Population: The analysis was performed in PP1 set for core study (Year 1) and PP2 set for extension study (Year 2). Here, Number of subjects analysed signifies the subjects assessed for LIC and serum ferritin during the study for each arm, respectively.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Deferasirox | Correlation of LIC and Serum Ferritin at Core and Extension Study | 0.291 Correlation coefficient |
| Japanese Participants | Correlation of LIC and Serum Ferritin at Core and Extension Study | 0.325 Correlation coefficient |
Secondary
Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), Adverse Event of Special Interest (AESI), Discontinuation and Interruption
Adverse events (AEs) were defined as any unfavorable and unintended diagnosis, symptom, sign (including an abnormal laboratory finding), syndrome or disease which either occurs during study, having been absent at baseline, or, if present at baseline, appears to worsen. Serious adverse events (SAEs) were defined as any untoward medical occurrences that result in death, are life threatening, require hospitalisation, cause persistent or significant disability/incapacity, result in congenital anomalies or birth defects, or are other conditions which in judgement of investigators represent significant hazards. Death was defined as a fatal event leading to permanent cessation of all vital functions of the body.
Time frame: From the Baseline up to Year 2 (End of extension study)
Population: The analysis was performed in the safety set (SAF) population, defined as subjects who received at least one dose of study drug, which was defined as at least one administration record with a valid date and an actual total daily dose administrated above zero, and Japanese sub-group.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Deferasirox | Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), Adverse Event of Special Interest (AESI), Discontinuation and Interruption | Adverse Events | 97 participants |
| Deferasirox | Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), Adverse Event of Special Interest (AESI), Discontinuation and Interruption | Serious Adverse Events (SAE) | 46 participants |
| Deferasirox | Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), Adverse Event of Special Interest (AESI), Discontinuation and Interruption | Serious Adverse Events (SAE) with suspected relationship to study drug | 10 participants |
| Deferasirox | Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), Adverse Event of Special Interest (AESI), Discontinuation and Interruption | Death | 6 participants |
| Deferasirox | Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), Adverse Event of Special Interest (AESI), Discontinuation and Interruption | Adverse event leading to discontinuation of study drug | 14 participants |
| Deferasirox | Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), Adverse Event of Special Interest (AESI), Discontinuation and Interruption | Adverse event leading to dose adjustment/interruption | 67 participants |
| Deferasirox | Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), Adverse Event of Special Interest (AESI), Discontinuation and Interruption | Adverse Event of Special Interest (AESI) | 62 participants |
| Deferasirox | Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), Adverse Event of Special Interest (AESI), Discontinuation and Interruption | Adverse Event With Suspected Relationship to Study drug | 65 participants |
Secondary
Number of Participants With Clinically Significant Ophthalmological Abnormalities
Clinically significant changes in left eye and right eye were assessed by the investigator based on methods like visual acuity, slit lamp examination, tonometry and fundus oculi.
Time frame: At 2 years (End of extension study)
Population: The analysis was performed in the SAF population, defined as subjects who received at least one dose of study drug, which was defined as at least one administration. These participants comprise 2 year completer groups
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Deferasirox | Number of Participants With Clinically Significant Ophthalmological Abnormalities | Normal | 24 participants |
| Deferasirox | Number of Participants With Clinically Significant Ophthalmological Abnormalities | Abnormal, Clinically Insignificant | 14 participants |
| Deferasirox | Number of Participants With Clinically Significant Ophthalmological Abnormalities | Abnormal, Clinically Significant | 9 participants |
| Deferasirox | Number of Participants With Clinically Significant Ophthalmological Abnormalities | Not Available | 3 participants |
| Deferasirox | Number of Participants With Clinically Significant Ophthalmological Abnormalities | Total | 50 participants |
Secondary
Total Body Iron Elimination Rate (TBIE), Iron Intake, Iron Excretion/Iron Intake and Chelation Efficiency After 2 Years
Total body iron excretion (TBIE)was used to investigate the chelation efficacy of Deferasirox therapy. TBIE rate was estimated based on the iron influx as determined by the amount of red cells transfused and the change in total body iron (TBI) stores.
Time frame: From the Baseline, Year 2 (End of extension study)
Population: The analysis was performed in PP2 set population and Japanese/tim subgroup. Here, Number of participants analyzed included all participants who were evaluable for the specified categories.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Deferasirox | Total Body Iron Elimination Rate (TBIE), Iron Intake, Iron Excretion/Iron Intake and Chelation Efficiency After 2 Years | TBIE | 0.46 mg/kg/day | Standard Deviation 0.252 |
| Deferasirox | Total Body Iron Elimination Rate (TBIE), Iron Intake, Iron Excretion/Iron Intake and Chelation Efficiency After 2 Years | Iron intake | 0.27 mg/kg/day | Standard Deviation 0.15 |
| Deferasirox | Total Body Iron Elimination Rate (TBIE), Iron Intake, Iron Excretion/Iron Intake and Chelation Efficiency After 2 Years | Iron excretion/iron intake | 2.00 mg/kg/day | Standard Deviation 1.368 |
| Deferasirox | Total Body Iron Elimination Rate (TBIE), Iron Intake, Iron Excretion/Iron Intake and Chelation Efficiency After 2 Years | Chelation efficiency | 0.40 mg/kg/day | Standard Deviation 0.221 |
| Japanese Participants | Total Body Iron Elimination Rate (TBIE), Iron Intake, Iron Excretion/Iron Intake and Chelation Efficiency After 2 Years | Chelation efficiency | 0.50 mg/kg/day | Standard Deviation 0.177 |
| Japanese Participants | Total Body Iron Elimination Rate (TBIE), Iron Intake, Iron Excretion/Iron Intake and Chelation Efficiency After 2 Years | TBIE | 0.54 mg/kg/day | Standard Deviation 0.215 |
| Japanese Participants | Total Body Iron Elimination Rate (TBIE), Iron Intake, Iron Excretion/Iron Intake and Chelation Efficiency After 2 Years | Iron excretion/iron intake | 2.44 mg/kg/day | Standard Deviation 1.417 |
| Japanese Participants | Total Body Iron Elimination Rate (TBIE), Iron Intake, Iron Excretion/Iron Intake and Chelation Efficiency After 2 Years | Iron intake | 0.27 mg/kg/day | Standard Deviation 0.16 |