Efficacy and Safety of Deferasirox in Patients With Chronic Anemia and Transfusional Hemosiderosis

Study Overview
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Brief Summary
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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.

Official Title
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A Multi-Center, Open-label, Non Comparative, Phase II Trial on Efficacy and Safety of ICL670 Given for 1 Year With Dose Adjustments Based on Serum Ferritin in Patients With Chronic Anemia and Transfusional Hemosiderosis Including an Additional 1 Year Extension.

Conditions
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Chronic Anemia, Transfusional Hemosiderosis

Intervention / Treatment
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* Drug: Deferasirox (ICL670)


Participation Criteria
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Eligibility Criteria
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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/exclusion criteria may apply.

Ages Eligible for Study
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Minimum Age: 2 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Deferasirox<br>Participants received initial dose of 20 milligrams per kilogram (mg/kg) Deferasirox tablets was administered orally once daily (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. | Drug: Deferasirox (ICL670)<br>* The recommended initial daily dose of Deferasirox is 20 mg/kg body weight.<br>* Other names: ICL670;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | From the Baseline, Year 1 (End of core study) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | From the Baseline to End of Year 2 (End of extension study) | 
| 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. | From the Baseline, End of Year 1 (End of core study), End of Year 2 (End of extension study) | 
| 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. | From the Baseline up to Year 2 (End of extension study) | 
| 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. | From the Baseline, Year 1 (End of core study), Year 2 (End of extension study) | 
| 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. | From the Baseline, Year 2 (End of extension study) | 
| 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. | From the Baseline, Year 1 (End of core study), Year 2 (End of extension study) | 
| 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. | From the Baseline up to Year 2 (End of extension study) | 
| 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. | At 2 years (End of extension study) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Iron Overload,, Chelation,, MDS,, Chronic Anemia,, Deferasirox,, Transfusional hemosiderosis,