Efficacy and Safety of Deferasirox in Non-transfusion Dependent Thalassemia Patients With Iron Overload and a One Year Open-label Extension Study

Study Overview
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Brief Summary
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CICL670A2209: This study will evaluate the safety and efficacy of deferasirox in non-transfusion dependent thalassemia patients with iron overload. Patients will be treated either with active treatment (deferasirox) or placebo for 12 months (core study phase). Patients who complete the core study phase will be offered to continue their study with the active treatment (deferasirox) in a 12 months extension phase. During the core and extension, the effects of treatment on iron overload in the liver will be evaluated using magnetic resonance imaging (MRI) assessments. CICL670A2209E1: A one-year open-label extension to a randomized, double-blind, placebo-controlled, phase II study to evaluate efficacy and safety of deferasirox in non-transfusion dependent thalassemia patients with iron overload (Thalassa).

Official Title
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A Randomized, Double-blind, Placebo-controlled, Phase II Study to Evaluate Efficacy and Safety of Deferasirox in Non-transfusion-dependent Thalassemia Patients With Iron Overload

Conditions
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Non-transfusion Dependent Thalassemia

Intervention / Treatment
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* Drug: deferasirox
* Drug: placebo


Participation Criteria
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Eligibility Criteria
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Core Inclusion Criteria: Male or female aged ≥ 10 years with non-transfusion dependent syndromes, not requiring transfusion within 6 months prior to study start. Note: there was a local country amendment for Greece only to change the age specific inclusion criteria to ≥ 18 years old Liver iron concentration ≥ 5 mg/g dry weight measured by Magnetic resonance imaging (MRI) before study start Serum ferritin >300 ng/mL at screening Core Exclusion Criteria: Hemoglobin S (HbS)-variants of thalassemia syndromes Anticipated regular transfusion program during the study. Patients having a sporadic transfusion (e.g. in case of infection) throughout the study course will not be excluded Any blood transfusion 6 months prior to study start Creatinine clearance ≤ 60 mL/min at screening Serum creatinine above the upper limit of normal at both screening visits Significant proteinuria as indicated by a urine protein/urine creatinine ratio > 1.0 mg/mg Alanine aminotransferase (ALT) of > 5 x the upper limit of normal at both screening visits Concomitant therapy with hydroxyurea, erythropoietin, butyrate History of deferasirox treatment Pediatric patients: a patient's weight of below 20 kg Extension Inclusion Criteria: Patients who completed the core CICL670A2209 clinical trial Written informed consent obtained prior entry to one year extension study CICL670A2209 Extension Exclusion Criteria: Patients with a continuous increase in serum creatinine ≥ 33% above the baseline value and > ULN who did not improve after drug interruption or dose reduction in the core study Patients with a continuous increase in ALT greater than 2 times the baseline value and > 5 times ULN who did not improve after drug interruption or dose reduction in the core study Patients with progressive proteinuria, as assessed by the investigator, who did not improve after drug interruption or dose reduction in the core study Significant medical condition interfering with the ability to partake in this study (e.g.systemic uncontrolled hypertension, unstable cardiac disease not controlled by standard medical therapy, systemic disease (cardiovascular, renal, hepatic, etc.) Other protocol-defined inclusion/exclusion criteria may apply

Ages Eligible for Study
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Minimum Age: 10 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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 5 mg/kg/day deferasirox<br>Participants received a starting dose of 5 mg/kg/day deferasirox tablets orally each day in the morning for 52 weeks. After 24 weeks of treatment Liver Iron Concentration (LIC) was assessed. Based on the LIC and change from baseline in LIC participants were eligible for dose escalation. In the Extension Study participants received deferasirox once daily (dose based on LIC) for 52 weeks. | Drug: deferasirox<br>* Supplied as 125 mg, 250 mg and 500 mg tablets.<br>Drug: placebo<br>* Supplied as matching 125 mg, 250 mg and 500 mg tablets.<br>|
| Experimental: 10 mg/kg/day deferasirox<br>Participants received a starting dose of 10 mg/kg/day deferasirox tablets orally each day in the morning for 52 weeks. After 24 weeks of treatment Liver Iron Concentration (LIC) was assessed. Based on the LIC and change from baseline in LIC participants were eligible for dose escalation. In the Extension Study participants received deferasirox once daily (dose based on LIC) for 52 weeks. | Drug: deferasirox<br>* Supplied as 125 mg, 250 mg and 500 mg tablets.<br>Drug: placebo<br>* Supplied as matching 125 mg, 250 mg and 500 mg tablets.<br>|
| Placebo Comparator: 5 mg/kg/day placebo<br>Placebo tablet matching 5 mg/kg/day orally in the morning each day for 52 weeks. After 24 weeks of treatment Liver Iron Concentration (LIC) was assessed. Based on the LIC and change from baseline in LIC participants were eligible for dose escalation. In the Extension Study participants received deferasirox once daily (dose based on LIC) for 52 weeks. | Drug: placebo<br>* Supplied as matching 125 mg, 250 mg and 500 mg tablets.<br>|
| Placebo Comparator: 10 mg/kg/day placebo<br>Placebo tablet matching 10 mg/kg/day orally in the morning each day for 52 weeks. After 24 weeks of treatment Liver Iron Concentration (LIC) was assessed. Based on the LIC and change from baseline in LIC participants were eligible for dose escalation. In the Extension Study participants received deferasirox once daily (dose based on LIC) for 52 weeks. | Drug: placebo<br>* Supplied as matching 125 mg, 250 mg and 500 mg tablets.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Core Study: Change in Liver Iron Concentration (LIC) From Baseline to Week 52 | LIC was measured by magnetic resonance imaging technique at baseline and Week 52. Estimates were obtained from an Analysis of Covariance (ANCOVA) model for change in LIC between baseline and Week 52 with treatment as factor and baseline LIC as covariate. | Baseline, Week 52 | 
| Extension Study: Percentage of Participants Reaching a Liver Iron Concentration (LIC) < 5 mg Fe/g dw From Core Baseline to End of Extension Study | Liver iron concentration was measured at Core Baseline and at the end of the Extension Study. Magnetic Resonance Imaging (MRI) scans were analyzed at a central laboratory to determine the LIC value. The percentage of participants with LIC < 5 mgFe/g dw (milligram iron/gram dry weight) change from Baseline at the end of the Extension Study is reported. | Core Baseline to End of Extension Study (up to 24 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Core Study: Change in Liver Iron Concentration (LIC) From Baseline to Week 24 | LIC was measured by magnetic resonance imaging technique at baseline and Week 24. Estimates were obtained from an Analysis of Covariance (ANCOVA) model for change in LIC between baseline and Week 24 with treatment as factor and baseline LIC as covariate. | Baseline, Week 24 | 
| Core Study: Change in Serum Ferritin Between Baseline and Fourth Quarter | Baseline serum ferritin average was the average of all available ferritin values from screening to last sample prior to the first intake of study drug. Fourth quarter serum ferritin average was the average of all serum ferritin values obtained within days 286- End of Study. Change from baseline: fourth quarter serum ferritin average - baseline serum ferritin average. | Baseline, (Day 286 to End of Study [Day 365]) | 
| Core Study: Change in Serum Ferritin Between Baseline and Second Quarter | Baseline serum ferritin average was the average of all available ferritin values from screening to last sample prior to the first intake of study drug. Second quarter serum ferritin average was the average of all serum ferritin values obtained within days 106-195. Change from baseline: second quarter serum ferritin average - baseline serum ferritin average. | Baseline, (Day 106 to Day 195) | 
| Core Study: Percentage of Participants With Adverse Events Graded Mild, Moderate and Severe | Percentage of Participants with Mild, Moderate and Severe adverse events (AE) any primary system organ class regardless of study drug relationship. A patient with multiple occurrences of an AE is counted only once in the AE category for that treatment. A patient with multiple severity ratings for an AE while on a treatment is only counted once under the maximum rating. | 52 Weeks | 
| Core Study: Change in Liver Iron Concentration (LIC) From Baseline At Week 24 and Week 52 in Patients With Dose Increases After Week 24 | LIC was measured by magnetic resonance imaging technique at baseline, Week 24 and Week 52. Dose Doubling (Dose Increases) began at Week 24. | Baseline, Week 24, Week 52 | 
| Core Study: Correlation Between Serum Ferritin and LIC (Liver Iron Concentration) | The correlation between serum ferritin and LIC was investigated using a scatter plot with a regression line for the following cases: Baseline serum ferritin versus baseline LIC Serum ferritin difference from baseline at fourth quarter versus difference from baseline in LIC at Week 52. A value of 1.0 indicates a perfect correlation. | Baseline, 52 weeks | 
| Core Study: Change From Baseline in Hemoglobin at Month 12 | Blood was collected for Hemoglobin at baseline and Month 12. Change from baseline= Month 12 hemoglobin - baseline hemoglobin. | Baseline, Month 12 | 
| Core Study: Change From Baseline in Transferrin Saturation at Month 12 | Blood was collected for transferrin saturation at Baseline and Month 12. Change from baseline= Month 12 transferrin saturation - baseline transferrin saturation. | Baseline, Month 12 | 
| Core Study: Change in Liver Iron Concentration (LIC) in Placebo Patients From Baseline to Week 52 | LIC was measured by magnetic resonance imaging technique at baseline and Week 52. The change in liver iron concentration for participants in the placebo arm was used to assess the iron accumulation rate. | Baseline, Week 52 | 
| Core Study: Percentage of Participants With Notable Abnormal Post-baseline Laboratory Results | The percentage of participants with notable laboratory results: Platelet count: (<100 x 10^9/L) Absolute neutrophils: (<1.5 x 10^9/L) Alanine aminotransferase (ALT): (>5 x Upper limit normal (ULN) and >2 x baseline). Aspartate aminotransferase (AST): (>5 x ULN and >2 x baseline) Serum creatinine: (>33% increase from baseline and >ULN at ≥2 consecutive post-baseline values) Creatinine clearance: (<60 mL/min at ≥2 consecutive post-baseline values) Urinary protein/creatinine ratio: (≥ 1.0 mg/mg at ≥2 consecutive post-baseline values) | 52 Weeks | 
| Core Study: Percentage of Participants With Notably Abnormal Post-baseline Systolic Blood Pressure | Systolic blood pressure was measured at each visit after the patient rested in the sitting position for at least 3 minutes. A Notably Abnormal Systolic Blood Pressure was defined as a measurement in one of the following two categories: High: ≥180 with an increase from baseline ≥20 mmHg Low: ≤90 with a decrease from baseline ≥20 mmHg | Baseline, 52 Weeks | 
| Core Study: Percentage of Participants With Notably Abnormal Post-baseline Diastolic Blood Pressure | Diastolic blood pressure was measured at each visit after the patient rested in the sitting position for at least 3 minutes. A Notably Abnormal Diastolic Blood Pressure was defined as a measurement in one of the following two categories: High: ≥105 with an increase from baseline ≥15 mmHg Low: ≤50 with a decrease from baseline ≥15 mmHg | Baseline, 52 Weeks | 
| Core Study: Percentage of Participants With Notably Abnormal Post-baseline Pulse Rate | Pulse Rate was measured at each visit. A Notably Abnormal Pulse Rate was defined as a measurement in one of the following two categories: High: ≥120 with an increase from baseline ≥15 beats per minute (bpm) Low: ≤50 with a decrease from baseline ≥15 bpm | Baseline, 52 Weeks | 
| Extension Study: Absolute Change in Serum Ferritin From Baseline to Eighth Quarter | Blood was collected for serum ferritin at Core Baseline and monthly during the Eighth quarter of the Extension Study. Absolute change from Baseline: quarterly average - baseline average. A negative change from baseline indicated improvement. | Core Baseline, Eighth Quarter (last 3 months of the study) | 
| Extension Study: Change in Liver Iron Concentration (LIC) From Baseline at Month 24 | LIC was measured by magnetic resonance imaging technique at Baseline and Month 24. A negative change from baseline indicated improvement. | Core Baseline, Month 24 | 
| Extension Study: Correlation Between Serum Ferritin and LIC (Liver Iron Concentration) | The correlation between serum ferritin and LIC was investigated using a scatter plot with a regression line for serum ferritin difference from Baseline at Month 24 versus LIC difference from Baseline at Month 24. A value of 1.0 indicates a perfect correlation. | Core Baseline, Month 24 | 
| Extension Study: Change From Baseline in Hemoglobin at Month 24 | Blood was collected for Hemoglobin at Baseline and Month 24. Change from Baseline= Month 24 hemoglobin - Baseline hemoglobin. | Core Baseline, Month 24 | 
| Extension Study: Change From Baseline in Transferrin Saturation at Month 24 | Blood was collected for transferrin saturation at Baseline and Month 24. Change from baseline= Month 24 transferrin saturation - baseline transferrin saturation. | Core Baseline, Month 24 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Thalassemia, thalassemia intermedia, alpha-thalassemia, beta-thalassemia, deferasirox, iron overload, non-transfusion dependent