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

Novartis Pharmaceuticals166 enrolled

Overview

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).

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

TRIPLE

Enrollment

166

Conditions

Non-transfusion Dependent Thalassemia

Interventions

Eligibility

Sex: ALLMin age: 10 Years

Medical Language ↔ Plain English

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

Locations (21)

Children's Hospital & Research Center Oakland

Oakland, California, United States

Children's Memorial Hospital/Division of Hematology/Oncology

Chicago, Illinois, United States

New York Presbyterian Hospital/Weill Medical College of Cornell University

New York, New York, United States

Novartis Investigative Site

Athens, Greece

Novartis Investigative Site

Pátrai, Greece

Novartis Investigative Site

Thessaloniki, Greece

Novartis Investigative Site

Cagliari, Italy

Novartis Investigative Site

Genova, Italy

Novartis Investigative Site

Milan, Italy

Novartis Investigative Site

Napoli, Italy

...and 11 more locations

Outcomes

Primary Outcomes

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.

Time frame: 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.

Time frame: Core Baseline to End of Extension Study (up to 24 months)

Secondary Outcomes

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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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)

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: Core Baseline, Month 24