Efficacy and Safety of Deferasirox in Non-transfusion Dependent Thalassemia Patients With Iron Overload and a One Year Open-label Extension Study (THALASSA)
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| ClinicalTrials.gov Identifier: NCT00873041 |
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Recruitment Status :
Completed
First Posted : April 1, 2009
Results First Posted : September 25, 2012
Last Update Posted : July 9, 2013
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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).
| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Non-transfusion Dependent Thalassemia | Drug: deferasirox Drug: placebo | Phase 2 |
| Study Type : | Interventional (Clinical Trial) |
| Actual Enrollment : | 166 participants |
| Allocation: | Randomized |
| Intervention Model: | Parallel Assignment |
| Masking: | Triple (Participant, Care Provider, Investigator) |
| Primary Purpose: | Treatment |
| Official Title: | 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 |
| Study Start Date : | November 2008 |
| Actual Primary Completion Date : | June 2011 |
| Actual Study Completion Date : | June 2012 |
| Arm | Intervention/treatment |
|---|---|
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Experimental: 5 mg/kg/day deferasirox
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.
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Drug: deferasirox
Supplied as 125 mg, 250 mg and 500 mg tablets. Drug: placebo Supplied as matching 125 mg, 250 mg and 500 mg tablets. |
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Experimental: 10 mg/kg/day deferasirox
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.
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Drug: deferasirox
Supplied as 125 mg, 250 mg and 500 mg tablets. Drug: placebo Supplied as matching 125 mg, 250 mg and 500 mg tablets. |
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Placebo Comparator: 5 mg/kg/day placebo
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
Supplied as matching 125 mg, 250 mg and 500 mg tablets. |
|
Placebo Comparator: 10 mg/kg/day placebo
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
Supplied as matching 125 mg, 250 mg and 500 mg tablets. |
- Core Study: Change in Liver Iron Concentration (LIC) From Baseline to Week 52 [ Time Frame: Baseline, 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.
- Extension Study: Percentage of Participants Reaching a Liver Iron Concentration (LIC) < 5 mg Fe/g dw From Core Baseline to End of Extension Study [ Time Frame: Core Baseline to End of Extension Study (up to 24 months) ]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 Study: Change in Liver Iron Concentration (LIC) From Baseline to Week 24 [ Time Frame: Baseline, 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.
- Core Study: Change in Serum Ferritin Between Baseline and Fourth Quarter [ Time Frame: Baseline, (Day 286 to End of Study [Day 365]) ]
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.
- Core Study: Change in Serum Ferritin Between Baseline and Second Quarter [ Time Frame: Baseline, (Day 106 to Day 195) ]
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.
- Core Study: Percentage of Participants With Adverse Events Graded Mild, Moderate and Severe [ Time Frame: 52 Weeks ]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.
- Core Study: Change in Liver Iron Concentration (LIC) From Baseline At Week 24 and Week 52 in Patients With Dose Increases After Week 24 [ Time Frame: Baseline, Week 24, Week 52 ]LIC was measured by magnetic resonance imaging technique at baseline, Week 24 and Week 52. Dose Doubling (Dose Increases) began at Week 24.
- Core Study: Correlation Between Serum Ferritin and LIC (Liver Iron Concentration) [ Time Frame: Baseline, 52 weeks ]
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.
- Core Study: Change From Baseline in Hemoglobin at Month 12 [ Time Frame: Baseline, Month 12 ]Blood was collected for Hemoglobin at baseline and Month 12. Change from baseline= Month 12 hemoglobin - baseline hemoglobin.
- Core Study: Change From Baseline in Transferrin Saturation at Month 12 [ Time Frame: Baseline, Month 12 ]Blood was collected for transferrin saturation at Baseline and Month 12. Change from baseline= Month 12 transferrin saturation - baseline transferrin saturation.
- Core Study: Change in Liver Iron Concentration (LIC) in Placebo Patients From Baseline to Week 52 [ Time Frame: Baseline, 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.
- Core Study: Percentage of Participants With Notable Abnormal Post-baseline Laboratory Results [ Time Frame: 52 Weeks ]
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)
- Core Study: Percentage of Participants With Notably Abnormal Post-baseline Systolic Blood Pressure [ Time Frame: Baseline, 52 Weeks ]
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
- Core Study: Percentage of Participants With Notably Abnormal Post-baseline Diastolic Blood Pressure [ Time Frame: Baseline, 52 Weeks ]
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
- Core Study: Percentage of Participants With Notably Abnormal Post-baseline Pulse Rate [ Time Frame: Baseline, 52 Weeks ]
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
- Extension Study: Absolute Change in Serum Ferritin From Baseline to Eighth Quarter [ Time Frame: Core Baseline, Eighth Quarter (last 3 months of the study) ]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.
- Extension Study: Change in Liver Iron Concentration (LIC) From Baseline at Month 24 [ Time Frame: Core Baseline, Month 24 ]LIC was measured by magnetic resonance imaging technique at Baseline and Month 24. A negative change from baseline indicated improvement.
- Extension Study: Correlation Between Serum Ferritin and LIC (Liver Iron Concentration) [ Time Frame: Core Baseline, Month 24 ]
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.
- Extension Study: Change From Baseline in Hemoglobin at Month 24 [ Time Frame: Core Baseline, Month 24 ]Blood was collected for Hemoglobin at Baseline and Month 24. Change from Baseline= Month 24 hemoglobin - Baseline hemoglobin.
- Extension Study: Change From Baseline in Transferrin Saturation at Month 24 [ Time Frame: Core Baseline, Month 24 ]Blood was collected for transferrin saturation at Baseline and Month 24. Change from baseline= Month 24 transferrin saturation - baseline transferrin saturation.
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| Ages Eligible for Study: | 10 Years and older (Child, Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
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
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00873041
| United States, California | |
| Children's Hospital & Research Center Oakland | |
| Oakland, California, United States, 94609-1809 | |
| United States, Illinois | |
| Children's Memorial Hospital/Division of Hematology/Oncology | |
| Chicago, Illinois, United States, 60614-3394 | |
| United States, New York | |
| New York Presbyterian Hospital/Weill Medical College of Cornell University | |
| New York, New York, United States, 10021 | |
| Greece | |
| Novartis Investigative Site | |
| Athens, Greece | |
| Novartis Investigative Site | |
| Patras, Greece | |
| Novartis Investigative Site | |
| Thessaloniki, Greece | |
| Italy | |
| Novartis Investigative Site | |
| Cagliari, Italy | |
| Novartis Investigative Site | |
| Genova, Italy | |
| Novartis Investigative Site | |
| Milano, Italy | |
| Novartis Investigative Site | |
| Napoli, Italy | |
| Novartis Investigative Site | |
| Rome, Italy | |
| Lebanon | |
| Novartis Investigative Site | |
| Beirut, Lebanon | |
| Malaysia | |
| Novartis Investigative Site | |
| Ampang Selangor, Malaysia | |
| Novartis Investigative Site | |
| Kuala Lumpur, Malaysia | |
| Taiwan | |
| Novartis Investigative Site | |
| Taipei, Taiwan | |
| Thailand | |
| Novartis Investigative Site | |
| Bangkok, Thailand | |
| Turkey | |
| Novartis Investigative Site | |
| Adana, Turkey | |
| Novartis Investigative Site | |
| Ankara, Turkey | |
| Novartis Investigative Site | |
| Istanbul, Turkey | |
| Novartis Investigative Site | |
| Izmir, Turkey | |
| United Kingdom | |
| Novartis Investigative Site | |
| London, United Kingdom | |
| Study Director: | Novartis Pharmaceuticals | Novartis Pharmaceuticals |
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
| Responsible Party: | Novartis Pharmaceuticals |
| ClinicalTrials.gov Identifier: | NCT00873041 |
| Obsolete Identifiers: | NCT01185106 |
| Other Study ID Numbers: |
CICL670A2209 EudraCT 2007-007000-15 ( Registry Identifier: EudraCT ) |
| First Posted: | April 1, 2009 Key Record Dates |
| Results First Posted: | September 25, 2012 |
| Last Update Posted: | July 9, 2013 |
| Last Verified: | May 2013 |
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Thalassemia thalassemia intermedia alpha-thalassemia beta-thalassemia |
deferasirox iron overload non-transfusion dependent |
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Thalassemia Iron Overload Anemia, Hemolytic, Congenital Anemia, Hemolytic Anemia Hematologic Diseases Hemoglobinopathies Genetic Diseases, Inborn |
Iron Metabolism Disorders Metabolic Diseases Deferasirox Iron Chelating Agents Chelating Agents Sequestering Agents Molecular Mechanisms of Pharmacological Action |