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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier:
NCT00873041
First received: March 30, 2009
Last updated: May 20, 2013
Last verified: May 2013
  Purpose

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 Intervention Phase
Non-transfusion Dependent Thalassemia
Drug: deferasirox
Drug: placebo
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, 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

Resource links provided by NLM:


Further study details as provided by Novartis:

Primary Outcome Measures:
  • Core Study: Change in Liver Iron Concentration (LIC) From Baseline to Week 52 [ Time Frame: Baseline, Week 52 ] [ Designated as safety issue: No ]
    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) ] [ Designated as safety issue: No ]
    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.


Secondary Outcome Measures:
  • Core Study: Change in Liver Iron Concentration (LIC) From Baseline to Week 24 [ Time Frame: Baseline, Week 24 ] [ Designated as safety issue: No ]
    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]) ] [ Designated as safety issue: No ]

    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) ] [ Designated as safety issue: No ]

    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]

    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]

    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 ] [ Designated as safety issue: No ]

    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 ] [ Designated as safety issue: No ]

    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 ] [ Designated as safety issue: No ]

    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) ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]

    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    Blood was collected for transferrin saturation at Baseline and Month 24. Change from baseline= Month 24 transferrin saturation - baseline transferrin saturation.


Enrollment: 166
Study Start Date: November 2008
Study Completion Date: June 2012
Primary Completion Date: June 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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.
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.
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.
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.
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.

  Eligibility

Ages Eligible for Study:   10 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00873041

Locations
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
Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
  More Information

Additional Information:
No publications provided by Novartis

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier: NCT00873041     History of Changes
Obsolete Identifiers: NCT01185106
Other Study ID Numbers: CICL670A2209, EudraCT 2007-007000-15
Study First Received: March 30, 2009
Results First Received: June 20, 2012
Last Updated: May 20, 2013
Health Authority: United States: Food and Drug Administration
European Union: European Medicine Agency
Greece: Ministry of Health and Welfare
Italy: The Italian Medicines Agency
Lebanon: Institutional Review Board
Taiwan: Health Authority
Malaysia: Ministry of Health
Thailand: Ministry of Public Health
Turkey: Ministry of Health
United Kingdom: Medicines and Healthcare Products Regulatory Agency

Keywords provided by Novartis:
Thalassemia
thalassemia intermedia
alpha-thalassemia
beta-thalassemia
deferasirox
iron overload
non-transfusion dependent

Additional relevant MeSH terms:
Iron Overload
Thalassemia
Anemia
Anemia, Hemolytic
Anemia, Hemolytic, Congenital
Genetic Diseases, Inborn
Hematologic Diseases
Hemoglobinopathies
Iron Metabolism Disorders
Metabolic Diseases
Deferasirox
Chelating Agents
Iron Chelating Agents
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Sequestering Agents

ClinicalTrials.gov processed this record on October 29, 2014