Evaluating Use of Deferasirox as Compared to Deferoxamine in Treating Cardiac Iron Overload (CORDELIA)

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier:
NCT00600938
First received: January 14, 2008
Last updated: August 13, 2014
Last verified: August 2014
  Purpose

This is a clinical research study in patients who have iron overload in the heart due to chronic blood transfusions.

The study will have 2 treatment groups and will compare the safety and efficacy of chelation therapy with a medicine called deferasirox (ICL670) with another medicine called deferoxamine (DFO). The study is aimed at finding out which of the two medicines is the best for treating iron overload in the heart.

Patients will be treated for 12 months (core study phase). Patients who complete the core study phase will be offered to continue their study treatment in a 12 months extension phase. During the core and extension, the effects of treatment on iron overload in the heart and the liver will be evaluated using specific magnetic resonance imaging (MRI) assessments.


Condition Intervention Phase
Transfusional Iron Overload
Transfusional Hemosiderosis
Drug: Core Study: Deferasirox
Drug: Core Study: Deferoxamine
Drug: Extension: deferoxamine to deferasirox
Drug: Extension: deferasirox to deferoxamine
Drug: Deferasirox
Drug: Deferoxamine
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Multicenter, Randomized, Open-label Phase II Trial Evaluating Deferasirox Compared With Deferoxamine in Patients With Cardiac Iron Overload Due to Chronic Blood Transfusions

Resource links provided by NLM:


Further study details as provided by Novartis:

Primary Outcome Measures:
  • Core Study: Change From Baseline in Myocardial T2* (Magnetic Resonance T2-star (T2*) Technique for the Measurement of Tissue Iron) After 12 Months Treatment [ Time Frame: 12 Month ] [ Designated as safety issue: No ]
    Non- inferiority in efficacy of deferasirox compared to deferoxamine (DFO) in treating cardiac iron overload as measured by T2*. A non-inferiority margin of 0.9 (90%) was applied. Due to limitations in performing heart biopsies, T2* (T2 star), a Magnetic Resonance (MR) relaxation parameter expressed in milliseconds, as is an important tool to noninvasively quantify cardiac iron concentration. Studies have shown that myocardial T2* evaluations may predict cardiac events, e.g., impaired (<56%) left ventricular ejection fraction (LVEF) is prevalent among patients with low T2*: found in 62% of patients with T2*<8 ms; 20% with T2* of 8-12 ms; and in 5% with T2* >12 ms (Tanner 2006)


Secondary Outcome Measures:
  • Core Study: Cardiac Function After 12 Months of Treatment With Deferasirox vs. Deferoxamine, by Change in Left Ventricular Ejection Fraction (LVEF) [ Time Frame: 12 Month ] [ Designated as safety issue: No ]
    An absolute change from baseline in LVEF after 12 months treatment with deferasirox and compared to.DFO was tested using an analysis of covariance model including baseline left ventricular ejection fraction (LVEF) as a covariate.

  • Core Study: Cardiac Function After 6 Months of Treatment With Deferasirox vs. Deferoxamine, by Change in Left Ventricular Ejection Fraction (LVEF) [ Time Frame: 6 Month ] [ Designated as safety issue: No ]
    An absolute change from baseline in LVEF after 6 months treatment with deferasirox and DFO was summarized

  • Core Study: Change From Baseline in Myocardial T2* After 6 Months Treatment [ Time Frame: 6 Month ] [ Designated as safety issue: No ]
    Summary statistics of T2* ratio Month 6/baseline

  • Core Study: Cardiac Function After 6 and 12 Months Treatment With Deferasirox vs. Deferoxamine, by Change in Left Ventricular End Systolic Volume Indices (LVESVI) [ Time Frame: 6 Month, 12 Month ] [ Designated as safety issue: No ]
    An absolute change from baseline in LVESVI after 6 and 12 months treatment with deferasirox and DFO was summarized. Changes in cardiovascular magnetic resonance (CMR) measured left ventricular end systolic after 6 and 12 months treatment. Left ventricular (LV) end-systolic volume indexed to body surface area (ESVI) is a simple yet powerful echocardiographic marker of LV remodeling that can be measured easily. Left ventricular (LV) end-systolic volume (ESV) has been shown to be an important determinant of survival after myocardial infarction (MI)

  • Core Study: Core Study: Cardiac Function After 6 and 12 Months of Treatment With Deferasirox vs. Deferoxamine, by Change in Left Ventricular End Diastolic Volume Indices (LVEDVI) [ Time Frame: 6 Month, 12 Month ] [ Designated as safety issue: Yes ]
    An absolute change from baseline in LVEDVI after 6, and 12 months treatment with deferasirox and DFO was summarized

  • Core Study: Cardiac Function After 6 and 12 Months of Treatment With Deferasirox vs. Deferoxamine, by Change in Left Ventricular Mass Indices (LVMI) [ Time Frame: 6 Month, 12 Month ] [ Designated as safety issue: No ]
    An absolute change from baseline in LVMI after 6, and 12 months treatment with deferasirox and DFO was summarized

  • Core Study: Cardiac Function and the Proportion of Patients Dropping Out Due to Cardiac Dysfunction After Treatment With Deferasirox vs. Deferoxamine [ Time Frame: 12 Month ] [ Designated as safety issue: No ]
    The number of patients withdrawn from the study due to LVEF <50%, T2* <6 ms or significant decreases in T2* ≥ 33% from baseline was provided per treatment group.

  • Core Study: Safety and Tolerability of Deferasirox vs Deferoxamine Over the 12 Months Treatment Period. [ Time Frame: 12 Month ] [ Designated as safety issue: Yes ]
    Number of patients with adverse events, serious adverse events and death

  • Core Study: Single and Repeated Dose Pharmacokinetics of Deferasirox, Area Under the Plasma Concentration-time Curve for a Dosing Interval (AUCtau) [ Time Frame: 12 Month ] [ Designated as safety issue: No ]
    The plasma level of deferasirox (ICL670) obtained in this study was summarized descriptively. Plasma concentration was plotted by patient and by visit. Descriptive statistics included the mean, median, SD, and CV, min and max. deferasirox pharmacokinetics (PK) trough levels over the 12 months of treatment and obtained PK profiles for the 40 mg/kg/day deferasirox dose, area under the plasma concentration-time curve for a dosing interval (AUCtau)

  • Core Study: Single and Repeated Dose Pharmacokinetics of Deferasirox, Maximum Plasma Concentration (Cmax) [ Time Frame: 12 Month ] [ Designated as safety issue: No ]
    The plasma level of deferasirox (ICL670) obtained in this study was summarized descriptively. Plasma concentration was plotted by patient and by visit. Descriptive statistics included the mean, median, SD, and CV, min and max. deferasirox pharmacokinetics (PK) trough levels over the 12 months of treatment and obtained PK profiles for the 40 mg/kg/day deferasirox dose, maximum plasma concentration (Cmax)

  • Core Study: Single and Repeated Dose Pharmacokinetics of Deferasirox, Time Points of Concentration Data [ Time Frame: Month 1 and month 2 (pre-dose, 1,2 and 4 hours post-dose) ] [ Designated as safety issue: No ]
    The plasma level of deferasirox (ICL670) obtained in this study was summarized descriptively. Plasma concentration was plotted by patient and by visit. For trough concentration assessments, a 2-mL blood sample was to be taken on arrival at the study site, i.e. prior to the patient receiving the daily deferasirox dose (pre-dose blood sample). A second 2-mL blood sample was to be taken 2 hours later (post-dose sample). At all other visits (Visits 3 - 14), a pre-dose sample was to be taken. For PK profile assessments, 3 blood samples were taken after 1, 2, and 4 hours post-dose in addition to the 2-mL pre-dose

  • Extension Study: Change From Baseline in Myocardial T2* After 24 Months Treatment [ Time Frame: Months 6, 12, 18 and 24 ] [ Designated as safety issue: No ]
    The measured T2* values, the ratio (post-baseline / baseline T2*) at Month 6, 12, 18 and 24 was summarized for FAS population along with two-sided 95% CIs. The geometric means of the ratio was presented for all treatment groups

  • Extension Study: Cardiac Function From Baseline to Month 24 by Change in Left Ventricular Ejection Fraction (LVEF) [ Time Frame: Months 6, 12, 18 and 24 ] [ Designated as safety issue: No ]
    Cardiac function endpoints (LVEF) obtained by CMR at baseline, Months 6, 12, 18 and 24 were summarized by means of descriptive statistics. These analyses were conducted for the measured values as well as for the absolute changes from baseline

  • Extension Study: Cardiac Function From Baseline to Month 24 by Change in Left Ventricular End Systolic Volume Indices (LVESVI) [ Time Frame: Months 6, 12, 18 and 24 ] [ Designated as safety issue: No ]
    Cardiac function endpoints (LVESVI) obtained by CMR at baseline, Months 6, 12, 18 and 24 were summarized by means of descriptive statistics. These analyses were conducted for the measured values as well as for the absolute changes from baseline

  • Extension Study: Cardiac Function From Baseline to Month 24 by Change in Left Ventricular End Diastolic Volume Indices (LVEDVI) [ Time Frame: Months 6, 12, 18 and 24 ] [ Designated as safety issue: No ]
    Cardiac function endpoint (LVEDVI ) obtained by CMR at baseline, Months 6, 12, 18 and 24 were summarized by means of descriptive statistics. These analyses were conducted for the measured values as well as for the absolute changes from baseline

  • Extension Study: Cardiac Function From Baseline to Month 24 by Change in Left Ventricular Mass Indices (LVMI) [ Time Frame: Months 6, 12, 18 and 24 ] [ Designated as safety issue: No ]
    Cardiac function endpoints (LVMI) obtained by CMR at baseline, Months 6, 12, 18 and 24 were summarized by means of descriptive statistics. These analyses were conducted for the measured values as well as for the absolute changes

  • Extension Study: The Cardiac Iron Concentration From T2* Values [ Time Frame: Months 6, 12, 18 and 24 ] [ Designated as safety issue: No ]
    Cardiac iron concentration (derived from T2* values) at baseline, Months 6, 12, 18 and 24 were summarized by descriptive statistics. The absolute change from baseline at Months 6, 12, 18 and 24 were also summarized by treatment group. Lliver iron concentration is expressed in units (mg of iron / g of liver tissue dry weight (dw)

  • Extension Study: Change in Liver Iron Concentration (LIC) From Baseline at Month 24 [ Time Frame: Months 6, 12, 18 and 24 ] [ Designated as safety issue: No ]
    Results of liver iron content (LIC) measurements by MRI was summarized by descriptive statistics. The absolute value and the absolute change from baseline in LIC at Months 6, 12, 18 and 24 were provided by treatment group.

  • Extension Study: Change in Serum Ferritin From Baseline by Month [ Time Frame: Months 6, 12, 18 and 24 ] [ Designated as safety issue: No ]
    Serum ferritin values was summarized by descriptive statistics. Absolute value and the absolute change from baseline in serum ferritin by month was provided by treatment group.

  • Core Study: Single and Repeated Dose Pharmacokinetics of Deferasirox, Maximum Plasma Concentration (Tmax) [ Time Frame: 12 Month ] [ Designated as safety issue: No ]
    The plasma level of deferasirox (ICL670) obtained in this study was summarized descriptively. Plasma concentration was plotted by patient and by visit. Descriptive statistics included the mean, median, SD, and CV, min and max. deferasirox pharmacokinetics (PK) trough levels over the 12 months of treatment and obtained PK profiles for the 40 mg/kg/day deferasirox dose, time to reach maximum plasma concentration (Tmax)


Enrollment: 197
Study Start Date: November 2007
Study Completion Date: March 2013
Primary Completion Date: March 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Deferasirox
20 mg/kg/day once daily (od) for 2 weeks, followed by 30 mg/kg/day od for 1 week and a subsequent continuation of 40 mg/kg/day
Drug: Core Study: Deferasirox
20 mg/kg/day once daily (od) for 2 weeks, followed by 30 mg/kg/day od for 1 week and a subsequent continuation of 40 mg/kg/day
Other Name: "ICL to ICL"
Drug: Deferasirox
Active Comparator: Deferasirox Placebo
50 mg/kg/day to 60 mg/kg/day infused subcutaneously in 8- to 12-hour intervals administered 5 to 7 days/week
Drug: Core Study: Deferoxamine
50 mg/kg/day to 60 mg/kg/day infused subcutaneously in 8- to 12-hour intervals administered 5 to 7 days/week
Other Name: "DFO to DFO"
Drug: Deferoxamine
Experimental: Extension: deferoxamine to deferasirox
"DFO to ICL" (patients who switched from DFO to deferasirox in extension)
Drug: Extension: deferoxamine to deferasirox
40 mg/kg deferasirox once daily administered 30 minutes before taking food.
Other Name: "DFO to ICL"
Experimental: Extension: deferasirox to deferoxamine
"ICL to DFO" (patients who switched from deferasirox to DFO in extension)
Drug: Extension: deferasirox to deferoxamine
DFO at a target range of 50 mg/kg/day to 60 mg/kg/day via subcutaneous (sc) infusion lasting a period of 8 to 12 hrs administered for 5 to 7 days per week,
Other Name: "ICL to DFO"

  Eligibility

Ages Eligible for Study:   10 Years to 65 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion criteria:

  • Male or female patients, aged 10 years and above, with β-thalassemia major or DBA or sideroblastic anemia on chronic transfusion therapy, having given written consent to participate in the study.
  • Patients with cardiac iron as measured by a myocardial T2* value that is ≥ 6ms but not ≥ 20 ms.
  • Patients with a lifetime history of at least 50 units of red cell transfusions, and must be receiving at least ≥10 units/yr of red blood cells transfusions.
  • Patients with a left ventricular ejection fraction (LVEF) ≥ 56 % as determined by cardiovascular magnetic resonance (CMR).
  • Patients with liver iron content (LIC) value ≥ 3 mg Fe / g dw, as determined by liver MRI.

Exclusion criteria:

  • Patients with clinical symptoms of cardiac dysfunction.
  • Patients unable to undergo study assessments including MRI
  • Patients participating in another clinical trial or receiving an investigational drug.

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: NCT00600938

Locations
Canada, Ontario
Novartis Investigative Site
Toronto, Ontario, Canada, M5G 1X8
China, Guangxi
Novartis Investigative Site
Nanning, Guangxi, China, 530021
Cyprus
Novartis Investigative Site
Limassol, Cyprus, 3304
Egypt
Novartis Investigative Site
Cairo, Egypt
Novartis Investigative Site
Mansoura, Egypt
Italy
Novartis Investigative Site
Cagliari, CA, Italy, 09121
Novartis Investigative Site
Genova, GE, Italy, 16128
Lebanon
Novartis Investigative Site
Hazmiyeh, Lebanon
Taiwan
Novartis Investigative Site
Taipei, Taiwan, 10002
Thailand
Novartis Investigative Site
Bangkok, Thailand, 10700
Novartis Investigative Site
Bangkok, Thailand, 10330
Turkey
Novartis Investigative Site
Adana, Turkey, 01330
Novartis Investigative Site
Ankara, Turkey, 06100
Novartis Investigative Site
Antalya, Turkey, 07070
Novartis Investigative Site
Istanbul, Turkey, 34093
Novartis Investigative Site
Izmir, Turkey, 35040
United Arab Emirates
Novartis Investigative Site
Dubai, United Arab Emirates, 9115
United Kingdom
Novartis Investigative Site
Leeds, West Yorkshire, United Kingdom, LS9 7TF
Novartis Investigative Site
Leeds, United Kingdom, LS9 7TF
Novartis Investigative Site
London, United Kingdom, N19 5NF
Novartis Investigative Site
London, United Kingdom, NW1 2PJ
Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
  More 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: NCT00600938     History of Changes
Other Study ID Numbers: CICL670A2206, 2007-000766-20
Study First Received: January 14, 2008
Results First Received: February 21, 2014
Last Updated: August 13, 2014
Health Authority: United States: Food and Drug Administration
Brazil: Ministry of Health
Canada: Health Canada
China: Food and Drug Administration
Colombia: Ministry of Health
Cyprus: Bioethics Committee
Egypt: Ministry of Health and Population
Greece: Ministry of Health and Welfare
Italy: Ministry of Health
Lebanon: Ministry of Public Health
Thailand: Ministry of Public Health
Turkey: Ministry of Health
Taiwan: Department of Health
United Arab Emirates: Drug Control Department - Medicines and Pharmacy Control - Ministry of Health
United Kingdom: Medicines and Healthcare Products Regulatory Agency

Keywords provided by Novartis:
iron overload
cardiac iron
haemosiderosis
myocardial T2*
left ventricular ejection fraction
LVEF
cardiac dysfunction
thalassaemia
Diamond Blackfan anemia
DBA
sideroblastic anemia
myelodysplastic syndromes
MDS (low and INT-1 risk as per the IPSS for MDS)
liver MRI
deferasirox
deferoxamine
ICL670
DFO
cardiovascular magnetic resonance imaging

Additional relevant MeSH terms:
Iron Overload
Hemosiderosis
Iron Metabolism Disorders
Metabolic Diseases
Deferasirox
Deferoxamine
Iron Chelating Agents
Chelating Agents
Sequestering Agents
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Siderophores

ClinicalTrials.gov processed this record on September 22, 2014