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

Transfusional Iron Overload Clinical Trial

— CORDELIA  

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00600938
• Other study ID #: CICL670A2206
• Secondary ID: 2007-000766-20
• Status: Completed
• Phase: Phase 2
• First received: January 14, 2008
• Last updated: August 13, 2014
• Start date: November 2007
• Est. completion date: March 2013

Study information

• Verified date: August 2014
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug AdministrationBrazil: Ministry of HealthCanada: Health CanadaChina: Food and Drug AdministrationColombia: Ministry of HealthCyprus: Bioethics CommitteeEgypt: Ministry of Health and PopulationGreece: Ministry of Health and WelfareItaly: Ministry of HealthLebanon: Ministry of Public HealthThailand: Ministry of Public HealthTurkey: Ministry of HealthTaiwan: Department of HealthUnited Arab Emirates: Drug Control Department - Medicines and Pharmacy Control - Ministry of HealthUnited Kingdom: Medicines and Healthcare Products Regulatory Agency
• Study type: Interventional

Clinical Trial Summary

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 197
• Est. completion date: March 2013
• Est. primary completion date: March 2013
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 10 Years to 65 Years

Eligibility

Inclusion criteria:

• Male or female patients, aged 10 years and above, with ß-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.

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Hemosiderosis
• Iron Overload
• Transfusional Hemosiderosis
• Transfusional Iron Overload

Intervention

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
• 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
• Extension: deferoxamine to deferasirox
40 mg/kg deferasirox once daily administered 30 minutes before taking food.
• 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,
• Deferasirox

• Deferoxamine

Locations

Country	Name	City	State
Canada	Novartis Investigative Site	Toronto	Ontario
China	Novartis Investigative Site	Nanning	Guangxi
Cyprus	Novartis Investigative Site	Limassol
Egypt	Novartis Investigative Site	Cairo
Egypt	Novartis Investigative Site	Mansoura
Italy	Novartis Investigative Site	Cagliari	CA
Italy	Novartis Investigative Site	Genova	GE
Lebanon	Novartis Investigative Site	Hazmiyeh
Taiwan	Novartis Investigative Site	Taipei
Thailand	Novartis Investigative Site	Bangkok
Thailand	Novartis Investigative Site	Bangkok
Turkey	Novartis Investigative Site	Adana
Turkey	Novartis Investigative Site	Ankara
Turkey	Novartis Investigative Site	Antalya
Turkey	Novartis Investigative Site	Istanbul
Turkey	Novartis Investigative Site	Izmir
United Arab Emirates	Novartis Investigative Site	Dubai
United Kingdom	Novartis Investigative Site	Leeds	West Yorkshire
United Kingdom	Novartis Investigative Site	Leeds
United Kingdom	Novartis Investigative Site	London
United Kingdom	Novartis Investigative Site	London

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Countries where clinical trial is conducted

Canada,  China,  Cyprus,  Egypt,  Italy,  Lebanon,  Taiwan,  Thailand,  Turkey,  United Arab Emirates,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Core Study: Change From Baseline in Myocardial T2* (Magnetic Resonance T2-star (T2*) Technique for the Measurement of Tissue Iron) After 12 Months Treatment	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)	12 Month	No
Secondary	Core Study: Cardiac Function After 12 Months of Treatment With Deferasirox vs. Deferoxamine, by Change in Left Ventricular Ejection Fraction (LVEF)	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.	12 Month	No
Secondary	Core Study: Cardiac Function After 6 Months of Treatment With Deferasirox vs. Deferoxamine, by Change in Left Ventricular Ejection Fraction (LVEF)	An absolute change from baseline in LVEF after 6 months treatment with deferasirox and DFO was summarized	6 Month	No
Secondary	Core Study: Change From Baseline in Myocardial T2* After 6 Months Treatment	Summary statistics of T2* ratio Month 6/baseline	6 Month	No
Secondary	Core Study: Cardiac Function After 6 and 12 Months Treatment With Deferasirox vs. Deferoxamine, by Change in Left Ventricular End Systolic Volume Indices (LVESVI)	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)	6 Month, 12 Month	No
Secondary	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)	An absolute change from baseline in LVEDVI after 6, and 12 months treatment with deferasirox and DFO was summarized	6 Month, 12 Month	Yes
Secondary	Core Study: Cardiac Function After 6 and 12 Months of Treatment With Deferasirox vs. Deferoxamine, by Change in Left Ventricular Mass Indices (LVMI)	An absolute change from baseline in LVMI after 6, and 12 months treatment with deferasirox and DFO was summarized	6 Month, 12 Month	No
Secondary	Core Study: Cardiac Function and the Proportion of Patients Dropping Out Due to Cardiac Dysfunction After Treatment With Deferasirox vs. Deferoxamine	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.	12 Month	No
Secondary	Core Study: Safety and Tolerability of Deferasirox vs Deferoxamine Over the 12 Months Treatment Period.	Number of patients with adverse events, serious adverse events and death	12 Month	Yes
Secondary	Core Study: Single and Repeated Dose Pharmacokinetics of Deferasirox, Area Under the Plasma Concentration-time Curve for a Dosing Interval (AUCtau)	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)	12 Month	No
Secondary	Core Study: Single and Repeated Dose Pharmacokinetics of Deferasirox, Maximum Plasma Concentration (Cmax)	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)	12 Month	No
Secondary	Core Study: Single and Repeated Dose Pharmacokinetics of Deferasirox, Time Points of Concentration Data	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	Month 1 and month 2 (pre-dose, 1,2 and 4 hours post-dose)	No
Secondary	Extension Study: Change From Baseline in Myocardial T2* After 24 Months Treatment	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	Months 6, 12, 18 and 24	No
Secondary	Extension Study: Cardiac Function From Baseline to Month 24 by Change in Left Ventricular Ejection Fraction (LVEF)	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	Months 6, 12, 18 and 24	No
Secondary	Extension Study: Cardiac Function From Baseline to Month 24 by Change in Left Ventricular End Systolic Volume Indices (LVESVI)	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	Months 6, 12, 18 and 24	No
Secondary	Extension Study: Cardiac Function From Baseline to Month 24 by Change in Left Ventricular End Diastolic Volume Indices (LVEDVI)	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	Months 6, 12, 18 and 24	No
Secondary	Extension Study: Cardiac Function From Baseline to Month 24 by Change in Left Ventricular Mass Indices (LVMI)	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	Months 6, 12, 18 and 24	No
Secondary	Extension Study: The Cardiac Iron Concentration From T2* Values	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)	Months 6, 12, 18 and 24	No
Secondary	Extension Study: Change in Liver Iron Concentration (LIC) From Baseline at Month 24	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.	Months 6, 12, 18 and 24	No
Secondary	Extension Study: Change in Serum Ferritin From Baseline by Month	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.	Months 6, 12, 18 and 24	No
Secondary	Core Study: Single and Repeated Dose Pharmacokinetics of Deferasirox, Maximum Plasma Concentration (Tmax)	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)	12 Month	No