Efficacy and Safety of Deferasirox in Combination With Deferoxamine Followed by Deferasirox Monotherapy in Severe Cardiac Iron Overload

Study Overview
=================
Brief Summary
-----------------
This study will evaluate the efficacy and safety of deferasirox in combination with deferoxamine followed be deferasirox monotherapy in patients with severe iron overload due to chronic blood transfusions.

Official Title
-----------------
Phase II, Open-label, Single-arm, Multicenter Study to Evaluate the Efficacy and Safety of Deferasirox in Combination With Deferoxamine Followed by Deferasirox Monotherapy in Patients With Severe Cardiac Iron Overload Due to Chronic Blood Transfusion (HYPERION)

Conditions
-----------------
Cardiac Iron Overload

Intervention / Treatment
-----------------
* Drug: Deferasirox and Deferoxamine


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patients with β-thalassemia major or Diamond-Blackfan anemia (DBA) or congenital sideroblastic anemia on chronic transfusion therapy Myocardial T2* value that is ≥ 5 and < 10 ms Left ventricular ejection fraction (LVEF) ≥ 56% as determined by Magnetic resonance imaging (MRI) Liver Iron Concentration (LIC) ≥ 7 mg Fe /g dw as determined by R2 MRI. Lifetime history of at least 50 units of red blood cell transfusions, and must be receiving at least ≥ 8 units/yr of red blood cell transfusions Serum ferritin ≥ 1000 ng/mL Exclusion Criteria: Patients with clinical symptoms of cardiac dysfunction (shortness of breath at rest or exertion, orthopnea, exercise intolerance, lower extremity edema, arrhythmias) Patients unable to undergo study assessments including MRI Patients with serum creatinine greater than Upper limit of normal ULN)range or with significant proteinuria as indicated by a urinary protein/creatinine ratio (UPCR) ≥1.0 mg/mg in a non-first void urine sample at baseline. Other protocol-defined inclusion/exclusion criteria may apply

Ages Eligible for Study
-----------------
Minimum Age: 10 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Deferasirox<br>Deferoxamine combination followed by Deferasirox monotherapy | Drug: Deferasirox and Deferoxamine<br> <br> |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Cardiac Iron Content From Baseline to Month 12 | Cardiac T2* is the most sensitive and reproducible test in detecting myocardial iron load. A cardiac T2* value of <10 ms is defined as severe cardiac iron overload. Participants who do not have baseline T2* or do not have any post-baseline T2* are excluded from the analysis. | From Baseline to Month 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With T2*>=10 ms and at Least 10% Relative Increase From Baseline at Month 6, 12, 18 and 24 | The number of evaluable participants at each visit were used as the denominator for the calculation of proportion at each visit. | From the Months 6, 12, 18 and 24 | 
| Change in Cardiac Iron Content From Baseline to Month 6,18 and 24 | The change in cardiac iron content was calculated as ratio of Cardiac T2* at different time points; the efficacy endpoint analyses were performed on the Full Analysis Set (FAS). | From Baseline to Months 6, 18 and 24 | 
| Change in Left Ventricular Ejection Fraction (LVEF) From Baseline to Month 6, 12, 18 and 24 | Magnetic resonance imaging (MRI)-measured cardiac T2* and cardiac function reflected by left and right ventricle ejection fraction. A standardized MRI protocol for T2* acquisition technique will be used in the centers. Images will be reviewed centrally by an expert MRI reader. | From the Months 6, 12, 18 and 24 | 
| Change in Right Ventricular Ejection Fraction (RVEF) From Baseline to Month 6, 12, 18 and 24 | Magnetic resonance imaging (MRI)-measured cardiac T2* and cardiac function reflected by left and right ventricle ejection fraction. A standardized MRI protocol for T2* acquisition technique will be used in the centers. Images will be reviewed centrally by an expert MRI reader. | From the Months 6, 12, 18 and 24 | 
| Time to Achieve From Baseline (FAS) of at Least 10% at Month 24 | Time from date of start of study treatment to date when first achieving T2* ≥ 10 ms (but at least 10% relative increase from baseline) was summarized using the reverse Kaplan-Meier estimates (1 - Kaplan-Meier estimates) for the FAS. | At 24 months | 
| Cardiac Iron Concentration Levels From Baseline and at Month 6, 12, 18 and 24 | Cardiac iron concentration (mg Fe/g dw) was quantified using the formula (cardiac iron concentration (mg Fe/g dw) = 45 * T2* (ms) ^ (-1.22) and analyzed over time. | From the Baseline, Month 6, 12, 18 and Month 24 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Cardiac iron overload,, deferasirox,, deferoxamine