Cardiac Iron Overload
Conditions
Keywords
Cardiac iron overload,, deferasirox,, deferoxamine
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.
Interventions
DRUGDeferasirox and Deferoxamine
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
10 Years to No maximum
Healthy volunteers
No
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/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Cardiac Iron Content From Baseline to Month 12 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Cardiac Iron Content From Baseline to Month 6,18 and 24 | From Baseline to Months 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). |
| Change in Left Ventricular Ejection Fraction (LVEF) From Baseline to Month 6, 12, 18 and 24 | From the Months 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. |
| Percentage of Participants With T2*>=10 ms and at Least 10% Relative Increase From Baseline at Month 6, 12, 18 and 24 | From the Months 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. |
| Time to Achieve From Baseline (FAS) of at Least 10% at Month 24 | At 24 months | 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. |
| Cardiac Iron Concentration Levels From Baseline and at Month 6, 12, 18 and 24 | From the Baseline, Month 6, 12, 18 and Month 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. |
| Change in Right Ventricular Ejection Fraction (RVEF) From Baseline to Month 6, 12, 18 and 24 | From the Months 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. |
Countries
Canada, Egypt, Greece, Italy, Taiwan, Thailand, Turkey (Türkiye), United Kingdom
Participant flow
Recruitment details
The study was conducted at 18 centers in 8 countries.
Pre-assignment details
A total 60 participants were enrolled in the study of which 34 completed the study.
Participants by arm
| Arm | Count |
|---|---|
| All Participants Participants received an initial combined dose of Deferasirox (DFX) 20 mg/kg/day every day and Deferoxamine (DFO) 40 mg/kg/day (DFO: 5 days/week for at least 8 hours/day). Deferasirox was increased to 30 mg/kg/day every day at Month 1 Further dose increases upto 40 mg/kg/day every day at Month 6 visit. Participants could be switched from the Deferasirox - Deferoxamine (DFX - DFO) combination to Deferasirox monotherapy at the highest tolerable dose (30-40 mg/kg/day) at any time point after 6 months. | 60 |
| Total | 60 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Abnormal test procedure result | 5 |
| Overall Study | Administrative problems | 2 |
| Overall Study | Adverse Event | 5 |
| Overall Study | Death | 1 |
| Overall Study | Lost to Follow-up | 6 |
| Overall Study | Protocol deviation | 1 |
| Overall Study | Withdrawal by Subject | 6 |
Baseline characteristics
| Characteristic | All Participants |
|---|---|
| Age, Continuous | 22.8 years STANDARD_DEVIATION 7.33 |
| Sex: Female, Male Female | 32 Participants |
| Sex: Female, Male Male | 28 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 1 / 60 |
| other Total, other adverse events | 52 / 60 |
| serious Total, serious adverse events | 17 / 60 |
Outcome results
Primary
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.
Time frame: From Baseline to Month 12
Population: The Full Analysis Set includes all participants to whom study treatment had assigned. Participants were considered evaluable for the efficacy endpoint if they had received at least one dose of study treatment and had baseline and a post baseline assessment prior to or on the time of the assessment of the corresponding efficacy endpoint.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| All Participants | Change in Cardiac Iron Content From Baseline to Month 12 | 1.09 ratio |
Secondary
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.
Time frame: From the Baseline, Month 6, 12, 18 and Month 24
Population: The Full Analysis Set includes all participants to whom study treatment had assigned. Participants were considered evaluable for the efficacy endpoint if they had received at least one dose of study treatment and had baseline and a post baseline assessment prior to or on the time of the assessment of the corresponding efficacy endpoint.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| All Participants | Cardiac Iron Concentration Levels From Baseline and at Month 6, 12, 18 and 24 | Month 18 | 3.51 mg Fe/g dw | Standard Deviation 1.348 |
| All Participants | Cardiac Iron Concentration Levels From Baseline and at Month 6, 12, 18 and 24 | Baseline | 4.18 mg Fe/g dw | Standard Deviation 1.045 |
| All Participants | Cardiac Iron Concentration Levels From Baseline and at Month 6, 12, 18 and 24 | Month 6 | 4.31 mg Fe/g dw | Standard Deviation 1.442 |
| All Participants | Cardiac Iron Concentration Levels From Baseline and at Month 6, 12, 18 and 24 | Month 12 | 3.93 mg Fe/g dw | Standard Deviation 1.429 |
| All Participants | Cardiac Iron Concentration Levels From Baseline and at Month 6, 12, 18 and 24 | Month 24 | 3.14 mg Fe/g dw | Standard Deviation 1.381 |
Secondary
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).
Time frame: From Baseline to Months 6, 18 and 24
Population: The Full Analysis Set includes all participants to whom study treatment had assigned. Participants were considered evaluable for the efficacy endpoint if they had received at least one dose of study treatment and had baseline and a post baseline assessment prior to or on the time of the assessment of the corresponding efficacy endpoint. Here, Number of participants analyzed included all participants who were evaluable for the specified timepoints.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| All Participants | Change in Cardiac Iron Content From Baseline to Month 6,18 and 24 | Month 6 | 1.02 ratio |
| All Participants | Change in Cardiac Iron Content From Baseline to Month 6,18 and 24 | Month 18 | 1.17 ratio |
| All Participants | Change in Cardiac Iron Content From Baseline to Month 6,18 and 24 | Month 24 | 1.30 ratio |
Secondary
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.
Time frame: From the Months 6, 12, 18 and 24
Population: The Full Analysis Set includes all participants to whom study treatment had assigned. Participants were considered evaluable for the efficacy endpoint if they had received at least one dose of study treatment and had baseline and a post baseline assessment prior to or on the time of the assessment of the corresponding efficacy endpoint.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| All Participants | Change in Left Ventricular Ejection Fraction (LVEF) From Baseline to Month 6, 12, 18 and 24 | Baseline | 66.5 Percent Ejection Fraction | Standard Deviation 5.32 |
| All Participants | Change in Left Ventricular Ejection Fraction (LVEF) From Baseline to Month 6, 12, 18 and 24 | Month 6 | 0.1 Percent Ejection Fraction | Standard Deviation 4.62 |
| All Participants | Change in Left Ventricular Ejection Fraction (LVEF) From Baseline to Month 6, 12, 18 and 24 | Month 12 | -0.2 Percent Ejection Fraction | Standard Deviation 4.84 |
| All Participants | Change in Left Ventricular Ejection Fraction (LVEF) From Baseline to Month 6, 12, 18 and 24 | Month 18 | 0.6 Percent Ejection Fraction | Standard Deviation 7.04 |
| All Participants | Change in Left Ventricular Ejection Fraction (LVEF) From Baseline to Month 6, 12, 18 and 24 | Month 24 | 0.9 Percent Ejection Fraction | Standard Deviation 5.98 |
Secondary
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.
Time frame: From the Months 6, 12, 18 and 24
Population: The Full Analysis Set includes all participants to whom study treatment had assigned. Participants were considered evaluable for the efficacy endpoint if they had received at least one dose of study treatment and had baseline and a post baseline assessment prior to or on the time of the assessment of the corresponding efficacy endpoint.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| All Participants | Change in Right Ventricular Ejection Fraction (RVEF) From Baseline to Month 6, 12, 18 and 24 | Baseline | 67.1 Percent Ejection Fraction | Standard Deviation 5.55 |
| All Participants | Change in Right Ventricular Ejection Fraction (RVEF) From Baseline to Month 6, 12, 18 and 24 | Month 6 | -1.2 Percent Ejection Fraction | Standard Deviation 5.35 |
| All Participants | Change in Right Ventricular Ejection Fraction (RVEF) From Baseline to Month 6, 12, 18 and 24 | Month 12 | -1.6 Percent Ejection Fraction | Standard Deviation 4.4 |
| All Participants | Change in Right Ventricular Ejection Fraction (RVEF) From Baseline to Month 6, 12, 18 and 24 | Month 18 | -2.1 Percent Ejection Fraction | Standard Deviation 6.1 |
| All Participants | Change in Right Ventricular Ejection Fraction (RVEF) From Baseline to Month 6, 12, 18 and 24 | Month 24 | -1.4 Percent Ejection Fraction | Standard Deviation 4.25 |
Secondary
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.
Time frame: From the Months 6, 12, 18 and 24
Population: The Full Analysis Set includes all participants to whom study treatment had assigned. Participants were considered evaluable for the efficacy endpoint if they had received at least one dose of study treatment and had baseline and a post baseline assessment prior to or on the time of the assessment of the corresponding efficacy endpoint. Here, Number of participants analyzed included all participants who were evaluable for the specified timepoints.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| All Participants | Percentage of Participants With T2*>=10 ms and at Least 10% Relative Increase From Baseline at Month 6, 12, 18 and 24 | Month 6 | 12.50 percentage of participants |
| All Participants | Percentage of Participants With T2*>=10 ms and at Least 10% Relative Increase From Baseline at Month 6, 12, 18 and 24 | Month12 | 19.23 percentage of participants |
| All Participants | Percentage of Participants With T2*>=10 ms and at Least 10% Relative Increase From Baseline at Month 6, 12, 18 and 24 | Month 18 | 33.33 percentage of participants |
| All Participants | Percentage of Participants With T2*>=10 ms and at Least 10% Relative Increase From Baseline at Month 6, 12, 18 and 24 | Month 24 | 47.22 percentage of participants |
Secondary
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.
Time frame: At 24 months
Population: The Full Analysis Set includes all participants to whom study treatment had assigned. Participants were considered evaluable for the efficacy endpoint if they had received at least one dose of study treatment and had baseline and a post baseline assessment prior to or on the time of the assessment of the corresponding efficacy endpoint.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| All Participants | Time to Achieve From Baseline (FAS) of at Least 10% at Month 24 | 722.0 milliseconds/ms |