Cardiac Iron Overload, Transfusion-dependent β-thalassemia Patients
Conditions
Keywords
Severe cardiac iron overload, deferasirox, β-thalassaemia, cardiac dysfunction
Brief summary
The primary efficacy endpoint of this interventional study was to evaluate the number of patients achieving a complete response (CR), defined as patients switching from intensive deferasirox -DFO treatment, at any time point during the 24 months of study, to deferasirox monotherapy based on improvement in the cardiac magnetic resonance imaging (MRI) T2\* value to \>10ms, and continue to maintain their MRI T2\* to values \>10 msec.
Detailed description
This study was planned to recruit 52 transfusion-dependent β-thalassemia patients with severe cardiac iron overload. However only 13 patients participated in the study during a 3 year and 5 month timeframe. The study was terminated due to the slow enrollment rate due to scarcity of the patient population with severe cardiac iron overload.
Interventions
DRUGDeferasirox
20-40 mg/kg/day orally, once daily
40 mg/kg/day subcutaneous (sc) infusion, 3-4 days per week
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Male or female patients with β-thalassemia major, at least 18 years old, having given written consent to participate in the study. * Cardiac MRI T2\* value ranging from \<=4 to \<=10 ms. * LVEF ≥ 56 % as determined by CMR. * Patients with LIC \> 10mg Fe/g dw will be included in the protocol. Study will evaluate the first 10 patients at 6 months, and if no safety signals are present, patients with LIC\>5 mg Fe/g dw will be allowed to be included. * Prior iron chelation treatment with DFO, DFP, DFX or combination DFO-DFP
Exclusion criteria
* Patients with symptoms of cardiac dysfunction symptoms (shortness of breath at rest or exertion, orthopnea, exercise intolerance, lower extremity edema, arrhythmias). * Patients with cardiac T2\* MRI \< 4 or \> 10 ms. * Patients not compliant to intensive iron chelation therapy regimens such i.v DFO 24 hr infusions or DFO-DFP combination. * Patients with documented liver failure (presence of portal hypertension, hepatic edemas, ascites). * Patients unable to undergo study assessments, including blood sampling, MRI, e.g., are claustrophobic to MRI, have a pacemaker, ferromagnetic metal implants other than those approved as safe for use in MRI scanners (e.g., some types of aneurysm clips, shrapnel in proximity to vital organs such as the retina), are obese (exceeding the equipment limits). * Patients with serum creatinine \> ULN or with significant proteinuria as indicated by a urinary protein/creatinine ratio ≥ 1.0 in a non-first void urine sample at baseline. Patients with creatinine clearance \<60 ml/min will be excluded. * Patients with ALT (SGPT) levels \> 5 x ULN. * Patients with considerable impaired gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral deferasirox / ICL670 (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection. * History or clinical evidence of pancreatic injury or pancreatitis. * Patients with a known hypersensitivity to any of the study drugs or the drug's excipients. * History of clinically relevant ocular and/or auditor toxicity related to iron chelation therapy. * Patients with psychiatric or addictive disorders which prevent them from giving their informed consent or undergoing any of the treatment options or patients unwilling or unable to comply with the protocol. * Patients with a known history of HIV seropositivity (Elisa or Western blot). * History of malignancy of any organ system, treated or untreated, within the past 5 years whether or not there is evidence of local recurrence or metastases, with the exception of localized basal cell carcinoma of the skin. * Female patients who are pregnant or breast feeding. * Female patients of reproductive potential not employing an effective method of birth control. Women of childbearing potential must have a negative serum pregnancy test ≤ 48 hours prior to the study drugs. * Patients participating in another clinical trial or receiving an investigational drug. * History of non-compliance with medical regimens or patients who are considered potentially unreliable and/or not cooperative, unwilling or unable to comply with the protocol. Other protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients Achieving a Complete Response (CR) | 24 months | Complete Response is defined as patients that stop intensive deferasirox -DFO treatment, at any time point during the 24 months of study, based on an improvement in the cardiac Magnetic Resonance Imaging T2 star technique (MRI T2\*) value being \>10ms, and continue to be treated with deferasirox monotherapy without any further need for reverting back to intensive iron chelation treatment during the 24 months of study. |
| Number of Patients Achieving a Partial Response (PR) | 24 months | Partial Response is defined as patients that stop intensive deferasirox -DFO treatment at any time point during the 24 months study and transition to receive deferasirox monotherapy, but due to a deterioration in cardiac MRI T2\* to a value \< 10 ms revert back to intensive deferasirox -DFO iron chelation therapy during the 24 months of study. |
| Number of Patients With Stable Disease (SD) | 24 months | Stable Disease is defined as those patients that never achieved an improvement in the cardiac MRI T2\* to values \>10ms during the 24 months of study. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Correlation Between Change From Baseline in Serum Ferritin and LIC Levels | Baseline, 6, 12, 18, 24 months | Spearman correlation coefficients between serum ferritin and LIC changes from baseline levels were reported. |
| Change From Baseline in Cardiac Iron Overload of Patients in Intensive Iron Chelation Therapy Consisting of Deferasirox-DFO and After Transition to Deferasirox Monotherapy | Baseline, 6, 12, 18, 24 months | Cardiac iron overload was determined by cardiac MRI T2\*. Cardiac iron overload also was measured by the monthly velocity of heart MRI T2\*. |
| Left Ventricular Ejection Fraction (LVEF) | 6, 12, 18, 24 months | LVEF % was measured by cardiac magnetic resonance (CMR). |
| Time to Response | 24 months | Time to response was defined as the time from baseline when the participant had severe cardiac iron overload to the time when the participant achieved mild/moderate cardiac overload (T2\*\>10 milliseconds \[ms\]). |
| Change From Baseline in Liver Iron Concentration (LIC) | Baseline, 6, 12, 18, 24 months | Change from baseline in LIC was determined by change in liver MRI T2\*. |
Countries
Greece
Participant flow
Recruitment details
In this open-label, single arm study 31 participants were enrolled (one participant was screened twice and was assigned 2 screening numbers; therefore the number enrolled = 32). Of these enrolled participants, 13 were randomized.
Participants by arm
| Arm | Count |
|---|---|
| Deferasirox / Deferasirox + Deferoxamine (DFO) During Phase A, the induction treatment at entry, participants received Deferasirox -DFO combination. During Phase B, when participants transitioned to less intensive chelation therapy, participants received Deferasirox monotherapy. | 13 |
| Total | 13 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 1 |
| Overall Study | Lost to Follow-up | 1 |
| Overall Study | Physician Decision | 1 |
Baseline characteristics
| Characteristic | Deferasirox / Deferasirox + Deferoxamine (DFO) |
|---|---|
| Age, Continuous | 32.7 Years STANDARD_DEVIATION 4 |
| Sex: Female, Male Female | 8 Participants |
| Sex: Female, Male Male | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 12 / 13 |
| serious Total, serious adverse events | 5 / 13 |
Outcome results
Primary
Number of Patients Achieving a Complete Response (CR)
Complete Response is defined as patients that stop intensive deferasirox -DFO treatment, at any time point during the 24 months of study, based on an improvement in the cardiac Magnetic Resonance Imaging T2 star technique (MRI T2\*) value being \>10ms, and continue to be treated with deferasirox monotherapy without any further need for reverting back to intensive iron chelation treatment during the 24 months of study.
Time frame: 24 months
Population: The full analysis set included all the participants entered in the study with at least a valid post-baseline assessment of the primary efficacy variable.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Deferasirox / Deferasirox + Deferoxamine (DFO) | Number of Patients Achieving a Complete Response (CR) | 4 Participants |
Primary
Number of Patients Achieving a Partial Response (PR)
Partial Response is defined as patients that stop intensive deferasirox -DFO treatment at any time point during the 24 months study and transition to receive deferasirox monotherapy, but due to a deterioration in cardiac MRI T2\* to a value \< 10 ms revert back to intensive deferasirox -DFO iron chelation therapy during the 24 months of study.
Time frame: 24 months
Population: The full analysis set included all the participants entered in the study with at least a valid post-baseline assessment of the primary efficacy variable.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Deferasirox / Deferasirox + Deferoxamine (DFO) | Number of Patients Achieving a Partial Response (PR) | 0 Participants |
Primary
Number of Patients With Stable Disease (SD)
Stable Disease is defined as those patients that never achieved an improvement in the cardiac MRI T2\* to values \>10ms during the 24 months of study.
Time frame: 24 months
Population: The full analysis set included all the participants entered in the study with at least a valid post-baseline assessment of the primary efficacy variable.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Deferasirox / Deferasirox + Deferoxamine (DFO) | Number of Patients With Stable Disease (SD) | 8 Participants |
Secondary
Change From Baseline in Cardiac Iron Overload of Patients in Intensive Iron Chelation Therapy Consisting of Deferasirox-DFO and After Transition to Deferasirox Monotherapy
Cardiac iron overload was determined by cardiac MRI T2\*. Cardiac iron overload also was measured by the monthly velocity of heart MRI T2\*.
Time frame: Baseline, 6, 12, 18, 24 months
Population: The full analysis set included all the participants entered in the study with at least a valid post-baseline assessment of the primary efficacy variable. Here 'n' number analyzed signifies number of participants evaluable at each time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Deferasirox / Deferasirox + Deferoxamine (DFO) | Change From Baseline in Cardiac Iron Overload of Patients in Intensive Iron Chelation Therapy Consisting of Deferasirox-DFO and After Transition to Deferasirox Monotherapy | 6 months | 0.1 Milliseconds (ms) | Standard Deviation 1.4 |
| Deferasirox / Deferasirox + Deferoxamine (DFO) | Change From Baseline in Cardiac Iron Overload of Patients in Intensive Iron Chelation Therapy Consisting of Deferasirox-DFO and After Transition to Deferasirox Monotherapy | 12 months | 0.7 Milliseconds (ms) | Standard Deviation 1.9 |
| Deferasirox / Deferasirox + Deferoxamine (DFO) | Change From Baseline in Cardiac Iron Overload of Patients in Intensive Iron Chelation Therapy Consisting of Deferasirox-DFO and After Transition to Deferasirox Monotherapy | 18 months | 1.3 Milliseconds (ms) | Standard Deviation 2.4 |
| Deferasirox / Deferasirox + Deferoxamine (DFO) | Change From Baseline in Cardiac Iron Overload of Patients in Intensive Iron Chelation Therapy Consisting of Deferasirox-DFO and After Transition to Deferasirox Monotherapy | 24 months | 2.4 Milliseconds (ms) | Standard Deviation 3.9 |
Secondary
Change From Baseline in Liver Iron Concentration (LIC)
Change from baseline in LIC was determined by change in liver MRI T2\*.
Time frame: Baseline, 6, 12, 18, 24 months
Population: The full analysis set included all the participants entered in the study with at least a valid post-baseline assessment of the primary efficacy variable. Here 'n' number analyzed signifies number of participants evaluable at each time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Deferasirox / Deferasirox + Deferoxamine (DFO) | Change From Baseline in Liver Iron Concentration (LIC) | 6 months | -5 mg of iron/gram of dry weight of liver | Standard Deviation 7.7 |
| Deferasirox / Deferasirox + Deferoxamine (DFO) | Change From Baseline in Liver Iron Concentration (LIC) | 12 months | -10.3 mg of iron/gram of dry weight of liver | Standard Deviation 9.2 |
| Deferasirox / Deferasirox + Deferoxamine (DFO) | Change From Baseline in Liver Iron Concentration (LIC) | 18 months | -10.2 mg of iron/gram of dry weight of liver | Standard Deviation 10.7 |
| Deferasirox / Deferasirox + Deferoxamine (DFO) | Change From Baseline in Liver Iron Concentration (LIC) | 24 months | -12.4 mg of iron/gram of dry weight of liver | Standard Deviation 10.1 |
Secondary
Correlation Between Change From Baseline in Serum Ferritin and LIC Levels
Spearman correlation coefficients between serum ferritin and LIC changes from baseline levels were reported.
Time frame: Baseline, 6, 12, 18, 24 months
Population: Full analysis set included all participants entered in study with at least a valid post-baseline assessment of the primary efficacy variable. Here 'N' (overall number of participants analyzed) signifies number of participants evaluable for this outcome measure and 'n' (number analyzed) signifies number of participants evaluable at each time point.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Deferasirox / Deferasirox + Deferoxamine (DFO) | Correlation Between Change From Baseline in Serum Ferritin and LIC Levels | 6 months | 0.091 Spearman correlation coefficient |
| Deferasirox / Deferasirox + Deferoxamine (DFO) | Correlation Between Change From Baseline in Serum Ferritin and LIC Levels | 12 months | -0.033 Spearman correlation coefficient |
| Deferasirox / Deferasirox + Deferoxamine (DFO) | Correlation Between Change From Baseline in Serum Ferritin and LIC Levels | 18 months | 0.347 Spearman correlation coefficient |
| Deferasirox / Deferasirox + Deferoxamine (DFO) | Correlation Between Change From Baseline in Serum Ferritin and LIC Levels | 24 months | 0.273 Spearman correlation coefficient |
Secondary
Left Ventricular Ejection Fraction (LVEF)
LVEF % was measured by cardiac magnetic resonance (CMR).
Time frame: 6, 12, 18, 24 months
Population: The full analysis set included all the participants entered in the study with at least a valid post-baseline assessment of the primary efficacy variable. Here 'n' number analyzed signifies number of participants evaluable at each time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Deferasirox / Deferasirox + Deferoxamine (DFO) | Left Ventricular Ejection Fraction (LVEF) | Baseline | 65 Percentage of ejection fraction | Standard Deviation 4.4 |
| Deferasirox / Deferasirox + Deferoxamine (DFO) | Left Ventricular Ejection Fraction (LVEF) | 6 months | 65.4 Percentage of ejection fraction | Standard Deviation 5 |
| Deferasirox / Deferasirox + Deferoxamine (DFO) | Left Ventricular Ejection Fraction (LVEF) | 12 months | 64.8 Percentage of ejection fraction | Standard Deviation 4.6 |
| Deferasirox / Deferasirox + Deferoxamine (DFO) | Left Ventricular Ejection Fraction (LVEF) | 18 months | 65.1 Percentage of ejection fraction | Standard Deviation 4.8 |
| Deferasirox / Deferasirox + Deferoxamine (DFO) | Left Ventricular Ejection Fraction (LVEF) | 24 months | 66.2 Percentage of ejection fraction | Standard Deviation 4.6 |
Secondary
Time to Response
Time to response was defined as the time from baseline when the participant had severe cardiac iron overload to the time when the participant achieved mild/moderate cardiac overload (T2\*\>10 milliseconds \[ms\]).
Time frame: 24 months
Population: The full analysis set included all participants entered in the study with at least a valid post-baseline assessment of the primary efficacy variable. Here 'N' (overall number of participants analyzed) signifies number of participants evaluable for this outcome measure at the specified time-point.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Deferasirox / Deferasirox + Deferoxamine (DFO) | Time to Response | 13.0 ms | Standard Deviation 1.1 |