Back to resultsCombination Study of Deferasirox and Erythropoietin in Patients With Low- and Int-1-risk Myelodysplastic Syndrome.
Primary Purpose
Low and Int 1-risk Myelodysplastic Syndrome
Status
Completed
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
Deferasirox DFX, DT
Erythropoietin alpha
Deferasirox DFX, FCT
Sponsored by
About this trial
This is an interventional treatment trial for Low and Int 1-risk Myelodysplastic Syndrome focused on measuring myelodysplastic syndrome, MDS, myelodysplasia, blood disorder, cytopenias, low blood counts, progressive bone marrow failure, adult, ICL570, deferasirox, erythropoietin, erythropoiesis, NF-kB pathway, hematopoiesis.
Eligibility Criteria
Key Inclusion Criteria:
- Patients who had low- and Int-1-risk myelodysplastic syndrome
- Documented diagnosis of the following:
Myelodysplastic syndrome that lasted ≥ 3 months and < 3 years Disease must not have been secondary to treatment with radiotherapy, chemotherapy, and/or immunotherapy for malignant or autoimmune diseases
- A hemoglobin < 10 g/dL and ≥ 8 g/dL
- History of transfusions < 10 RBC units and must not have been RBC transfusion dependent
- 300 ng/mL < serum ferritin < 1,500 ng/mL (Values within 10% difference above 1500 ng/ml or 10% difference below 300 ng/ml could have been accepted at the investigator's discretion.
- Endogenous erythropoietin levels < 500 units/L
- Serum creatinine ≤ 1.5 times upper limit of normal (ULN)
- Creatinine clearance above the concentration limit in locally approved prescribing information (PI). Patients with creatinine clearance between 40 and less than 60 mL/min, who did not present with additional risk factors that might impair renal function, were eligible at the discretion of the investigator
Key Exclusion Criteria:
- Patients who had MDS with isolated del(5q)
- Patients who had received prior EPO treatment or other recombinant growth factors regardless of the outcome (Patient who had received prior EPO treatment or other recombinant growth factors for less than 4 weeks and not within 3 months before screening without a documented response are allowed)
- Patients who had received steroids or immunosuppressive therapy for the improvement of hematological parameters (stable steroid treatment for adrenal failure or chronic medical conditions, and intermittent dexamethasone as antiemetics were allowed).
- B12 and folate deficient patients with and without clinical symptoms (patients were rescreened after successful therapy of B12 and folate deficiency)
- Uncontrolled seizures or uncontrolled hypertension
Sites / Locations
- Novartis Investigative Site
- Novartis Investigative Site
- Novartis Investigative Site
- Novartis Investigative Site
- Novartis Investigative Site
- Novartis Investigative Site
- Novartis Investigative Site
- Novartis Investigative Site
- Novartis Investigative Site
- Novartis Investigative Site
- Novartis Investigative Site
- Novartis Investigative Site
- Novartis Investigative Site
- Novartis Investigative Site
- Novartis Investigative Site
- Novartis Investigative Site
- Novartis Investigative Site
- Novartis Investigative Site
- Novartis Investigative Site
- Novartis Investigative Site
- Novartis Investigative Site
- Novartis Investigative Site
- Novartis Investigative Site
- Novartis Investigative Site
- Novartis Investigative Site
- Novartis Investigative Site
- Novartis Investigative Site
- Novartis Investigative Site
- Novartis Investigative Site
- Novartis Investigative Site
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Experimental
Arm Label
Erythropoietin alpha
Deferasirox + Erythropoietin alpha
Arm Description
Patients will receive erythropoietin 40,000 units/week. If after 4 weeks erythroid improvement is inadequate, dose will be escalated to 60,000 units/week. If after 12 weeks of treatment, erythroid improvement in inadequate, patients will be switched to the combination arm. At any time when erythroid response is achieved, erythropoietin treatment will be stopped until end of study.
Patients will receive deferasirox dispersible tablet (DT) 10 mg/kg/day or deferasirox film-coated tablet (FCT) 7 mg/kg/day in combination with erythropoietin 40,000 units/week. If after 4 weeks erythroid improvement is inadequate, erythropoietin dose will be escalated to 60,000 units/week. If after 12 weeks of treatment, erythroid improvement in inadequate, patients will be discontinued from the study. At any time when erythroid response is achieved, erythropoietin treatment will be stopped until end of study. Patients will continue deferasirox treatment.
Outcomes
Primary Outcome Measures
Difference in Percentage of Patients Achieving Erythroid Response Within 12 Weeks, by Treatment Group (Full Analysis Set)
Difference in percentage of patients achieving an erythroid response within 12 weeks of treatment between the two arms according to modified IWG 2006 criteria increase in hemoglobin (Hb) ≥ 1.5 g/dL. Erythroid response is defined as the increase in Hb from baseline ≥ 1.5 g/dL. Patients achieving erythroid response at least once within 12 weeks were considered responders
Secondary Outcome Measures
Absolute Change From Baseline to Post-baseline Value for Hemoglobin(g/dL)(Full Analysis Set)
Hematological response criteria defined as: Erythroid response: hemoglobin (Hb) increase from baseline >= 1.5 g/dL (baseline < 11 g/dL), neutrophil response: increase from baseline >= 100% and increase > 0.5 × 10^9/L (baseline <1 × 10^9/L), platelet response: increase from baseline >= 30 × 10^9/L (baseline <100 × 10^9/L) according to modified IWG 2006 criteria
Summary of Hematologic Improvement in Patients Randomized to EPO+DFX and EPO Alone, Within 24 Weeks of Treatment (Full Analysis Set)
Percentage of participants achieving an hematologic improvement defined as: neutrophil improvement: increase from baseline >0.5 × 10^9/L (baseline = 1.0 × 10^9/L ), platelet improvement: increase from baseline ≥ 30 × 10^9/L (baseline = 100 × 10^9/L), hemoglobin improvement: Hb increase from baseline ≥ 1 g/dL (baseline<11 g/dL)
Absolute Change in Hemoglobin Values up to 24 Weeks
Absolute change in hemoglobin values for patients showing improvement: Hemoglobin improvement Hb increase from baseline ≥ 1 g/dL (baseline<11 g/dL)
Absolute Change in Platelets and Neutrophil Levels up to 24 Weeks
Absolute change in platelets and neutrophil levels for participants showing improvement: neutrophil improvement: increase from baseline >0.5 × 10^9/L (baseline = 1.0 × 10^9/L ), platelet improvement: increase from baseline ≥ 30 × 10^9/L (baseline = 100 × 10^9/L)
Summary of Erythroid Response in Participants Randomized to EPO Alone at Baseline and Switched to EPO+DFX After 12 Weeks of Treatment (Full Analysis Set)
Erythroid response: hemoglobin increase from baseline > = 1.5 g/dL (baseline <11 g/dL)
Summary of Erythroid Response Within 24 Weeks in Participants Randomized to EPO at Baseline and Not Switched to EPO+DFX After 12 Weeks of Treatment (Full Analysis Set)
Erythroid response: hemoglobin increase from baseline > = 1.5 g/dL (baseline <11 g/dL). Percentages are based on N. Confidence intervals are calculated using Clopper-Pearson method. Hemoglobin value is at time of first response
Absolute Change in Serum Ferritin up to 24 Weeks for Erythropoietin Alpha Arm (Full Analysis Set)
Absolute change in serum ferritin from baseline
Absolute Change in Serum Ferritin up to 24 Weeks for Deferasirox + Erythropoietin Alpha Arm (Full Analysis Set)
Absolute change in serum ferritin from baseline
Absolute Change in Serum Ferritin up to 24 Weeks for EPO+DFX at 12 Weeks Arm (Full Analysis Set)
Absolute change in serum ferritin from baseline
Absolute Change in Hemoglobin (Hb) From Baseline for Erythropoietin Alpha Arm (Full Analysis Set)
This analysis included patients randomized either to EPO or DFX+EPO at baseline as well as patients who did not have erythroid response at week 12 in the EPO group and switched to combination therapy.
Absolute Change in Hemoglobin (Hb) From Baseline for Deferasirox + Erythropoietin Alpha Arm (Full Analysis Set)
This analysis included patients randomized either to EPO or DFX+EPO at baseline as well as patients who did not have erythroid response at week 12 in the EPO group and switched to combination therapy.
Absolute Change in Hemoglobin (Hb) From Baseline for EPO+DFX at 12 Weeks Arm (Full Analysis Set)
This analysis included patients randomized either to EPO or DFX+EPO at baseline as well as patients who did not have erythroid response at week 12 in the EPO group and switched to combination therapy. The time-course of Hb and its absolute changes from baseline was summarized by descriptive statistics by visit and erythroid response. Patients randomized to EPO and not switching after 12 weeks to EPO+DFX would consist of only responders.
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT01868477
Brief Title
Combination Study of Deferasirox and Erythropoietin in Patients With Low- and Int-1-risk Myelodysplastic Syndrome.
Official Title
An Open-label, Phase II, Randomized, Pilot Study to Assess the Effect in Term of Erythroid Improvement of Deferasirox Combined With Erythropoietin Compared to Erythropoietin Alone in Patients With low-and Int-1-risk Myelodysplastic Syndrome.
Study Type
Interventional
2. Study Status
Record Verification Date
October 2018
Overall Recruitment Status
Completed
Study Start Date
January 28, 2014 (Actual)
Primary Completion Date
March 22, 2017 (Actual)
Study Completion Date
April 5, 2017 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Novartis Pharmaceuticals
4. Oversight
Data Monitoring Committee
No
5. Study Description
Brief Summary
The primary purpose of this trial was is to assess the effect of treatment with deferasirox combined with erythropoietin vs. erythropoietin alone on erythropoiesis in patients with low- and int-1-risk myelodysplastic syndrome. The addition of deferasirox to erythropoietin can lead to a potential synergism with the reduction of reactive oxygen species, through both the NF-kB pathway and the control of free toxic iron. This may create a better environment in the bone marrow for a better response with erythropoietin.
This study was designed to test in a prospective way the combination of deferasirox with erythropoietin in terms of their effect on hematopoiesis.
Detailed Description
This study did not meet the original enrollment objective of 60 patients and was terminated without extending enrollment past original planned LPFV of 31-Oct-2016.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Low and Int 1-risk Myelodysplastic Syndrome
Keywords
myelodysplastic syndrome, MDS, myelodysplasia, blood disorder, cytopenias, low blood counts, progressive bone marrow failure, adult, ICL570, deferasirox, erythropoietin, erythropoiesis, NF-kB pathway, hematopoiesis.
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
28 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Erythropoietin alpha
Arm Type
Experimental
Arm Description
Patients will receive erythropoietin 40,000 units/week. If after 4 weeks erythroid improvement is inadequate, dose will be escalated to 60,000 units/week. If after 12 weeks of treatment, erythroid improvement in inadequate, patients will be switched to the combination arm. At any time when erythroid response is achieved, erythropoietin treatment will be stopped until end of study.
Arm Title
Deferasirox + Erythropoietin alpha
Arm Type
Experimental
Arm Description
Patients will receive deferasirox dispersible tablet (DT) 10 mg/kg/day or deferasirox film-coated tablet (FCT) 7 mg/kg/day in combination with erythropoietin 40,000 units/week. If after 4 weeks erythroid improvement is inadequate, erythropoietin dose will be escalated to 60,000 units/week. If after 12 weeks of treatment, erythroid improvement in inadequate, patients will be discontinued from the study. At any time when erythroid response is achieved, erythropoietin treatment will be stopped until end of study. Patients will continue deferasirox treatment.
Intervention Type
Drug
Intervention Name(s)
Deferasirox DFX, DT
Intervention Description
provided as dispersible tablets for oral use in 125 and 250, 500 mg
Intervention Type
Drug
Intervention Name(s)
Erythropoietin alpha
Intervention Type
Drug
Intervention Name(s)
Deferasirox DFX, FCT
Intervention Description
provided as film-coated tablet for oral use in 90, 180, 360 mg strengths
Primary Outcome Measure Information:
Title
Difference in Percentage of Patients Achieving Erythroid Response Within 12 Weeks, by Treatment Group (Full Analysis Set)
Description
Difference in percentage of patients achieving an erythroid response within 12 weeks of treatment between the two arms according to modified IWG 2006 criteria increase in hemoglobin (Hb) ≥ 1.5 g/dL. Erythroid response is defined as the increase in Hb from baseline ≥ 1.5 g/dL. Patients achieving erythroid response at least once within 12 weeks were considered responders
Time Frame
Baseline up to 12 weeks
Secondary Outcome Measure Information:
Title
Absolute Change From Baseline to Post-baseline Value for Hemoglobin(g/dL)(Full Analysis Set)
Description
Hematological response criteria defined as: Erythroid response: hemoglobin (Hb) increase from baseline >= 1.5 g/dL (baseline < 11 g/dL), neutrophil response: increase from baseline >= 100% and increase > 0.5 × 10^9/L (baseline <1 × 10^9/L), platelet response: increase from baseline >= 30 × 10^9/L (baseline <100 × 10^9/L) according to modified IWG 2006 criteria
Time Frame
Baseline up to 24 weeks
Title
Summary of Hematologic Improvement in Patients Randomized to EPO+DFX and EPO Alone, Within 24 Weeks of Treatment (Full Analysis Set)
Description
Percentage of participants achieving an hematologic improvement defined as: neutrophil improvement: increase from baseline >0.5 × 10^9/L (baseline = 1.0 × 10^9/L ), platelet improvement: increase from baseline ≥ 30 × 10^9/L (baseline = 100 × 10^9/L), hemoglobin improvement: Hb increase from baseline ≥ 1 g/dL (baseline<11 g/dL)
Time Frame
Baseline up to 24 weeks
Title
Absolute Change in Hemoglobin Values up to 24 Weeks
Description
Absolute change in hemoglobin values for patients showing improvement: Hemoglobin improvement Hb increase from baseline ≥ 1 g/dL (baseline<11 g/dL)
Time Frame
Baseline up to 24 weeks
Title
Absolute Change in Platelets and Neutrophil Levels up to 24 Weeks
Description
Absolute change in platelets and neutrophil levels for participants showing improvement: neutrophil improvement: increase from baseline >0.5 × 10^9/L (baseline = 1.0 × 10^9/L ), platelet improvement: increase from baseline ≥ 30 × 10^9/L (baseline = 100 × 10^9/L)
Time Frame
Baseline up to 24 weeks
Title
Summary of Erythroid Response in Participants Randomized to EPO Alone at Baseline and Switched to EPO+DFX After 12 Weeks of Treatment (Full Analysis Set)
Description
Erythroid response: hemoglobin increase from baseline > = 1.5 g/dL (baseline <11 g/dL)
Time Frame
Week 13 up to 24 weeks
Title
Summary of Erythroid Response Within 24 Weeks in Participants Randomized to EPO at Baseline and Not Switched to EPO+DFX After 12 Weeks of Treatment (Full Analysis Set)
Description
Erythroid response: hemoglobin increase from baseline > = 1.5 g/dL (baseline <11 g/dL). Percentages are based on N. Confidence intervals are calculated using Clopper-Pearson method. Hemoglobin value is at time of first response
Time Frame
baseline up to 24 weeks
Title
Absolute Change in Serum Ferritin up to 24 Weeks for Erythropoietin Alpha Arm (Full Analysis Set)
Description
Absolute change in serum ferritin from baseline
Time Frame
Baseline up to 24 weeks
Title
Absolute Change in Serum Ferritin up to 24 Weeks for Deferasirox + Erythropoietin Alpha Arm (Full Analysis Set)
Description
Absolute change in serum ferritin from baseline
Time Frame
Baseline up to 24 weeks
Title
Absolute Change in Serum Ferritin up to 24 Weeks for EPO+DFX at 12 Weeks Arm (Full Analysis Set)
Description
Absolute change in serum ferritin from baseline
Time Frame
Baseline up 24 weeks
Title
Absolute Change in Hemoglobin (Hb) From Baseline for Erythropoietin Alpha Arm (Full Analysis Set)
Description
This analysis included patients randomized either to EPO or DFX+EPO at baseline as well as patients who did not have erythroid response at week 12 in the EPO group and switched to combination therapy.
Time Frame
Baseline up to 24 weeks
Title
Absolute Change in Hemoglobin (Hb) From Baseline for Deferasirox + Erythropoietin Alpha Arm (Full Analysis Set)
Description
This analysis included patients randomized either to EPO or DFX+EPO at baseline as well as patients who did not have erythroid response at week 12 in the EPO group and switched to combination therapy.
Time Frame
Baseline up to 24 weeks
Title
Absolute Change in Hemoglobin (Hb) From Baseline for EPO+DFX at 12 Weeks Arm (Full Analysis Set)
Description
This analysis included patients randomized either to EPO or DFX+EPO at baseline as well as patients who did not have erythroid response at week 12 in the EPO group and switched to combination therapy. The time-course of Hb and its absolute changes from baseline was summarized by descriptive statistics by visit and erythroid response. Patients randomized to EPO and not switching after 12 weeks to EPO+DFX would consist of only responders.
Time Frame
Baseline up to 24 weeks
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Key Inclusion Criteria:
Patients who had low- and Int-1-risk myelodysplastic syndrome
Documented diagnosis of the following:
Myelodysplastic syndrome that lasted ≥ 3 months and < 3 years Disease must not have been secondary to treatment with radiotherapy, chemotherapy, and/or immunotherapy for malignant or autoimmune diseases
A hemoglobin < 10 g/dL and ≥ 8 g/dL
History of transfusions < 10 RBC units and must not have been RBC transfusion dependent
300 ng/mL < serum ferritin < 1,500 ng/mL (Values within 10% difference above 1500 ng/ml or 10% difference below 300 ng/ml could have been accepted at the investigator's discretion.
Endogenous erythropoietin levels < 500 units/L
Serum creatinine ≤ 1.5 times upper limit of normal (ULN)
Creatinine clearance above the concentration limit in locally approved prescribing information (PI). Patients with creatinine clearance between 40 and less than 60 mL/min, who did not present with additional risk factors that might impair renal function, were eligible at the discretion of the investigator
Key Exclusion Criteria:
Patients who had MDS with isolated del(5q)
Patients who had received prior EPO treatment or other recombinant growth factors regardless of the outcome (Patient who had received prior EPO treatment or other recombinant growth factors for less than 4 weeks and not within 3 months before screening without a documented response are allowed)
Patients who had received steroids or immunosuppressive therapy for the improvement of hematological parameters (stable steroid treatment for adrenal failure or chronic medical conditions, and intermittent dexamethasone as antiemetics were allowed).
B12 and folate deficient patients with and without clinical symptoms (patients were rescreened after successful therapy of B12 and folate deficiency)
Uncontrolled seizures or uncontrolled hypertension
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Novartis Pharmaceuticals
Organizational Affiliation
Novartis Pharmaceuticals
Official's Role
Study Director
Facility Information:
Facility Name
Novartis Investigative Site
City
Oran
ZIP/Postal Code
31000
Country
Algeria
Facility Name
Novartis Investigative Site
City
Sidi Bel abbes
ZIP/Postal Code
22000
Country
Algeria
Facility Name
Novartis Investigative Site
City
Caba
State/Province
Buenos Aires
ZIP/Postal Code
C1425DND
Country
Argentina
Facility Name
Novartis Investigative Site
City
La Plata
State/Province
Buenos Aires
ZIP/Postal Code
B1900AWT
Country
Argentina
Facility Name
Novartis Investigative Site
City
Vancouver
State/Province
British Columbia
ZIP/Postal Code
V6Z1Y6
Country
Canada
Facility Name
Novartis Investigative Site
City
Hamilton
State/Province
Ontario
ZIP/Postal Code
L8V 5C2
Country
Canada
Facility Name
Novartis Investigative Site
City
Toronto
State/Province
Ontario
ZIP/Postal Code
M4N 3M5
Country
Canada
Facility Name
Novartis Investigative Site
City
Beijing
State/Province
Beijing
ZIP/Postal Code
100730
Country
China
Facility Name
Novartis Investigative Site
City
Guangzhou
State/Province
Guangdong
ZIP/Postal Code
51000
Country
China
Facility Name
Novartis Investigative Site
City
Nanjing
State/Province
Jiangsu
Country
China
Facility Name
Novartis Investigative Site
City
Chengdu
State/Province
Sichuan
ZIP/Postal Code
610041
Country
China
Facility Name
Novartis Investigative Site
City
Hangzhou
State/Province
Zhejiang
ZIP/Postal Code
310003
Country
China
Facility Name
Novartis Investigative Site
City
Shanghai
ZIP/Postal Code
200025
Country
China
Facility Name
Novartis Investigative Site
City
Berlin
ZIP/Postal Code
12203
Country
Germany
Facility Name
Novartis Investigative Site
City
Dresden
ZIP/Postal Code
01307
Country
Germany
Facility Name
Novartis Investigative Site
City
Duesseldorf
ZIP/Postal Code
40225
Country
Germany
Facility Name
Novartis Investigative Site
City
Lütten-Klein
ZIP/Postal Code
18107
Country
Germany
Facility Name
Novartis Investigative Site
City
Wuerzburg
ZIP/Postal Code
97080
Country
Germany
Facility Name
Novartis Investigative Site
City
Cagliari
State/Province
CA
ZIP/Postal Code
09126
Country
Italy
Facility Name
Novartis Investigative Site
City
Reggio Calabria
State/Province
RC
ZIP/Postal Code
89124
Country
Italy
Facility Name
Novartis Investigative Site
City
Roma
State/Province
RM
ZIP/Postal Code
00161
Country
Italy
Facility Name
Novartis Investigative Site
City
Seoul
State/Province
Korea
ZIP/Postal Code
06351
Country
Korea, Republic of
Facility Name
Novartis Investigative Site
City
Badalona
State/Province
Catalunya
ZIP/Postal Code
08916
Country
Spain
Facility Name
Novartis Investigative Site
City
Girona
State/Province
Catalunya
ZIP/Postal Code
17007
Country
Spain
Facility Name
Novartis Investigative Site
City
Hospitalet de LLobregat
State/Province
Catalunya
ZIP/Postal Code
08907
Country
Spain
Facility Name
Novartis Investigative Site
City
Gothenburg
ZIP/Postal Code
413 45
Country
Sweden
Facility Name
Novartis Investigative Site
City
Linköping
ZIP/Postal Code
SE-581 85
Country
Sweden
Facility Name
Novartis Investigative Site
City
Lulea
ZIP/Postal Code
SE 971 80
Country
Sweden
Facility Name
Novartis Investigative Site
City
Stockholm
ZIP/Postal Code
SE-141 86
Country
Sweden
Facility Name
Novartis Investigative Site
City
Oldham
State/Province
Lancashire
ZIP/Postal Code
OL1 2JH
Country
United Kingdom
12. IPD Sharing Statement
Learn more about this trial
Combination Study of Deferasirox and Erythropoietin in Patients With Low- and Int-1-risk Myelodysplastic Syndrome.
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