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Safety and Efficacy of Exjade in the Treatment of Transfusion-dependent Iron Overload in Aplastic Anemia Patients

Sponsor
Novartis Pharmaceuticals (Industry)
Overall Status
Terminated
CT.gov ID
NCT01818726
Collaborator
(none)
15
Enrollment
1
Location
2
Arms
27.8
Actual Duration (Months)
0.5
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Evaluated Exjade efficacy and safety in patients with aplastic anemia and transfusion-dependent iron overload, undergoing treatment programs of immunosuppressive treatment (Cyclosporine A) , in comparison with a group of patients undergoing treatment programs of immunosuppressive treatment (Cyclosporine A) without chelation therapy.

Condition or Disease Intervention/Treatment Phase
Phase 4

Detailed Description

The secondary endpoints that were originally planned for this study were not analyzed as the study ended prematurely.

Study Design

Study Type:
Interventional
Actual Enrollment :
15 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
Open-label Study of Exjade in the Treatment of Transfusion-dependent Iron Overload in Aplastic Anemia Patients Undergoing Treatment Programs in Comparison With Control Group
Actual Study Start Date :
Jun 23, 2014
Actual Primary Completion Date :
Oct 17, 2016
Actual Study Completion Date :
Oct 17, 2016

Arms and Interventions

Arm Intervention/Treatment
Experimental: Serum ferritin level ≥ 1,000 μg/l

Transfusion-dependent adult patients with AA and serum ferritin ≥ 1000 mg/L on programmed immune suppressive treatment with cyclosporine A who were receiving chelation with Exjade (deferasirox) during the study

Drug: ICL670
ICL670 was supplied in registered packages as 250mg or 500mg dispersible tablets.
Other Names:
  • Deferasirox

    • Drug: Chelation
    Main group of patients with aplastic anemia and transfusion-dependent iron overload underwent treatment programs of standard immunosuppressive treatment (immunosupressant - Cyclosporine A) and received chelation with ICL670 (deferasirox).
    Experimental: Serum ferritin level < 1,000 μg/l

    Transfusion-dependent adult patients with AA and serum ferritin < 1,000 mg/L on programmed immune suppressive treatment with cyclosporine A who were not receiving the investigational product

    Drug: No chelation
    Comparative group of patients with aplastic anemia and transfusion-dependent iron overload underwent treatment programs of standard immunosuppressive treatment ( immunosupressant -Cyclosporine A)

    Outcome Measures

    Primary Outcome Measures

    1. Change in Serum Ferritin Values [Screening, Week (Wk) 4, Wk 8, Wk 12, Wk 16, Wk 20, Wk 24, Wk 28, Wk 32, Wk 36, Wk 40, Wk 44, Wk 48, Wk 52]

      Change from baseline was be summarized descriptively for all on-treatment study visits. Changes to the planned statistical analysis were related to significant withdrawal of patients from the Per-Protocol Analysis Set due to a large number of patients who discontinued the study (lack of assessments of iron exchange parameters at visits) and deviations from the Protocol affecting the assessment of efficacy parameters. Because of that, the additional efficacy analysis in the Per-Protocol Analysis Set was not performed.

    2. Change in Transferrin Saturation With Iron (TSI) Values [Screening, Week (Wk) 4, Wk 8, Wk 12, Wk 16, Wk 20, Wk 24, Wk 28, Wk 32, Wk 36, Wk 40, Wk 44, Wk 48, Wk 52]

      Mean percentage change from baseline in transferrin saturation with iron was summarized descriptively for all on-treatment study visits.

    3. Change in Serum Total Iron-binding Capacity (TIBC) [Screening, Week (Wk) 4, Wk 8, Wk 12, Wk 16, Wk 20, Wk 24, Wk 28, Wk 32, Wk 36, Wk 40, Wk 44, Wk 48, Wk 52]

      Mean change from baseline in serum total iron-binding capacity was summarized descriptively for all on-treatment study visits.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:

    • Main diagnosis: aplastic anemia

    • Absence of severe and/or uncontrolled comorbidities

    • Confirmed iron overload (serum ferritin ≥ 1000 mkg/L)

    • Serum creatinine is not higher than the upper limit of normal for the given age

    • Absence of severe proteinuria. Protein/Creatinine ratio should be < 0.5 mg/mg

    • Liver enzymes are < 5 ULN

    • Completion of a scheduled cycle of immunosuppressive treatment program, with no severe infectious or generalized hemorrhagic complications

    • WHO (ECOG) performance status ≤ 2

    Exclusion Criteria:

    • No signed informed consent form

    • Patient is under 18 years old

    • Severe concomitant condition

    • Severe infectious and generalized haemorrhagic complication following regular planned cycle of programmed immune suppressive treatment.

    • History of increased sensitivity to active substance and any other ingredient of the medicinal product.

    • Creatinine clearance (CC) < 60 ml/min and/or creatinine concentration in blood serum is 2 or more times higher than upper limit of age normal by results of 2 tests at Visits 1 and 2.

    • Severe liver disorders (class C by Child-Pugh scale).

    • Patients with aplastic anaemia in which chelator treatment will be ineffective due to rapid progression of the disease.

    • Significant proteinuria basing on protein creatinine ratio > 1.0 mg/ml in urine sample from second urination at Visits 1 and 2 (or as an alternative in 2 of 3 urine samples at screening);

    • Rare hereditary disorders related to galactose intolerance, severe deficit of lactase or glucose-galactose malabsorption;

    • Pregnancy, lactation;

    • Level of liver enzymes higher than 5 upper limits of age normal at Visits 1 and 2.

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Novartis Investigative Site Moscow Russian Federation 125167

    Sponsors and Collaborators

    • Novartis Pharmaceuticals

    Investigators

    • Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    Novartis Pharmaceuticals
    ClinicalTrials.gov Identifier:
    NCT01818726
    Other Study ID Numbers:
    • CICL670ARU02
    First Posted:
    Mar 26, 2013
    Last Update Posted:
    Aug 16, 2019
    Last Verified:
    Jul 1, 2019
    Individual Participant Data (IPD) Sharing Statement:
    Yes
    Plan to Share IPD:
    Yes
    Studies a U.S. FDA-regulated Drug Product:
    No
    Studies a U.S. FDA-regulated Device Product:
    No
    Keywords provided by Novartis Pharmaceuticals
    Aplastic anemia
    deferasirox
    ICL670
    renal function
    transfusion-dependent iron overload
    immunosuppressive treatment
    Cyclosporine A
    unosuppressive treatment without chelation therapy
    Additional relevant MeSH terms:
    Anemia
    Anemia, Aplastic
    Iron Overload
    Deferasirox

    Study Results

    Participant Flow

    Recruitment Details Estimated number of patients was 25; the actual number of patients enrolled in the study and included in efficacy analysis was 15.
    Pre-assignment Detail The study enrolled adult transfusion-dependent patients with Aplastic Anaemia (AA) on programmed immune suppressive treatment.
    Arm/Group Title Serum Ferritin Level ≥ 1,000 μg/l Serum Ferritin Level < 1,000 μg/l
    Arm/Group Description Transfusion-dependent adult patients with AA and serum ferritin ≥ 1000 mg/L on programmed immune suppressive treatment with cyclosporine A who were receiving chelation with Exjade (deferasirox) during the study Transfusion-dependent adult patients with AA and serum ferritin < 1,000 mg/L on programmed immune suppressive treatment with cyclosporine A who were not receiving the investigational product
    Period Title: Overall Study
    STARTED 10 5
    COMPLETED 4 3
    NOT COMPLETED 6 2

    Baseline Characteristics

    Arm/Group Title Serum Ferritin Level ≥ 1,000 μg/l Serum Ferritin Level < 1,000 μg/l Total
    Arm/Group Description Transfusion-dependent adult patients with AA and serum ferritin ≥ 1000 mg/L on programmed immune suppressive treatment with cyclosporine A who were receiving chelation with Exjade (deferasirox) during the study Transfusion-dependent adult patients with AA and serum ferritin < 1,000 mg/L on programmed immune suppressive treatment with cyclosporine A who were not receiving the investigational product Total of all reporting groups
    Overall Participants 10 5 15
    Age (Years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [Years]
    34.0
    (9.33)
    37.0
    (10.10)
    35.0
    (9.34)
    Sex: Female, Male (Count of Participants)
    Female
    6
    60%
    4
    80%
    10
    66.7%
    Male
    4
    40%
    1
    20%
    5
    33.3%
    Race/Ethnicity, Customized (Number) [Number]
    Caucasian
    10
    100%
    5
    100%
    15
    100%

    Outcome Measures

    1. Primary Outcome
    Title Change in Serum Ferritin Values
    Description Change from baseline was be summarized descriptively for all on-treatment study visits. Changes to the planned statistical analysis were related to significant withdrawal of patients from the Per-Protocol Analysis Set due to a large number of patients who discontinued the study (lack of assessments of iron exchange parameters at visits) and deviations from the Protocol affecting the assessment of efficacy parameters. Because of that, the additional efficacy analysis in the Per-Protocol Analysis Set was not performed.
    Time Frame Screening, Week (Wk) 4, Wk 8, Wk 12, Wk 16, Wk 20, Wk 24, Wk 28, Wk 32, Wk 36, Wk 40, Wk 44, Wk 48, Wk 52

    Outcome Measure Data

    Analysis Population Description
    Full Analysis Set included all patients of the Safety Analysis Set with available baseline data & data obtained at follow-up visits &/or final visit, for evaluation of at least 1 efficacy parameter. Statistical analysis was not performed due to large number of patients discontinuing & thus lack of assessments of iron exchange parameters at visits.
    Arm/Group Title Serum Ferritin Level ≥ 1,000 μg/l Serum Ferritin Level < 1,000 μg/l
    Arm/Group Description Transfusion-dependent adult patients with AA and serum ferritin ≥ 1000 mg/L on programmed immune suppressive treatment with cyclosporine A who were receiving chelation with Exjade (deferasirox) during the study Transfusion-dependent adult patients with AA and serum ferritin < 1,000 mg/L on programmed immune suppressive treatment with cyclosporine A who were not receiving the investigational product
    Measure Participants 10 5
    Screening
    2866.14
    (1460.13)
    769.02
    (230.36)
    Week 0
    2895.62
    (1245.81)
    727.68
    (299.61)
    Week 4
    2089.62
    (638.29)
    640.75
    (292.14)
    Week 8
    2498.58
    (1165.94)
    623.14
    (223.27)
    Week 12
    2262.12
    (916.65)
    653.62
    (311.72)
    Week 16
    2164.01
    (886.93)
    647.58
    (225.28)
    Week 20
    2054.23
    (729.14)
    646.80
    (147.73)
    Week 24
    1710.67
    (653.13)
    680.08
    (182.24)
    Week 28
    1446.07
    (395.17)
    526.17
    (122.40)
    Week 32
    1626.28
    (689.86)
    687.37
    (114.47)
    Week 36
    1709.07
    (1153.94)
    699.13
    (217.38)
    Week 40
    1897.05
    (1107.95)
    717.33
    (306.63)
    Week 44
    1301.80
    (460.31)
    661.13
    (267.15)
    Week 48
    1740.00
    (1493.24)
    709.50
    (305.32)
    Week 52
    1288.80
    (NA)
    655.07
    (277.98)
    2. Primary Outcome
    Title Change in Transferrin Saturation With Iron (TSI) Values
    Description Mean percentage change from baseline in transferrin saturation with iron was summarized descriptively for all on-treatment study visits.
    Time Frame Screening, Week (Wk) 4, Wk 8, Wk 12, Wk 16, Wk 20, Wk 24, Wk 28, Wk 32, Wk 36, Wk 40, Wk 44, Wk 48, Wk 52

    Outcome Measure Data

    Analysis Population Description
    Full Analysis Set (FAS) included all patients of the Safety Analysis Set with the available baseline data, as well as data obtained at follow-up visits and/or the final visit, for evaluation of at least one efficacy parameter.
    Arm/Group Title Serum Ferritin Level ≥ 1,000 μg/l Serum Ferritin Level < 1,000 μg/l
    Arm/Group Description Transfusion-dependent adult patients with AA and serum ferritin ≥ 1000 mg/L on programmed immune suppressive treatment with cyclosporine A who were receiving chelation with Exjade (deferasirox) during the study Transfusion-dependent adult patients with AA and serum ferritin < 1,000 mg/L on programmed immune suppressive treatment with cyclosporine A who were not receiving the investigational product
    Measure Participants 10 5
    Screening
    88.80
    (10.01)
    53.70
    (10.28)
    Week 0
    87.19
    (10.49)
    54.88
    (14.50)
    Week 4
    73.37
    (8.55)
    50.10
    (14.14)
    Week 8
    72.68
    (9.49)
    49.54
    (17.12)
    Week 12
    72.43
    (5.98)
    49.04
    (10.15)
    Week 16
    68.60
    (9.21)
    52.78
    (9.21)
    Week 20
    68.14
    (19.64)
    50.65
    (11.45)
    Week 24
    74.30
    (11.79)
    5.90
    (5.59)
    Week 28
    65.05
    (7.57)
    52.67
    (12.49)
    Week 32
    75.75
    (12.98)
    49.90
    (11.96)
    Week 36
    65.94
    (13.87)
    47.83
    (4.91)
    Week 40
    66.05
    (9.51)
    43.07
    (2.57)
    Week 44
    69.22
    (16.95)
    33.27
    (9.63)
    Week 48
    71.07
    (12.87)
    44.20
    (1.39)
    Week 52
    83.40
    (11.74)
    43.57
    (4.09)
    3. Primary Outcome
    Title Change in Serum Total Iron-binding Capacity (TIBC)
    Description Mean change from baseline in serum total iron-binding capacity was summarized descriptively for all on-treatment study visits.
    Time Frame Screening, Week (Wk) 4, Wk 8, Wk 12, Wk 16, Wk 20, Wk 24, Wk 28, Wk 32, Wk 36, Wk 40, Wk 44, Wk 48, Wk 52

    Outcome Measure Data

    Analysis Population Description
    Full Analysis Set (FAS) included all patients of the Safety Analysis Set with the available baseline data, as well as data obtained at follow-up visits and/or the final visit, for evaluation of at least one efficacy parameter.
    Arm/Group Title Serum Ferritin Level ≥ 1,000 μg/l Serum Ferritin Level < 1,000 μg/l
    Arm/Group Description Transfusion-dependent adult patients with AA and serum ferritin ≥ 1000 mg/L on programmed immune suppressive treatment with cyclosporine A who were receiving chelation with Exjade (deferasirox) during the study Transfusion-dependent adult patients with AA and serum ferritin < 1,000 mg/L on programmed immune suppressive treatment with cyclosporine A who were not receiving the investigational product
    Measure Participants 10 5
    Screening
    4.51
    (9.34)
    66.68
    (14.95)
    Week 0
    49.98
    (10.17)
    49.10
    (5.73)
    Week 4
    78.70
    (20.93)
    49.00
    (4.95)
    Week 8
    73.90
    (10.97)
    47.44
    (5.09)
    Week 12
    83.56
    (19.86)
    47.20
    (4.68)
    Week 16
    85.31
    (23.12)
    49.53
    (8.03)
    Week 20
    74.34
    (18.95)
    48.63
    (4.46)
    Week 24
    81.90
    (27.17)
    46.53
    (5.82)
    Week 28
    101.90
    (23.71)
    45.97
    (4.14)
    Week 32
    72.85
    (25.92)
    48.23
    (2.05)
    Week 36
    76.56
    (19.13)
    47.53
    (2.60)
    Week 40
    83.50
    (19.74)
    46.30
    (4.49)
    Week 44
    71.56
    (23.95)
    44.10
    (4.22)
    Week 48
    74.30
    (11.61)
    45.70
    (5.57)
    Week 52
    67.10
    (26.87)
    46.77
    (5.39)

    Adverse Events

    Time Frame Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 376 days.
    Adverse Event Reporting Description
    Arm/Group Title Serum Ferritin Level ≥ 1,000 μg/l Serum Ferritin Level < 1,000 μg/l
    Arm/Group Description Transfusion-dependent adult patients with AA and serum ferritin ≥ 1000 mg/L on programmed immune suppressive treatment with cyclosporine A who were receiving chelation with Exjade (deferasirox) during the study Transfusion-dependent adult patients with AA and serum ferritin < 1,000 mg/L on programmed immune suppressive treatment with cyclosporine A who were not receiving the investigational product
    All Cause Mortality
    Serum Ferritin Level ≥ 1,000 μg/l Serum Ferritin Level < 1,000 μg/l
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 0/10 (0%) 0/5 (0%)
    Serious Adverse Events
    Serum Ferritin Level ≥ 1,000 μg/l Serum Ferritin Level < 1,000 μg/l
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 0/10 (0%) 0/5 (0%)
    Other (Not Including Serious) Adverse Events
    Serum Ferritin Level ≥ 1,000 μg/l Serum Ferritin Level < 1,000 μg/l
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 4/10 (40%) 0/5 (0%)
    Gastrointestinal disorders
    Nausea 1/10 (10%) 2 0/5 (0%) 0
    Constipation 1/10 (10%) 1 0/5 (0%) 0
    Diarrhea 1/10 (10%) 1 0/5 (0%) 0
    General disorders
    Weakness 1/10 (10%) 2 0/5 (0%) 0
    Investigations
    Blood creatine increased 2/10 (20%) 2 0/5 (0%) 0
    Skin and subcutaneous tissue disorders
    Rash 1/10 (10%) 1 0/5 (0%) 0

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of pooled data (i.e.,data from all sites) in clinical trial or disclosure of trial results in their entirety

    Results Point of Contact

    Name/Title Study Director
    Organization Novartis Pharmaceuticals
    Phone 862-778-8300
    Email novartis.email@novartis.com
    Responsible Party:
    Novartis Pharmaceuticals
    ClinicalTrials.gov Identifier:
    NCT01818726
    Other Study ID Numbers:
    • CICL670ARU02
    First Posted:
    Mar 26, 2013
    Last Update Posted:
    Aug 16, 2019
    Last Verified:
    Jul 1, 2019