Safety and Efficacy of Deferasirox in Combination With Desferoxamine in β-thalassaemia Patients With Severe Cardiac Iron Overload

Sponsor
Novartis Pharmaceuticals (Industry)
Overall Status
Terminated
CT.gov ID
NCT01459718
Collaborator
(none)
32
Enrollment
4
Locations
1
Arm
41
Duration (Months)
8
Patients Per Site
0.2
Patients Per Site Per Month

Study Details

Study Description

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.

Condition or DiseaseIntervention/TreatmentPhase
Phase 2

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.

Study Design

Study Type:
Interventional
Actual Enrollment :
32 participants
Allocation:
N/A
Intervention Model:
Single Group Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Multicenter Open Label Phase II Study to Evaluate the Safety and Efficacy of Deferasirox in Combination With Deferoxamine Followed by Transitioning to Deferasirox Monotherapy in β-thalassemia Patients With Severe Cardiac Iron Overload
Study Start Date :
Jan 1, 2011
Actual Primary Completion Date :
Jun 1, 2014
Actual Study Completion Date :
Jun 1, 2014

Arms and Interventions

ArmIntervention/Treatment
Experimental: 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.

Drug: Deferasirox
20-40 mg/kg/day orally, once daily
Other Names:
  • ICL670, Exjade
  • Drug: Deferoxamine (DFO)
    40 mg/kg/day subcutaneous (sc) infusion, 3-4 days per week
    Other Names:
  • DFO, Desferal
  • Outcome Measures

    Primary Outcome Measures

    1. 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.

    2. 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.

    3. 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 Outcome Measures

    1. 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*.

    2. 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]).

    3. 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*.

    4. 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.

    5. Left Ventricular Ejection Fraction (LVEF) [6, 12, 18, 24 months]

      LVEF % was measured by cardiac magnetic resonance (CMR).

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts 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/exclusion criteria may apply

    Contacts and Locations

    Locations

    SiteCityStateCountryPostal Code
    1Novartis Investigative SiteAthensGRGreeceGR-115 27
    2Novartis Investigative SiteAthensGreece11527
    3Novartis Investigative SiteAthensGreeceGR
    4Novartis Investigative SitePatrasGreece265 00

    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:
    NCT01459718
    Other Study ID Numbers:
    • CICL670AGR02
    • 2009-018091-34
    First Posted:
    Oct 26, 2011
    Last Update Posted:
    Oct 23, 2019
    Last Verified:
    Oct 1, 2019

    Study Results

    Participant Flow

    Recruitment DetailsIn 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.
    Pre-assignment Detail
    Arm/Group TitleDeferasirox / Deferasirox + Deferoxamine (DFO)
    Arm/Group DescriptionDuring 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.
    Period Title: Overall Study
    STARTED13
    Safety Analysis Set13
    COMPLETED10
    NOT COMPLETED3

    Baseline Characteristics

    Arm/Group TitleDeferasirox / Deferasirox + Deferoxamine (DFO)
    Arm/Group DescriptionDuring 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.
    Overall Participants13
    Age (Years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [Years]
    32.7
    (4.0)
    Sex: Female, Male (Count of Participants)
    Female
    8
    61.5%
    Male
    5
    38.5%

    Outcome Measures

    1. Primary Outcome
    TitleNumber of Patients Achieving a Complete Response (CR)
    DescriptionComplete 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 Frame24 months

    Outcome Measure Data

    Analysis Population Description
    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/Group TitleDeferasirox / Deferasirox + Deferoxamine (DFO)
    Arm/Group DescriptionDuring 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.
    Measure Participants12
    Count of Participants [Participants]
    4
    30.8%
    2. Primary Outcome
    TitleNumber of Patients Achieving a Partial Response (PR)
    DescriptionPartial 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 Frame24 months

    Outcome Measure Data

    Analysis Population Description
    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/Group TitleDeferasirox / Deferasirox + Deferoxamine (DFO)
    Arm/Group DescriptionDuring 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.
    Measure Participants12
    Count of Participants [Participants]
    0
    0%
    3. Primary Outcome
    TitleNumber of Patients With Stable Disease (SD)
    DescriptionStable 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 Frame24 months

    Outcome Measure Data

    Analysis Population Description
    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/Group TitleDeferasirox / Deferasirox + Deferoxamine (DFO)
    Arm/Group DescriptionDuring 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.
    Measure Participants12
    Count of Participants [Participants]
    8
    61.5%
    4. Secondary Outcome
    TitleChange From Baseline in Cardiac Iron Overload of Patients in Intensive Iron Chelation Therapy Consisting of Deferasirox-DFO and After Transition to Deferasirox Monotherapy
    DescriptionCardiac iron overload was determined by cardiac MRI T2*. Cardiac iron overload also was measured by the monthly velocity of heart MRI T2*.
    Time FrameBaseline, 6, 12, 18, 24 months

    Outcome Measure Data

    Analysis Population Description
    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/Group TitleDeferasirox / Deferasirox + Deferoxamine (DFO)
    Arm/Group DescriptionDuring 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.
    Measure Participants12
    6 months
    0.1
    (1.4)
    12 months
    0.7
    (1.9)
    18 months
    1.3
    (2.4)
    24 months
    2.4
    (3.9)
    5. Secondary Outcome
    TitleTime to Response
    DescriptionTime 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 Frame24 months

    Outcome Measure Data

    Analysis Population Description
    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/Group TitleDeferasirox / Deferasirox + Deferoxamine (DFO)
    Arm/Group DescriptionDuring 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.
    Measure Participants5
    Mean (Standard Deviation) [ms]
    13.0
    (1.1)
    6. Secondary Outcome
    TitleChange From Baseline in Liver Iron Concentration (LIC)
    DescriptionChange from baseline in LIC was determined by change in liver MRI T2*.
    Time FrameBaseline, 6, 12, 18, 24 months

    Outcome Measure Data

    Analysis Population Description
    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/Group TitleDeferasirox / Deferasirox + Deferoxamine (DFO)
    Arm/Group DescriptionDuring 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.
    Measure Participants12
    6 months
    -5
    (7.7)
    12 months
    -10.3
    (9.2)
    18 months
    -10.2
    (10.7)
    24 months
    -12.4
    (10.1)
    7. Secondary Outcome
    TitleCorrelation Between Change From Baseline in Serum Ferritin and LIC Levels
    DescriptionSpearman correlation coefficients between serum ferritin and LIC changes from baseline levels were reported.
    Time FrameBaseline, 6, 12, 18, 24 months

    Outcome Measure Data

    Analysis Population Description
    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/Group TitleDeferasirox / Deferasirox + Deferoxamine (DFO)
    Arm/Group DescriptionDuring 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.
    Measure Participants11
    6 months
    0.091
    12 months
    -0.033
    18 months
    0.347
    24 months
    0.273
    8. Secondary Outcome
    TitleLeft Ventricular Ejection Fraction (LVEF)
    DescriptionLVEF % was measured by cardiac magnetic resonance (CMR).
    Time Frame6, 12, 18, 24 months

    Outcome Measure Data

    Analysis Population Description
    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/Group TitleDeferasirox / Deferasirox + Deferoxamine (DFO)
    Arm/Group DescriptionDuring 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.
    Measure Participants12
    Baseline
    65
    (4.4)
    6 months
    65.4
    (5)
    12 months
    64.8
    (4.6)
    18 months
    65.1
    (4.8)
    24 months
    66.2
    (4.6)

    Adverse Events

    Time Frame
    Adverse Event Reporting Description
    Arm/Group TitleDeferasirox / Deferasirox + Deferoxamine (DFO)
    Arm/Group DescriptionDuring 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.
    All Cause Mortality
    Deferasirox / Deferasirox + Deferoxamine (DFO)
    Affected / at Risk (%)# Events
    Total/ (NaN)
    Serious Adverse Events
    Deferasirox / Deferasirox + Deferoxamine (DFO)
    Affected / at Risk (%)# Events
    Total5/13 (38.5%)
    Blood and lymphatic system disorders
    Haemolysis1/13 (7.7%)
    Cardiac disorders
    Cardiac discomfort1/13 (7.7%)
    Sinus tachycardia1/13 (7.7%)
    Gastrointestinal disorders
    Abdominal discomfort1/13 (7.7%)
    Abdominal pain1/13 (7.7%)
    Gastritis1/13 (7.7%)
    Pancreatitis acute1/13 (7.7%)
    Rectal haemorrhage1/13 (7.7%)
    Vomiting1/13 (7.7%)
    General disorders
    Chest pain1/13 (7.7%)
    Fatigue1/13 (7.7%)
    Pyrexia1/13 (7.7%)
    Immune system disorders
    Hypersensitivity1/13 (7.7%)
    Infections and infestations
    Sepsis1/13 (7.7%)
    Urinary tract infection1/13 (7.7%)
    Renal and urinary disorders
    Nephrolithiasis1/13 (7.7%)
    Renal colic2/13 (15.4%)
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea1/13 (7.7%)
    Surgical and medical procedures
    Lithotripsy1/13 (7.7%)
    Other (Not Including Serious) Adverse Events
    Deferasirox / Deferasirox + Deferoxamine (DFO)
    Affected / at Risk (%)# Events
    Total12/13 (92.3%)
    Blood and lymphatic system disorders
    Thrombocytosis1/13 (7.7%)
    Cardiac disorders
    Angina pectoris1/13 (7.7%)
    Atrial fibrillation1/13 (7.7%)
    Sinus tachycardia1/13 (7.7%)
    Ear and labyrinth disorders
    Ear pain1/13 (7.7%)
    Hypoacusis1/13 (7.7%)
    Tinnitus1/13 (7.7%)
    Endocrine disorders
    Hyperthyroidism1/13 (7.7%)
    Gastrointestinal disorders
    Abdominal discomfort1/13 (7.7%)
    Abdominal distension1/13 (7.7%)
    Abdominal pain3/13 (23.1%)
    Abdominal pain lower2/13 (15.4%)
    Abdominal pain upper2/13 (15.4%)
    Constipation2/13 (15.4%)
    Diarrhoea6/13 (46.2%)
    Gastric disorder1/13 (7.7%)
    Gastrointestinal disorder3/13 (23.1%)
    Nausea2/13 (15.4%)
    Toothache1/13 (7.7%)
    Vomiting1/13 (7.7%)
    General disorders
    Chest pain1/13 (7.7%)
    Discomfort1/13 (7.7%)
    Fatigue1/13 (7.7%)
    Gait disturbance1/13 (7.7%)
    Malaise1/13 (7.7%)
    Pyrexia4/13 (30.8%)
    Immune system disorders
    Hypersensitivity2/13 (15.4%)
    Seasonal allergy1/13 (7.7%)
    Infections and infestations
    Abscess1/13 (7.7%)
    Bronchitis1/13 (7.7%)
    Ear infection1/13 (7.7%)
    Gastroenteritis2/13 (15.4%)
    Nasopharyngitis1/13 (7.7%)
    Respiratory tract infection2/13 (15.4%)
    Rhinitis2/13 (15.4%)
    Tooth abscess1/13 (7.7%)
    Upper respiratory tract infection3/13 (23.1%)
    Viral infection2/13 (15.4%)
    Viral upper respiratory tract infection2/13 (15.4%)
    Injury, poisoning and procedural complications
    Arthropod bite1/13 (7.7%)
    Muscle contusion1/13 (7.7%)
    Investigations
    Blood pressure increased1/13 (7.7%)
    Musculoskeletal and connective tissue disorders
    Arthralgia5/13 (38.5%)
    Back pain3/13 (23.1%)
    Bone pain1/13 (7.7%)
    Musculoskeletal pain1/13 (7.7%)
    Myalgia2/13 (15.4%)
    Nervous system disorders
    Dizziness2/13 (15.4%)
    Facial neuralgia1/13 (7.7%)
    Headache4/13 (30.8%)
    Hypotonia1/13 (7.7%)
    Presyncope1/13 (7.7%)
    Sciatica1/13 (7.7%)
    Syncope1/13 (7.7%)
    Reproductive system and breast disorders
    Dysmenorrhoea1/13 (7.7%)
    Genital burning sensation1/13 (7.7%)
    Menstrual disorder1/13 (7.7%)
    Respiratory, thoracic and mediastinal disorders
    Catarrh3/13 (23.1%)
    Cough4/13 (30.8%)
    Dysphonia1/13 (7.7%)
    Paranasal sinus discomfort1/13 (7.7%)
    Respiratory distress1/13 (7.7%)
    Rhinitis allergic1/13 (7.7%)
    Skin and subcutaneous tissue disorders
    Photosensitivity reaction1/13 (7.7%)
    Surgical and medical procedures
    Tooth extraction2/13 (15.4%)
    Tooth repair1/13 (7.7%)
    Wisdom teeth removal1/13 (7.7%)

    Limitations/Caveats

    Study was terminated. Efficacy was not powered for analysis due to the low enrollment of only 13 patients.

    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 the pooled data (i.e., data from all sites) in the clinical trial or disclosure of trial results in their entirety.

    Results Point of Contact

    Name/TitleStudy Director
    OrganizationNovartis Pharmaceuticals
    Phone862-778-1873
    Email
    Responsible Party:
    Novartis Pharmaceuticals
    ClinicalTrials.gov Identifier:
    NCT01459718
    Other Study ID Numbers:
    • CICL670AGR02
    • 2009-018091-34
    First Posted:
    Oct 26, 2011
    Last Update Posted:
    Oct 23, 2019
    Last Verified:
    Oct 1, 2019