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IronIC: Intravenous Iron Supplement for Iron Deficiency in Cardiac Transplant Recipients

Sponsor
Oslo University Hospital (Other)
Overall Status
Completed
CT.gov ID
NCT03662789
Collaborator
Pharmacosmos A/S (Industry)
102
Enrollment
1
Location
2
Arms
22.1
Actual Duration (Months)
4.6
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Iron deficiency is prevalent in heart transplant recipients, and may be associated with reduced functional capacity. The IronIC trial is designed to assess the effect of intravenous iron isomaltoside on exercise capacity, muscle strength, cognition and quality of life in iron-deficient heart transplant recipients

Condition or Disease Intervention/Treatment Phase
  • Drug: Iron Isomaltoside 1000
  • Other: Placebo: NaCl 0,9%
 Phase 2/Phase 3

Detailed Description

Iron deficiency is prevalent in patients with heart failure. Iron deficiency is associated with a worse prognosis, and randomised controlled trials have shown that correction of iron deficiency with intravenous iron therapy improves functional capacity, quality of life, and 6-minute walk distance. Current guidelines therefore recommend intravenous iron substitution in patients with heart failure with reduced ejection fraction and iron deficiency. Intravenous iron is more effective, better tolerated, and improves quality of life to a greater extent than oral iron supplements. In the IRONOUT HF trial, in which 225 patients with systolic heart failure were randomised to oral iron supplement or placebo, there was no effect on oxygen uptake, 6-minute walk distance, or quality of life. The authors attributed the negative results to the minimal effect on iron stores, suggesting that oral iron does not adequately replenish iron stores in patients with heart failure.

Cardiac allograft recipients resemble patients with heart failure in many respects. Prior to transplantation, and in some instances after heart transplantation, they have had overt heart failure. Moreover, due to the immunologic challenge posed by the allograft, and their susceptibility to infection due to immunosuppressive treatment, cardiac allograft recipients have low-grade inflammation. This low-grade inflammation makes it difficult to interpret iron stores, and results in dysregulated iron metabolism.

There have been no studies to assess the effect of intravenous iron therapy in heart transplant recipients who have iron deficiency. There is reason to believe that a liberal definition of iron deficiency should be used in cardiac allograft recipients, and the investigators have elected to use the well-established definition used in patients with heart failure: serum ferritin < 100 µg/l or ferritin between 100 and 300 µg/l in combination with a transferrin saturation < 20 %. Because oral iron supplement is less effective then intravenous iron in general, and in patients with heart failure in particular, the investigators assume that oral iron supplement is inadequate in heart transplant recipients. the investigators have designed the IronIC trial to assess the effect of intravenous iron isomaltoside on exercise capacity, muscle strength, cognition and quality of life in iron-deficient heart transplant recipients.

Study Design

Study Type:
Interventional
Actual Enrollment :
102 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Intervention Model Description:
Randomized, placebo controlled, parallel group, double blind designRandomized, placebo controlled, parallel group, double blind design
Masking:
Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description:
Opaque envelopes, infusion administered by third party, concealed infusion
Primary Purpose:
Treatment
Official Title:
Intravenous Iron Supplement for Iron Deficiency in Cardiac Transplant Recipients
Actual Study Start Date :
Apr 25, 2018
Actual Primary Completion Date :
Feb 27, 2020
Actual Study Completion Date :
Feb 27, 2020

Arms and Interventions

Arm Intervention/Treatment
Active Comparator: Iron isomaltoside 1000

The active drug, iron isomaltoside 1000 will be administered as a single, intravenous infusion of 20 mg/kg body weight (rounded off to the nearest 100 mg) dissolved in 100 ml NaCl as recommended by the drug manufacturer ("on-label" treatment).

Drug: Iron Isomaltoside 1000
Intravenous infusion
Other Names:
  • Monofer B03AC-

    		•
    Placebo Comparator: Placebo

    Patients allocated to placebo will receive an intravenous infusion of 100 ml NaCl 0.9%

    Other: Placebo: NaCl 0,9%
    Intravenous infusion

    Outcome Measures

    Primary Outcome Measures

    1. Peak Oxygen Consumption [6 months after intervention]

      The primary endpoint will be the baseline-adjusted between-group difference in peak oxygen consumption as measured on a treadmill exercise test

    Secondary Outcome Measures

    1. Iron Deficiency [6 months after intervention]

      The number of patients with absolute or functional iron deficiency

    2. Muscle Strength [6 months after intervention]

      Baseline-adjusted muscle strength as measured by a hand-grip dynamometer

    3. Health Related Quality of Life: SF-36, Physical Component Summary (PCS) [6 months after intervention]

      Baseline-adjusted quality of life as assessed with the 36-item short form survey (SF-36), which measures each of the following 8 health domains: 1= general health, 2= physical function, 3= role physical, 4= bodily pain, 5= vitality, 6= social function, 7= role emotional, 8= mental health. Total score for each domain are scaled 0 (minimum) to 100 (maximum), where higher scores represented higher level of functioning. Two norm-based sum scores, the physical and the mental component summaries with a mean of 50±10, were generated from the eight scale scores using a T-score transformation. Higher scores represented higher level of functioning.

    4. N-terminal Pro-B-type Natriuretic Peptide (NT-proBNP) [6 months after intervention]

      The between-group difference in baseline-adjusted NT-proBNP

    5. Cardiac Troponin T (TnT) [6 months after intervention]

      The between-group difference in baseline-adjusted TnT

    6. Health Related Quality of Life: SF-36, Mental Component Summary (MCS) [6 months after intervention]

      Baseline-adjusted quality of life as assessed with the 36-item short form survey (SF-36), which measures each of the following 8 health domains: 1= general health, 2= physical function, 3= role physical, 4= bodily pain, 5= vitality, 6= social function, 7= role emotional, 8= mental health. Total score for each domain are scaled 0 (minimum) to 100 (maximum), where higher scores represented higher level of functioning. Two norm-based sum scores, the physical and the mental component summaries with a mean of 50±10, were generated from the eight scale scores using a T-score transformation. Higher scores represented higher level of functioning.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years to 80 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:

    • Cardiac allograft.

    • Presentation at least one year after heart transplantation.

    • Iron deficiency defined as serum ferritin < 100 µg/l or ferritin between 100 and 300 µg/l in combination with a transferrin saturation < 20 %.

    • Age between 18 and 80 years.

    • Informed consent obtained and documented according to Good Clinical Practice (GCP), and national/regional regulations.

    Exclusion Criteria:

    • Anaemia (Haemoglobin < 100 mg/l)

    • Haemochromatosis

    • Haemosiderosis

    • Porphyria cutanea tarda

    • Blood dyscrasias or any disorders causing haemolysis or unstable red blood cells

    • Decompensated liver disease (Child-Pugh score 7 or higher)

    • End-stage renal failure, i.e. estimated glomerular filtration rate < 15 ml/min or on renal replacement therapy

    • Planned cardiac surgery or angioplasty within 6 months

    • Planned major surgery within 6 months

    • Medical history of unresolved cancer (except for basal cell carcinoma)

    • Treatment with systemic steroids more than the equivalent of 10 mg Prednisone/day at the time of informed consent or change in dosage of thyroid hormones within 6 weeks prior to informed consent

    • Any uncontrolled endocrine disorder except type 2 diabetes

    • Pregnancy

    • On erythropoietin analogues

    • Known sensitivity or intolerance to iron isomaltoside or other parenteral iron preparations

    • Intravenous iron supplement within 6 months prior to inclusion

    • On oral iron substitution (unless the subject agrees to stop treatment prior to randomisation)

    • Ongoing rejections or infections

    • Alcohol or drug abuse within 3 months of informed consent that would interfere with trial participation or any ongoing condition leading to decreased compliance with study procedures or study drug intake

    • Intake of an investigational drug in another trial within 30 days prior to intake of study medication in this trial or participating in another trial involving an investigational drug and/or follow-up

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Oslo university Hospital, Rikshospitalet Oslo Norway 0372

    Sponsors and Collaborators

    • Oslo University Hospital
    • Pharmacosmos A/S

    Investigators

    • Principal Investigator: Lars Gullestad, MD, PhD, Oslo University Hospital

    Study Documents (Full-Text)

    More Information

    Publications

    Responsible Party:
    Lars Gullestad, Professor, Oslo University Hospital
    ClinicalTrials.gov Identifier:
    NCT03662789
    Other Study ID Numbers:
    • IronIC
    First Posted:
    Sep 7, 2018
    Last Update Posted:
    May 25, 2021
    Last Verified:
    Apr 1, 2021
    Individual Participant Data (IPD) Sharing Statement:
    No
    Plan to Share IPD:
    No
    Studies a U.S. FDA-regulated Drug Product:
    No
    Studies a U.S. FDA-regulated Device Product:
    No
    Product Manufactured in and Exported from the U.S.:
    No
    Keywords provided by Lars Gullestad, Professor, Oslo University Hospital
    Heart transplant
    Iron deficiency
    Intravenous iron supplement
    Peak oxygen consumption
    Cardiopulmonary exercise test
    Cognitive function
    Muscle strength
    Additional relevant MeSH terms:
    Anemia, Iron-Deficiency
    Iron isomaltoside 1000

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail
    Arm/Group Title Iron Isomaltoside 1000 Placebo
    Arm/Group Description The active drug, iron isomaltoside 1000 will be administered as a single, intravenous infusion of 20 mg/kg body weight (rounded off to the nearest 100 mg) dissolved in 100 ml NaCl as recommended by the drug manufacturer ("on-label" treatment). Iron Isomaltoside 1000: Intravenous infusion Patients allocated to placebo will receive an intravenous infusion of 100 ml NaCl 0.9% Placebo: NaCl 0,9%: Intravenous infusion
    Period Title: Overall Study
    STARTED 52 50
    COMPLETED 47 43
    NOT COMPLETED 5 7

    Baseline Characteristics

    Arm/Group Title Iron Isomaltoside 1000 Placebo Total
    Arm/Group Description The active drug, iron isomaltoside 1000 will be administered as a single, intravenous infusion of 20 mg/kg body weight (rounded off to the nearest 100 mg) dissolved in 100 ml NaCl as recommended by the drug manufacturer ("on-label" treatment). Iron Isomaltoside 1000: Intravenous infusion Patients allocated to placebo will receive an intravenous infusion of 100 ml NaCl 0.9% Placebo: NaCl 0,9%: Intravenous infusion Total of all reporting groups
    Overall Participants 52 50 102
    Age (Count of Participants)
    <=18 years
    0
    0%
    0
    0%
    0
    0%
    Between 18 and 65 years
    34
    65.4%
    39
    78%
    73
    71.6%
    >=65 years
    18
    34.6%
    11
    22%
    29
    28.4%
    Age (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    55
    (15)
    55
    (14)
    55
    (14)
    Sex: Female, Male (Count of Participants)
    Female
    18
    34.6%
    19
    38%
    37
    36.3%
    Male
    34
    65.4%
    31
    62%
    65
    63.7%
    Race and Ethnicity Not Collected (Count of Participants)
    Count of Participants [Participants]
    0
    0%
    Region of Enrollment (participants) [Number]
    Norway
    52
    100%
    50
    100%
    102
    100%
    Peak oxygen consumption (ml/kg/min) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [ml/kg/min]
    24.3
    (7.3)
    22.3
    (6.0)
    23.4
    (6.8)

    Outcome Measures

    1. Primary Outcome
    Title Peak Oxygen Consumption
    Description The primary endpoint will be the baseline-adjusted between-group difference in peak oxygen consumption as measured on a treadmill exercise test
    Time Frame 6 months after intervention

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Iron Isomaltoside 1000 Placebo
    Arm/Group Description The active drug, iron isomaltoside 1000 will be administered as a single, intravenous infusion of 20 mg/kg body weight (rounded off to the nearest 100 mg) dissolved in 100 ml NaCl as recommended by the drug manufacturer ("on-label" treatment). Iron Isomaltoside 1000: Intravenous infusion Patients allocated to placebo will receive an intravenous infusion of 100 ml NaCl 0.9% Placebo: NaCl 0,9%: Intravenous infusion
    Measure Participants 47 43
    Mean (Standard Deviation) [ml/kg/min]
    23.9
    (6.6)
    22.0
    (6.1)
    2. Secondary Outcome
    Title Iron Deficiency
    Description The number of patients with absolute or functional iron deficiency
    Time Frame 6 months after intervention

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Iron Isomaltoside 1000 Placebo
    Arm/Group Description The active drug, iron isomaltoside 1000 will be administered as a single, intravenous infusion of 20 mg/kg body weight (rounded off to the nearest 100 mg) dissolved in 100 ml NaCl as recommended by the drug manufacturer ("on-label" treatment). Iron Isomaltoside 1000: Intravenous infusion Patients allocated to placebo will receive an intravenous infusion of 100 ml NaCl 0.9% Placebo: NaCl 0,9%: Intravenous infusion
    Measure Participants 47 43
    Count of Participants [Participants]
    7
    13.5%
    40
    80%
    3. Secondary Outcome
    Title Muscle Strength
    Description Baseline-adjusted muscle strength as measured by a hand-grip dynamometer
    Time Frame 6 months after intervention

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Iron Isomaltoside 1000 Placebo
    Arm/Group Description The active drug, iron isomaltoside 1000 will be administered as a single, intravenous infusion of 20 mg/kg body weight (rounded off to the nearest 100 mg) dissolved in 100 ml NaCl as recommended by the drug manufacturer ("on-label" treatment). Iron Isomaltoside 1000: Intravenous infusion Patients allocated to placebo will receive an intravenous infusion of 100 ml NaCl 0.9% Placebo: NaCl 0,9%: Intravenous infusion
    Measure Participants 47 43
    Mean (Standard Deviation) [kg]
    40
    (13)
    38
    (12)
    4. Secondary Outcome
    Title Health Related Quality of Life: SF-36, Physical Component Summary (PCS)
    Description Baseline-adjusted quality of life as assessed with the 36-item short form survey (SF-36), which measures each of the following 8 health domains: 1= general health, 2= physical function, 3= role physical, 4= bodily pain, 5= vitality, 6= social function, 7= role emotional, 8= mental health. Total score for each domain are scaled 0 (minimum) to 100 (maximum), where higher scores represented higher level of functioning. Two norm-based sum scores, the physical and the mental component summaries with a mean of 50±10, were generated from the eight scale scores using a T-score transformation. Higher scores represented higher level of functioning.
    Time Frame 6 months after intervention

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Iron Isomaltoside 1000 Placebo
    Arm/Group Description The active drug, iron isomaltoside 1000 will be administered as a single, intravenous infusion of 20 mg/kg body weight (rounded off to the nearest 100 mg) dissolved in 100 ml NaCl as recommended by the drug manufacturer ("on-label" treatment). Iron Isomaltoside 1000: Intravenous infusion Patients allocated to placebo will receive an intravenous infusion of 100 ml NaCl 0.9% Placebo: NaCl 0,9%: Intravenous infusion
    Measure Participants 47 43
    Median (Inter-Quartile Range) [t-score]
    49
    45
    5. Secondary Outcome
    Title N-terminal Pro-B-type Natriuretic Peptide (NT-proBNP)
    Description The between-group difference in baseline-adjusted NT-proBNP
    Time Frame 6 months after intervention

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Iron Isomaltoside 1000 Placebo
    Arm/Group Description The active drug, iron isomaltoside 1000 will be administered as a single, intravenous infusion of 20 mg/kg body weight (rounded off to the nearest 100 mg) dissolved in 100 ml NaCl as recommended by the drug manufacturer ("on-label" treatment). Iron Isomaltoside 1000: Intravenous infusion Patients allocated to placebo will receive an intravenous infusion of 100 ml NaCl 0.9% Placebo: NaCl 0,9%: Intravenous infusion
    Measure Participants 47 43
    Median (Inter-Quartile Range) [ng/l]
    421
    349
    6. Secondary Outcome
    Title Cardiac Troponin T (TnT)
    Description The between-group difference in baseline-adjusted TnT
    Time Frame 6 months after intervention

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Iron Isomaltoside 1000 Placebo
    Arm/Group Description The active drug, iron isomaltoside 1000 will be administered as a single, intravenous infusion of 20 mg/kg body weight (rounded off to the nearest 100 mg) dissolved in 100 ml NaCl as recommended by the drug manufacturer ("on-label" treatment). Iron Isomaltoside 1000: Intravenous infusion Patients allocated to placebo will receive an intravenous infusion of 100 ml NaCl 0.9% Placebo: NaCl 0,9%: Intravenous infusion
    Measure Participants 47 43
    Median (Inter-Quartile Range) [ng/l]
    13.0
    15.0
    7. Secondary Outcome
    Title Health Related Quality of Life: SF-36, Mental Component Summary (MCS)
    Description Baseline-adjusted quality of life as assessed with the 36-item short form survey (SF-36), which measures each of the following 8 health domains: 1= general health, 2= physical function, 3= role physical, 4= bodily pain, 5= vitality, 6= social function, 7= role emotional, 8= mental health. Total score for each domain are scaled 0 (minimum) to 100 (maximum), where higher scores represented higher level of functioning. Two norm-based sum scores, the physical and the mental component summaries with a mean of 50±10, were generated from the eight scale scores using a T-score transformation. Higher scores represented higher level of functioning.
    Time Frame 6 months after intervention

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Iron Isomaltoside 1000 Placebo
    Arm/Group Description The active drug, iron isomaltoside 1000 will be administered as a single, intravenous infusion of 20 mg/kg body weight (rounded off to the nearest 100 mg) dissolved in 100 ml NaCl as recommended by the drug manufacturer ("on-label" treatment). Iron Isomaltoside 1000: Intravenous infusion Patients allocated to placebo will receive an intravenous infusion of 100 ml NaCl 0.9% Placebo: NaCl 0,9%: Intravenous infusion
    Measure Participants 47 43
    Median (Inter-Quartile Range) [t-score]
    56
    53

    Adverse Events

    Time Frame 6 months
    Adverse Event Reporting Description Adverse events were registered at the follow up at 6 months for all participants.
    Arm/Group Title Iron Isomaltoside 1000 Placebo
    Arm/Group Description The active drug, iron isomaltoside 1000 will be administered as a single, intravenous infusion of 20 mg/kg body weight (rounded off to the nearest 100 mg) dissolved in 100 ml NaCl as recommended by the drug manufacturer ("on-label" treatment). Iron Isomaltoside 1000: Intravenous infusion Patients allocated to placebo will receive an intravenous infusion of 100 ml NaCl 0.9% Placebo: NaCl 0,9%: Intravenous infusion
    All Cause Mortality
    Iron Isomaltoside 1000 Placebo
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 0/52 (0%) 1/50 (2%)
    Serious Adverse Events
    Iron Isomaltoside 1000 Placebo
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 5/52 (9.6%) 12/50 (24%)
    Cardiac disorders
    ST-elevation myocardial infarction 1/52 (1.9%) 1 0/50 (0%) 0
    Heart failure 0/52 (0%) 0 1/50 (2%) 1
    Deceased 0/52 (0%) 0 1/50 (2%) 1
    Endocrine disorders
    Hyperthyreosis 0/52 (0%) 0 1/50 (2%) 1
    Hepatobiliary disorders
    Cholelitiasis 1/52 (1.9%) 1 0/50 (0%) 0
    Infections and infestations
    Infection 0/52 (0%) 0 8/50 (16%) 8
    Musculoskeletal and connective tissue disorders
    Fracture 1/52 (1.9%) 1 1/50 (2%) 1
    Respiratory, thoracic and mediastinal disorders
    Dyspnea 2/52 (3.8%) 2 0/50 (0%) 0
    Other (Not Including Serious) Adverse Events
    Iron Isomaltoside 1000 Placebo
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 22/52 (42.3%) 18/50 (36%)
    Blood and lymphatic system disorders
    Bleeding 0/52 (0%) 0 4/50 (8%) 4
    Endocrine disorders
    Diabetes 1/52 (1.9%) 1 0/50 (0%) 0
    Gastrointestinal disorders
    Hernia 0/52 (0%) 0 1/50 (2%) 1
    Reflux 0/52 (0%) 0 1/50 (2%) 1
    Pancreatitis 0/52 (0%) 0 1/50 (2%) 1
    Hepatobiliary disorders
    Elevated liver enzymes 1/52 (1.9%) 1 0/50 (0%) 0
    Infections and infestations
    Infection 12/52 (23.1%) 12 5/50 (10%) 5
    Musculoskeletal and connective tissue disorders
    Gout 1/52 (1.9%) 1 2/50 (4%) 2
    Musculoskeletal pain 1/52 (1.9%) 1 3/50 (6%) 3
    Fatigue 1/52 (1.9%) 1 0/50 (0%) 0
    Skin and subcutaneous tissue disorders
    Hair loss 1/52 (1.9%) 1 0/50 (0%) 0
    Spotty facial discoloration 1/52 (1.9%) 1 0/50 (0%) 0
    Generalized Rash 2/52 (3.8%) 2 0/50 (0%) 0
    Local rash 0/52 (0%) 0 1/50 (2%) 1
    Vascular disorders
    Syncope 1/52 (1.9%) 1 0/50 (0%) 0

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    All Principal Investigators ARE employed by the organization sponsoring the study.

    There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

    Results Point of Contact

    Name/Title Dr. Lars Gullestad
    Organization Oslo University Hospital
    Phone 0047 97644772
    Email lars.gullestad@medisin.uio.no
    Responsible Party:
    Lars Gullestad, Professor, Oslo University Hospital
    ClinicalTrials.gov Identifier:
    NCT03662789
    Other Study ID Numbers:
    • IronIC
    First Posted:
    Sep 7, 2018
    Last Update Posted:
    May 25, 2021
    Last Verified:
    Apr 1, 2021