Intravenous Iron Supplement for Iron Deficiency in Cardiac Transplant Recipients

Status

Completed

Phases

Phase 2Phase 3

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT03662789

Acronym

IronIC

Enrollment

102

Registered

2018-09-07

Start date

2018-04-25

Completion date

2020-02-27

Last updated

2021-05-25

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Heart Transplant Recipients

Keywords

Heart transplant, Iron deficiency, Intravenous iron supplement, Peak oxygen consumption, Cardiopulmonary exercise test, Cognitive function, Muscle strength

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

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.

Interventions

DRUGIron Isomaltoside 1000

Intravenous infusion

OTHERPlacebo: NaCl 0,9%

Intravenous infusion

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)

Masking description

Opaque envelopes, infusion administered by third party, concealed infusion

Intervention model description

Randomized, placebo controlled, parallel group, double blind design

Eligibility

Sex/Gender

ALL

Age

18 Years to 80 Years

Healthy volunteers

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

Design outcomes

Primary

Measure	Time frame	Description
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

Measure	Time frame	Description
Muscle Strength	6 months after intervention	Baseline-adjusted muscle strength as measured by a hand-grip dynamometer
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.
Iron Deficiency	6 months after intervention	The number of patients with absolute or functional iron deficiency
Cardiac Troponin T (TnT)	6 months after intervention	The between-group difference in baseline-adjusted TnT
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.
N-terminal Pro-B-type Natriuretic Peptide (NT-proBNP)	6 months after intervention	The between-group difference in baseline-adjusted NT-proBNP

Countries

Norway

Participant flow

Participants by arm

Arm	Count
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). Iron Isomaltoside 1000: Intravenous infusion	52
Placebo Patients allocated to placebo will receive an intravenous infusion of 100 ml NaCl 0.9% Placebo: NaCl 0,9%: Intravenous infusion	50
Total	102

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	Could not perform treadmill test	4	4
Overall Study	Death	0	1
Overall Study	Lost to Follow-up	1	2

Baseline characteristics

Characteristic	Total	Iron Isomaltoside 1000	Placebo
Age, Categorical <=18 years	0 Participants	0 Participants	0 Participants
Age, Categorical >=65 years	29 Participants	18 Participants	11 Participants
Age, Categorical Between 18 and 65 years	73 Participants	34 Participants	39 Participants
Age, Continuous	55 years STANDARD_DEVIATION 14	55 years STANDARD_DEVIATION 15	55 years STANDARD_DEVIATION 14
Peak oxygen consumption	23.4 ml/kg/min STANDARD_DEVIATION 6.8	24.3 ml/kg/min STANDARD_DEVIATION 7.3	22.3 ml/kg/min STANDARD_DEVIATION 6
Race and Ethnicity Not Collected	0 Participants	—	—
Region of Enrollment Norway	102 participants	52 participants	50 participants
Sex: Female, Male Female	37 Participants	18 Participants	19 Participants
Sex: Female, Male Male	65 Participants	34 Participants	31 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	0 / 52	1 / 50
other Total, other adverse events	22 / 52	18 / 50
serious Total, serious adverse events	5 / 52	12 / 50

Outcome results

Primary

Peak Oxygen Consumption

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