Effect of Ferric Carboxymaltose on Exercise Capacity After Kidney Transplantation

Study Overview
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Brief Summary
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Iron deficiency is common in kidney transplant recipients and is associated with impaired exercise tolerance and an unfavourable prognosis. This multicentre double-blind, placebo-controlled randomized controlled clinical trial will allow the investigators to analyse the effects of intravenous iron correction with ferric(III) carboxymaltose on exercise tolerance and other parameters, in comparison to a placebo.

Detailed Description
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Rationale: Iron deficiency is common in kidney transplant recipients. The presence of iron deficiency is associated with an unfavourable prognosis in these patients. In patients with heart failure and iron deficiency, treatment with intravenous iron improved exercise capacity and quality of life. Whether such beneficial effects may also occur in kidney transplant recipients is unknown. Objective: Our main objective is to address whether correction of iron deficiency with ferric(III) carboxymaltose improves exercise tolerance and quality of life in iron-deficient kidney-transplant recipients. Study design: A multicentre double-blind, placebo-controlled randomized controlled clinical trial will be performed to compare the effects of ferric(III) carboxymaltose with placebo. Study population: 158 iron-deficient kidney transplant recipients. The intervention arm will receive 10 mL of ferric(III) carboxymaltose (50 mg Fe3/mL, intravenously) every six weeks, with a total of four dosages. The control arm receives an intravenous placebo solution (saline). Main study parameters/endpoints: The primary endpoint is the distance walked in six minutes, as quantified by the six-minute-walking-test at the end of follow-up. The investigators expect that iron-deficient kidney transplant recipients will benefit from ferric(III) carboxymaltose treatment as a result of an improvement in exercise tolerance and general wellbeing.

Official Title
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Effect of Ferric Carboxymaltose on Exercise Capacity After Kidney Transplantation: a Multicenter Randomized Controlled Trial

Conditions
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Iron-deficiency, Transplant-Related Disorder

Intervention / Treatment
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* Drug: Ferric carboxymaltose
* Drug: Sodium chloride


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Kidney transplant recipient Iron deficiency, defined by a ferritin level of ≤100 ug/L, or 100-299 ug/L combined with a transferrin saturation of ≤20% At least six months after transplantation at baseline Age ≥18 years Ability to comply with the study protocol Informed consent Exclusion Criteria: Intolerance to any intravenous iron solution Severe anemia (Hb <10.5 g/dL, <6.5 mmol/L), microcytic anemia (MCV <80 fl) or progressive anemia (˃3.2 g/dL per month decline for two months or more) A positive feces occult blood test or otherwise demonstrated gastrointestinal, or urogenital, blood loss Blood transfusion in the past six weeks Polycythemia (Hb >15.3 g/dL, 9.5 mmol/L) Estimated glomerular filtration rate (eGFR) of ≤ 30 ml/min per 1.73 m2 History of haemochromatosis Unstable angina or myocardial infarction during the previous month Disability to walk Severe hypophosphatemia in the month before baseline (serum phosphate <0.35 mmol/L) Pregnancy or inability to take adequate contraceptive measures when at childbearing age (women) Any signs of an active systemic infection Participation in another interventional study

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: The study is designed as a 24 week, multicentre, randomized placebo-controlled clinical trial with two parallel arms to investigate the effect of ferric(III) carboxymaltose on exercise tolerance, cardiac function, skeletal muscle function, quality of life, the gut microbiota and on the immune system, to be performed at the University Medical Center Groningen (UMCG) and the Erasmus MC, University Medical Center Rotterdam.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Ferric(III) carboxymaltose<br>The intervention group will be treated with four dosages of 500 mg iron in the form of 10 mL ferric(III) carboxymaltose dissolved in 240 mL of NaCl 0.9%, with interval periods of six weeks. | Drug: Ferric carboxymaltose<br>* Four intravenous dosages of ferric(III) carboxymaltose<br>|
| Placebo Comparator: Placebo<br>The placebo-controlled group will receive four dosages of 250 mL of NaCl 0.9% solution with interval periods of six weeks. | Drug: Sodium chloride<br>* Four intravenous dosages of sodiumchloride<br>* Other names: Placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Exercise tolerance | The between-group difference in change in exercise tolerance quantified by the six-minute walk test (6MWT) | 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hemoglobin level | The between-group difference in change in hemoglobin level | 24 weeks | 
| Iron status | The between-group difference in change in iron parameters (plasma iron, ferritin, transferrin saturation) | 24 weeks | 
| Cardiac function | The between-group difference in change in cardiac structure, function and strain, analysed with a transthoracic echocardiography | 24 weeks | 
| Muscle strength 1 | The between-group difference in change in muscle strength measured by the 'Five-Times-Sit-to-Stand-test (FTSTS) | 24 weeks | 
| Muscle strength 2 | The between-group difference in change in muscle strength measured by the timed-up-and-Go test (TUG) | 24 weeks | 
| Muscle strength 3 | The between-group difference in change in muscle strength measured by handgrip dynamometry | 24 weeks | 
| Muscle mass | The between-group difference in change in muscle mass assessed using 24-hour urinary creatinine excretion | 24 weeks | 
| Phosphate level | The between-group difference in change in phosphate level | 24 weeks | 
| Calcium level | The between-group difference in change in calcium level | 24 weeks | 
| Vitamin D status | The between-group difference in change in vitamin D level | 24 weeks | 
| Parathyroid hormone | The between-group difference in change in parathyroid hormone level level | 24 weeks | 
| FGF23 | The between-group difference in change in FGF23 level | 24 weeks | 
| Intestinal microbiota | The between-group difference in change in intestinal microbiota | 24 weeks | 
| Incidence of any infection | The between-group difference in incidence of infections | 24 weeks | 
| Incidence of hospitalisation | The between-group difference in incidence of hospitalisation | 24 weeks | 
| Incidence of cardiac events | The between-group difference in incidence of cardiac events | 24 weeks | 
| Incidence of graft failure | The between-group difference in incidence of graft failure | 24 weeks | 
| Lymphocyte production of cytokines | The between-group difference in lymphocyte cytokine espression (measured with facs) | 24 weeks | 
| Lymphocyte production of immunoglobulins | The between-group difference in lymphocyte IgG production (measured with ELISA) | 24 weeks | 
| Lymphocyte proliferation rate | The between-group difference in lymphocyte proliferation rate (assessed with FACS) | 24 weeks | 
| B-lymphocyte differentiation rate | The between-group difference in B-lymphocyte plasma cell formation (assessed with Facs) | 24 weeks | 
| Cognitive performance (memory span) | The between-group difference in change in cognitive performance quantified with neuropsychological testing (Digit Span Forward Test, minimum value 0, maximum value 9, a higher score means a better outcome) | 24 weeks | 
| Cognitive performance (verbal memory) | The between-group difference in change in cognitive performance quantified with neuropsychological testing (15 word test, minimum value 0, maximum value 75, a higher score means a better outcome) | 24 weeks | 
| Cognitive performance (semantic memory) | The between-group difference in change in cognitive performance quantified with neuropsychological testing (Word Fluency Test, minimum value 0, no maximum value, a higher score means a better outcome) | 24 weeks | 
| Cognitive performance (processing speed) | The between-group difference in change in cognitive performance quantified with neuropsychological testing (symbol digit modalities test, minimum value 0, maximum value 110, a higher score means a better outcome) | 24 weeks | 
| Cognitive performance (visuomotor and mental speed) | The between-group difference in change in cognitive performance quantified with neuropsychological testing (Trail Making Test A, minimum value 1, no maximum value, a lower score means a better outcome) | 24 weeks | 
| Cognitive performance (cognitive flexibility) | The between-group difference in change in cognitive performance quantified with neuropsychological testing (Trail Making Test B, minimum value 1, no maximum value, a lower score means a better outcome) | 24 weeks | 
| Cognitive performance (executive control) | The between-group difference in change in cognitive performance quantified with neuropsychological testing (Controlled Oral Word Association Test, minimum score 1, no maximum score, a higher score means a better outcome) | 24 weeks | 
| Cognitive performance (working memory) | The between-group difference in change in cognitive performance quantified with neuropsychological testing (Digit Span Backward, minimum score 0, maximum score 8, a higher score means a better outcome) | 24 weeks | 
| Plasma creatinine | The between-group difference in change in plasma creatinine | 24 weeks | 
| Quality of Life (health) | The between-group difference in change in quality of life quantified with SF36 questionnaire. A higher score means a better outcome. | 24 weeks | 
| Quality of Life (subjective fatigue) | The between-group difference in change in quality of life quantified with the Dutch Checklist individual Strength). A higher score means worse fatigue. | 24 weeks | 
| Quality of Life (long-lasting fatigue) | The between-group difference in change in quality of life quantified with the Dutch Multifactor Fatigue Scale). A higher score means worse fatigue. | 24 weeks | 
| Quality of Life (overall) | The between-group difference in change in quality of life quantified with EuroQol-5D-5L | 24 weeks | 
| Severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) vaccination IgG response | The between-group difference in severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) specific antibody titre after vaccination. | 12 months | 
| Severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) vaccination T-lymphocyte response | The between-group difference in severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) specif T-lymphocyte response after vaccination. | 12 months | 
| Gastro-intestinal symptoms | The between-group difference in change in gastro-intestinal symptoms assessed with the gastrointestinal symptom rating scale. | 24 weeks | 
| Hepatic injury | The between-group difference in change in plasma hepatic enzyme levels (aspartate transaminase and alanine transaminase) | 24 weeks | 
| Restless legs | The between-group difference in prevalence of restless legs symptoms before and after treatment | 24 weeks | 
| Kidney graft rejection and injury | The between-group difference in change in urine kidney injury marker levels | 24 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Renal Transplantation, Kidney Transplantation, Iron Deficiency