Effect of Ferric Carboxymaltose on Exercise Capacity After Kidney Transplantation (EFFECT-KTx)

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

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.

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.

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.

All participants, care providers and researchers will be blinded, except for the nurse who will administer the medication.

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.

The placebo-controlled group will receive four dosages of 250 mL of NaCl 0.9% solution with interval periods of six weeks.

The between-group difference in change in exercise tolerance quantified by the six-minute walk test (6MWT)

The between-group difference in change in iron parameters (plasma iron, ferritin, transferrin saturation)

The between-group difference in change in cardiac structure, function and strain, analysed with a transthoracic echocardiography

The between-group difference in change in muscle strength measured by the 'Five-Times-Sit-to-Stand-test (FTSTS)

The between-group difference in change in muscle mass assessed using 24-hour urinary creatinine excretion

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)

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)

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)

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)

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)

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)

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)

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)

The between-group difference in change in quality of life quantified with SF36 questionnaire. A higher score means a better outcome.

The between-group difference in change in quality of life quantified with the Dutch Checklist individual Strength). A higher score means worse fatigue.

The between-group difference in change in quality of life quantified with the Dutch Multifactor Fatigue Scale). A higher score means worse fatigue.

The between-group difference in severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) specific antibody titre after vaccination.

The between-group difference in severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) specif T-lymphocyte response after vaccination.

The between-group difference in change in gastro-intestinal symptoms assessed with the gastrointestinal symptom rating scale.

The between-group difference in change in plasma hepatic enzyme levels (aspartate transaminase and alanine transaminase)

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

To protect participant privacy, public access to the dataset or individual participant data will not be provided. However, after deidentification of these data and after publication of the main results, requests for the re-use of all pseudo-anonymised individual participant data by researchers who provide a methodologically sound proposal for a secondary analysis or meta-analysis will be evaluated by the Principal Investigator. Data may be shared if the research question falls within the scope of the informed consent. Proposals should be directed to m.h.de.borst@umcg.nl and requestors will need to sign a data access agreement.

The study protocol, including a statistical data analysis plan, will be published in a peer-reviewed journal.