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.

Study Overview

• Status: Active, not recruiting
• Conditions: Iron-deficiency; Transplant-Related Disorder
• Intervention / Treatment: Drug: Ferric carboxymaltose; Drug: Sodium chloride

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 148
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Anna-Sophie Vinke, MD; Phone Number: 0031503611697; Email: j.s.j.vinke@umcg.nl

Study Locations

• Netherlands
  • Groningen, Netherlands, 9713 GZ
    • University Medical Center Groningen
  • Utrecht, Netherlands
    • University Medical Center Utrecht

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Ferric(III) carboxymaltose; 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; Four intravenous dosages of ferric(III) carboxymaltose
Placebo Comparator: Placebo; 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; Four intravenous dosages of sodiumchloride; Other Names: Placebo

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: University Medical Center Groningen
• Collaborators: Dutch Kidney Foundation; Vifor Fresenius Medical Care Renal Pharma
• Investigators: Principal Investigator: Martin de Borst, MD/PhD, University Medical Center Groningen

Study record dates

Study Major Dates

• Study Start (Actual): August 2, 2019
• Primary Completion (Estimated): September 1, 2024
• Study Completion (Estimated): September 1, 2024

Study Registration Dates

• First Submitted: December 3, 2018
• First Submitted That Met QC Criteria: December 6, 2018
• First Posted (Actual): December 7, 2018

Study Record Updates

• Last Update Posted (Actual): February 26, 2024
• Last Update Submitted That Met QC Criteria: February 23, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: Renal Transplantation; Kidney Transplantation; Iron Deficiency
• Additional Relevant MeSH Terms: Metabolic Diseases; Hematologic Diseases; Anemia, Hypochromic; Anemia; Iron Metabolism Disorders; Anemia, Iron-Deficiency; Iron Deficiencies
• Other Study ID Numbers: 201800450

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: 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.
• IPD Sharing Time Frame: The study protocol, including a statistical data analysis plan, will be published in a peer-reviewed journal.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No