Iron and Phosphaturia Trial (ExplorIRON-CKD)
Research type
Research Study
Full title
Exploratory single centre prospective 12-week comparative double blinded randomised trial of the impact of high-dose iron isomaltoside vs iron carboxymaltose on measures of FGF23, bone metabolism and Hb in patients with Chronic Kidney Disease and iron deficiency.
IRAS ID
272279
Contact name
Xenophon Kassianides
Contact email
Sponsor organisation
Hull University Teaching Hospitals NHS Trust
Eudract number
2019-004370-26
Duration of Study in the UK
1 years, 0 months, 0 days
Research summary
Summary of Research
Individuals with advanced chronic kidney disease (CKD) often suffer with anaemia. One of the commonest reasons for anaemia is low iron. Iron can be replaced using a number of different intravenous preparations. Studies have suggested that different intravenous iron preparations affect the bones in a different way. This could mean that they also affect the heart differently.
During the study we will be comparing two different intravenous iron preparations - Ferrous Carboxymaltose (Ferrinject ®) and Iron isomaltoside (Monofer ®). They are both proven to be effective in patients with CKD and have a similar safety profile. Thirty patients over the age of 18 with CKD 3a-5 will be divided randomly to two groups. Fifteen participants will receive Ferrinject and fifteen will receive Monofer. We will monitor blood markers (for iron, anaemia, kidneys) bone markers, heart markers, heart tracings (ECG) and any arterial stiffening using pulse wave velocity measurement. We will also assess the participant’s general function after transfusion using specially designed questionnaires.
The study will take 3 months and will involve two iron transfusions a month apart and four further visits for doctor’s assessment regarding participants’ health and any side effects experience. Any blood taking, analysis of urine and other tests will take place during those visits. It will take place at the Hull University Teaching Hospitals NHS Trust
This allows us to determine whether any difference exists to the bones and the heart depending on the iron used. This can guide us further into tailoring iron use per patient individually. It will also help us decide whether further research should be placed into this topic and help design such research effectively and efficiently. It will also aid in finding out more about the way the kidneys interact with the bone and the heart.Summary of Results
The study took place at Hull University Teaching Hospitals NHS Trust Academic Renal Department, which covers a large area including East Riding of Yorkshire, Hull and North/North-east Lincolnshire. The study took place between March 2020 and July 2021 The study was done to find out more about iron side effects in patients with chronic kidney disease. Iron through the vein is a safe and effective treatment, however some iron compounds (ferric carboxymaltose) seem to lower phosphate more than others (ferric derisomaltose). This happens because of a hormone called fibroblast growth factor 23. We do not know whether different modern iron products cause a different effect on phosphate in patients with chronic kidney disease and patients with kidney disease often have problems with their bones. This is why we created this study to learn more about using intravenous iron, and its effects.
The main questions of the study were to find out how different irons can affect phosphate and fibroblast growth factor 23 in patients with chronic kidney disease. Also the study sought information on how these changes may be related to changes in other bone markers (like vitamin D, parathyroid hormone), the heart, quality of life and performance of daily activities. These two modern iron preparations (ferric derisomaltose and ferric carboxymaltose) have never been compared before in patients with chronic kidney disease.
Adult patients with chronic kidney disease but not needing dialysis (stages 3a-5) that had low iron levels and normal/low haemoglobin (the substance carrying oxygen in the blood) were invited to the study. Thirty-five patients agreed to be seen, and twenty-seven (27) were eligible. Twenty-six (26) entered the study.
During the study, the participants were given either ferric carboxymaltose or ferric derisomaltose twice through the vein. They received 1000 mg in the beginning of the study, and either 500 mg or 1000 mg depending on their weight and haemoglobin one month later. All of the participants received at least one dose of iron.
The participant involvement lasted for 3 months and patients received one of the two medications (ferric carboxymaltose or ferric derisomaltose) twice, a month apart. The participants were reviewed 8 different times (screening, first dose, 1-2 days after first dose, 2 weeks after first dose, 1 month after first dose (had second dose), 1-2 days after second dose, 2 months after first dose and 3 months after first dose). The participants had blood tests, urine tests, heart tracing, were monitored on how stiff their arteries were, and completed a number of questionnaires.
The participants were divided into two groups by chance (randomised) to reduce differences between the groups. Placing people into groups by chance helps to make the two groups equal. Reducing differences between the groups in this way, makes the comparison between the groups fairer.
This trial was also “double-blinded”. This means that neither patients nor doctors knew who was given which treatment. This was done to make sure that the trial results were not influenced in any way.
Side effects are unwanted medical events (such as a headache) that happen during the study and are reported because the trial doctor (investigator) believed the side effects were related to the treatments in the trial. Serious adverse reactions are reactions that are life threatening or require the individual to have to go to hospital. No side effects or serious adverse reactions were found to be related to any treatment given. Any events were reviewed by both trial doctors and a clinician independent to the study that was part of the Research and Development Department of Hull University Teaching Hospitals NHS Trust.
Fourteen participants were randomly allocated to the ferric derisomaltose group (8 male, 6 female). Twelve participants were randomly allocated to the ferric carboxymaltose group (9 male, 3 female). The two groups were very similar with the exception of age (participants in the ferric derisomaltose were younger than those in the ferric carboxymaltose). The average age in the ferric carboxymaltose group was 73 years old, and the average age in the ferric derisomaltose was 63 years old. The two groups also differed in the amount of phosphate in urine over 24 hours (there was more phosphate in the urine of participants in the ferric derisomaltose than those in the ferric carboxymaltose in the beginning of the study over 24 hours). Also according to one of the questionnaires (fatigue severity scale), patients in the ferric derisomaltose group were more tired in the beginning of the study than those in the ferric carboxymaltose group. These differences are likely to be by chance. No difference in the groups existed in terms of the main outcomes (fibroblast growth factor 23 or phosphate), anaemia and chronic kidney disease.
The amount of fibroblast growth factor 23 increased more in participants receiving ferric carboxymaltose than those receiving ferric derisomaltose 1-2 days after each dose was given, and was higher than the one baseline measurement by the end of the study. Phosphate also changed more in participants receiving ferric carboxymaltose than ferric derisomaltose, but remained close to the initial measurement by the end of the study.
The study also measured to see if those receiving ferric carboxymaltose or ferric derisomaltose had both a significant increase in fibroblast growth factor 23 (>200%) and a significant decrease in phosphate (>20%). These events were measured together (combined) because according to research one (increase in fibroblast growth factor 23) can lead to the second (decrease in phosphate). No participant developed both an increase in fibroblast growth factor 23 (>200%) and a decrease in phosphate (>20%) within 2 weeks in the ferric derisomaltose group. One participant in the ferric carboxymaltose had both an increase in fibroblast growth factor 23 and a decrease in phosphate (1 out of 12 participants – 8.3%). During the study, no participant in the ferric derisomaltose group had a significant increase in fibroblast growth factor 23 and a significant decrease in phosphate. Three (3/12 – 25%) participants in the ferric carboxymaltose group had a combined increase in fibroblast growth factor 23 and a significant decrease in phosphate.
The results of the primary outcomes of the study (the main goals) suggest that ferric carboxymaltose can lead to lower phosphate secondary to an increase in fibroblast growth factor 23 in patients with chronic kidney disease, but not as much or as low as that reported in research of patients with normal kidney function.
The decrease in the amount of Vitamin D was greater in participants receiving ferric carboxymaltose than ferric derisomaltose 1-2 days after iron. This could be related to the increase in fibroblast growth factor 23 seen in that group, but this is only the result of one trial. No change in parathyroid hormone was seen between the two groups.
There was no difference between the groups in the improvement of markers of iron stores. There was no effect and no difference between the two groups on kidney function. There was no effect on heart function or any negative effect to arteries.
There was no difference in the effect on quality of life or ability to perform activities of daily living between the two groups. Power and stamina as tested by the 1-minute-sit-to-stand test improved in both groups and in the whole cohort. Physical function also improved in both groups and the whole cohort as examined by the Short-Form 36 questionnaire. Fatigue improved in the ferric derisomaltose group and the whole cohort as examined by the Short-Form 36 questionnaire.
The study found that more participants had an increase in fibroblast growth factor 23 following ferric carboxymaltose than ferric derisomaltose, but there was no hypophosphataemia (low phosphate) in any group. All groups had an improvement in physical function and 1-minute-sit-to-stand test. People in both groups had similar results in terms of markers of iron stores, haemoglobin and kidney function and heart function.
These are the results of one small study only, and it is important to always take in consideration many studies before making any conclusions about the safety and usefulness of any drug.
Researchers look at the results of many studies to understand how drugs work and what their effects on biomarkers (molecules found in blood) can mean regarding a disease. It takes lots of people in many studies all around the world to advance medical science. This summary only shows the results from this small study in patients with chronic kidney disease not on dialysis. No preparations have been found to be superior or safer than the other during this clinical trial.
Results are limited to the particular people studied and cannot be assumed to be true for everybody. Not all participants in each part of the study had the same results.
The study is not “powered” – this means that the statistical tests performed cannot accurately detect whether an effect was seen due to chance or due to a change in the body. Also, not all participants took part at all the tests at all times, therefore limiting the analysis of the results. In addition, this study focuses on the effect of iron on a biomarker (fibroblast growth factor 23). Researchers are not yet completely sure as how these changes in fibroblast growth factor 23 can be related to any diseases.
This research helps future patients and families by helping us understand more about each iron product being studied. Findings can be used to help create further research combining the measurement of fibroblast growth factor 23 with more objective imaging of bones. Also it helps create studies looking more on the effect of iron on quality of life and ability to perform activities of daily living. It helps creating research in how these biomarkers/blood results can affect the quality of life too.
Please note you should not change your treatment based on the results of this study without first taking to your doctor/healthcare professional.
The research group undertaking this study is not currently planning on any further clinical trials with either ferric derisomaltose or ferric carboxymaltose.
A number of clinical trials throughout the world regarding ferric derisomaltose or ferric carboxymaltose are ongoing and further trials are planned.REC name
Yorkshire & The Humber - Leeds West Research Ethics Committee
REC reference
20/YH/0005
Date of REC Opinion
14 Feb 2020
REC opinion
Further Information Favourable Opinion