Date of publication: August 30, 2016

Expert Perspectives

Expert Video: How Can We Design Randomised Controlled Trials to Evaluate IV Iron Therapies?

Professor Iain C Macdougall is Professor of Clinical Nephrology at King’s College London and is renowned for his expertise in anaemia associated with chronic kidney disease. In this expert video, recorded for COMPACT RENAL, Professor Macdougall discusses:

  • The strengths and limitations of past RCTs of IV iron
  • Good clinical endpoints for IV iron trials, including endpoints designed to show non-hematologic benefits
  • The ongoing PIVOTAL study

Reference: PIVOTAL Study Design

PIVOTAL Study Design


What are the strengths and limitations of past RCTs of IV iron in CKD

The strengths of randomised control trials of intravenous iron really relate to the ability of intravenous iron to augment the response to ESA therapy, both by enhancing the erythropoietic response, a better haemoglobin increment, as well as saving on the dose requirements and cost of ESA therapy. That’s the major strength of all the trials. They universally show that – their evidence base is very strong in that theme.

The weaknesses largely relate to the length and sample size of many of the trials, in that they’re largely, a lot of them are very small and of low duration, which casts some doubt on the long-term safety of intravenous iron in this population. That has not been ascertained at all in the evidence to date.

So the end points of randomised control trials in intravenous iron traditionally have related to the haemoglobin increment and the ESA dose and costs of anaemia therapy. The gaps in the end points relate to things like quality of life, functional capacity for patients, and long-term safety and impact on cardiac function, which could be good or bad, as well as stroke, heart failure, etc. The hard end points that are classically used in randomised control trials.

There’s a lot of evidence that suggests that intravenous iron might improve skeletal-muscle function, cardiac-muscle function, neurological function, restless leg syndrome, etc., and unfortunately, the evidence base in that area is not robust enough that it could become standard of care, but there’s a lot of evidence that that could be the case.

So looking at things like six-minute walk and quality of life and cardiac function are really the gaps in our knowledge base of intravenous iron.

What are good clinical endpoints for RCTs with IV iron in patients with CKD and why?

In pre-dialysis CKD, I think the evidence base is that intravenous iron will augment the response to ESA therapy in terms of haemoglobin. It will also allow many patients to have an improvement in anaemia without the need for ESA therapy or saving blood transfusions and so on. Because anaemia at that stage is milder than in dialysis patients, and so that it’s possible with intravenous iron alone, there’s enough circulating erythropoietin still around, to allow an improvement in anaemia with intravenous iron alone. That’s not the case in dialysis patients, which we’ll come on to.

And in terms of benefits for these patients, there’s evidence that even in the pre-dialysis setting, many of these patients have skeletal-muscle problems in terms of muscle function, fatigue, restless leg syndrome, poor exercise capacity, which could potentially be improved by correction of iron deficiency.

In dialysis patients, I think the end points that need to be looked at carefully, are the impact on harder end points such as death and heart attack, stroke, heart failure, and so on. I think, again, we know that intravenous iron will save costs and allow lowering of the ESA doses.

There’s some evidence that high levels of ESA might be harmful and therefore saving on ESA dose could be of benefit to the patient. That needs to be proven more robustly in terms of hard clinical outcomes. So I think in the dialysis patients, there’s a real need for hard end point clinical trials.

What endpoints could be selected to prove a non-hematologic benefit of iron in patients with CKD?

There’s increasing evidence that iron impacts many physiological systems beyond red cell production, particularly in terms of nerve function, muscle function, energy generation, and so on. And I think that’s where there needs to be much more research focused. And we know that iron will improve anaemia, but we don’t know what it does in terms of other functional measures for the patient, which is particularly important.

So the end points that we can use to measure the non-haematological effects would be things other than haemoglobin and ESA dose. It would be things like six-minute walk test, which is a well-validated functional measure of physical capacity, questionnaires, restless leg questionnaires, fatigue questionnaires, cardiac function, which could be assessed by cardiac MRI, modern-day echocardiography, and so on. So these would be the measures that one can use to assess the potential benefits of intravenous iron in the non-haematological theme.

When considering IV iron therapy, which CKD patient populations are currently under-represented in RCTs?

Regarding RCTs in CKD patients, they focus on the dialysis patients first of all. So there are many randomised control trials in the 1990s showing that haemoglobin response was better and ESA dose was saved and cost savings as well with the use of intravenous iron. So that’s the strong evidence base in the dialysis population.

In the pre-dialysis patients, there’s much less literature. The trials are generally quite small and of short duration. There was a meta-analysis that was published about nearly, well, just over 10 years ago now, which looked at all the trials and the conclusion was that there was a lot of heterogeneity of the trials and there was a need for better trials.

In recent times there have been two larger clinical trials, the REVOKE trial and the FIND-CKD trial. Unfortunately, the results of these trials were diametrically opposed, in that one of the trials, the FIND-CKD trial, couldn’t find any hint of a safety signal, whereas the REVOKE trial found some safety concerns. So we’re left more confused than ever.

Although there were limitations of each of the trials perhaps, nevertheless, the average nephrologist in the street is left confused about where they are with intravenous iron. So that’s the downside of the pre-dialysis setting.

What are the challenges today in conducting a robust RCT of IV iron?

Challenges of conducting randomised control trials of IV iron are perhaps no different from the challenges of any randomised control trial. There’s a need for a huge infrastructure, they’re incredibly expensive, and getting the required number of patients to be able to say anything meaningful is quite difficult. You need to have a very coordinated set-up to be able to achieve that.

How can we improve on current RCTs of IV iron in CKD so as to provide more clinically meaningful data?

So improving on the randomised control trials for intravenous iron, to give us more meaningful data, I think that the main bit of data we need is long-term safety and hard end points. That’s where the evidence base is lacking.

We had that situation with ESA therapy many years ago, and now I think we have much more clarity with the balance of the use of ESA therapy. We know that potentially using a lot of ESAs could be quite harmful. I think we need to know the same with intravenous iron.

What are the landmark studies that may help address open questions in IV iron therapy?

The landmark studies that help address the open questions in intravenous iron, there are one or two recently published, the FIND-CKD study and also REVOKE study as well. FIND-CKD study was considered a landmark study in non-dialysis patients. It unfortunately, again, focused on anaemia management and didn’t have much robust evidence for safety.

It wasn’t designed for the safety of hard clinical end points, it had only a one-year follow-up, which is not long enough really to look at long-term safety. So that was considered a landmark study.

In dialysis patients, we have the ongoing PIVOTAL study, which is a large, UK multi-centre study in the UK that I lead across 50 sites. Sample size for that is 2,080 patients. We are 97% recruited and we expect recruitment to finish in the next month. And that will look at the hard . . . The primary end point is a composite of death, heart attack, stroke, and heart failure, with a large number of secondary end points. And the duration of that study is a minimum of two years’ follow-up, and some patients will be followed-up for four years in that study.

So I think this will be considered the ultimate landmark study investigating a large amount of intravenous iron versus a little, a smaller amount of intravenous iron, and see if we can get some clarity on the appropriate balance of intravenous iron in the dialysis population.


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