CME Slides Forum - B. Feldt-Rasmussen

A joint Congress by ERA-EDTA and ISN

GROWTH HORMONE IMPROVES NUTRITION, QUALITY OF LIFE AND CARDIOVASCULAR RISK FACTORS IN ESRD

Bo Feldt-Rasmussen, Copenhagen, Denmark

Chair: Peter Barany, Stockholm, Sweden

William Mitch, Houston, USA

feldt-rasmussen

Dr B. Feldt-Rasmussen
Department of Nerphrology
Rigshospitalet
Copenhagen, Denmark

Thank you Bill and Peter. We now heard about the seriousness of protein energy wasting, the poor prognosis of our patients with protein energy wasting and obviously new treatments are needed for that. Actually growth hormone may be such a new candidate for treatment in these patients.

Therefore, I was very pleased to be asked to join this symposium to discuss growth hormone as a potential candidate for new treatment. I was looking forward to presenting the data of our phase II trial actually, in the title indicating that growth hormone treatment improves nutrition, quality of life and cardiovascular risk factors.

But also to share with you an update of the phase III trial that was the consequence of the phase II trial namely the OPPORTUNITY trial which I should say was a randomized clinical trial of growth hormone on outcome in hemodialysis patients. It was a large scaled study, 2500 patients should be enrolled and the endpoint should be mortality and morbidity. So this should be the trial to show if there is room for growth hormone treatment in these patients. Unfortunately, it was stopped prematurely and therefore, the talk will be about the phase II trial and what new information we can still get from the OPPORTUNITY trial.

Now why would we consider growth hormone at all in treating ESRD patients? Well, I think we got an idea from discussing the protein energy wasting syndrome; we need something anabolic to reverse this condition. Advanced uraemia is a wasting illness, it is multifactorial and will require a multifaceted approach and there is a potential for combined use with other interventions.

We know already from smaller scaled studies before our phase II trials in the time from 1994-1999 that treatment with growth hormone can improve nutritional status, quality of life, energy level, appetite, reduce body fat mass and increase muscle mass and that it has in this study been shown to reduce protein catabolism or breakdown.
So in theory treatment with growth hormone should be able to do this and maybe through this also improve morbidity and mortality.

So with this in mind we approached our sponsor who was NovoNordisk A/S who was a manufacturer of growth hormone and asked if they would join us in a phase III trial based on these smaller scaled studies and actually they would join us but they would have a larger scale phase II trial first because of course, it’s a risky business to go into this. So we performed a proof of concept and dose finding study.

The hypothesis was, if growth hormone therapy for dialysis treated adults with chronic renal failure could improve markers of nutrition and markers of mortality. As I said, it was a proof of concept and a dose finding study.

Therefore, three groups were studied, a low dose, medium dose and a high dose and actually none of these doses were very high compared to what the previous studies had used.

So 139 patients were screened and randomised to one of these 4 groups, then treated for 6 months. The key inclusion criteria were markers of malnutrition, protein energy wasting and we use serum albumin below 38 and later on due to recruitment problems below 40. Male or female, age 18 to 75 years and they were all hemodialysis patients and they had to be in a good quality of dialysis Kt/V over 1.2 or at least 12 hours of treatment per week.

Excluded were patients with diabetes, we included those in the OPPORTUNITY trial later on but in this study diabetes was excluded. (pointing to the slide) PTH, blood pressure and we didn’t want patients with these comorbidities.

They were fairly well-randomised in the 4 groups, you can see similar numbers, gender, as always there is always some group that does differently though not significantly so and also when it came to the duration, one group made differently but otherwise they were quite well-matched.

The key results were lean body mass and serum albumin and it was decided before the study that we would consider the concept proven if one of those increased significantly and the other showed a trend and these were the secondary endpoints.

As you can see from the key results shown here that the change in lean body mass which I would say is an increase in muscle mass was seen in all treatment groups with growth hormone and this is actually quite an increase, it’s an average of 2.5 kg of muscle mass. The serum albumin increased in all groups but not significantly so but there was a trend and I cannot explain to you why apparently the high dosage group did worse.

I show here the significant results. I would say all significant changes were beneficial. There were none that were against a hypothesis. So I’m showing the significant beneficial results and after that we can have a discussion on reverse epidemiology. What is “beneficial” ? but let’s take it without the reverse epidemiology for starters.
So as you can see, transferrin was increased as a marker of nutrition.

The HDL cholesterol was significantly higher and as you know this is the “good” cholesterol.

The homocysteine and now we come to reverse epidemiology was lower which may be good, we considered it good.

One marker of quality of life, the role of physical marker was significantly better in the growth hormone treated group.This is a way to tell how the patients perceived themselves in a physical surrounding. How am I doing? This is from a clinical and a statistical point of view a significant improvement.

Then we had all these non-significant results, Prealbumin, CRP so the markers of inflammation now keeping in mind the protein energy wasting syndrome they didn’t show anything actually.

I would say if you look at their mortality the placebo group 4, then 2, 3, 6 a total of 15-11%. It was a 6 month study so this is equivalent to about 22% annual mortality which I believe we all actually have to live with so to speak. The hospitalised were also quite similar.

There were quite a number of emergent adverse events. 92% of the population had them but this population already have a lot of complications to report. Most of them were those that we already know infections, gastrointestinal disorders and only 13% were rated as possible or possibly related to trial product.

There was a tendency towards increased numbers of possible or probable adverse events with increasing dose.
Now, growth hormone is known to be diabetogenic, so there is a risk of inducing diabetes or prediabetes but we did not. In this study of 139 patients there were no patients developing diabetes, the fasting blood glucose went up after 2 months but went down again and was totally normal. So was HbA1c, so was the IGF-1 and IGFBP-3 these are the proteins that you affect directly using the growth protein treatment and they can cause some damage themselves but we found levels way below what is seen when you use growth hormone for treatment in children or in other conditions, so it seemed to be safe. It has been described that you can increase the left ventricular mass during growth hormone treatment. We had echocardiography in all these patients and there were absolutely no changes in left ventricular mass using these dosages as we did in this study.
Nothing regarding these.

So from this we concluded that the lean body mass increased significantly at all doses compared to placebo.
We did find a significant change in lean body mass and a trend in serum albumin and we found those beneficial changes in other biomarkers of mortality.

It was well-tolerated and safe, not associated with structural changes in the heart which was a concern. The low dose seemed to be optimal because we didn’t have the side effects and we did have all the effects. Actually, if we translate these changes in albumin and lean body mass to the survival curves that we’ve just seen, “what is the impact of a low serum albumin on mortality?”, then we should able to or we could hypothesise that these could be translated into improved survival. But of course now this is a critical question really because it could be but is it in fact so?

Ok the sponsor accepted and would take us further on into a phase III trial, the OPPORTUNITY trial and I think it was a fantastic study really.It was almost global and I believe many of you have joined us in the OPPORTUNITY trial and it had the power to give an answer to this question. With 2500 randomised we would know if this was worthwhile because it’s an expensive treatment so of course we cannot just recommend it out of beliefs.

Unfortunately, it was decided, due to randomisation problems, that it should be stopped and I would say that we were all very sad weren’t we? We were angry but that’s a fact. But we will get some new information I can tell you that. It is a lost opportunity to find the mortality maybe even the morbidity but the fact is that the data came in and it was released 3 days ago.At the time it closed there were about 800 randomised patients and in the phase II trial I just discussed with you we included 139, so I would say it’s not a small study in patients on chronic maintenance hemodialysis it is of size. The mean follow up was 21 weeks and we had a 19 week follow up in phase II. So it is 6 times larger and so it is better powered, so I’m not saying we will not get any answer to the crucial questions. I’m sure we should analyze this, shouldn’t we?

I think we’ll still get a lot of information out of that at least to show, maybe, I don’t know, pathophysiology which may be indicative that there is room for it (growth hormone) in rare cases. I don’t know but it is really sad that the sponsor didn’t have patients and perhaps money to continue up to the 2500 included. Thank you.

Question: Luchelli from Italy I have two questions. First of all, do you have an idea of giving growth hormones in patients with chronic kidney disease stage III or IV not in dialysis patients? Like proteinuric patients, first question. Second question how do you calculate lean body mass? Because we have a lot of data in clinical waste circumference, waste to hip ratio but to calculate exactly lean body mass at least in my hands is terrible.

Dr. Feldt-Rasmussen: Well it is and at the end of the day it’s water we are measuring. We believe the water is muscle, so of course I think there’s a good argument that it is indeed muscle that we have but ok it’s not easy. We’re using Dexa scans. The first question about stage III, I have absolutely no idea. I would say that perhaps one concern could be, there could be many concerns but one concern could be the sodium volume retention that we actually expected or we were worried about sodium volume expansion, we didn’t know in patients with no kidney function where we dialysed everything out whether it would be an issue, it wasn’t but it could be in stage III kidney disease.

Chairman: While he’s coming to the microphone I think it’s fair to say that it was not stopped because of some adverse consequence nor was any danger spotted it was stopped for what reason?

Dr. Feldt-Rasmussen: Well, I agree with you the safety committee had no complaints. Absolutely, it was up and running. The problem was recruitment concerns from the sponsor. I mean they should answer for themselves but the way I tried to understand it I think it was a matter of having too many patients in “unlabelled treatment for too long a time when the project went on longer than the planned three years. I mean to my mind we were doing well recruiting, we were increasing recruiting and having joined the SHARP study and other studies having seen how things take time and how they speed up during the study I would say it was possible to randomize all of these patients but it would have taken at least one year longer than we had anticipated and here we are.Sad.

Question: Thank you for an excellent presentation and interesting and positive data because the impression is as you say that much of it was very positive. My question is about serum albumin which we know is not a good marker of nutritional state. In fact when we try to relate it to other components which measure nutritional status often there is no relationship and this is for example, because a low serum albumin level is a very good marker of inflammation which is a very catabolic situation and it would be interesting to see, do you have any idea, what do you think about this yourself and it’s a common problem in nutritional interventional studies in uremic patients. As a rule low serum albumin patients are included but I doubt that we should rule out in these patients that they’re not inflamed. So the question is did you do that and can you do a subanalysis I suppose with those who have very low values and take them away?

Dr. Feldt-Rasmussen: Well it’s a long reply but I’ll try to do it. I agree with you that serum albumin is not easy to handle and it reflects a lot of conditions. The only way that we could exclude anything was that they had to have stable dialysis for some months, they should not have been hospitalised, inflamed, infected and so on and so forth. Because obviously if you have been with an infection the albumin goes down and so on. It turned out that we cannot measure albumin, none of us can, so we think we can and we know that it’s low in our patients but if we compare between labs it’s hopeless.We spent more than a year to find out that it was hopeless. But the fact is we would like to have those (with lower range albumin), well not with the highest range of albumin so to speak. But the previous, the smaller scale studies, they had no limitations on that (albumin level). They included every level but in this study, in order to get power and knowing that albumin was associated with mortality, (I mean not knowing why but knowing that it was associated) it seemed to be a good idea to look at a lower segment anyway.