To answer some of the questions in the aHUS Patients Research Agenda clinical trials will be needed.
Take the issue of withdrawal from complement inhibitor treatment. Setting up a trial to establish how stopping treatment can be done safely for a small number of rare disease patients involves the same robust methodology as major clinical trials. It is involves a considerable amount of professional expertise and skill to do it successfully . The author knows that because he has witnessed it over the past six years in the UK’s clinical trial of Stopping Eculizumab Treatment Safely, or SETS.
A recently published article* in the British Medical Journal is not about the results of a clinical trial, but about the way the trial was designed, set up and conducted.
Trial results have been delayed because monitoring of some patient participants is still continuing. This is because trial recruitment had to be paused during the COVID-19 pandemic. The trial timeline had to be extended. And that needed unprecedented trial management intervention.
The article illustrates clearly all the the protocols that need to be put in place to ensure that whatever outcome results emerge, they are clinically sound and authoritative for future clinical decision making to be based on it.
The need for such a trial began seven years ago when a health policy making group in England , the National Institute of health and care Excellence (NICE) made it a condition of its approval of the use of eculizumab for aHUS treatment in England. These things take time.
For a while it was thought that a pan EU trial for withdrawal of treatment would be the way forward. A group of aHUS clinical researchers thought such a collaboration would be preferable. An opportunity to expand the number of trialists together across countries. But funding was turned down by the EU institution responsible because ” too few people would benefit”. A non politically correct response in the rare disease world these days.
So EU countries were left to conduct their own studies and find ways to fund them. Millions of euros would be needed.
In the UK , or more precisely in England, a National Centre for aHUS would have to lead such a trial, and use the trial management resources of the University of Newcastle upon Tyne Hospital Trust. Funding would be needed from the National Institute of Health Research and a clinical trial management team ( including the author) was set up in late 2016 to make the case for call on its research funds. To do that the objectives of the trial would need to be clearly defined, i.e the why , and the trial protocols set out , i.e. the who , where, when and how, in the format needed by the NIHR. That took some time to do and to get NIHR approval. The painstaking attention to detail would help not only with the funding decision but make things run smoothly later.
Eventually NIHR did approve a trial and then the trial plans could be put into practice. The first patient was recruited in November 2018, nearly four years ago. Gradually more patients decided to join the trial and numbers moved towards the 30 target participants which was thought sufficient number for a very rare disease like aHUS with small numbers of patients suitable for participation.
The trial itself was subject to its own safety control through use of a statistical technique ( Bayesian) . If the trial reached inferiority, where the number of patient relapses were more than statistically expected, then the trial would be stopped as unsafe. It has not been stopped and continues.
The COVID -19 pandemic happened. Recruitment levels had not reached target, and additional time was needed once UK hospitals had the capacity to do other things like trials, and recruitment could begin again. All patients entering the trial would need to be monitored for 24 months the pause would have a consequential effect of when the trial results would eventually be reported.
So the details about whether and how many patients remained in remission for at least 24 months are not yet available, but the way in which the trial was conducted has been revealed. Hence the article.
It was multi centre trial involving hospitals around the UK and not just the Newcastle hospital. It was single arm i.e. there would not be a group of patients withdrawing from treatment without any of the safety protocols to compare with. And open label i.e. everyone involved knew which drug was being withdrawn – eculizumab.
It was prospective, but not a randomised trial where patients would have been chosen to participate by chance. aHUS patients were chosen and offered the chance to participate. It would their decision of course. They would only be chosen if after screening they met clinical criteria and importantly had a known low risk pathogenic susceptibility to relapse. Or no known genetic susceptibility. Safety is built into the trial design all along.
Ongoing safety monitoring, which tapered off from weekly to monthly with time during the 24 months of follow up, watched for not only for signs of relapse but also clinical stability off treatment.
An important part of the monitoring protocol was for patients to self monitor using urine tests. Daily at first, then every other day until 24 months. A burden yes, but reassuring in the early stages of withdrawal when evidence has shown that a new TMA is most likely. Control of their own monitoring would also build up confidence about a lasting remission as time goes by and when there would be fewer visits to hospital, more like normality. Once the trial follow up time was completed, patients and their local physicians would decide the way they would self monitor going forward. That was not within the scope of the trial. Maybe one day patients may reveal their preferences that worked for them long term.
Another feature of the protocols is the assured and swift return to treatment should there be confirmed evidence of a possible manifestation of a TMA. When caught in the early stages of development, a quick return to treatment within 24 hours can maintain kidney function at pre onset levels. This is a key difference to patients’ first experience of aHUS when, unmonitored, they would have been unaware of a TMA brewing in those first few hours. They would have only noticed symptoms several days or weeks later when greater damage had been done.
So the clinical trial was also about a withdrawal protocol itself, which had patients at its core and which:
- has an informed patient risk assessment before considering suitability for treatment withdrawal;
- the patient is central to the decision making
- clinical monitoring tapering of over time from withdrawal for reassurance and confidence building
- patients involved in their own monitoring and their long term preferences
- assured and swift return to treatment
One other element of the trial will be a qualitative study of what patients thought about participating in the trial and having treatment withdrawn. Something which will be of interest to other aHUS patients. The first such research to the best of Global Action’s knowledge. So patient centric to the end.
All that just to determine whether eculizumab can be withdrawn safely.
Back in the day when aHUSUK was active its mantra was ” eculizumab for all patients who need it for as long as needed”. Studies on withdrawal give answers to how long it is needed.
And what it is about some patients who do not need it for a life time but only a short time. and then some not at all.
The NICE decision gave access to aHUS treatment when needed. NICE will get an answer to its decision “qualification” from this clinical trial about withdrawal .
But SETS along with STOPECU , CUREiHUS , Ardissino Group and other studies will collectively gather more evidence to help patients make the decision to withdraw from treatment or not . And enable them to make that decision with much more confidence.
It too important for it to be a “tossing a coin” or “scratching a belly” choice , and demands understandable risk based information, and surrounded by protocols that ensure that no harm results if anything untoward happens. Can health care practitioners do that?
As the old song goes ” It ain’t what you do its the way that you do it ” The way SETS has been done is as important as the outcome at an emotional and stressful time in the aHUS patient’s journey. The Clinical Trial Management Team for SETS has helped patients on that journey.
The author has been a non clinical participant and an observer in the SETS clinical trial project for over six years now. And even before that, knowing it was going to happen at some time. Being so involved it was difficult not to be impressed with the professional way such studies are managed through planning and implementation stages. As well as the amount of work required to keep investigation site data flowing and accurate. Then to monitor progress and act on unforeseen problems. Problems like a global pandemic impacting on health care priorities. Let alone to have do it all remotely from home for the duration.
Clinical trials? They are not easy to do.
Read the original article which can be seen HERE.
Article No. 543