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Case study: Using an adaptive model to trial a new treatment for rare kidney disease

The NIHR research infrastructure supports the delivery of complex and innovative clinical trials.

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The adaptive dose-ranging model

Clinical need

IgA nephropathy, also known as Berger's disease, is a rare form of kidney disease. IgA (Immunoglobulin A) is an antibody - a protein made by the immune system to protect the body from foreign substances such as bacteria or viruses. People with IgA nephropathy have a defective version of immunoglobulin A which causes IgA deposits (protein chains) to build up in the kidneys. This build up causes inflammation which damages the kidney tissues and impairs kidney function.

Professor Jonathan Barratt is an Honorary Consultant Nephrologist at Leicester General Hospital and the Mayer Professor of Renal Medicine at the University of Leicester. He explains why clinical trials are needed in this disease area:

“IgA nephropathy is diagnosed by biopsy which reveals that IgA deposits are building up in the kidneys. There is currently no disease modifying drug or treatment available. At the moment all we can do is try and slow the progress of the condition by managing blood pressure and reducing urine protein levels with medication. However, there is hope on the horizon.

“We don’t currently know what causes the production of defective IgA, but we do know that it is the build-up of specific proteins - known as complement proteins - that are driving the inflammation which ultimately causes the kidney damage.  New drugs are in development that, in the laboratory, have the ability to block complement proteins from causing inflammation. This could present a new treatment pathway for IgA nephropathy patients in the future.”

“Novartis is developing a new compound which has been shown to have this ‘blocking’ effect in the lab. We now need to conduct clinical trials to discover if it has the same effect in humans.”

“Novartis is developing a new compound which has been shown to have this ‘blocking’ effect in the lab. We now need to conduct clinical trials to discover if it has the same effect in humans.”

The Trial: Study of safety and efficacy of LNP023 in patients with kidney disease caused by inflammation

As described above, one of the modifications of an adaptive trial can be to adjust dosing levels. Professor Barratt describes how the adaptive model works in the context of this trial:

“This study is a phase IIa / IIb study which aims to answer questions such as:

  • Does the compound have a similar ‘blocking’ effect in patients who have kidney inflammation caused by IgA nephropathy?
  • What dose is required to effectively ‘treat’ kidney inflammation in patients who have IgA nephropathy?
  • Can IgA nephropathy patients tolerate the dose required to effectively ‘treat’ the disease?

“The trial design has different stages (cohorts) that are testing different doses. Each stage of the trial informs the next stage. The first cohort of data will be used to plan the second stage of the trial and so the study ‘evolves’ or ‘adapts’ as it progresses. For example, if one dose yields no positive results, ie if that dose has no effect, then that part of the trial is stopped and we continue to focus our resources where we can see that a dose is having an effect.”

UK recruitment to stage one of the trial is now complete and is in the analysis phase.  Professor Barratt is optimistic about the results so far:

“It’s a double blind placebo trial so my clinical team (and the patients) do not have any idea whether our patients are receiving active drug or placebo. However, the data being generated has enabled planning for stage two, which is now underway, and which will involve more sites and more patients.”

“This expansion of the trial is all covered in the study protocol and this is where the adaptive model works really well. There is no need to stop this trial and start a new one. The evidence we have so far allows us to move onto planning the next stage. It’s a seamless evolution of the same trial and is a much more effective and efficient way of working.  It is also a very practical model for a trial investigating the efficacy and safety of different doses of a particular drug.”

Philip Ross, Group Head Translational Clinical Trials for Novartis Pharmaceuticals UK is part of the team overseeing this study. He has seen an increase in trials adopting an adaptive approach and, while recognising the efficiencies this model can bring, he also points to where additional resource might be required:

“For the reasons outlined above, we do see adaptive clinical trial designs appearing more frequently in some of our protocols. Particularly in situations such as the case study presented here, or where it is advantageous to examine multiple combinations of different agents, [adaptive designs] offer the prospect of testing hypotheses more rapidly and increasing the efficiency with which decisions are reached. Building adaptability into the protocol from the start reduces the need for reactive protocol amendments that otherwise can increase the administrative burden on both sponsor and site.  An increased number of data analyses does require effective collaboration between Sponsor and site to ensure data cleaning is effectively managed to produce high quality data for ‘snapshots’ at decision- making points.”

UK strengths: Connected clinical communities

Like all rare disease research, finding and recruiting IgA Nephropathy patients can be challenging. However, Professor Barratt, who also works with Novartis on a consultancy basis, is quick to point out the advantages of conducting rare disease research in the UK:

“One of the key benefits of working in the UK is that the rare disease clinical community tends to be very active, and very connected. This is especially true in kidney disease, we are a very close knit community. For instance, I know what research my fellow nephrologists are doing, and what their specific areas of interest are. This means I can easily refer patients and recommend who to contact, for example, for research in cystic kidney disease, glomerular disease and tubulopathies.

“We also have the UK Kidney Research Consortium (UKKRC) which has existed since 2007. It is jointly hosted and supported by the Renal Association, Kidney Research UK and the British Renal Society. It brings together all the different renal research stakeholders across the UK, including the NIHR Clinical Research Network, and it coordinates a number of UK-wide Clinical Study Groups.  Through these groups, the renal research community meets and shares best practice with the aim of developing and delivering the best possible research to find the best possible treatments for our patients. There is nothing like this kind of collaborative model outside of the UK.

“Add to that our unified health service - the NHS - which underpins our ability to access patient data and has also enabled the creation of a National Registry of Rare Kidney Diseases (RaDaR). We estimate that 95% of rare kidney disease patients in the UK are included in this register. As of 1 July 2019 there were 23,150 patients in RaDaR from 100 different hospitals.

“We believe it is the best rare disease registry in the world.  It’s a fully automated system for collecting hugely important clinical data. It provides us with a national picture of who is being treated, how they are being treated and how they are responding to treatment.

“We believe it is the best rare disease registry in the world.  It’s a fully automated system for collecting hugely important clinical data. It provides us with a national picture of who is being treated, how they are being treated and how they are responding to treatment.

“Using the data we can conduct virtual screening for a study or trial. In addition, all patients are pre-consented to be contacted about clinical trials and studies. For researchers this means rapid access to patients with rare kidney disease. Some of these rare diseases, including IgA nephropathy, are also part of the NIHR BioResource. This means we have cohorts of patients with rare renal diseases in for whom real-time clinical data is being collected, are part of a national biobank including extensive genotyping, and have consented to be re-contacted for both clinical trials and recall scientific studies- a truly unique resource”

“Following fast in the footsteps of RaDaR, is the National Unified Renal Translational Research Enterprise (NURTuRE). This is a collaborative project with Kidney Research UK, industry and academia to establish the first renal biobank covering England, Wales and Scotland.  This biorepository, established at the NIHR National Biosample Centre in Milton Keynes, is collecting and storing biological samples from 3,000 patients with chronic kidney disease and 800 patients with idiopathic nephrotic syndrome. It’s almost finished recruiting and will soon provide a significant resource for fundamental and translational research.”

In addition to his roles as Leicester General Hospital and the University of Leicester, Professor Barratt is also the Renal Specialty Lead for the East Midlands branch of the NIHR Clinical Research Network – an organisation which also plays a key role in research delivery. He continues:

“A key objective of establishing the Clinical Study Groups and RaDaR was to aid identification of patients for clinical trials of novel therapies in the often neglected area of rare orphan diseases. To be able to deliver these trials we also need a well-resourced clinical trial delivery infrastructure. The East Midlands branch of the NIHR Clinical Research Network has been very supportive of developing renal research across our region and especially in Leicester. As the Renal Specialty Lead for the East Midlands Local Clinical Research Network, I can see first-hand how NIHR Clinical Research Network support has fundamentally improved our ability to deliver clinical trials in renal disease, and in particular in rare kidney diseases.”

Life science company perspective

When it comes to rare renal research the UK certainly has a number of unique selling points, some of which have contributed to successful recruitment to the IgA nephropathy study funded by Novartis.  Thirteen countries are taking part in this stage of the study with an overall global sample size of 48 patients. The UK was joint top recruiting country (with Belgium) recruiting a target of seven patients within planned timescales. In addition, Professor Barratt’s team at Leicester General Hospital also recruited the study’s first global patient which is considered a key performance indicator for the global life-sciences industry in research delivery as it shows that a country can support rapid study set-up and patient recruitment. 

Nick Webb, Novartis Translational Medicine Director and Global Medical Lead for the study commented on this and other recent UK achievements:

“The UK’s performance in this study has been exemplary, recruiting the first global patient as well as the joint-largest number of patients of all 13 participating countries. This has been closely followed by recruitment of the first global patient in a study of LNP023 in C3 glomerulopathy.  A further study of LNP023 in membranous nephropathy will commence recruitment in October 2019 and six UK sites have been selected to participate as a direct result of this [success]. Novartis has a number of compounds under development for other nephrology indications and the UK will hopefully additionally play a major role in the delivery of their Proof of Concept studies.”

Philip Ross agrees that the UK has a lot to offer and concludes by reminding us that ultimately it is our NHS and its patients who will benefit:

“The UK presents an attractive environment for translational studies in rare disease, given the scientific and clinical expertise within and the close working nature of clinicians described by Professor Barratt. This aids the logical selection of sites and offers the opportunity for patients within the UK to access clinical trials involving novel investigative agents.

“The UK presents an attractive environment for translational studies in rare disease, given the scientific and clinical expertise within and the close working nature of clinicians described by Professor Barratt. This aids the logical selection of sites and offers the opportunity for patients within the UK to access clinical trials involving novel investigative agents.

More about adaptive trial designs

There are a number of different approaches to delivering a trial which are categorised as ‘adaptive’ trial designs. These include platform, umbrella, basket, and MAMS (Multi-Arm Multi-Stage) designs, among others. All of these approaches have the same underlying principle of flexibility built into the study protocol which allows the trial to ‘adapt’ as the science evolves. This is achieved by analysing the data, usually at set points, as the trial progresses. The findings are used to modify the course of the trial according to pre-specified rules and parameters set out in the study protocol.

Example modifications may include the drug or combination of drugs being used, the dosage, the patient sample size, or the patient selection criteria. . In some cases the trial becomes an ongoing process, adding new arms for new therapies and/or new patient groups (such as patients with different biomarkers) as more data is acquired and analysed. Similarly, arms of the trial that fail to yield positive results can be closed down. In this way, adaptive trials are seamless - they do not need to stop and start a new trial for each modification.

The aim of this approach is to more quickly identify where a drug or device has a therapeutic effect and zoom in on the patient populations who are experiencing positive outcomes. Trials with an adaptive design are considered more efficient than trials with a fixed design. They have the potential to save both time and resources required for study set-up, and they often require fewer patients to be screened. In the long term, this approach could also help to speed up the overall drug development process and bring new treatments to patients faster.

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