The trial

The autoimmune diabetes Accelerator Prevention Trial (adAPT) is a randomised controlled trial (RCT) designed to prevent type 1 diabetes in young people, and to test the accelerator hypothesis, a new and alternative explanation for type 1 diabetes.

 

adAPT is sponsored by the University of Exeter, funded by JDRF (Juvenile Diabetes Research Foundation) and conducted in the UK by TCTU (Tayside Clinical Trials Unit)

 

What is adAPT testing?

There are three key players in type 1 diabetes – the beta cells which make insulin, the immune system that destroys them, and the type 1 (accelerator) genes that regulate the immune system. The immune reaction that characterises type 1 diabetes has been interpreted in two ways over the years – as either a faulty immune system that attacks the beta cells, or a normal, if intense, response of the immune system to some change in the beta cells which stresses them.

The accelerator prevention trial is testing the second possibility – that beta cell stress, which is part of modern life, damages the beta cells, while the immune response in those who carry the ‘accelerator’ genes speeds up the destruction of beta cells. adAPT will attempt to reduce the damage in the first place. Antibodies are the indication of beta cell damage. They are measured in the trial to tell us which children are at risk of type 1 diabetes, and how well the treatment is working.

In brief…

 

The accelerator hypothesis is a new way of looking at type 1 diabetes, and adAPT is a clinical trial to test the idea. A successful result could provide a way of preventing diabetes in children, which would be a important step forward. adAPT aims to find out whether a liquid medicine taken twice a day can so protect the insulin producing cells that they keep working. If the medication works, the body won’t run out of insulin, and diabetes will be prevented.

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There are several phases to the trial:

Screening

… will identify children and young people aged between 5 and 16 who are at high risk of developing type 1 diabetes.

Stage 1

… lasts four-months, and is designed to find out whether the trial is likely to work, and whether the medication is able to protect the beta cell.

Stage 2

… lasts 36 months, and will tell us what impact the trial medication has on slowing down the loss of beta cells.

Stage 3

… will count the numbers of children who become diabetic over the whole five years of the study to see if the medication works.

 

More detail…

 

First, we need to identify children and young people at high risk of developing type 1 diabetes, who might benefit from taking part in the trial. To do this, we will be asking clinic doctors to contact families where a member developed type 1 diabetes before the age of 25. We will then invite the offspring and/or siblings aged between 5 and 16 of the type 1 diabetic member for screening. The children who sign up – the adAPT family – will be a select and special group of young people who will be playing a key role in helping work out how to prevent type 1 diabetes.

Trial design

adAPT is the first paediatric trial to be conducted nationally across the whole of Scotland and in the North of England. It is registered as a portfolio study within the NHS, and has the support of the Scottish Office. As a national study, adAPT will be seeking to recruit participants from all 11 health boards, and will use the research networks set up by NHS Research Scotland (NRS) to do so. The networks of relevance to adAPT are the Children’s Research Network (CRN) and the Diabetes Research Network (DRN). The networks are given support by the NHS to encourage research, and doctors are helped to participate. adAPT is a conventional RCT involving a screening phase followed by three seamless stages. Progression to the next stage is contingent on the success of the previous one.

Screening

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We first need to identify children who are likely to benefit from the trial. We already know that the brothers and sisters of a diabetic child have an increased risk of diabetes because of their shared genes. The same is true for the offspring of a parent who became diabetic when young. So, we would like to ask each of them to give us a sample of blood (generally pain-free following local anaesthetic) to look for the risk of childhood diabetes.

 The risk is in reality a protein called an antibody, and the more antibodies that are present, the greater the risk of diabetes. Based on published research, we expect that only one in twenty of the siblings/offspring screened will have two or more antibodies. This is important, because studies have shown that the risk of diabetes is low if just one antibody present, and almost non-existent if there are none. Accordingly, 19 out of every 20 children (and their parents) will go home reassured by the screening test that diabetes is very unlikely to develop. To assemble the ‘double antibody positive’ numbers needed for such a trial, we will be asking all the families with childhood diabetes across Scotland and the North of England to take part in screening (see: How can I take part?).

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Stage 1

… a four-month pilot study in a small number of high-risk children to demonstrate feasibility. Stage 1 will test the recruitment strategy, the drop-out rate, children’s acceptance of the medication and the number of children needed for the later stages of the trial. It will also provide information on the effect that adAPT medication has on protecting the beta cell.

Stage 2

… tests the study design in a statistically robust way, where sufficient numbers will have been recruited to answer the trial questions. Over 36 months, it will test the ability of the trial drug to reduce the levels of chemicals produced by the body and found in the blood that are known to signal the speed of insulin loss.

Stage 3

… the complete trial, lasting up to 60 months. It will compare the numbers of children who become diabetic in the active treatment arm of the study with the numbers in the dummy treatment arm.

 

Mechanistic studies

Two additional and optional studies will be conducted in a subset of the children. Mechanistic studies are important because they help to explain how a trial works. Only by understanding the process can doctors design the changes that will improve the treatment.

The accelerator hypothesis suggests that type 1 diabetes is driven by beta cell stress through excess demand. Blood glucose determines insulin demand, and glucose exposure is measured most sensitively by continuous monitoring over a week using a sensor beneath the skin. The sensors record the blood glucose level every few minutes, and will pick up even small differences between the treatment and placebo groups in the trial.

The accelerator hypothesis suggests that the stress caused by high demand for insulin causes an immune response to the beta cells in people carrying particular immune response genes. The inflammation which speeds up cell loss should lessen if the stress which causes it is removed. The immune response has two parts – antibodies and the immune cells that produce them. adAPT is already measuring the antibodies as markers for ongoing beta cell damage. In the immune cell study, the immune cells will be collected in the participating children, and their reaction to it will be measured to see if the study drug has a positive effect. The finding would be key to arguing the direction of causation in childhood diabetes – does the immune activity cause the disease, or is the immune activity a response to the damage?

Where is adAPT taking place?

adAPT is sponsored by the University of Exeter in the south west of England, and it will start recruitment in Scotland, where the incidence of type 1 diabetes is now the third highest in the world. Medical record linkage in Scotland is second to none, and the cohesion of Scottish paediatric diabetologists through SSGCDY (Scottish Study Group for the Care of Diabetes in the Young) is strong – over 90% of Scotland’s health boards have signed up to the trial.

adAPT will also incorporate the Newcastle paediatric service, and recruit from the North of England. adAPT’s attempt to involve the whole of one geographical group in a single connected study is unusual and exciting in the implications for research in the NHS. Translational medicine (moving from theory to practice) has become the cornerstone of NHS research, and the demonstration that major disease issues can be tackled on a large scale will be important for future health research. adAPT is registered as a portfolio study with the National Institute for Health Research (NIHR) and NHS Research in Scotland (NRS), and has the support of the Chief Scientist for Scotland.

What lies behind adAPT?

There has been a five-fold increase in type 1 diabetes over recent years, but we still don’t know how to prevent it.

 

In brief…

 

cause-and-effect-350-x-250Diabetes Rising by Dan Hurley tells the human stories behind the five theories that try to explain the spectacular rise in childhood diabetes over recent years. At the root of each lies the question of whether the immune reaction (autoimmunity) which characterises type 1 diabetes is the cause of the beta cell damage, or the effect. The question is important, because successful prevention of type 1 diabetes will likely hinge on the answer. Prevention trials attempt to suppress the immune reaction if a faulty immune system is thought to be the cause, or to protect the beta cell from stress if the immune reaction is thought to be the response. The only way of demonstrating which is cause and which is effect is by a randomised clinical trial, and this trial – adAPT – has been set up to test the hypothesis that beta cell stress underlies type 1 diabetes.

 

 

More detail…

 

Originally, diabetes was one disease – if it developed in childhood, it was called ‘juvenile onset’, and if it developed in adulthood it was called ‘maturity onset’. The cause of diabetes was not known, and nobody suggested that juvenile onset and maturity onset diabetes were different diseases.

That changed in the 1970’s, when three important observations were reported in the medical literature – microscopic examination revealed immune cells spreading into the insulin-producing (beta) cells of children who had recently contracted diabetes. Blood tests revealed immune antibodies to their beta cells, and genetic studies showed a link with their immune genes. These findings were not seen in people who developed diabetes as adults.The three studies were together interpreted to mean that childhood diabetes was caused by a faulty immune system which attacked the beta cells, and destroyed them. Without insulin, the child became diabetic.

Diabetes was now classified into two diseases – type 1 an ‘autoimmune’ disorder, caused by a faulty immune system, and type 2 a metabolic disorder, caused largely by environmental factors. This simple and compelling classification was recognised by the World Health Organisation (WHO) in 1980.

Autoimmunity: attack, or defence?

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The accelerator hypothesis first emerged in 1986 as a gnawing concern that the autoimmunity of type 1 diabetes might have a different explanation. What if something different were causing beta cell stress, and that ‘autoimmunity’ was a response to the damage in the small minority of people who carry reactive immune genes?

Modern life is known to place a high demand on beta cells, which damages them with two effects. First, it wears the beta cells out quicker by stressing them, which partly accounts for the rise in diabetes generally. Second, it causes an immune response in the small number of people who carry the ‘immunity’ or ‘diabetes’ accelerator genes. The immune response is inflammatory and further increases beta cell damage. The immune response distinguishes type 1 from other forms of diabetes. It is the random distribution of the genes throughout the population that makes childhood diabetes so unpredictable.

The first article to turn cause and effect around was published in 1989, it is called ‘Autoimmunity: attack, or defence?’. A year later it was followed by ‘The primary lesion theory of autoimmunity’. The accelerator hypothesis was published in 2001 to sceptical readers. It nevertheless gained support, mainly because its predictions were increasingly seen in large population studies, and in 2012 JDRF invited an application to conduct a randomised trial to test the theory. The accelerator hypothesis is known internationally, but is nevertheless still specualtion, and will remain so until a clinical trial demonstrates its validity. However, it stands among the other theories as a possible, but unproven, explanation for type 1 diabetes, with a mechanism that can be tested.

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