Objective
The goal of this project is to deliver a clinical trial for a new treatment for type 1 diabetes (T1D). A clinical trial is a research project that compares 2 treatments in patients with a particular condition, to show us which treatment works best. The treatment we will study in our clinical trial is a medicine called Semaglutide. We have to do a clinical trial to show that Semaglutide works in T1D, to get a licence from the authorities to use as a new treatment in patients.
The main aim of the study (the primary objective) is to find out if a treatment called Semaglutide, given as an injection once a week as an add-on to usual treatment with insulin, can improve blood sugar levels in T1D. We have chosen this because blood sugar levels are important to people with diabetes; and high blood sugars over a long period of time can lead to complications. Many people with diabetes find it difficult to keep sugar levels under control, even with new insulins, pumps, and monitors. We think Semaglutide may help people to get better blood sugar levels. The study has to answer the main aim, and show whether Semaglutide helps or not.
Our other aims (the secondary objectives) are to check that Semaglutide treatment is safe, and to help us understand how it might be working in T1D. We want to check that it is safe to give Semaglutide as a treatment for children and young people with T1D (CYPD). We also want to find out from CYPD if Semaglutide, given as an injection under the skin once a week, is OK for them. Finally, we want to find out if Semaglutide can improve blood sugars by increasing the amount of time that blood sugar levels stay in a healthy range. We will also check if Semaglutide can improve body weight in people who are overweight.
We will test these aims by inviting CYPD to take part in a ‘trial’ in 4 hospital diabetes units. We will ask CYPD, and their parents or carers, for permission for them to take part. We will then divide them into 2 groups. One group will be given Semaglutide treatment as an add-on to their usual diabetes treatment. The other group will be given Semaglutide ‘placebo’ as the add-on to usual treatment. A ‘placebo’ means a ‘dummy’ medicine. It looks exactly the same as Semaglutide, but it does not have any medicine in it. We don’t decide who gets the Semaglutide and who gets the placebo; this is done at random by a computer, a bit like the toss of a coin. To make this a fair test, we are not allowed to know who is taking the Semaglutide and who the placebo. In the same way, people who take part are not allowed to know which treatment they are taking, until the end of the study. This is to make sure that the results are correct and reliable.
During the trial, we will see everybody taking part regularly, and follow them up with careful measurements. We will record your information anonymously on the trial database. This means your database record will be given a number exclusive to you; and we will not record your name or address or anything that might identify you.
At the end of the study, we will check whether people taking the Semaglutide treatment have better blood sugar control than people taking the placebo. If the treatment works, then we will try to get it licensed as an option for all children with T1D.
Background Rationale
Background: Type 1 diabetes (T1D) is a disease in which the cells that make insulin in the pancreas are mistakenly destroyed by the body’s immune system. This means the body is unable to make insulin. When the body stops making insulin, the blood sugar levels go up with food. This leads to long-term eye, kidney, nerve, and heart damage if not well looked after. T1D affects about 500,000 children worldwide, and about 96,000 children under 15 years of age develop T1D each year.
The treatment for T1D is to give insulin back into the body by daily injections, or by a pump as a constant delivery under the skin. This helps bring the blood sugar levels back to normal. There is a special blood test, called glycated hemoglobin (HbA1c) which shows how high the blood sugars have been over the past 6-8 weeks. A high HbA1c, over several years, can predict the development of long-term organ damage. A low HbA1c shows that a person’s sugar levels have been mostly in the normal range, and that person is much less likely to develop organ damage.
There are targets for HbA1c, for people to aim for, to keep their sugar levels close to normal. New treatments such as rapid-acting insulin, insulin pumps, and continuous sugar monitors, have helped many children and young people (CYPD) to reach these targets. However, even with these treatments, most CYPD struggle to reach them. In England and Wales, our national report shows that only 10% of CYPD reach the target set by the UK NHS guideline. This is partly because CYPD get large swings in blood sugar readings. It can be a challenge to match insulin treatment to food, especially when children are active, in hot weather, or during illness. If CYPD are overweight, insulin treatment does not work so well. High blood sugars over a long period of time can be harmful to organs such as kidneys, eyes and nerves. Therefore, the current treatments we have for T1D are not good enough to prevent most CYPD from getting long term complications.
Rationale
There is another type of diabetes, type 2 (T2D), which affects mainly adults. In T2D, the body makes insulin, but not enough to control blood sugar levels, and the insulin does not work so well. Lots of treatments have been developed for T2D which work very well. People have suggested that some of these treatments for T2D might also work for T1D when given with insulin treatment.
One group of treatments for T2D, are called Glucagon-Like Peptide 1 Receptor Agonists (GLP-1 RA’s). These work by boosting the body’s own production of insulin, and stopping the body making glucagon, a chemical which stops blood sugar levels falling. This reduces the large swings in blood sugar, makes you feel less hungry, and fuller after a meal. GLP-1 RA’s might help in T1D by making insulin treatment work better, making people feel less hungry, and helping keep a healthy weight.
One of these GLP-1 RA medicines is called Liraglutide. It has been tried in adults with T1D. It did work and improved HbA1c; but a side-effect was that blood sugars went too low, making people feel shaky, and needing treatment to bring the sugar levels back up.
A newer GLP-1 RA has been developed, called Semaglutide. This can be given as a once weekly injection under the skin, a bit like insulin injections. We think this can help more CYPD get to target HbA1c with fewer low blood sugars. This is why we would like to test this medicine in a ‘fair test’, called a clinical trial.
Description of Project
What do we want to do: We want to find out if a treatment for adults with type 2 diabetes, can help children and young people with type 1 diabetes (CYPD).
Why we are doing this: Diabetes causes high blood sugar levels. The commonest type of diabetes in children is called Type 1. CYPD need insulin treatment to keep blood sugar levels healthy. If blood sugars go above the healthy range for a long time, this can cause eye, kidney, nerve and heart damage. We know that keeping blood sugar levels healthy protects organs from damage. We have insulin, new ways to give it such as pumps, and minute-by-minute read-outs of blood sugar, to help keep blood sugars healthy. Even with all these, most CYPD have blood sugars that are too high. Right now, our treatments are not good enough to stop long term damage to organs.
There is a treatment used for adults with type 2 diabetes, called Semaglutide. It works by helping bring down blood sugar levels. It is given by an injection under the skin, just like insulin injections. However, Semaglutide is only given once a week. It is safe, and works well in adults with type 2 diabetes. We want to find out if Semaglutide can help bring down blood sugar levels, alongside insulin treatment, in CYPD. We want to work with CYPD to try this treatment, so that together, we will find ways to make diabetes management easier and more successful.
How we will do it: We will work with young people, their families, and diabetes staff to test Semaglutide as a treatment for CYPD. We will talk with those who ‘live the condition’ and together, put together a plan to do a fair test of Semaglutide. We will do the test in 2 hospitals in Birmingham. We will invite over 200 CYPD to take part. We will give half the CYPD the Semaglutide treatment as well as their usual insulin. We will give the other half a placebo or ‘dummy’ treatment as well as their usual insulin. We won’t know which treatment each CYPD is taking, and each CYPD won’t know which treatment he or she is taking. We will ask CYPD to take the treatment for 6 months. At the end of this time we will find out who has been taking which treatment. We will compare the blood sugars of the CYPD who were taking Semaglutide, with the blood sugars of the CYPD who were taking the dummy treatment. We hope to show that the blood sugars in the Semaglutide group are better than the blood sugars in the dummy treatment group. We want to show we can improve sugar control in CYPD using this treatment that is already prescribed for adults with type 2 diabetes in the NHS. If we can show this, we will ask the National Health Service (NHS) to offer it to all CYPD who need it. We believe this could reduce the number of CYPD getting long term organ damage.
How are patients and the public involved? We are working with Juvenile Diabetes Research Foundation (JDRF) children’s group, and involved our hospital Young Person’s Advisory Groups (YPAG) on 25th May, who advised on the information sheet. A YPAG led by JDRF will help us develop the trial at all stages.
Explaining our results: We will use social media for people living with diabetes so they can see what we are doing. We will have public meetings to discuss our results. We will write reports for doctors, nurses, dietitians and leading ‘influencers’ in diabetes and NHS care.
Anticipated Outcome
The goal of this project is to deliver a clinical trial for a new treatment for type 1 diabetes (T1D). The main aim of the study (the primary objective) is to find out if a treatment called Semaglutide, given as a once weekly injection as add-on to usual treatment with insulin, can improve blood sugar levels in T1D. We will deliver this through a trial of once weekly injection of Semaglutide (the treatment) compared with once weekly injection of Placebo (the dummy treatment) as add-on to usual insulin treatment in children and young people with type 1 diabetes (CYPD).
The main outcome of the trial, will be the difference in blood sugar levels between the 2 groups, after 26 weeks of treatment at a steady dose. We want to find out if CYPD treated with Semaglutide have lower blood sugar levels than CYPD treated with placebo. We will use a special measure of blood sugar, called glycated hemoglobin (HbA1c). This is a measure of the average sugar levels over the past 6-8 weeks. We have chosen this measure because it is important to people with diabetes. We have also chosen it because it can predict the risk for people to develop long term complications. A high HbA1c can predict people who are at high risk for long term complications such as eye, kidney, nerve and heart damage. A low HbA1c can predict people who are at lower risk for these complications. We know that for many CYPD, their HbA1c is too high. We want to find out if treatment with Semaglutide can help bring down the HbA1c.
In the UK, the average HbA1c is about 8%. This means that the likelihood of long-term complications is quite high. The target HbA1c in the UK is 6.5%. That target was chosen as at that level, the risk of long-term complications is almost the same as the risk in people who do not have diabetes. If we can find a new treatment that brings the HbA1c down by at least 0.5%, this will make a real difference to the chances of getting long term complications, by lowering that risk. We have made our trial able to detect if Semaglutide can bring down HbA1c by at least 0.5%.
We expect that once weekly injection Semaglutide, when added to usual insulin treatment in CYPD, will improve blood sugar levels in ways that we already know can help: these include having more blood sugar readings in the healthy range, less swings in blood sugar, help with maintaining a healthy weight, and in the long term, protection for the heart and other organs to reduce the risk for long term complications. We believe that Semaglutide can work alongside technologies such as insulin pumps and sugar monitors to improve blood sugars. The overall impact will be to improve diabetes care in CYPD who struggle to get good sugar control. We expect to publish at least 3 articles in leading diabetes journals, and get results to show that Semaglutide works. We will use social media for people living with diabetes so they can see what we are doing. We will have public meetings to discuss our results. We will write reports for doctors, nurses, dietitians and leading ‘influencers’ in diabetes and National Health Service (NHS) care. At the end of all this, we want to be able apply to the NHS for permission to offer Semaglutide to CYPD in our diabetes clinics.
Relevance to T1D
Type 1 diabetes (T1D) is a disease where the cells that make insulin in the pancreas, get destroyed. We all need insulin to keep healthy sugar levels in the blood, and let sugar into our cells to give us energy. Children and young people with T1D (CYPD) can no longer make their own insulin, and rely on putting insulin back into their bodies, by injections, or a pump. There are an estimated 20 million people worldwide affected by T1D, and about 29,000 CYPD in the UK.
The mission of the Juvenile Diabetes Research Foundation (JDRF) is to speed up the delivery of treatments that prevent, cure, and treat T1D and its complications. This proposal is to deliver a new treatment as an add-on to insulin, for T1D. The 2 pillars of JDRF’s research strategy are to cure T1D, and to improve the lives of people with T1D. This proposal aims to improve the lives of people with T1D. This proposal is to answer JDRF’s focus on improving overall outcomes in people with T1D and reduce complications.
Children living with diabetes have had many recent improvements such as new types of insulin, new insulin pumps, new sugar monitors that measure sugar levels every few minutes, and new education methods. Even with all these, we know that only about 10% of CYPD in England and Wales have blood sugar levels that are in target range. This means their sugar levels are low enough that their risk for long term complications is almost the same as people who do not have diabetes.
We need to find treatments for the other 90% of CYPD who do not get their blood sugar levels in target, even though they have new insulins, pumps, and monitors. One goal of JDRF is to improve HbA1c. We think that treatments used to improve HbA1c in type 2 diabetes, might also work in Type 1 diabetes. These are sometimes called ‘add-on’, or ‘adjunctive’ treatments, because they are added on to standard treatment with insulin.
One of these treatments for type 2 diabetes is a group of medicines called Glucagon-Like Peptide 1 Receptor Agonists (GLP-1 Ras). These medicines work by helping the body boost its own insulin secretion, helping insulin to work better, lowering another chemical called Glucagon which can push up sugar levels, reducing appetite, and making you feel fuller after meals. A GLP-1 RA called Liraglutide has been tried in adults with T1D. It did improve blood sugars as measured by HbA1c. However, it also caused more low blood sugars which needed treating.
There is a new GLP-1 RA called Semaglutide. This can be given as an injection under the skin once a week. We know that Semaglutide improves blood sugars in people with type 2 diabetes, and studies have suggested it may do this with fewer low blood sugars.
The main aim of our study is to find out if once weekly Semaglutide, given as an add-on to usual treatment with insulin, can improve blood sugar levels in CYPD, and so reduce the risk for long term complications such as organ damage. We have written our study so that the improvement in blood sugar levels will be big enough to be an important benefit for CYPD. Other people have calculated that the improvement we want to show, will result in fewer long-term complications of T1D, and savings to the National Health Service from not having to treat so many people with these complications.