Presymptomatics are not yet diagnosed with type-1 diabetes in the classic way, but current theory is that all of these people will eventually be diagnosed. It is just a matter of time. So in the same way I might say "Drug X starts a phase-I trial in honeymooners" or "Treatment Y starts a prevention trial" or "Drug Z starts a trial in people with established type-1 diabetes", I will also start to report "Drug W starts a phase-I trial in presymptomatics".
You can think of presymptomatics as pre-honeymooners. They are like honeymooners, but even earlier in the disease process.
I also want to stress that although the JDRF, the ADA, and the Endocrine Society agree that two autoantibodies is the earliest diagnostic for type-1 diabetes, this is not universal agreement, and what agreement there is, is only about 2 years old. Here are some web sites which describe this view of the stages of type-1 diabetes:
- https://www.trialnet.org/t1d-facts/stages-t1d
- http://www.jdrf.org/press-releases/jdrf-and-the-american-diabetes-association-in-collaboration-with-multiple-diabetes-organizations-publish-new-classification-and-staging-approach-for-presymptomatic-type-1-diabetes/
This also changes when "diagnosis" occurs. In the past, diagnosis occurred when symptoms were seen, and confirmed with a blood glucose measurement. However, now diagnosis occurs when two autoantibodies are measured, and this is often years before symptoms are seen, or blood glucose levels are noticeably abnormal.
So, moving forward, I will use the term "classic diagnosis" or to refer to people who were diagnosed because they showed symptoms, as was done in the past, so it's obvious what kind of diagnosis I'm talking about.
I expect there will be more studies like the two described below, that specifically target presymptomatics. After all, any treatment that researchers thought might work for honeymooners (but did not), should now be retested on presymptomatics. This is especially true of treatments which change the immune system.
In the past, it's generally been understood that to cure type-1 diabetes, you needed to change the immune system (so it stopped generating autoantibodies and stopped attacking beta cells), but you also needed to regrow beta cells. However, presymptomatics have enough beta cells so that they can regulate their own blood glucose levels. To cure them (ie. to prevent symptoms from ever showing up), "all" you need to do is change the immune system. No need to regrow any beta cells.
That sounds important, and it is, especially when you think about treatments that have already been shown to stop the destruction of beta cells. In the last 5-10 years, several treatments have been shown to "preserve beta cells" meaning that once given, beta cells stop being killed off by the immune system. Since these studies were typically done in honeymooners, this did not cure anybody, it just extended the honeymoon.
But if those same treatments showed the same results in presymptomatics, then it could be said that they prevented type-1 diabetes. I very much hope that every treatment which has previously been found to preserve beta cells, will now be tested on presymptomatics. Some of the treatments which have preserved beta cells in honeymoon diabetics (at least to some degree) are: T-Rex (polyclonal Tregs), Abatacept (Orencia), Etanercept (ENBREL), and Teplizumab.
Victoza / Liraglutide Starts A Phase-I Trial In Presymptomatics
About this trial: it's testing the theory that Liraglutide (sold as Victoza) might help people use less insulin or delay their use of insulin, when given to people before they are classically diagnosed with type-1 diabetes. This is an early phase-I trial. Only 10 people will be enrolled, and there is no control group. This trial recruits people who have started to have trouble generating insulin in response to food that they've eaten. They will be followed for one year. The trial started in March 2016 and they hope to finish by July 2018.
They are recruiting only by invitation at several nordic hospitals:
- University of Oulu and Oulu University Hospital, Dept of Children and Adolescents Oulu, Finland, 90029
- University of Tampere and Tampere University Hospital Tampere, Finland, 33520
- University of Turku and Turku University Hospital Turku, Finland, 20520
- Lund University and Skåne University Hospital Malmö, Sweden, 205 02
Discussion
The Clinical Trial Record lists this as a phase-II trial, but with only 10 people included and no control group, I consider it a phase-I trial.
I don't see how this trial could ever prove any level of effectiveness. We don't know how many people eligible to enroll in this study would "naturally" have type-1 diabetes symptoms within the one year study time. And, this trial has no control group. So there is no way to compare the results from this study to "normal" results to see if it worked or not.
It could show safety, but the drug being tested has been approved for use in overweight people and also people with type-2 diabetes for years, and is used "off label" by some people with type-1 diabetes, so safety is not really an issue.
Victoza / Liraglutide Starts A Phase-I Trial In Presymptomatics
This trial is similar to the one above, except that it is much larger, and recruiting a slightly different population. This second trial recruits people who have two autoantibodies and one of several different glucose abnormalities, so it's a larger group of people, and also more in tune with the "two autoantibodies means type-1 diabetes" definition of Presymptomatic.
This is an phase-II- trial which will enroll 82 people with half in a control group and half getting the treatment. People will be followed for one year. The trial started in 2016, and is expected to finish in mid 2019. They are recruiting by invitation only at the same hospitals listed in the previous trial.
Clinical Trial Record: https://clinicaltrials.gov/ct2/show/NCT02898506
Discussion
(As you read this remember that I'm not a statistician, and have never take a college level class in statistics.)
I'm a little worried about the statistical power of this study. They are going to have 41 people in their treatment group, and will follow them for one year. The data I've seen suggests that about 10% of the people with two more more autoantibodies will show classic type-1 diabetes systems each year. So that means that we should expect about 4 from this group to show symptoms by the end of the study. If this treatment were perfect in preventing type-1 diabetes, then 0 in the treated group would show symptoms. But the difference between 0 and 4 is not that large. And the treatment is unlikely to be perfect the first time it is tested. Let's say that 2 people in the treated group get symptoms, but 4 people in the untreated group get them. Is that a 50% reduction in diagnosis (which would be huge) or is that just a little good luck involving two patients? It's hard to tell, and that is what I'm worried about.
On the other hand, this is a phase-II study, so will not be the last word, in any case, and Victoza is already approved, so is not a particularly risky drug. Also, if the results for the first year are good, then it would be relatively easy to extend this trial for another year (or longer) which would increase its statistical power.
Joshua Levy
http://cureresearch4type1diabetes.blogspot.com
publicjoshualevy at gmail dot com
All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions. My daughter has type-1 diabetes and participates in clinical trials, which might be discussed here. My blog contains a more complete non-conflict of interest statement. Thanks to everyone who helps with the blog.
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