Friday, July 14, 2017

Phase-III Results from an Oral Insulin Clinical Trial In Presymptomatics

A Quick Introduction to Oral Insulin to Prevent T1D

Obviously, all type-1 diabetics need to take insulin in order to process carbohydrates. This insulin must be injected, because if it were taken orally it would be digested into smaller pieces and would not work as insulin [d1]. Injecting insulin in this way does not cure or prevent type-1 diabetes, it just treats it.

However, one of the autoantibodies that is associated with type-1 diabetes targets insulin molecules[d2]. Therefore, there is a theory that giving insulin to people with T1D might prevent or delay the onset of type-1 diabetes by training the body not to produce this autoantibody. The process is vaguely similar to giving small amounts of peanut proteins to people with peanut allergies[d3]. Insulin pills may work for this purpose even though they would not work as a treatment for type-1.

The Phase-III Study (Structure and Results)

These researchers started with 10,000s of TrialNet participants, and enrolled 560 people who were "presymptomatic". They showed two autoimmune markers, but no symptoms of type-1 diabetes. All of these people tested positive for one particular autoantibody associated with T1D (micro insulin autoantibody) [d2], but they were further subdivided into four groups based on the other autoantibodies they tested positive for, and how much insulin they were producing.

Each subgroup was split in half. One of these halves got oral insulin twice a day, and the other half got a placebo. They were followed for a year or longer to see how many people in each group developed type-1 diabetes as measured by "classic" symptoms.

If you look at the entire study, oral insulin did not have a statistically significant effect. However, if you looked at one subgroup specifically [d4], that subgroup did show a statistically significant effect. For that one subgroup, about 18% of the treated group came down with T1D, while 34% of the untreated group did. The researchers viewed this as delaying the onset of type-1 diabetes by 2.5 years (on average) for this subgroup.

Presentation Slides:

News Coverage:

Clinical Trial Record:

Discussion Of This Study

The results of this study are clearly "bad news on one hand, good news on the other". If you look at the study as applied to all presymptomatics, it was not successful. On the other hand, if you look at it for one specific subgroup, then it was successful. So the obvious thing to do is to try to replicate the results on the specific subgroup where it was previously successful. If so, this could turn into a delaying or preventative treatment for the 10% of patients who fall into this group. Since this subgroup had a specific combination of autoantibodies, it is straightforward to test ahead of time, and give oral insulin to people with this same combination, but not other combinations (where it did not work).

This trial was the size of a phase-III trial. However, the success was only seen in a subgroup, and that subgroup was the size of a phase-II trial. So I would not think of this as a successful phase-III trial, but rather as a successful phase-II trial (meaning that at least two phase-III trials should be expected before it becomes commonly available) [d5].

It is also important to remember that as group size gets smaller, the chance for accidental correlation gets bigger. With these sorts of subset analysis, it is always possible that the effect seen is cause by luck rather than effect. In this particular case, the results were statistically significant even for the smaller group, which is a good sign, but only larger studies will be conclusive.
The History of Oral Insulin

Oral Insulin has a long, complex history of clinical trials, and the results are very mixed (like this study). Just before I started my blog (so 10+ years ago), the results of an oral insulin for prevention trial were announced, and the trial was unsuccessful. However, the researchers analysed the data in more depth after the study concluded, and realized that it had worked for one subgroup (sound familiar?) That was the micro insulin autoantibody subgroup, and that's why everyone in this study had that antibody.

But the idea that oral insulin might prevent/delay type-1 is a popular one, and there are at least three clinical trials running right now. All three of these studies are similar, except for size: the first is 44 people, the second is 220, and the third is 92.

Oral Insulin Starts a Phase-II Trial In Germany (pre-POINT Early)
Forschergruppe Diabetes, Klinikum rechts der Isar, Technische Universität München, Lehrstuhl für Diabetes und Gestationsdiabetes der Technischen Universität München, München, Germany, 80804
Started in Aug 2015 and expected to finish in Aug 2017
News: Vaccination against type 1 diabetes may soon be available to young children:
Clinical Trial:

Phase-II Oral Insulin Trial In Germany (Fr1da)
Forschergruppe Diabetes, Klinikum rechts der Isar, Technische Universität München, Lehrstuhl für Diabetes und Gestationsdiabetes, der Technischen Universität München, München, Deutschland (DEU), Germany, 80804
Anette-G. Ziegler, Prof. Dr., MD +49 (0)800 464 ext 8835
Started in Dec 2015 and expected to finish in June 2021
Clinical Trial:

Phase-II Oral Insulin Trial In The US (TN20)
Not recruiting.
Started in Jan 2016 and expected to finish in Dec 2017.
Clinical Trial:
Extra Discussion

[d1] To complicate things, several researchers are working on creating a form of insulin which could be eaten, but which would avoid digestion, so that it could be used to treat type-1 diabetes. This is also called "oral insulin" research. In this blog posting, I'm talking about oral insulin as a cure or preventative for T1D, not as a treatment.

[d2] Autoantibodies are the malfunctioning antibodies which cause the immune system to attack beta cells. There are five autoantibodies associated with type-1 diabetes, and there may be more that we haven't discovered yet. The five we know about are:
* micro insulin autoantibodies (mIAA or just IAA)
* islet-cell antibodies (ICA)
* glutamic acid decarboxylase (GAD) antibodies
* islet antigen-2 (IA-2) antibodies
* zinc-transporter 8 (ZnT8) autoantibodies
The last one was not used in this study, possibly because it tends to show up later in the disease process.

[d3] It is important to realize that type-1 diabetes is NOT a conventional allergy to insulin. It is similar to allergies in that it is the body's immune system overreacting to something that it should not react to, but other than that, is quite different. Allergies involve the immune system overproducing histamines. These histamines attempt to get physical irritants, like pollen, out of your body. You can counter this histamine reaction by taking antihistamines. Type-1 diabetes involves the immune system overproducing malfunctioning killer T-cells (or perhaps under producing regulatory T-cells). These malfunctioning killer T-cells mistakenly kill beta cells, thinking they are foreign cells (ie. living creatures like viruses, that have invaded the body). So the mechanism is different (histamines vs. T-cells), and the mistaken target is different (physical things, like pollen or wheat vs. living organisms, like viruses).

[d4] The subgroup that showed the effect was the micro insulin autoantibody (which everyone in this study had), and either the ICA autoantibody or both the GAD and IA-2 antibodies, and also low insulin secretion at the start of the study.

[d5] As far as I can tell, oral insulin is not approved for the treatment of any disease in the US, and is not available either by prescription or "over the counter". Therefore, it will need to go through full US FDA approval, which requires two phase-III trials. I don't know if the FDA would consider this a phase-III trial for approval purposes.

Joshua Levy
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.


Rick said...

We have to hope it works out, I mean we need new insulin delivery mechanisms. So why not?

Celsus said...

Why all this interest in preventing new cases when that will simply discourage funding for cures for established cases?