Sunday, December 27, 2020

Results from a Faecal Microbiota Transplantation Phase-I Clinical Trial

Faecal Microbiota Transplantation (FMT) is a surgical procedure where stool is transferred from a healthy donor into the gastrointestinal tract (usually the colon) of the patient.  The standard use is to treat people whose gut microbiota has been decimated by antibiotic treatment or who have a runaway Clostridioides difficile infection (commonly called "C. diff").  The goal is to seed the regrowth of a healthy microbiota.  This is sometimes called "bacteriotherapy" or "fecal transplant".

Recently some researchers have thought that type 1 diabetes might be triggered or encouraged by something in the gut microbiota.  I reviewed this theory (in the context of probiotics) a year ago:

The DIMID1 Study

This study enrolled 20 adults with T1D during their honeymoon phase (within 6 weeks of diagnosis).  Half got transplants from healthy people, and half got transplants from themselves.  Both groups went through the same procedures, but the second group got no new microbiota.  Both groups got three procedures in the first four months, and were followed for a year.  The exact times are marked with an arrow in the charts below. The primary results were C-peptide production (which measures the body's ability to generate insulin), and the secondary results were a wide variety of immunological, microbiota, and blood sugar control measurements.

This study was funded by the AMC Hospital several Dutch organizations.  It ran from 2013 to 2017 in the Netherlands. The researchers did not report on the ethnic composition of the participants.


The primary results are summarized below.  The blue lines represent the people who got the a transplant from a healthy (non-T1D) donor and the red represents people who got a transplant from themselves.  These are all people in their honeymoon phase, and you can see the "transplant from healthy" group C-peptide numbers drop (as expected from an untreated group) but the "transplant from self" group stays steady, which is better than expected.  After a year the "transplant from self" group has not gotten worse, but the "transplant from healthy" group has, and the difference is statistically significant.  The "C" results are for fasting (sometimes called "baseline") C-peptide generation, while the  "D" results are for C-peptide generated in response to eating a meal.

Copyrighted material provided for educational purposes only.

Journal article:
Personal note: this article is very well written, and easy to read.  The authors often describe why they chose to do one thing rather than another, so it is very informative.  People who want to understand why the gut microbiota might effect T1D can read the introduction for a quick, easy to understand justification.  

Clinical trial registry: 


Remembering that C-peptide is a measure of the body's ability to generate insulin, people who got the "transplant from self" treatment in their honeymoon phase did not deteriorate (in terms of generated C-peptide) over the next year.  Those who got the "transplant from healthy" treatment lost their ability to generate insulin (as would be expected over the course of the honeymoon).

But, what does this mean?  Is it important?  Will it lead to a cure?  These are the open questions. When I started this blog, results like this made me optimistic.  I thought that if a treatment could preserve beta cells in early testing, then as we learned more about it, later tests might show it increased beta cells and lead to a cure.  However, that has not happened in any of the treatments which showed this result early on.  Therefore, I'm no longer so positive about them. 

My current thinking is that these results are more likely to grow into a delay or prevention rather than a cure.  In particular, if this treatment had the same effect on people who were at-risk of T1D, as this study showed for people in the honeymoon phase, then it would naturally cause a delay.  If prevention turns out to be the natural result of a long delay, then this treatment could become that as well.  All that would be required is to see the same results seen here, but in at-risk people rather than honeymooners.  Of course, we can still hope for it turning in a cure, but that is less likely.

One interesting point about this result, is that the good effect was seen in the "transplant from self" group, rather than the "transplant from healthy" group.  It seems more likely that a transplantation from someone who did not have T1D would be beneficial while moving Microbiota around within the same person would not change anything.  However, in fact, the reverse is seen.  That is an odd result (at least to me) so I'm interested in seeing where it goes, if it goes anywhere.

The researchers wanted to include 34 people in their study (17 in each group).  Unfortunately, they were not funded enough to do that, so they ended up with 20 people (10 in each group).  Luckily, their results were strong enough to show up with the smaller numbers, but that is not often true.  So this study shows the practical impact of less money for research: fewer subjects in each study, and more uncertainty in the outcomes because of that. 

Other Research

Only one other clinical trial is testing FMT right now.  It is a pilot study, enrolling 10 people:

There are several clinical trials using probiotics to try to improve a patient's T1D.  This can be viewed as an alternate treatment to FMT, both of which are based on the same "gut based T1D" theory.


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.

Saturday, December 12, 2020

Glucose-Sensitive Insulin (NN1845) Starts A Phase-I Clinical Trial

Glucose sensitive insulin refers to any insulin formulation which becomes more available as blood glucose levels rise, and less available as those levels drop.  You can think of these insulins as self regulating or self dosing.  A person would inject enough to last for a day or more, but the insulin would only be used by the body when glucose levels were high.  A highly sensitive insulin could eliminate the need for measuring blood glucose levels and for determining insulin doses based on food, exercise, or anything else.  That would transform T1D management to the same injection each day.  In the same way people take high blood pressure medicine each day, a T1D could take glucose sensitive insulin each day, and otherwise ignore their T1D.  If successful, this could lead to a "practical cure" even if the person still "had" T1D. 

NN1845 is a glucose sensitive insulin under development by Novo Nordisk.

The Phase-I Clinical Trial

Officially, this is one clinical trial, but it is better to think of it as two separate clinical trials under one authorization. Both parts are focused on how NN1845 will act within the body (called pharmacology) and how safe it is.  Each part is expected to gather data for 10 days, so this study can be done quickly.  A total of 78 people will be enrolled.

The first part will give healthy people (people who do not have T1D) one dose of NN1845, to measure adverse effects (bad side effects), how their blood glucose changes over time, and what happens to the NN1845.  Half the people in this group will get NN1845 and half will get a placebo.

The second part will give people with established T1D either one dose of NN1845 or one dose of  insulin degludec (Tresiba®).  Again the researchers will look for adverse effects (bad side effects), how their blood glucose changes over time, and what happens to the NN1845.

This study is recruiting at the Novo Nordisk Investigational Site in Mainz, Germany, 55116.  The only contact information provided is an American phone number:     
(+1) 866-867-7178

One thing that I really like about this study is that it should be quick.  Each part only requires about 10 days of data collection.  This is in stark contrast to most trials I follow, which are often 1 or 2 years.  This is because NN1845 is being tested like a new insulin rather than a possible cure.  Insulins start out by being tested with one dose, and then for a few weeks, and then for longer.  But those first tests are very quick.  While people given a potential cure are generally followed for a year or two, and this is true even in the early clinical trials.  Therefore, they take a lot longer to move through the development pipeline.
But there are big issues here.  The first is that glucose sensitive insulin is not "fixing" someone's type-1 diabetes.  In many ways, it is closer to a pin holding together a bone.  The bone is still broken, but the pin allows the person to ignore the fact that the bone is broken.  Is that a cure?  Is it a practical cure?  I'm going to track this as a potential cure, because I think some people will consider it one.  However, not everyone will.  If you don't consider this a cure, then just ignore my coverage of it.
The second issue is that this insulin may not be glucose sensitive enough to be a practical cure.  If NN1845 is so sensitive that you can take it in the morning, and it will act as a background insulin all day, and react so quickly that you don't need to take extra insulin for meals, for me, that would be a practical cure.  But NN1845 may not be that sensitive or that fast acting.  Maybe it will act as a background insulin, and make it extra hard to go low, but is not sensitive enough to react to meals.  That has some advantages in terms of extra safety as a background insulin, but it is not a practical cure in my mind.  For this issue, only clinical trials will answer the question of how sensitive and how fast NN1845 is.  Therefore, I'll follow the research and see what we learn.
Other Glucose Sensitive Insulin Research
An earlier glucose sensitive insulin was known as "Smart Insulin".  That insulin was developed by Smart Cells, Inc. which was bought by Merck.  The insulin made it to Phase-I trials, but the results were not good enough to continue in clinical trials.
About two years ago, Novo Nordisk bought Ziylo, a company developing a glucose sensitive insulin.  However, NN1845 is not the Zilyo product.  Novo Nordisk development of the Ziylo product was in the news as recently as mid-2020, so the company is positive enough on the general idea of glucose sensitive insulins to develop two different candidates in parallel.  That is a strong commitment.

There are several other glucose sensitive insulins currently in animal testing.  Maybe a dozen over all.  I'll cover those when they move into human testing.

I want to specifically thank the JDCA (Juvenile Diabetes Cure Alliance) who tracked down some important background information about NN1845, Novo Nordisk, and Ziylo, and then kindly shared what they learned with me.  You can see their other research here:
JDCA does not fund T1D research.  They do publish the best public information on how money flows through the T1D research process, and great overviews of the research landscape in general.

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.