Possible Cures for Type-1 in the News (Mid Feburary)

Clinical Trial of Diamyd, Ibuprofen ("Advil") and Vitamin D

Diamyd (GAD65) is a protein which is one of the targets of the autoimmune attack that starts off type-1 diabetes. It was developed with the idea that giving it to people with type-1 diabetes would teach their immune systems to not attack their own beta cells. It would be like giving someone who is allergic to peanuts, just a tiny amount of the peanut protein that triggered their allergy, in the hopes that they would build up tolerance.

Unfortunately, although it worked in mice and (to some degree) in phase-II studies in people, it failed in phase-III studies in newly diagnosed type-1 diabetics.   There are still a couple of smaller on going studies.  For example, to see if Diamyd will help prevent type-1 in high risk people who have not yet been diagnosed with the disease.

So that brings us to this study. The idea behind it is:

1. Give more Diamyd vaccine than was given in the past. About twice as much.
2. The Vitamin D is supposed to stimulate the part of the immune system that reacts to the Diamyd vaccine, so it makes for a more powerful vaccination effect.
3. The Ibuprofen ("Advil") lowers the inflammation in the pancreas, which may help save beta cells, and may help the vaccine work better, and may do both.

The study will include 60 children (aged 10 to 18) in the honeymoon phase. They will be followed for 30 months, but expect some results after only 6 months. The participants will be divided into 4 groups of 15. One will be a placebo group, and the other three will each get different combinations of the three treatments.  Since they hope to start in February 2013, I think it is reasonable to expect the 6 month results in the second half of 2015 and the 30 month results by the end of 2017.  That's assuming it takes them 2 years to recruit 60 people.  I have not yet seen a clinical trials record for this, yet.

Press release: http://www.diamyd.com/docs/pressClip.aspx?section=investor&ClipID=738266

More About Diamyd

This is a full PhD thesis that was written based on data from Diamyd's phase-II clinical trial.
http://liu.diva-portal.org/smash/record.jsf?pid=diva2:562438
http://liu.diva-portal.org/smash/get/diva2:562438/FULLTEXT01

Imatinib ("Gleevec" / "Glivec") Starts a Phase-II Clinical Trial

This study has not yet started recruiting, but when it does, it will be a 66 person trial.  It is double blind and placebo controlled.   It is open to honeymooners (first 100 days), including children.  They hope to start in April 2013 and end by April 2017.  I"m not sure of the details, but I think patients will take a pill daily for the first year.  They will have clinic visits monthly for the first year, and twice a year thereafter.

Imatinib is a relatively new cancer drug, which is popular because it targets an enzyme that only cancer cells have, so it is relatively non-toxic to non-cancer cells.  (The buzzword is "targeted".)  The obvious question is why would it be expected to work on type-1 diabetes.   The work done so far in mice suggests that it is a different pathway entirely, which leads to it's effect against type-1.

Some background on why this might work (in order, earliest to most recent):
   Animal models 2007: http://www.fasebj.org/content/21/2/618.abstract
   More mice 2008: http://www.ncbi.nlm.nih.gov/pubmed?term=19015530
   Press release: http://www.ucsf.edu/news/2008/11/4166/cancer-drugs-type-1-diabetes
   Human tissue 2011: http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0024831

Notice the progression, and the speed:  First tested in animals in 2007.  First tested in people in 2013.  And remember: this is for a drug that is already approved, for another disease!

Wikipedia: http://en.wikipedia.org/wiki/Imatinib
Clinical Trial Record: http://www.clinicaltrials.gov/ct2/show/NCT01781975

Vitamin D Starts a Phase-II Clinical Trial

So far, there is no evidence that Vitamin D can cure or treat type-1 diabetes, and only a little evidence that it can prevent the disease.  This trial is trying to cure or treat type-1 diabetes by giving Vitamin D during the honeymoon phase.

The trial is being done in Nationwide Children's Hospital (Columbus, Ohio, USA) by Dr.Kathryn J Stephens and Dr. Robert P Hoffman.  It has not started enrollment, but they plan to enroll 54 people.  Half will get vitamin D for 9 months, half will get a placebo.  They hope to have results in March 2014.

I had previously reported on a vitamin D trial, but that was a population based trial, not an intervention trial.  This is an intervention trial, which are typically much higher quality. 

Clinical Trial Record: http://www.clinicaltrials.gov/ct2/show/NCT01724190

A Note About Terminology

I know that some people are very emotional about saying "a person who has type-1 diabetes" vs. saying "a type-1 diabetic", as in "they gave the drug to five people with type-1 diabetes" vs. "they gave the drug to five type-1 diabetics".  Some people object strongly to the second form, because they think that it defines the person by the disease; that it signals in some way that the disease is the person or the person is the disease.

Personally, I usually use the first form, because I prefer it and because I know that some people really object to the second form.  But I'm not fanatical about it, and you will occasionally see me refer to "type-1 diabetics".  I'm not trying to insult anyone when I use the second form.

Joshua Levy
All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions. My blog contains a more complete non-conflict of interest statement.   Thanks to everyone who helps with the blog.
Clinical Trials Blog: http://cureresearch4type1diabetes.blogspot.com
Cured in Mice Blog: http://t1dcuredinmice.blogspot.com/

Possible Cures for Type-1 in the News (Early Feburary)

These two news updates are both interesting, and each probably deserves it's own blog entry.  However, since I'm backlogged, I'm putting them together in one posting (together with a Zhao update).  Even after this posting, I'm still a month or more behind.

Results from a Polish Trial of Polyclonal Tregs

What is being tested?  I call this technique "Polyclonal Tregs", but I'm not sure if it has a more official name.  Basically, the researchers remove one specific type of T regulator cell (called a "CD3(+)CD4(+)CD25(high)CD127(-)" T regulator) from a person with type-1 diabetes.  They use these cells to grow a lot more of these cells outside of the body, and then put them back in the body.  Since regulatory T cells naturally regulate the body's immune system, the hope is that they will prevent the autoimmune attack which causes type-1 diabetes.  Previous research in both animals and people has supported the idea that increasing regulator T cells may be a path to a cure.  

The Polish group tested this technique on 10 recently diagnosed (within 2 months) type-1 patients and compared them to 10 patients who did not get the treatment.  4 people got a lower dose (10 × 10^6 Tregs/kg) and 6 people got a high dose (twice as much).  In my opinion, they packed a lot of research into a small trial.  However there were no differences between the lower dose group and the higher dose group.  

Because it was an early trial, safety was an important consideration, and there were no safety related issues.  So that was good.  The publication had effectiveness data from a short (four month) follow up.  Basically:

• The treated patients generated about 50% more C-peptide than untreated.
• The treated patients used about half the injected insulin as untreated.
• A1c levels were about the same.

You can see that here:
http://care.diabetesjournals.org/content/35/9/1817/F1.large.jpg
Remember: grey bars are untreated and white bars are treated.

But remember, these people were within 2 months of diagnosis, and even at the end of the data presented here, were within 7 months of diagnosis, so well within the common honeymoon timeframe.  So I think longer follow on is critical to understanding how important these results are.  If these patients are still using half the insulin that untreated patients are using after 2 years, that would be wonderful.

The good news right now is that they already have one year follow up data, and expect to get it published later in 2013.  Beyond that, they have some improvements to the protocol, and hope to start a follow on trial with an updated protocol soon.  

The Other Polyclonal Treg Study ...

This is not the only study using this "Polyclonal Treg" method.  About two years ago a very similar study started in San Francisco.  Dr. Gitelman is running it, and results are expected in 2016.   I've blogged in the past about this trial here:
http://cureresearch4type1diabetes.blogspot.com/2011/01/possible-cures-for-type-1-in-news-jan.html

This trial has now enrolled its first two groups (out of four total).  I'm told all subjects are doing well with stable pancreas function. The researchers are currently in the middle of the 3rd group, and they anticipate completing the full study enrollment this year.  Each group gets 8 times as large a dose as the previous group so the last group will get about 500 times as much as the first.

... and the Ethics of Experimenting on Children

There is an obvious question here: If both studies started at about the same time, why does one have results 4 years sooner than the other?  I think there are two answers to this question.  The first is pretty simple: the Polish researchers published data covering 4 months after treatment.  The American researchers are gathering data for years.  But that only explains about 20 months of difference.

The second reason might be more important: The American researchers are only enrolling adults, people over 18 years old.  The Polish researchers enrolled children, 5-18 years old.  Obviously, when you are looking for recently diagnosed type-1 diabetics, there are a lot more to be found in the 5-18 year range than the 18+ year range.  By limiting recruitment to adults, the Americans have a much smaller pool of people, and it will therefore take them much longer to fully populate their trial.

But why are the American researchers only enrolling adults?  That answer is a combination of ethics and previous experience.  There is a general ethical principal (enshrined in various FDA rules, and international guidelines) that research should be done on adults first, before it is done on children, if that is feasible.  That makes a lot of sense, of course, but here we see the impact.  For a disease like type-1 diabetes, it is possible to recruit recently diagnosed adults, but it is far harder and slower.  So if we insist that the first bunch of patients are adults, it serves to slow down research disproportionately.

The Polish group had previously run a similar clinical trial in adults with a different disease (graft vs. host disease).  Now measuring safety in adults with one disease is not exactly the same as measuring safety in adults with a different disease, but it is similar.  Therefore, they could recruit children based on the safety profile with adults in the previous study.  Also, they could test different doses more quickly, again based on the previous experience.

Abstract: http://www.ncbi.nlm.nih.gov/pubmed/22723342
Full paper: http://care.diabetesjournals.org/content/35/9/1817.long (Thanks to ADA's DiabetesCare.)

Clinical trial record for the American study: http://clinicaltrials.gov/show/nct01210664

More Details on This Treatment

One way to view the immune system is a balancing act.  We want aggressive immune cells to attack foreign cells, but overly aggressive cells might attack our own beta cells and cause type-1 diabetes.  So we also want regulatory immune cells to keep the aggressive cells in line.  But we don't want those cells too strong, because then they would prevent an attack on the foreign cells.  In this view, type-1 diabetes can be seen as a too aggressive immune system, and therefor boosting the regulatory side might be a cure.

The regulatory cells which are been grown out (or "amplified" might be a better word) are general purpose regulatory cells.  That's a good place to start, but it would be even better if the researchers could multiply a regulatory cell that specifically targeted autoimmune cells (the "bad" cells that are attacking the wrong target).  Unfortunately, the technology is not there yet, although people are working on it.  But in any case, we need to start somewhere.

Below is a link to a study that suggests that newly diagnosed type-1 diabetic children have lower levels of these T regulator cells, than children who do not have type-1 diabetes.  (Although it was a small group.)  http://www.ncbi.nlm.nih.gov/pubmed/19454187

A Note About "Remission"

Some type-1 researchers use the term "remission".  Specifically, they use it to mean "Uses less than 1/2 a unit of insulin per kg of body weight per day".   Don't be confused.  Non-researchers think of "remission" as meaning "doesn't use insulin", but that is NOT how researchers use the term.   If your child weighs 40 kg (about 88 pounds), and uses 20 units of insulin, or less, then they are "in remission", and this does happen to some people during the honeymoon.


Perle Bioscience Starts two Phase-III Clinical Trials of Cyclosporine and Lansoprazole ("Prevacid")

Dr. Claresa Levetan at Perl Bioscience has filed the paperwork to start two very interesting studies.   Both studies are looking at a combination of Cyclosporine and Lansoprazole (commonly known as "Prevacid") as a cure for type-1 diabetes.  The two studies are identical, but one recruits honeymooners and the other established type-1 diabetics.  These are combo clinical trials exactly like many people have been hoping for, for years:  Cyclosporine is known to stop the autoimmune attack and Lansoprazole is known to encourage the natural regrowth of pancreatic beta cells.  Both are approved drugs (for other diseases).  Lansoprazole (as "Prevacid") is over the counter, so has a very good safety profile.  Cyclosporine has a more complex safety profile.  I'm sure if this study pans out, the relative safety of Cyclosporine is going to be an important topic of discussion.

Both studies are expected to enroll 200 people (half getting the treatment and half getting placebo).  They plan to start in September 2013 and end by March 2014 (so very quick).   There will be four groups: one group getting both drugs, one just getting Cyclosporine, one just getting Lansoprazole, and one getting neither.  This is good experimental design for a two drug combination. They will measure C-peptide in response to eating, A1c, and insulin usage.

Note on phases: The researchers running this trial have described it as a "phase-III trial", however I consider it a phase-II trial.  Why the difference?  For me, size is the most important issue.  At 200 people, it is right on the border between what I consider phase-II and phase-III for clinical trials aimed at curing type-1 diabetes.  (For comparison, all eight recent phase-III trials have involved 300 people.  That seems to be the magic number for FDA approval as a pivotal trial in type-1 diabetes.)  Also, this combination of drugs has never (to my knowledge) been tested on type-1 diabetics before.  Since both drugs are approved for other things, I'm willing to call it phase-II (rather than phase-I), but with zero experience with the combination, I'm not willing to call it a phase-III.

Of course, the important question is not what I consider the trial, or even what the researchers consider the trial, the real question is how will the FDA consider the trial?  That remains to be seen, but remember: since both drugs are already approved for other uses, your doctor can prescribe this combination right now.  It would be an off label use.

The researcher working on this, Dr. Claresa Levetan, previously worked on CureDM, and sold that to Sanofi-Aventis two years ago.  My understanding is that they are developing the CureDM technology (a peptide which stimulates beta cell development) for the type-2 market.

Wikipedia on Lansoprazole: http://en.wikipedia.org/wiki/Lansoprazole
Wikipedia on Cyclosporine: http://en.wikipedia.org/wiki/Cyclosporine
Clinical Trial Record (Honeymoon): http://www.clinicaltrials.gov/ct2/show/NCT01762644
Clinical Trial Record (Established): http://www.clinicaltrials.gov/ct2/show/NCT01762657

More Background on
http://www.ncbi.nlm.nih.gov/pubmed?term=3125434

Zhao Updates from Spain 

Previous blogging on Zhao's "Stem Educator" is here:
http://cureresearch4type1diabetes.blogspot.com/search/label/Zhao

These two links go to Spanish language news reports on people getting treated with the Stem Educator in Spain.  I found that using Chrome to translate them into English worked pretty well for me:
http://www.rtpa.es/ciencia:El-HUCA-busca-financiacion-para-un-proyecto-pionero-en-el-tratamiento-de-la-diabetes_111357993752.html
http://diabetesmadrid.org/2012/12/05/el-huca-lidera-la-lucha-contra-la-diabetes/

The basic summary is that the clinical trial in Spain has started.  Two patients had their first session of stem cell educator therapy in December 2012.  The plan is to treat a total of 30 people.  (Not sure how many are placebo and how many will get the real treatment.)  The two treated so far have had type-1 for over 10 years.  This trial is expected to end in September 2014, but we will not know with certainty until it is fully enrolled.

JDCA State of the Cure 2012


The JDCA (Juvenile Diabetes Cure Alliance) is trying to focus more research dollars into cure research (as opposed to treatment research, cause research, etc.)  They publish research papers, which are often quite interesting.  They use my blog as a source, and we sometimes discuss various research issues.

The article below is their year end summary, and well worth a read.  Although I certainly don't agree with everything in it, it is a rich source of information.  (I especially object to their not including Dr. Zhao's research as a possible cure, and JDCA did cover Zhao in a report after this one.)

http://www.thejdca.org/wp-content/uploads/2012/11/State-of-the-Cure-report.pdf

A Final Note

In the past, I have included a specific "thank you" when people reviewed a blog posting, provided information for it, or pointed out the news to me (when only one person did so).  Unfortunately, keeping track of who helped with what, and also making sure it was OK to thank them by name, has become too much of a burden.
So I'm going to stop doing that.

I'm very sorry I will not be able to thank people individually for their help in writing this blog.  But I do want to thank:

• My wife, who improves my English, and puts up with the hours I spend yelling at the computer when I should be talking with her.
• All the researchers who have answered my questions and provided extra information.
• Everyone who emails me when they see news that I should cover.

Joshua Levy
All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions. My blog contains a more complete non-conflict of interest statement. 
Clinical Trials Blog: http://cureresearch4type1diabetes.blogspot.com
Cured in Mice Blog: http://t1dcuredinmice.blogspot.com/

Possible Cures for Type-1 in the News (January)

I feel like I'm about two month behind, but this will get me closer to current news.

Kamada Reports Early Results from A Phase-I Trial

News: http://www.globes.co.il/serveen/globes/docview.asp?did=1000799026&fid=1725
Press Release: http://www.kamada.com/press_item.php?ID=29
Clinical trial record: http://www.clinicaltrials.gov/ct2/show/NCT01304537

I struggled quite a while with their press release, but in the end, this is my summary:

Kamada releases results from their phase-I trial, which they describe as "positive". However the data in the press release is too vague for me to come to any conclusion about weather their drug worked. I'm looking forward to a complete, peer reviewed paper.

Kamada manufactures Alpha-1 Antitrypsin (AAT).   You can read more about it here:

http://cureresearch4type1diabetes.blogspot.com/p/drugs-and-treatments-in-clinical-trials.html

and my previous blogging here:

http://cureresearch4type1diabetes.blogspot.com/search/label/AAT

AAT is an anti-inflammatory chemical which the body makes naturally, and which is already FDA approved for people who have a rare condition where a person doesn't make enough of it on their own.

These are the first results from the first phase-I clinical trial completed.  Unfortunately, there was no control group for this trial, so there is no way to compare people who got AAT with people who did not. The company's press release said that "almost all patients reached glycemic control below 7.5%" and that "the majority of the patients maintained levels of C peptide higher than ... 0.2 pmol/mL".

None of that is bad news, but this trial was for honeymooners (within 6 months of diagnosis).  So none of those results sound particularly stellar to me.  This is where a control group would be particularly helpful, because we could have seen a difference between the two groups, if there was one.  Because people with type-1 diabetes naturally vary a lot during their honeymoon, it is at this time that control groups are most important.  

I've asked the company when the full results will be published, and those might be much more interesting.  At the very least we should be able to see how the C-peptide numbers change over the  study.  That can be compared to the "normal" drop during the honeymoon phase.  My general feeling is that if this data is all the data they publish, then the trial was a failure.  They need to publish more data, especially C-peptide changes to show success.

Discussion

This study is important for a couple of reasons.  First, because of the number of AAT clinical trials. I know of a five AAT clinical trials aimed at type-1 diabetes going on now.  That's a lot; more than any other single drug.  So having mediocre results from the first study completed is not welcome news for any of the others.  Second, because of it's impact on the inflammation theory of type-1 diabetes.  This theory holds that inflammation destroys the beta cells in the pancreas.  The autoimmune reaction triggers inflammation, but does not directly destroy the beta cells.  This theory has never been the majority viewpoint (most researchers think that inflammation is a side effect of the destruction of beta cells, rather than a cause) but it is an active minority opinion.  Since AAT is an anti-inflammation drug, it is one of the first drugs to test this theory.  Since AAT does not appear to have a strong effect, that suggests that the whole inflammation theory might be wrong as well.  That would be unfortunate, since stopping inflammation is a lot easier than stopping the auto-immune attack!  Because there are lots of anti-inflammatories out there, there would have been lots of potential drugs to prevent type-1, if this theory panned out.

It is interesting to me, that even though this study did not have a placebo group (an untreated group), they did have three different levels of treatment.  Some people got 40mg of AAT, some people 60mg, and some people 80mg.  The press release did not include any difference in results between these groups.  That's a little ominous for me.  For a drug that is effective, I would expect one dose to be the most effective; others less so.  On the other hand, if the drug has no effect, then all the groups would be the same, and in this case, no differences were reported.

LCT Updates

Background: LCT is developing an encapsulated pig beta cell cure for type-1 diabetes.
The coating allows blood sugar in, and insulin out, but does not allow the body's immune system to attack the beta cells. It also allows nutrients in and waste products out. This allows the beta cells to naturally grow and to react to the body's sugar by generating insulin which goes into the body's blood system. Meanwhile, the body's autoimmune attack can not target these beta cells, and you don't need to take any immunsuppression drugs (as you would for a normal beta cell transplantation).

When last we left LCT, they were finishing a small phase-II trial in New Zealand, and starting a small phase-II trial in Argentina.  Links to press releases for the results and the follow on trial are below:
http://www.lctglobal.com/html/blob.php/121122%20LCT%20-%20Strong%20interim%20results%20in%20Argentinian%20%20DIABECELL%20trial.pdf?attach=0&documentCode=4774&elementId=20084
http://www.lctglobal.com/html/blob.php/121122%20LCT%20starts%20DIABECELL%20Phase%20IIb%20trial%20in%20Argentina.pdf?attach=0&documentCode=4775&elementId=20084

The Argentinian Trial

All the patients got two rounds of implanted islet cells, 12 weeks apart.  Half the patients got a base level, and the other half got twice this level.  The patients who got more islets had better results, which were:

• average insulin dose reduced by 20%
• a reduction of HbA1c from a pre-transplant average of 8.6% to an average of 6.7% at 12 weeks following the second implant
• up to 70% reduction in unaware hypoglycaemic events.

Obviously, this isn't a cure in it's current form (but see below for follow on products).  This study involved a total of 8 people, and so an obvious thing to do is to expand it, and the expansion was also announced.  LCT will implant an additional 20 people, all at the higher dose level.  For me the most interesting information in their press release is this:

“We are using an ‘adaptive trial design’ for our pivotal studies and so the data generated in this 20 patient trial will likely form the foundation data for our registration package,” said Dr Andrea Grant, Chief Executive, LCT. “We remain on track to meet our goal of completing clinical trials of DIABECELL by 2015 and having a product commercially available by 2016.”

I'm not an expert in this area, but I would be surprised if they could register a new medical implant for use in the US based on data from one study of 20 people (and their previous studies which contain about 24 people all together).  Especially with no clinical trials actually done in the US.  I assume that commercial availability will be in one or more of the countries where they have done research: New Zealand, Argentina, etc.

If you want even more information, you can read their CEO presentation, also done in November 2012, here:
http://www.lctglobal.com/html/blob.php/LCT%20AGM%20CEO%20Presentation%20Nov%202012.pdf?attach=0&documentCode=4762&elementId=20084

Which includes a slide "DIABECELL -- The path to patients" which lists four studies:
      A New Zealand phase II study [8 people]
      An Argentinian phase-II study [8 people]
      An Argentinian phase-II/III study [20 people, discussed above]
      A New Zealand and/or German Phase-III study [unknown size, not discussed above]
That forth study would make more sense to me, although I'm still not sure that this would get them approved in the US.  For comparison, the recent anti-CD3 drug approval attempts used two 300 person studies, one of which was done in the US.  And the pivotal DiaPep277 studies on-going right now are the same: two studies of 300 people each.  Maybe implants require less, but that much less?

No News from Russia

I'm also a little mystified because LCT had previously announced that their product had already been approved for sale in Russia:
http://cureresearch4type1diabetes.blogspot.com/2010/12/lct-gets-commercial-approval-in-russia.html
However, since then I can not find any reference to anyone selling it in Russia, or LCT getting any revenues from such sales. (But I don't speak Russian so can't search effectively in that language. If there are any Russian speakers out there, who would like to do some searches, please look for "LCT Biomedical Limited" (the company name) and/or "Natalia Dolgova" (the first company director) and tell me if they are selling anything in Russia.  If you find the web pages, I can Google Translate them.  But so far, I haven't even found them.)

LCT General Update

It is very rare for any executive at a medical company to make predictions about the future.  There are all kinds of rules about what they can and can not say.  So I was quite surprised (and happy!) to see these public posts from "elliott" in a posting on www.islet.org.  Dr. Bob Elliott is a founder of LCT.

Multi-centre Phase 3 studies will comemnce Q1 2013 and be completes by Q1 2015.
Registration based on a successful outcome will take anything up to a year, so we anticipate the LCT product will be marketed by Q1 2016 ie three years from now.
It will not cure diabetes, but is likely to be a valuable way of treating unstable diabetes.
'Fast follower' products will start to be tested clinically in 2014.

'Fast Follower' refers to the next generation of products. We are always seeking ways to improve the product but each improvement as seen in preclinicla studies in animals has to be tested in humans.   I have not give up on the idea of complete insulin independence, and we are making steady progress.

'Unstable' diabetes is the indication we are working on in the trials. But of course all Type 1 diabetics have unstable blood glucose control to a greater or lesser degree, so it really becomes a matter of how bad things are. 

He also said that they have improved the product since the peer-reviewed results were published in 2007, with the implication that they expect better results in the future then they reported in 2007.

Note that his statement that "Registration ... will take anything up to a year" might be true in some countries, but my belief is that in the US, marketing approval (our version of commercial registration) takes 1 to 2 years, especially if measured from the end of a phase-III trial.  I would not be surprised if other countries where LCT operates have faster registration processes.

Finally, I want to say that although LCT describes this 20 person Argentinian trial as "Pivotal" and "Phase-III", I will continue to refer to it as phase-II because of it's size. To be honest, I've seen phase-I trials with more than 20 people enrolled, so I think calling it a phase-II is proper.  Now if LCT gets approval in the US based on a 20 person trial, then I might change my standards. :-)

LCT's web page is http://www.lctglobal.com

Rituxan Safety in Rheumatoid Arthritis

Rituxan (also known as Rituximab or MabThera) is a monoclonal antibody which is being tested as a possible cure, or part of a cure, for type-1 diabetes.  My previous blogging is here:
http://cureresearch4type1diabetes.blogspot.com/search/label/Rituximab
Monoclonal antibodies are a relatively new technology for developing drugs (only about 20 years old), but already about half of new drug approvals are monoclonal antibodies.  However, some people have expressed worries that, as a class, monoclonal antibodies are unsafe, or their safety profile is unknown or suspect.

This study is a big step towards putting those fears to rest. Since Rituximab is already approved for rheumatoid arthritis, these researchers followed people who used it for that purpose for many years.  The basic result was that people on the drug had a lower disease rate than similar people not on the drug:

The rate of serious infectious events for the 1,145 patients on Rituximab for more than 5 years was 2.76 per 100-person-years, and the rate for the 818 placebo patients in the studies was 3.6 per 100-patient years, they said.

"No new safety signals were observed with increasing duration of exposure including in patients with more than 5 years of follow-up."

"the rates of myocardial infarction [type of heart attack] (0.40 per 100 patient-years) and malignancies were consistent with those observed in epidemiological data from other RA cohorts (0.48 to 0.59 per 100-patient years for MI)."

News: http://www.medpagetoday.com/MeetingCoverage/ACR/35895

Note that many monoclonal antibodies have names that end in mab.  So if you see a drug named Joshuamab or Curecommoncoldmab or anything ending with mab, it is likely to be a monoclonal antibody.

Rituxan as an Injectable Drug

Currently, Rituxan must be given intravenously, rather than being injected under the skin, like insulin.  The difference is important, because intravenous administration usually requires a "medical setting" (like a hospital or clinic, or at least trained medical staff).  While we all know that under skin injections are commonly done everywhere and by anyone, with a little training.

Recently Roche announced publication of two studies showing that they had a formulation of Rituxan which could be injected and was "not inferior" to the intravenous formulation already approved.  Since "not inferior" is the FDA's requirement for approval in situations like this, that's good news.  Even better news is that the basic technology that they used to convert a previously intravenous formulation into an injectable formulation can be applied to other drugs as well.  So with luck, they will be able to make lots of drugs easier to administer.

Press release: http://www.roche.com/med-cor-2012-12-08b.htm

Update from Scott King on Islet Sheet Project

An Islet Sheet is a specific beta cell encapsulation technique, similar to what LCT is trying to do.  Because Islet Sheets have not yet started human trials, I don't follow this research very closely.  However, I know others are very interested in it, and Scott King posted an update on his blog, which you can read here:
http://www.hanumanmedicalfoundation.org/blog/2012/11/26/signal-breakthrough-islet-sheets-thrive-in-pig/

They are hoping for more animal trials in 2013.  King is a very insightful guy and previous blog postings are interesting as well.

Joshua Levy
All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions. My blog contains a more complete non-conflict of interest statement. 
Clinical Trials Blog: http://cureresearch4type1diabetes.blogspot.com
Cured in Mice Blog: http://t1dcuredinmice.blogspot.com/

Funding Existing Drugs

This is a blog posting which I wrote several years ago.  I think in 2009. I lost track of it, and it never got posted.  But I recently came across it while cleaning old entries.  I think it is still valuable today, so I'm posting it.  Also, it makes a nice pairing with my last blog posting on Vitamin D.

Discussion about the argument that "Treatment X can't get funded because it uses an old / cheap / generic / unpatented drug so there is no profit in it!"

One complaint that is sometimes heard about the funding of cures for type-1 diabetes, is that some treatments can not get funded because they are generic drugs, so no one will fund development. Most recently, this argument is often used by fans of BCG and LDN to explain why they have so much trouble getting funded: it's because they are generic drugs, according to this line of reasoning.

This argument has never made sense to me, and below I've included two counter arguments and one example: an argument based on data from drug trials, one based on common sense, and the example of aspirin.

Clinical Research on Old, Generic, or Cheap Drugs

Since I track only clinical trials, I thought I would take a look at how this argument ("generics / existing drugs / old drugs can't get funded") compared to the actual clinical trials that I track. It turns out that this argument simply doesn't match with reality. Several generic treatments are being funded right now, by several different organizations.

There are a total of 27 treatments that are in clinical (human) trials to cure type-1 diabetes (remember, this was in 2009). Several of these treatments involve more than one drug.  Out of the those 26 treatments, 7 use only "old drugs" or drugs that are unpatented. They are:

• Thymoglobulin (also known as ATG) by Gitelman
• Umbilical Cord Blood Infusion by Haller at University of Florida
• Brod at University of Texas-Health Science Center
  
• Atorvastatin (Lipitor) by Willi at Children's Hospital of Philadelphia (Generics available 2011)
  
• ATG and autotransplant by Burt at University of Sao Paulo
  
• GCSF by Haller at University of Florida
• GCSF and autotransplant by Esmatjes at Hospital Clinic of Barcelon

That means that 27% of drugs currently in clincial trials are exactly the kind of old or unpatented drugs that these guys say can not get funded. It is the ultimate proof that they can get funded: they are being funded!

BCG Specifically

When Dr. Fastuman's supporters claim that she can't get funded because she is using a generic that no one will profit from, an even more specific data set is available. The drug that Dr. Faustman is currently testing is BCG. So an obvious question to ask is this: have any clinical trials of BCG been funded in the time period from about 2002-2008 (which is when she was looking for funding). If her trial could not get funded because BCG is a profitless generic, then certainly no other clinical trial of BCG could get funded, either.

But, when I look at the US Government web site (www.clinicaltrails.gov) which tracks human trials there are 15 BCG trials in progress (ie. records updated) between 2002 and 2008. I limited my count to trials that were testing BCG's effects, so I excluded trials that were comparing a newer treatment to BCG, and I also excluded all trials that used BCG and another treatment (even if that other treatment were old / cheap / generic, etc.)  Even with all those exclusions, there were 15 different clinical trials using BCG.

Think about that: at the same time Dr. Faustman's supporters are claiming that her BCG research could not get funded because it was not a patentable/big profit drug, 15 other researchers were getting funded to study that exact same drug! Obviously, the supporters are wrong about this reason why Dr. Faustman had so much trouble getting funded.

Low Dose Naltrexone (LDN)

The story was similar for LDN: there were currently five separate LDN studies recruiting patients at the same time a type-1 diabetes study had not been funded. So obviously, the economics are such that LDN research can get funding, even though it is an old drug which is no longer covered by patients. Indeed, just recently, it did get funded, even though it is still an old / cheap / unpatented drug.

The Common Sense Argument

Every drug that you can buy today, is made by some company that is making a profit off that drug. And if they sold more of it, they would make more profit. So every drug made today has a company (or many companies) behind it.  Companies that want to make more of it. It doesn't matter if it is an old drug or a new one or if it is covered by a patient or not. Sure the exact dollars are different, but the basic profit motive doesn't change. Older drugs might be lower profit, but they are also cheaper to use in experiments, and much cheaper to get approved.  Usually they are already approved for marketing!

Right now there are at least three large drug companies that make a profit by selling BCG.  And, they want to sell more.  At least one of them (SSI) does not sell any diabetes treatment equipment or supplies, so they would be particularly interested in funding Dr. Faustman's work, if it had any chance of working.

Furthermore, this whole argument is based on the idea that the only groups that fund research are profit-motivated companies. But we all know that is not true. Sure companies fund a lot of research, but so do private non-profits (not just JDRF, but DRI, ADA, JLN, etc.). Plus there are government agencies. In the US there are at least four that commonly fund diabetes cure research, and that's not counting countries all over the world which also fund diabetes research. And to push that idea even a little bit farther: many non-profits or government agencies actually prefer to fund research on unpatented drugs. It is easier to justify, and can help more people more cheaply than a patented drug. So those guys will be biased in favor of an unpatented drug, not against them.

Aspirin

As a very quick example, consider aspirin to prevent heart attack. In the 1970s, aspirin was the ultimate in old, generic, unpatentable drugs.  It has been first discovered over 100 years before, and the "modern" form was over 70 years old even then!  Yet when early research suggested a completely new use for aspirin, preventing heart attacks, there was no difficulty in running several very large studies.  Some of these studies involved thousands of people, and more than enough were done to get aspirin approved by the FDA for a new use.  Surely if research into new uses for low-profit, old, unprotected drugs could not be funded, then the research into aspirin as a heart attack preventative in the 1970s and 1980s would never have happened.

For all these reasons, whenever I hear someone say "it's a generic drug, so it can't get funded" I always think to myself "no, the reason it can't get funded, because the people who might fund it don't think it will work".

Joshua Levy
All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions. My blog contains a more complete non-conflict of interest statement. 
Clinical Trials Blog: http://cureresearch4type1diabetes.blogspot.com
Cured in Mice Blog: http://t1dcuredinmice.blogspot.com/

Vitamin D for Prevention

This blog posting is discussing the recent news about using Vitamin D as a preventative for type-1 diabetes (not a cure).  You can read more about the study here (and many other places on the net):

News: http://drugstorenews.com/article/study-vitamin-d3-could-help-prevent-type-1-diabetes
Abstract: http://www.springerlink.com/content/j71m8203335h874v/
More personal and emotional news article: http://www.theatlantic.com/health/archive/2012/12/if-we-had-been-giving-our-daughter-vitamin-d-would-she-still-have-developed-diabetes/266010/

Quick Summary:  The researchers measured Vitamin D levels in the blood of people who were later diagnosed with type-1 diabetes, and compared that to levels in the blood of people who were not diagnosed.  The levels in the diagnosed group were significantly lower.  There was an obvious correlation.  Vitamin D was not an absolute preventative.  There was not a specific amount of Vitamin D where if you took more than that you would avoid type-1.  Rather there is a change in probabilities.  Higher levels of Vitamin D led, on average, to lower levels of type-1 diabetes.    Some people with high levels of Vitamin D still got type-1 diabetes, it was just less likely.  The reverse was also true: some people with low levels of Vitamin D avoided type-1 diabetes, but it was less likely.

A Little Background: It has been well known for decades that people who live near the equator have lower rates of type-1 diabetes than people who live nearer the poles.  However, it is not known why this is true.  Some people believe that a lack of sunlight or Vitamin D increases the rate of type-1 diabetes.  Other people think it might be wealth, genetics, diet, or any one of a huge number of differences.  (In the Americas, for example, Mexico is closer to the equator and has a lower rate, while USA is farther from the equator and has a higher rate.  But there are also large differences in wealth, genetics, diet, and so on.)

A Little More Background:  Research studies can broadly be put into two groups: population based studies and intervention studies.  Population based studies are studies that take two groups of people and compare them in some way.  Hopefully, the two groups should be as similar as possible, except for the one thing being studied.  Intervention studies take one group of people, and gives some of them a treatment (the intervention) and not the others, and then compares them.

It is important to remember that there is a clear difference in quality between the two types of studies: intervention studies are generally much higher quality and are much easier to interpret.  Population based studies are often apples to oranges comparisons where the differences seen have nothing to do with the change being studied.  The Mexico to USA comparison is an example.  Is Mexico's lower type-1 rate due to genetics?  sunlight?  wealth?  cleanliness?  With a population based study, it is usually impossible to know.

This study was a population study, and so it is not as strong evidence as an intervention study.

Understanding This Research

For the recent Vitamin D study, the researchers followed people in the military.  When they entered the military some of their blood was frozen.  So later (on average 1 year later), if they were diagnosed with type-1 diabetes, the blood was tested for Vitamin D levels.  Soldiers who were similar, but who did not come down with type-1 diabetes served as a control group.  It's a very resourceful experimental design, because normally it would be very hard to test Vitamin D levels months or years before diagnoses, so finding the store of available frozen blood was brilliant insight.

This research was unique in several ways.  For one thing, it is the first study I have seen that looked at relatively old people.  Previous studies that I have seen have dealt with infants.

This study has avoided many of the common pitfalls of population based research.  In particular, population based studies often compare people from different countries or different regions, who often have many differences.  In this study both the control group and the diabetes group were taken from the same pool of people (American service members), which is a huge advantage over many population based studies.

Should People Without Type-1 Diabetes Take Vitamin D?

Remember this study says nothing about the effects of Vitamin D on people who already have type-1 diabetes, so it provides no support for the idea that people who already have type-1 should take Vitamin D.  However, the open question is this: should people who don't yet have type-1 diabetes, especially brothers and sisters of people with type-1, take extra Vitamin D?

That depends entirely on your personal beliefs about how much evidence is required, before you will pay money for a treatment.  Right now there are two population based studies that suggest that Vitamin D has a protective effect (one is here: http://www.ncbi.nlm.nih.gov/pubmed/11705562).  Only you can decide if that is enough support for you to change your behavior and spend your money.  There have also been studies on Vitamin D that have shown no difference, and I'm sorry I don't have time for a full review of all the studies.  But the link below will take you to the 13 studies listed in clinical trials for "type-1 diabetes" which study vitamin d, if you want to review them all:
link to www.clinicaltrials.gov for type-1 and Vitamin D

For comparison, the FDA generally requires 4 intervention studies (and there are other quality requirements on these studies, as well) to approve a new drug.  Population studies don't count.  Of course, Vitamin D isn't a new drug.  Nevertheless, if it were, the FDA would say there is not yet enough data to approve it's use.

If you are considering extra Vitamin D, I strongly recommend you discuss it with your doctor first.  There are blood tests for Vitamin D that your doctor can order.  These are the exact words of Dr. Garland, who worked on this study:

“While there are a few conditions that influence vitamin D metabolism, for most people, 4,000 IU per day of vitamin D3 will be needed to achieve the effective levels,” Garland suggested. He advised interested patients to ask their healthcare provider to measure their serum calcidiol before increasing vitamin D3 intake. “This beneficial effect is present at these intakes only for vitamin D3,” Garland said. “Reliance should not be placed on different forms of vitamin D and mega doses should be avoided ..."

This research was funded by the US government via a grant to the Diabetes Research Institute (DRI).  It was published in Diabetologia, a first rate European diabetes medical journal.

I have blogged twice before about Vitamin D, here:
http://cureresearch4type1diabetes.blogspot.com/2012/01/possible-cures-for-type-1-in-news.html
http://cureresearch4type1diabetes.blogspot.com/2010/08/cinnamon-and-vitamin-d.html

Other researchers are studying Vitamin D, and in particular Dr. Taback is organizing a large, intervention study.  If you are the patient type, you might want to wait until it is complete.  That is the first intervention study that I know of, and intervention studies are a much stronger form of evidence than population studies.  Unfortunately, Dr. Taback's work will take years to complete.

Personal note: I rarely blog on population based studies, like this one.  In general, I'm very nervous about their level of quality.  (I've seen some particularly bad studies in the area of nutrition, Vitamins, and related fields.)  I think one of the main problems with science reporting is that it is far too optimistic in reporting the results of population based research, much of which turns out to be wrong.  I'm also sensitive to the fact that they do not help get a drug approved.  A treatment supported by 10 or even more population based studies will not get approved by the FDA, unless intervention trials are done.  However, I am blogging about this study, because I think these researchers did a particularly good job of designing their study.  But it is still just one population based study.  Even for intervention studies, I don't consider one study alone to be definitive, and even less so for a population based study.  This is a step down a path, not the end of a journey.

Excess Vitamin D can accumulate in the body, and you can overdose (especially smaller children, if given adult doses).   Do not think "It's a Vitamin, so it's always safe" or "It's a Vitamin so everyone can take it" or "if taking X amount is good, then taking 10 times that much must be better!".  None of these things are true, and all of them can be dangerous.


For examples of study where giving vitamin D to people who already had type-1 did nothing:

No protective effect of calcitriol on beta-cell function in recent-onset type 1 diabetes: the IMDIAB XIII trial.
http://www.ncbi.nlm.nih.gov/pubmed/20805274?dopt=Abstract

No effect of the 1alpha,25-dihydroxyvitamin D3 on beta-cell residual function and insulin requirement in adults with new-onset type 1 diabetes.

http://www.ncbi.nlm.nih.gov/pubmed/20357369?dopt=Abstract


Joshua Levy
All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions. My blog contains a more complete non-conflict of interest statement. 
Clinical Trials Blog: http://cureresearch4type1diabetes.blogspot.com
Cured in Mice Blog: http://t1dcuredinmice.blogspot.com/

Possible Cures for Type-1 in the News (Nov-2012)

Summary of Three Months of New Trials

This is a quick summary of all of the new clinical trials into type-1 that started between July 1st and October 1st, 2012.  These are trials which were entered for the first time during these three months.  I got this list from the FDA's clinical trial database, which is on line here:
www.clinicaltrials.com

37 New clinical trials in total
-- ----------------------------
14 Delivery / New Insulins / New Test Kits
06 Long Term Side Effects
03 Artificial Pancreas
03 CGM
01 AAT
01 Psychological
08 Other (1 of these was a Vitamin-D trial)

My only comment is that only one of these (the AAT one) might lead to a cure.  That's not a lot.

What's Up with AAT (alpha-1 antitrypsin)?

The new AAT study reminded me that there are now a total of five AAT studies ongoing, and that's enough to have a summary of AAT research, so here it is.

I've blogged on AAT before, here:
http://cureresearch4type1diabetes.blogspot.com/search/label/AAT
and some background on AAT is here:
http://cureresearch4type1diabetes.blogspot.com/p/drugs-and-treatments-in-clinical-trials.html


Study Number  Phase Size Sponsor   Duration  Completion Date
NCT01304537     I    24  Kamada    1 year    November 2012
NCT01319331     I    15  Omni Bio  2 years   September 2013
NCT01183468    II    16  NIAID     2 years   November 2014
NCT01183455    II    66  NIAID     2 years   November 2014
NCT01661192    II    24  Kamada    3 years   December 2016

Initially, that looks pretty good.  Unfortunately, one of these trials (the second one, by Omni Bio) released some early data, and this data was only slightly positive.  The treatment showed no benefit to people with established type-1, and relatively small improvements to people who took it soon after diagnosis.  No specific numbers were published, which I consider to be a bad sign.  The first complete study (Kamada's) should be done very soon, and that should give us a much better "feel" for the level of success.  By 2015 we should have results on four studies, which should be definitive.
Another Trial for Zhao's Cell Educator (if they raise money)

I've previously blogged on Zhao's work here:
http://cureresearch4type1diabetes.blogspot.com/search/label/Zhao

It looks like researchers in New Zealand are raising money specifically to replicate Dr. Zhao's work.

Here is their description of what they want to do:

In the first trial we would infuse activated stem cells back into the patient and measure their ability to switch the behaviour of aggressive T lymphocytes to ‘peaceful’ T regulator cells. Trials like this are occurring internationally but without the activation step, and results are not yet clear. The second trial will be similar to the Chicago study [Zhao's trial, which was actually done in China]. The stem cells from each person will be used in the laboratory to ‘condition’ their white blood cells in the laboratory, before re-infusing the white blood cells.

I don't usually put information about donating money in my blog posts, but I've gotten several requests for information on how to help fund Zhao.  I don't know how an individual can do that effectively, but the researchers in New Zealand have these instructions:

If you would like to make a donation towards this cause, then the Spinal Cord Society NZ website www.scsnz.org.nz provides a means for you to do that. An email plus a donation will ensure that your contribution goes only towards the joint SCSNZ-Diabetes research work.

Please remember: I know nothing about these guys or this organization.  I am not endorsing them!

News: http://www.scsnz.org.nz/assets/Uploads/diabetes-winter-2012-focus-2.pdf
News: http://www.stuff.co.nz/national/health/7914909/Stem-cell-study-holds-diabetes-cure-promise

I want to especially thank Brian Braxton for the information and sources he provided, and everyone else (there were several) who pointed this news out to me.

Joshua Levy
All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions. My blog contains a more complete non-conflict of interest statement.
Clinical Trials Blog: http://cureresearch4type1diabetes.blogspot.com
Cured in Mice Blog: http://t1dcuredinmice.blogspot.com/

Type-1 Impact on the Brain

This posting is not about cure research, but is a summary of a talk about type-1's effect on the brain.

CarbDM  recently hosted a talk by Dr. Tandy Aye, who studies the impact of type-1 diabetes on developing brains.  That sounded to me like a very interesting talk, so I attended.  Below are my notes.  Please remember that these are my thoughts on the topic (not Dr. Aye's!) and that I only wrote a little during the talk, so most of this is from memory.

Historical Background

Diabetes effects on many parts of the body has been well known for decades, however study of type-1 diabetes's effects on the brain started in 1985.  Various IQ type tests have been used, and also various brain imaging technologies.  When a new brain imaging technique is developed, it is first applied to adults, and then to children, and then the next advance comes along, and the cycle repeats.

Doing brain imaging on child is more difficult than for adults, because most of these technologies require the patient to lie vary still, in a small, enclosed space, sometimes while the machine makes strange noises or vibrates.  Children are not good at this.  However, a major breakthrough was to have a monitor play movies that the kids could watch, and that would freeze if the kid moved.  This quickly teaches the kid not to move!

Brain Studies

Various brain studies have been published since 1985, mostly on adults, but a few on children.  A good summary (actually a meta-analysis) of the adult studies was published by Gaudieri in 2008.

Aye's pilot study included just under 30 children with type-1 diabetics, ran for a few years (3?), and is complete and published.   Dr. Aye had originally submitted a study proposal for a large multi-site study that would have told us a lot about how type-1 effects brain development.  That study was rejected because the reviewers thought that children would never sit still in an MRI machine long enough to get a clear image.  One of the main goals of this pilot study was to prove to the reviewers that children could do that (if properly motivated and supported).  This part of the trial was a complete success as the much larger study has now been approved.

A second, much larger study (about 200 children) that Dr. Aye is also participating in, has started, but is still underway.  Dr. Aye could only share some of the data from the patients when they started the study, but nothing about what happened during the study.

Results

There are three conclusions which I took away from the talk.  These conclusions come from Dr. Aye's completed small trial, from the initial measurements from the much larger trial, and (to a lessor degree) from the summary of all previous research, and especially the 2008 meta-analysis.

First, Type-1 diabetes does appear to effect the brain, although as a small effect.   For example, adults with type-1 have decreased grey matter density, on average, as compared to non-type-1s.  White matter (a different part of the brain) is expected to grow during childhood, but (on average) grows less or not at all in type-1 diabetics.  There were some differences in neurons, as well.  None of these changes pushed type-1 diabetics outside the normal range of human growth.  They were just statistical differences in overall populations.

Second, this effect (overall) is not good.  Gaudieri's meta analyses showed an over all decrease in IQ by about 5 points.  That's an average over all the people involved in all the different studies that were included in the meta analysis.  Verbal IQ scores seemed to be effected the most.  Some other IQ tests were not effected at all.  Another study showed that type-1s with A1c above 8.8 had a about 9% lower numbers than those with A1c below 7.4.  (My notes are unclear if this one one specific test, or all tests, or what.)

Note: I do not want to get into an argument about the accuracy or "truthfulness" of IQ tests.  If you don't believe in the accuracy or truthfulness of standard IQ tests, then you probably should not be reading this post at all.  Dr. Aye stressed that all of her tests were aimed at general IQ, not specific scholastic achievement.  Obviously, the arguments about the usefulness of these tests (compared to other tests, or no tests) are endless.

Third, type-1's effect on the brain is correlated with high BG levels, not with low BG levels.  (But see the "correlation vs. causation" discussion below.)  This focus on high BGs is a major change of view from the previous conventional wisdom.  I can remember very clearly being told (when my daughter was diagnosed, before 2008) that low BGs might effect brain development, and especially that there was nervousness that seizures specifically were bad for the developing brain.  But the data generally does not support this nervousness   Instead, it suggests that high BG numbers are correlated with whatever is hurting the brain.  (Much like high BG numbers are associated with other bad, long term side effects of type-1.)

The analysis of low BG looked at two different measures: first, the number of seizures that child had, and second, the overall-lifetime A1c.  The first is tied to "short deep" low BG numbers, and the second to "long average" low BG numbers.  But neither was associated with lower IQs.  (Side note: about 1/3 of the kids in the pilot study had at least one seizure.   I had no idea they were that common.)

The analysis of high BG numbers looked at he overall-lifetime A1c, and that showed a very clear correlation to lower Verbal IQ (not to other IQ measurements).  The graph showed generally higher verbal IQs at A1c of 6, and linearly dropping as the A1c rose to 9.

There was some discussion about "correlation vs. causation" for this data, as there should be.

One of the parents in the audience pointed out that the flow of causality might flow from IQ to low A1c, and not the other way around.  I thought this was an excellent point.  He pointed out that kids with higher IQ might remember more of their boluses.  They might be better at dosing, or they might just be more careful and thoughtful about managing their type-1 diabetes.  Therefore, high IQ might be a cause of lower A1c, and not the other way around (higher A1c causing lower IQ).  The big study is likely to provide strong data in this area, since it will measure IQ at the start and at the end of a multi-year test period.

Of course, we know that one of the long term bad side effects of type-1 diabetes is peripheral nerve damage ("Diabetic Peripheral Neuropathy") , and this is correlated with high A1c numbers.  So it is very reasonable to think that high A1c numbers might cause nerve damage in the brain as well.

So at the end of the day, we need to wait for the larger clinical trial to get data to answer the causality question.  And even then: one study is unlikely to answer all the questions, but it would be a nice start.

(An unrelated note, but I found interesting: is that people who were depressed tended to have noticeably higher A1c numbers.  I think this data came mostly from adults, but it makes sense to me, and was an important reminder that -- especially with type-1 diabetes -- a positive outlook really does help.  Also, while numbers are very important to managing type-1 diabetes, they are not the be-all and end-all of management feelings do matter.)

Thanks very much to CarbDM for organizing this event!

Joshua Levy
All the views expressed here are those of Joshua Levy, and nothing here is official JDRF, JDCA, or CarbDM news, views, policies or opinions. My blog contains a more complete non-conflict of interest statement. 
Clinical Trials Blog: http://cureresearch4type1diabetes.blogspot.com
Cured in Mice Blog: http://t1dcuredinmice.blogspot.com/