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/

Zhao Starts Phase-II Clinical Trial of "Stem Cell Educator"

Zhao Upgrades His Clinical Trial to Phase-II

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

He published his phase-I results in January 2012, and in July, he changed the basic nature of his clinical trial record from phase-I/II to phase-II.  Change a trial from I/II to II is uncommon, but it does happen. (The more common thing is to create a new clinical trial for the phase-II study.)  But the whole point of a I/II trial is that it can turn into a II if things go well.  In January, Dr. Zhao published data on 12 treated patients and 3 placebo patients, but the clinical trial record was for 100 people, so the remaining 80+ people (I assume) will be his phase-II trial.

Notice that it took him only 6 months to "turn around" from publishing his phase-I study to starting the phase-II study.  That's quicker than most research I follow.

The trial record was also updated in Augest and October, so if you group together all the changes made, here is a summary of the changes:

• Phase goes from 1 to 2.
• A second trial site has been added.  In addition to China, patients in Spain can enroll at Hospital Universitario Central de Asturias.
• Purpose goes from "Safety/Efficacy" to "Efficacy" Study.
• The study was expected to complete in 2012 now is expected to complete in September 2014.
• Sponsor goes from University of Illinois to Tianhe Stem Cell Biotechnologies (Zhao's company).
• Trial design went from single blind to open label, and 
• There is no mention of a placebo or control group.

Also, Tianhe (Zhao's company) has also started a separate clinical trial aimed at using this same technology to cure/treat Alopecia Areata, which is another autoimmune disease involving T-cells. The trial is being run in China.

Finally, another researcher (Dr. Mark Atkinson) has been funded by JDRF for a year to test Dr. Zhao's Cell Educator "ex vivo" (not in living organisms, but in tissue samples or similar). The goal is to independently verify parts of Dr. Zhao's results.  You can read details here:

JDRF "lay abstract": http://onlineapps.jdfcure.org/AbstractReport.cfm?grant_id=38534&abs_type=LAY

Discussion

From my point of view, there is both good and bad news here.  Going from single blind to open label is a step backwards, in my mind.  Not having a placebo group is also going the wrong direction.   On the other hand, another site, more people, and an end point in the near future are all good things.

Corporate web site: http://www.tianhecell.com/
Clinical Trial Record: http://www.clinicaltrials.gov/ct2/show/NCT01350219

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 (late Sept-2012)

Prochymal Failed Phase-II Trials

I missed this, when it was published back in May, but luckily Kelly Close (of Close Concerns, who publishes DiaTribe) reported on it:

At 1 year, intravenous infusions of Prochymal were reportedly well tolerated, with no differences in adverse event rates between the Prochymal and placebo groups. 

With regard to efficacy, no significant differences in stimulated C-peptide levels were observed between the two arms (the primary efficacy endpoint), although a trend towards fewer hypoglycemic events in the Prochymal arm was observed. 

A full analysis will be performed following an additional year of follow-up (for a total of 24 months)

My translation is this:

• The trial failed its primary endpoint.
• The researchers are trying to be optimistic about a small, vague result in one of the secondary endpoints.
• The study will get more data after another year, and they are hoping for better news.

Obviously, I'm hoping for better news next year, too.  But I'm not expecting it.

Scientific Press Coverage: http://onlinelibrary.wiley.com/doi/10.1111/j.1753-0407.2012.00197.x/full

DiaTribe is a free on line newsletter (http://www.diatribe.us/), which is is a great source of info on diabetes research, technology, etc.

NI-0401 by NovImmune Failed a Long Time Ago

Years ago a company called NovImmune started a phase-II trial for their drug NI-0401 aimed at type-1 diabetes.    After that, no news.  This drug was targeted at CD3, and all the other CD3 drugs failed, so I always assumed this one had, as well.  But there never was any news, and I never saw an official announcement.  However, NovImmune updated their entire web site, and NI-0401 is still there, but diabetes is not listed as a target at all.  Also, I found a European clinical trial registry, which showed that the long ago study had been canceled just months after it started.

So NI-0401 is dead, as far as I'm concerned, until I hear otherwise.

European clinical trials registry:
http://apps.who.int/trialsearch/trial.aspx?trialid=EUCTR2009-012988-34-AT
https://www.clinicaltrialsregister.eu/ctr-search/trial/2009-012988-34/AT

Corporate web site:
http://www.novimmune.com/products/ni-0401.html

DiaPep277 by Andromida is Fully Enrolled

This is the only treatment that I'm following that is currently in phase-III trials.  The results from previous work suggest it might be a "longer, strong honeymoon" type treatment, rather than a cure. they have already finished one phase-III trial, and this is their second.  The FDA requires two, so when this one completes, if it is successful, they will be ready to move into "marketing approval" phase, which takes a year or two.

Why is this important? For two reasons.  First, because it is now possible to predict when they will finish collecting data.  (Since this study gathers data for 2 years, it will finish about Sept 2014.) Second, because much of the uncertainty that surrounds clinical trials, is involved with recruiting participants.  It is often unclear how hard it will be to recruit people, and long it will take.   But that this point, all that cunertainty is behind the researchers.  From now on, it is just gather data, then analyze data, and then publish data.  Researchers have a lot more control over those later stages, then over recruiting people in the first place.

News: http://www.marketwatch.com/story/andromeda-biotech-successfully-completes-patient-recruitment-in-phase-iii-confirmatory-trial-for-its-lead-drug-diapep277-for-type-1-diabetes-2012-09-12

How Doctors Weigh Clinical Trial Funding

This was a very interesting study of doctors.  Basically, the researchers gave doctors summaries of research results.  These summaries breifly described a study's results, methodology, and source of funding.    The doctor was then asked questions to determine how much they trusted the results, and how willing they were to proscribe the medicine being tested, based on the trial.  (The research described was fictional, so the doctors did not have any prior knowledge of the drugs in question.)

Here is a summary of the results:

The study found that physicians weighted their assessment of the rigor of a trial based on pharma funding, and that they were half as willing to prescribe those disclosing industry sponsorship as they were those disclosing NIH funding, regardless of methodological rigor.

Discussion

I think these results are good in two separate (but related) ways.  First, they suggest to me that doctors properly "discount" clinical trials funded by industry.  Second, it suggests to me that when a doctor recommends a treatment, they are already taking into account who funded the studies suggesting its use.  The recent problems with pharma PR guys "ghost writing" research articles, and withholding placebos from some researchers has made some people nervous about the accuracy of studies they do fund.  I think it is proper that doctors are also nervous, and I feel good that the average doctor in the study took into account the funding source of clinical trials they read about.

Interestingly, the researchers who ran this particular trial are a little unhappy about their own results.  They seem to think that when comparing two studies, if the methodologies are equally rigorous, that the results should be weighted the same, no matter who did the funding.  They are specifically worried about doctors undervaluing what the researchers consider large scale, well designed, industry funded studies.   I disagree.  I think the prescribing doctors are doing the right thing by undervaluing (or "discounting") equally rigorous studies that are funded by industry.  I view the attitude of these researchers as being very "old school" (and in this case, out of date).  Sure, in the 1950s the idea was that rigorous trial methodology and peer review together were all that was needed to ensure accurate results.  The idea was that the scientific method was so good that who funded the trial was not critical to the quality of the results.  But 60 years later, I don't think that's the consensus opinion.   Now we know that quality starts with good methodology and peer review, but those alone are not enough.

News coverage: http://www.mmm-online.com/docs-downgrade-results-of-pharma-funded-clinical-trials/article/259981/

Symlin as a Treatment

Not for a cure, but of interest, are the results of two studies testing symlin in type-1 diabetics.  Only one was placebo controled, and it found:

analysis of 248 patients from a 29-week, placebo-controlled study, measurements in the normal range based on ADA criteria increased from 37.3 percent to 43.9 percent for SYMLIN-treated patients (n=115), compared to an increase from 38.2 percent to 40.9 percent in those receiving placebo (n=133). The percent of measurements in the normal range based on AACE criteria increased from 22.6 percent to 27.8 percent for SYMLIN-treated patients compared to an increase from 24.1 to 25.0 in those receiving placebo. The percentage of readings in the hypoglycemic range remained relatively stable.

Discussion

I'm not sure I'd take a second injection with meals (or a first injection for pump users) for that level of improvement, but it's still interesting.  I also think that A1c improvements would be a better measure of goodness than % inside of guidelines.   But you gotta start somewhere.

Maybe we'll end up with a tri-treatment artificial pancreas.  It will dose insulin for highs, glucagon for lows, and symlin with meal boluses.

Press Release: http://www.businesswire.com/news/home/20120609005027/en/SYMLIN%C2%AE-Helped-Patients-Type-2-Type-1

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/