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/

JDRF Funding for a Cure 2012

In the US, we are starting the "Walking Season" when JDRF asks us to walk to raise money for cure. So I'd like to do my part, by reminding you all how important JDRF is to the human trials of potential cures for type-1 diabetes, which I track.

Let me give you the punch line up front: 63% of the treatments currently in human trials have been funded by JDRF. (And the number is  66% for the later phase trials) This is an strong impact; one that any non-profit should be proud of.

This summary does not include Artificial Pancreas research or stem cell trials, which I discuss separately.  The list is a list of treatments, not a list of trials.  For example, the "ATG and autotransplant" treatment is actually running three trials, but since they are testing the same treatment, it is only one item in the list.  DiaPep277 is running several trials, Rituximab has two, and so on.  Finally, those treatments marked "(Established)" have at least one trial which is open to people who have had type-1 diabetes for over a year.  So those are open to non-honeymoon diabetics.

Also remember that I give an organization credit for funding a treatment if they funded it any any point in development; I don't limit it to the current trial.  For example, JDRF is not funding the current trials for DiaPep277, but they did fund much of the early research into it, which allowed it to grow into human trials.

Cures in Phase-III Human Trials
Summary: there is only one treatment in phase-III right now, and it has been funded by JDRF.

• Andromedia's DiaPep227 

This treatment has more than one study active right now.

Cures in Phase-II Human Trials
Summary: there are 14, and 9 of them have been funded by JDRF, either directly or indirectly through ITN. Here are the treatments that have been funded by JDRF:

• Abatacept by Orban at Joslin Diabetes Center
• Diabecell by Living Cell Technologies    (Established)
• Exsulin (previously INGAP) by Exsulin    (Established)
• Kineret / Anakinra by Mandrup-Poulsen at Steno Diabetes Center
• Rituximab by Pescovitz at Indiana
• Sitagliptin and Lansoprazole at Sanford Health
• Thymoglobulin (also known as ATG) by Gitelman
• Umbilical Cord Blood Infusion by Haller at University of Florida
• Xoma 52 by Xoma Corp  (Established)

Not funded by JDRF:

• ATG and autotransplant by Burt, and also Snarski, and also Li
• Atorvastatin (Lipitor) by Willi at Children's Hospital of Philadelphia
• Brod at University of Texas-Health Science Center
• Canakinumab by TrialNet
• NI-0401 by NovImmune

Cures in Phase-I Human Trials
Summary: there are 23, and 14 of the are funded by JDRF and 9 are not. Here is the list funded by JDRF:

• Alefacept by TrialNet
• AAT or Alpha-1 antitrypsin by OmniBio and also Kamada
• ATG and GCSF by Haller at University of Florida    (Established)
• BHT 3021 by Bayhill Theraputics   (Established)
• CGSF by Haller at University of Florida
• Trucco at Children’s Hospital of Pittsburgh    (Established)
• IBC-VS01 by Orban at Joslin Diabetes Center
• Leptin by Garg at University of Texas
• Nasal insulin by Harrison at Melbourne Health
• Polyclonal Tregs by Gitelman at University of California San Francisco
• Pro insulin peptide by Dayan at Cardiff University
• Proleukin and Rapamune by Greenbaum at Benaroya Research Institute    (Established)
• Lisofylline by DiaKine
• Stem Cell Educator by Zhao (Established).

Not funded by JDRF:

• BCG by Faustman at MGH (Established)
• CGSF and autotransplant by Esmatjes at Hospital Clinic of Barcelona  (Established)
• Encapsulated Islets at University clinical Hospital Saint-Luc    (Established)
• Etanercept (ENBREL) by Quattrin at University at Buffalo School of Medicine
• GABA by Lunsford at the University of Alabama at Birmingham.
• Monolayer Cellular Device (Established)
• Rilonacept by White at University of Texas
• The Sydney Project, Encapsulated Stem Cells (Established) 
• Pioglitazone by Wilson at Stony Brook 

Summary of all Trials
38 in total
24 funded by JDRF
So  63 % of the human trials currently underway are funded (either directly or indirectly) by JDRF. Everyone who donates to JDRF should be proud of this huge impact; and everyone who works for JDRF or volunteers for it, should be doubly proud.

Just Looking at Trials on Established Type-1 Diabetics
13 in total (34% of all trials)
8 funded by JDRF
So 62% of the trials recruiting established type-1 diabetics, are funded by JDRF.

Compared to Last Year
In 2011 there were 37 treatments in clinical trials, in 2012 there are  38  (growth of 3%)
In 2011 there was 1 treatments in Phase-III trials, in 2012 there is still  1  (no change).
In 2011 there were 16 treatments in Phase-II trials, in 2012 there are 13  (drop of 23%).
In 2011 there were 20 treatments in Phase-I trials, in 2012 there are 23 (growth of 13%).

In previous years I have included some drugs that were basically being tested as treatments (adjuncts to insulin that would give people better control or help them use less insulin).  This year, I have removed those from the list.  I included them before because there was always a chance they would lead to a cure.  I'm now of the opinion that was wishful thinking, so I'm no longer including them here.

How I Count Trials for This Comparison

• I give an organization credit for funding a cure if it funded that cure at any point in it's development cycle.
• I mark the start of a research trial when the researchers start recruiting patients (and if there is any uncertainty, when the first patient is dosed).  Some researchers talk about starting a trial when they submit the paper work, which is usually months earlier.
• For trials which use combinations of two or more different treatments, I give funding credit, if the organization in the past funded any component of a combination treatment, or if they are funding the current combined treatment. Also, I list experiments separately if they use at least one different drug.
• The ITN (Immune Tolerance Network) has JDRF as a major funder, so I count ITN as indirect JDRF funding.
• I have made no attempt to find out how much funding different organizations gave to different research. This would be next to impossible for long research programs, anyway.
• Funding of research is not my primary interest, so I don't spend a lot of time tracking down details in this area. I might be wrong on details.
• I use the term "US Gov" for all the different branches and organizations within the United States of America's federal govenment (so includes NIDDK, NIAID, NICHD, etc.)
• I don't work for the US Gov, JDRF, or any of the other organizations discussed here. I'm an adviser to JDCA. I also own stock in several of the companies discussed here.

This is an update and extension to blog postings that I've made for the previous four years:
http://cureresearch4type1diabetes.blogspot.com/2011/10/jdrf-funding-research-for-cure-2011.html
http://cureresearch4type1diabetes.blogspot.com/2010/09/jdrf-funding-research-for-cure-2010.html
http://cureresearch4type1diabetes.blogspot.com/2009/09/jdrf-funding-research-for-cure.html
http://cureresearch4type1diabetes.blogspot.com/2008/10/jdrf-funding-of-cure-research-phases-ii.html

Please think of this posting as being my personal  "thank you" note to all the JDRF staff, volunteers, and everyone who donates money to research a cure for type-1 diabetes:

Thank You!

Finally, if you see any mistakes or oversights in this posting, please tell me!  There is a lot of information packed into this small posting, and I've made mistakes in the past.

Here is a chart of the number of total clinical trials, and broken down by phases, for each of the last few years:



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. 
Blog: http://cureresearch4type1diabetes.blogspot.com
Cured in Mice Blog: http://t1dcuredinmice.blogspot.com/

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

Phase-II Trial to Test Intranasal Insulin for Type-1 Prevention

Several different groups are experimenting with using insulin to prevent or cure type-1 diabetes.  This is similar to giving people with food allergies the food they are allergic to in tiny doses, gradually building up the dose over years until they are no longer allergic.  Because insulin is basically a protein, it gets digested, so you can't take pills of insulin.  Different groups are experimenting with different methods of getting insulin into a person, in the hopes that it will result in a cure.

This particular group is using a nasal spray.  They want to enroll 120 people, and started back in 2006, but I've not previously blogged on it.  They are now hoping to finish in late 2016.  Obviously, it's been going on for a long time.  Because it is being done in Australia (with it's lower population), I'm sure it is taking them longer than they would like to fully enroll it.

News: http://au.news.yahoo.com/today-tonight/health/article/-/14475192/diabetes-vaccine-trial
Web site: http://www.stopdiabetes.com.au/
Clinical Trial Record: http://www.clinicaltrials.gov/ct2/show/NCT00336674


IL-2 and Sirolimus Fail in Phase-I

This clinical trial failed in phase-I, in a pretty obvious way.  Here's the quote from the researchers:

Rapamycin/IL-2 therapy, as given in this phase 1 study, resulted in transient β-cell dysfunction despite an increase in Tregs.

So it hurt the patients (although only temporarily) and did not help them.   Plus they threw in this (which should really go in my "Cured in Mice" blog:

Such results highlight the difficulties in translating therapies to the clinic and emphasize the importance of broadly interrogating the immune system to evaluate the effects of therapy.

They sure do!

News: http://medicalxpress.com/news/2012-08-experimental-combo-treatment-worsens-diabetes.html
Abstract: http://diabetes.diabetesjournals.org/content/early/2012/06/15/db12-0049.abstract?sid=2b59c310-a735-4fc8-a3e1-f14f9678c935
Clinical Trial Record: http://www.clinicaltrials.gov/ct2/show/NCT00525889


Phase-I Clinical Trial of IL-2 is Complete

This is the other IL-2 clinical trial.  It involves 25 people who have had type-1 for less than 2 years.  It is complete, meaning they have gathered all the data needed, but have not yet published the results.  Since they were complete in April, if they have a positive result, I would expect publication by April 2013, and if they have a neutral, negative, or hard to interpret result, publication after that.

Clinical Trial Record: http://www.clinicaltrials.gov/ct2/show/NCT01353833

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/