Saturday, January 17, 2015

Artificial Pancreas Update (Jan 2015)

Sound track for this blog is "Living After Midnight" by Judas Priest, but performed by The Donnas:
http://grooveshark.com/#!/s/Living+After+Midnight+Judas+Priest/3ASqUY

Research into the Artificial Pancreas (AP) continues to move forward.  The term "artificial pancreas" refers to using a continuous glucose monitor (CGM) to feed data to a computer, which controls an insulin pump, and in some models, a glucagon pump as well.  Artificial pancreas refers to using existing technology in all these areas, but connecting them together so that a person does not need to worry about counting carbs or blood glucose levels.  It is all done automatically.

Metronic Starts Selling a "Step 2" Artificial Pancreas in Australia

The JDRF uses a 6 step model to get to the fully featured artificial pancreas that we wall want.  You can read about that model here:  http://jdrf.org/research/treat/artificial-pancreas-project/

Right now, Medtronic makes the only commercially available "step 1" artificial pancreas.  However, just recently they started publicising a "step 2" artificial pancreas in Australia.  The difference is that "step 1" APs cut off insulin if you are already too low, while "step 2" cuts you off before you get too low.    This is an important improvement in functionality, but it is also an important regulatory hurdle. The model number is 640G.  I can't find any press releases, or any notice on their web site, but karri on CWD posted this link to a promotional video:
https://www.youtube.com/watch?v=wl6WDkxXjBc
There are also several "Ambassador Reviews" on the Medtronic Diabetes ANZ youtube site.
It looks like they are taking orders for the device now.  However, I can't see anything on the web site related to the 640G.  Maybe they know I'm from the USA, and can't get it?

Of course, the next issue for us Americans is FDA approval.  Medtronic's "step 1" device took 31 months after European approval, before the FDA approved it!  It will be interesting to see if the FDA repeats that fiasco or not.  There has been a lot of progress, several meetings between the FDA and patient advocates (such as DOC, diaTribe, JDRF, etc.) and now we will see if any of that matters. But the clock is ticking now, and we will know a lot more when we see how long the FDA delay of approval is.


A Direct Single Hormone vs. Dual Hormone Comparison

In the past, I've tried to compare Single Hormone AP results to Dual Hormone AP results, by comparing similar results from different studies.  However, it's much better to compare the same result in the same study, rathern than combining data from different studies.  A group of researchers at Institut de Recherches Cliniques de Montreal, Montreal, QC, Canada (and elsewhere) recently did exactly this comparison.  They directly compared a regular pump plus CGM, to an insulin only AP, to a insulin and glucagon AP.  Patients (12 years or older) were treated for 3 24 hour periods.  The trial was not blinded. Funding was from the Canadian Diabetes Association, JDRF, and Medtronic (see above for involvement). They reported the following data:

Measure Pump + CGM Insulin AP Dual Hormone AP
Time spent in target range
51%
62%
63%
Hypoglycaemic events
52
13
9
Symptomatic hypoglycaemic events
12
5
0
Nocturnal hypoglycaemic events
13
0
0

Opinions

I think the clear result of this trial is that the dual hormone AP is very slightly better than the Insulin AP, and they are both noticeably better than the current standard pump and CGM.  This result is similar to previous studies.

Abstract: http://www.thelancet.com/journals/landia/article/PIIS2213-8587(14)70226-8/fulltext
Clinical Trial Registry: http://clinicaltrials.gov/ct2/show/NCT01754337

Many Articles in the January Journal of Diabetes Science and Technology

The Journal of Diabetes Science and Technology had a special issue on glucagon therapy.  There were a couple of articles on stable glucagon, which is required for a bihormonal artificial pancreas (such as Dr. Damiano is working on):

From this abstract http://dst.sagepub.com/content/9/1/8?etoc:
Data are presented that demonstrate long-term physical and chemical stability (~2 years) at 5°C, short-term stability (up to 1 month) under accelerated 37°C testing conditions, pump compatibility for up to 9 days, and adequate glucose responses in dogs and diabetic swine. These stable glucagon formulations show utility and promise for further development in artificial pancreas systems.
From this abstract http://dst.sagepub.com/content/9/1/24?etoc:
Data are presented that demonstrate physical and chemical stability under presumed storage conditions ([over] 2 years at room temperature) as well as “in use” stability and compatibility in an Insulet’s OmniPod® infusion pump. Also presented are results of a skin irritation study in a rabbit model and pharmacokinetics/pharmacodynamics data following pump administration of glucagon in a diabetic swine model.
Here is a diagram of their results.  Note that they are comparing their glucagon to standard glucagon, so their trial is successful if the same colored lines are close to each other, and they are:



Although both of these are animal trials, for this kind of test, I think results in animals are likely to mirror results in people.  They are really measuring the stability of the glucagon, and the test subject species doesn't have a big impact on that.  So my normal worries about "works in mice, fails in people" are pretty small for this kind of research.

Adding Physical Activity Measurements to Aritifical Pancreas Calculations

Also in The Journal of Diabetes Science and Technology, there is this paper:
http://dst.sagepub.com/content/9/1/80?etoc
(People in the San Francisco bay area will notice that the authors are mostly local: Drs. Stenerson, two Paynes, Ly, Wilson, and Buckingham.)

This paper attempted to use data on physical activity to improve an artificial pancreas's BG numbers. The idea is simple enough: we all know that physical activity lowers BG numbers.  If an artificial pancreas knew how active you were, could it do a better job of controlling BG numbers?   The kids in the study (average age 13), did a soccer workout ("football workout", in the rest of the world) on two separate occasions.  In one case, data from an accelerometer was used to help calculate real time insulin dosing, and in the other case, this data was not used.  BG and hypoglycemic events were measured both during the soccer, but also after it, until the next morning.  There were 18 kids in the study.

Overall BG numbers were similar in each group.  Hypoglycemia events were higher when not using the accelerometer, but the difference between groups was not statistically significant. (This is the scientific way of saying "close, but not quite".)

Discussion

From my point of view, there are a couple of ways to interpret this result:
  1. One could say that the study was just too early and too small to interpret the results, and it's really more of a proof of concept of how accelerometers could be tested in the future.  The most that can be said is that more research should be done. 
  2. Or, one could say that accelerometer data is not needed for an artificial pancreas, because it had no statistically significant effect here.  And this is a good thing, because it means we will not have to burden type-1 diabetics with accelerometers (in addition to pump(s) and a CGM), because the extra information they provide is not needed.
  3. Or, one could say that existing algorithms and accelerometers are not good enough, and we need to develop better ones in order to take advantages of this information.
  4. Or, one could sort of split the difference, and say that most people don't need accelerometer data (as also supported by the good BG numbers reported by other AP tests which don't use them). However, for serious athletes who do need this extra data, we need to develop better algorithms (or accelerometers), if we are going to successfully use this data. 
  5. Or, we can view this research as answering the question "how much physical exertion is needed before an AP needs exertion data to work well?"  The idea is that, of course at some level of vigorous exercise, accelerometer data will be needed.  This trial just shows that the soccer exercises wasn't enough, and we need to do something even more vigorous until it does matter.
No matter which interpretation appeals to you, we are still very early in the testing of accelerator enhanced APs.  I'm sure there will be more clinical trials before there is any consensus on the proper way to integrate accelerator data into APs.  

Interview with Dexcom

Here is a two part interview with the CEO of Dexcom, a big CGM maker.  He talks about future development, both in terms of CGMs for APs and CGMs as a replacement for finger sticks.  I found part 2 more interesting than part 1, but here are links to both:
http://www.meddeviceonline.com/doc/how-dexcom-plans-to-eliminate-the-finger-stick-and-bring-cgm-to-the-masses-part-one-0001
http://www.meddeviceonline.com/doc/how-dexcom-plans-to-eliminate-the-finger-stick-and-bring-cgm-to-the-masses-part-two-0001

Another Summary

Here is another writer's summary of artificial pancreas progress for 2014.
http://www.medpagetoday.com/Endocrinology/GeneralEndocrinology/49342

Homebrew Artificial Pancreas

As Dave Berry used to say: I'm not making this up!

This project is being called "Hacking an Artificial Pancreas" or "DIY Artificial Pancreas", but in the tradition of Silicon Valley, I would called it "Homebrew Artificial Pancreas".  It looks like we have reached the point where people can cobble together a functional AP in their garage.

You can see pictures here (two quite different paths):
https://scottleibrand.wordpress.com/2014/12/15/how-does-a-closed-loop-artificial-pancreas-work-when-you-diy-or-diyps-closed-loop-is-working/
http://circles-of-blue.winchcombe.org/index.php/2015/01/11/wearenotwaiting-thanks-to-dexdrip-introduction/
https://twitter.com/stephenistaken

If you speak twitter: #DIYPS #WeAreNotWaiting #dexdrip

Less than $100 in parts. A little soldering (sometimes).  What could possibly go wrong?
When Steve Jobs and Steve Wozniak made the Apple I they were basically making something that they could not buy, and that's what these guys are doing.  Of course the Steves were not replacing  an organ of the body.

I want to thank Dominik for sending me this. I will never look at a Raspberry Pi the same way, again.

Joshua Levy 
http://cureresearch4type1diabetes.blogspot.com 
publicjoshualevy at gmail dot com 
All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions. My daughter has type-1 diabetes and participates in clinical trials, which might be discussed here. My blog contains a more complete non-conflict of interest statement. Thanks to everyone who helps with the blog.

Saturday, January 10, 2015

A Cautionary Tale from Dr. Melton's Lab At Harvard

The soundtrack for this blog posting is the blues: Ball Peen Hammer sung by Joe Bonamassa:
http://grooveshark.com/#!/s/Ball+Peen+Hammer/2pulWL

This is a cautionary tale of research from Dr. Doug Melton's lab at Harvard.  I considered carefully if I should blog on this subject.  It is certainly a lot more fun to blog about successes, and new opportunities, than it is to blog about failures and mistakes.  However, I think it is critical to include both good news and bad news.  At the very least, so that people following type-1 research understand that mistakes get made, and that one of the strengths of the scientific method is the ability to recover from mistakes.

This posting is about Betatrophin, which I did not cover in my blog when it was first announced. The research was all done on animals, and I focus on human trials.  However, now that this research has gone full circle, I think it makes a useful scientific morality tale.  Obviously, lots of scientific research doesn't pan out for one reason or other.  Usually it dies a quiet and obscure death.  But this research was a little higher profile, and therefore it's death was a little higher profile as well, so more about it's life and death is known, than about your average research dead-end.

History

In early 2013 Dr. Melton's lab at Harvard released a "big news" research paper. They had identified a natural human hormone which caused beta cells to naturally regrow.  This one hormone, which they named "Betatrophin" had a huge impact in beta cell regrowth.  The research had been done in mice, and was published in Cell (a prestigious scientific journal).  Two big name pharmaceutical companies (Evotec and  Janssen Pharmaceuticals, a subsidiary of Johnson and Johnson) paid millions of dollars for the rights to Betatrophin.  The lead author of the paper (Dr. Peng Yi) was hired by an important diabetes research center (Joslin) to do research, including future clinical trials focused on Betatrophin.

But about 18 months later, it all collapsed.  A research group working for Regeneron Pharmaceuticals found that Betatrophin did not cause beta cells to regrow, and submitted a paper to that effect.  When the paper was sent to Dr. Melton for peer review, he endorsed it, and wrote a "Perspective" stating that his own lab had been unable to reproduce it's own previous findings.  It now appears that the conclusion in the first paper was incorrect.  I want to stress that no one has suggested that there was any fraud or mistakes in the research; it is just that the conclusion turned out to be wrong.

Discussion of Fallout

Betatrophin was the big news from this lab in 2013, but what about the big news in 2014?  In 2014 Dr. Melton's lab released a "big news" research paper showing that they could grow large amounts of functional beta cells from embryonic stem cells.  (Again, I did not blog on this, because it was not yet being used in a clinical trial.  However I was asked about it specifically on CWD, and posted some comments.)  How does the failure of the 2013 news, affect how we view the 2014 news?  This is the question that should be in the front of the mind of everyone following research aimed at curing type-1 diabetes.  Does the collapse of Betatrophin suggest that the beta cell breakthrough might collapse?

There is no way for me to have any insight into that question.  A pessimist would say that a lab that is wrong with one thing, could easily be wrong about the next thing;  that whatever caused the first incorrect conclusion could still be there for the second one.  An optimist would say that testing Betatrophin is a very different technology than transforming embryonic stem cells into beta cells, and the fact that the lab was wrong about one does not mean it is wrong about the other.

Of course, this brings up this question: if a world class scientist, working at one of the most highly regarded universities in the world, publishing in one of the most prestigious journals in the world, can still be wrong, how are we -- everyday people affected by a disease, but without extensive scientific knowledge -- to know what is correct and what is wrong?  How will we ever know?  (I discuss this in the conclusion section.)

Discussion of Peer Review

One of the interesting "side issues" that this brings up is conflict of interest in peer review.  When the scientific journal Cell got the paper showing that the research done in Dr. Melton's lab was wrong, they sent it to Dr. Melton as part of peer review.  I was a little shocked by that; but it makes sense in a pure-science sort of way.  Dr. Melton is a world expert on Betatrophin (by virtue of being "senior author" of the paper discovering it's function) so it makes perfect sense to ask him to peer review this paper.  However, from a human point of view, it seems nuts to have a person peer review a paper that directly undermines his own paper.  Even if there is not a monetary conflict of interest, there certainly is an intellectual one!  We were all well served by Dr. Melton's ethical actions after he was asked to be a peer reviewer.  But the opposite can happen as well.

This policy, of having papers which contradict previously published papers (in the same journal) reviewed by the authors of the previous paper, appears to be common in scientific journals.  At least it used to be.  The big name journal Nature did this in the 1990s.  More shocking, it then did not publish the second paper, based on a bad review from the author of the first paper.  Two other reviewers gave the second paper good reviews. You can read the sorry tale here:
http://retractionwatch.com/2013/06/19/why-i-retracted-my-nature-paper-a-guest-post-from-david-vaux-about-correcting-the-scientific-record/

Corporate vs. University Research

There is the growing trend to ignore corporate research in favor of academic research, often under the guise of "conflict of interest".  Obviously, some of this is a well earned reaction to various corporate attempts to manipulate scientific research (nuclear, tobacco, and pharmaceutical industries, just to name the ones who have gotten caught at it).

However, it is important to not take that attitude to extremes.  There are pressures to deliver in academia and the non-profit world as well.  In this case the wrong results were from university research and the right results came from industry.  I think it is important to remember that, in the face of a growing "corporation = evil" narrative.

The Original Paper Has Not Been Retracted

An interesting question (at least it's interesting to me) is should this paper be retracted?  It hasn't been, and it doesn't look like it will be.  It is certainly wrong in it's conclusions, but is that enough to retract it?   There are two schools of thought here.   One says that publications should only be retracted if they are "in error", meaning there was an error in design, data collection or analysis, or if there was fraud or ethics problems.  The other school of thought says that being wrong is enough.  If the authors / editors / publishers are sure it is wrong, then it should be retracted.

This sounds like a good topic of debate in a college level ethics class, with a scientific bent.
But one of the existing complications, is that there is no global standard.  Each publication is free to make their own decisions about retractions, and even in one publication, they don't have to be internally consistent, if they don't want to be.

My Summary

First, the press:

I have a very low opinion of how "the press" (ie. mass market news web sites) covers science and medicine.  Among their other sins, I think they over hype certain medical news, based on buzz words in press releases.  Although these "over hype triggering buzzwords" change slightly over time, a good PR firm or savvy researcher keeps up to date, so they can use the trendy buzz words to manipulate the press coverage.to get more than their research deserves.

For the last decade, I think "stem cell" is one of those triggering buzz words, and I think "Harvard" is one, too, and reports from big name universities are generally over hyped, in relation to universities with less name recognition.

Second, how to determine that science is correct:

This incident reinforces my belief that the only way to be sure a scientific paper is correct, is to follow it's research for a period of years after the paper is published, to see what happens.  There is no way to look at a freshly printed paper and know that it is correct.  I know that a lot of people try to take short cuts, and they say (or think) things like "it is a peer reviewed paper [so it must be right]", "the researcher is one of the most famous people in the field [so it must be right]", "the researcher is at an ivy league calibre institution [so it must be right]", "it was published in the leading journal in it's field [so it must be right]", "the researcher's family is affected by the disease so he's totally committed to the research [so it must be right]", "he is so personable, so articulate, and the description of what is happening makes perfect sense [so it must be right]", "the researcher has a great history and a great reputation [so it must be right]", and so on.

For Betatrophin, every one of those statements was true, and yet the research was flat out wrong.

This case is a clear example where the only way to see if research was correct, was to wait and see what happened to the research over time, as people tried to capitalize on it, to build on it, and to productize it.  The take home point is simple: there is no short cut.  There is no way to know quickly if research is correct.  Only the passing of years will tell us with certainty.

Now, I certainly don't claim perfection in this regard. I'm sure I've fallen into this trap myself. But it still is a trap, and something to be avoided.  I do stress peer reviewed results in this blog, almost to the exclusion of non-peer reviewed results, but that is different than implying that peer review means the research is good.  I consider peer review to be a necessary component of good research, but not sufficient to prove good research.  Put another way: if research is not peer reviewed, then it is not worthy of serious consideration.  But even if it is peer reviewed, it still might be wrong.

Some people, optimists, might look on this example as a fluke, but I think that's a mistake.  Most research does not pan out.  Most phase-I clinical trials do not lead to a marketed treatment. Therefore, the failures described here are quite common.  Maybe even normal.  I'm posting about this particular case because it made a bigger than usual news splash.  I get emails from people asking "remember research project X from years ago?  Whatever happened to that?  Did the money making, type-1 conspiracy suppress it?".  Nine times out of ten, the answer is that the research just didn't pan out at the next level.  Like Betatrohpin, the first publication was in error, and nothing could be built on it.

I'm always very nervous about the number of people who assume because they have not heard of it, that means it was really successful, and was therefore suppressed.  It creates a mindset where failure is taken as evidence of conspiracy.  In a world of research, where most new ideas do not pan out, this is spectacularly dangerous logic.

To join the two parts of this conclusion, notice that news organizations have an impossible conundrum: they are judged on how quickly they get (incredibly superficial) articles about scientific research out on the web, yet the only way to know if those articles are accurate is to wait, often months or years!   Yet as long as we reward news sources for speed, and ignore their accuracy (the current situation) this is the news we are asking for.

More Reading

Betatropin news at the time:
http://news.harvard.edu/gazette/story/2013/04/potential-diabetes-breakthrough/
http://jdrf.org/blog/2013/discovery-of-new-hormone-may-impact-t1d/

The papers:
Harvard paper: http://www.cell.com/abstract/S0092-8674(13)00449-2
Regeneron Pharmaceuticals: http://www.sciencedirect.com/science/article/pii/S0092867414011763
The Perspective: http://www.cell.com/cell/abstract/S0092-8674(14)01177-5

Discussion and fallout:
Retraction Watch: http://retractionwatch.com/2014/11/10/i-kind-of-like-that-about-science-harvard-diabetes-breakthrough-muddied-by-two-new-papers/
Blog: http://www.ipscell.com/2014/10/the-betatrophin-blues/
Pubpeer: https://pubpeer.com/publications/8EAC9ED889CC6E498199B11B1BC135 and also https://pubpeer.com/publications/0F7B9DF45743305575A36FDBA7FC9A
Money issues: http://seekingalpha.com/article/1730632-companies-race-to-develop-the-next-novel-blockbuster-diabetes-drug-part-2

A note on titles: In the past I have not been consistent about it, but in the future, in this blog, I will attempt to refer to anyone with a doctorate (PhD, PharmD, DVM, etc.) or a medical degree (MD) as Dr. X Y the first time they are named, and Dr. Y thereafter.   (Sorry lawyers, on this blog, you're not doctors, no matter what your degree says. :-)

Joshua Levy 
http://cureresearch4type1diabetes.blogspot.com 
publicjoshualevy at gmail dot com
All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions. My daughter has type-1 diabetes and participates in clinical trials, which might be discussed here. My blog contains a more complete non-conflict of interest statement. Thanks to everyone who helps with the blog.

Saturday, January 3, 2015

Two DiaPep277 Papers Retracted


I had previously reported here:
http://cureresearch4type1diabetes.blogspot.com/2014/09/diapep277-development-canceled-due-to.html
that DiaPep277 development had been canceled due to serious allegations of misconduct.
The "second shoe" has now dropped.  A key paper on DiaPep277 has been retracted.  You can read about it here:
http://care.diabetesjournals.org/content/38/1/178.full

Additionally, a second paper has also been retracted:
http://care.diabetesjournals.org/content/38/1/179.full
This paper reported on an unexpected difference in two different C-peptide measurement schemes, during the DiaPep277 testing.  Since it used the same data which now is in question, it is retracted.

The paper's authors don't have any new information, but are retracting the paper based on the already published allegations.  For me, the interesting part of the retraction, is that only the authors not employed by Andromeda Biotech took part. The authors who worked for (or still work for) Andromeda Biotech were "unavailable for comment and therefore are not part of this retraction process".

This story include a sort of "collateral damage" warning about the impact of fraud in science.  The alleged manipulation was all targeted at the first paper.  The goal of it was to make the drug look more effective than it actually was, and that was what the first paper reported.  However, the second paper represents a dangerous side effect.  Because the data was manipulated (allegedly), the second paper gave an unexpected result.  If the alleged manipulation had not been discovered, then the second paper might have caused unnecessary research to try to explain it's results.  Even more worrisome, perfectly good research that used the measurement schemes discussed in the second paper might have been cast into doubt.  Luckily, none of that will happen now.

I encourage you to read my previous blogging on DiaPep277.
Unfortunately, science that turns out to be wrong is going to be a mini-theme, as I'm putting the finishing touches on a blog posting describing another incorrect paper which was also important to type-1 diabetes research.  That blog should go out in early January.


Joshua Levy 
http://cureresearch4type1diabetes.blogspot.com 
publicjoshualevy at gmail dot com
All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions. My daughter has type-1 diabetes and participates in clinical trials, which might be discussed here. My blog contains a more complete non-conflict of interest statement. Thanks to everyone who helps with the blog.

Saturday, December 20, 2014

Phase-II Results from Rebooting The Immune System To Cure Type-1


First, a discussion about naming.  In the past, I've referred to this treatment as the "Burt" treatment, because that was the senior (last listed) author of the first paper I saw on it, and because I didn't have a better name for it.  I haven't seen Dr. Burt's name on clinical trial for this treatment in many years, so it's no longer an appropriate name.  But I don't have a better name.  In any case, you can read my previous blogging about this treatment under the label "Burt" on my blog:
http://cureresearch4type1diabetes.blogspot.com/search/label/Burt

Second, a little background. The original clinical trial of this treatment, in Brazil, was one of the very few clinical trials which actually cured people of type-1 diabetes. I know that is a provocative statement, so let me be clear: Some of the people treated in this trial did not need to use external insulin (yet still had reasonable A1C numbers while eating normal diets) for as long as the study ran. Some of these people were followed for years. This was not just a "couple of weeks" or even a "couple of months" event.

Third, some important safety issues. Basically, the treatment is to "reboot" the immune system, hobbling the immune system, and then treating it so that when it comes back, it does not attack the body's own beta cells. There are two serious safety issues here: first, during the time the immune system is down, the patient must stay in an isolation ward in a hospital, and is subject to opportunistic infections, which can cause death. Second, the act of shutting down the immune system is a big deal, and might cause problems "down the road". Cancerous tumors are a particular worry. Neither of these risks is completely unknown. Very similar immune system "reboots" are used today to treat cancer, and some other autoimmune diseases and their safety is understood. Never the less, the level of risk is higher than other possible cures for type-1 diabetes.

The Studies

This paper is not reporting on the results of one study.  Rather, it was reporting on a pool of patients enrolled at three different sites, one in Poland and two in China.  There were a total of 65 people included (24 in Poland, and 13 and 28 in China).  All studies enrolled people as young as 12, while the Polish study limited recruitment to the first 6 weeks after diagnosis, the Chinese studies accepted people for a year after diagnosis, but these are all honeymoon diabetics.  There were a few other differences in experimental procedures, as well.

The Results

The following points are all quotes from the abstract:
  • A total of 59% of individuals with T1D achieved insulin independence within the first 6 months
  • 32% remained insulin independent at the last time point of their follow-up
  • All treated subjects showed a decrease in HbA1c levels and an increase in C-peptide levels compared with pretreatment.
The authors' summary of their own results (also quoted from the abstract) is:
  1. That remission of T1D is possible by combining [bone marrow stem cells] transplantation and immunosuppression; 
  2. That [their procedure] represents an effective treatment for selected individuals with T1D; and,
  3. That safer ... therapeutic options [based on bone marrow stem cells] are required.
And I think that's an excellent summary.

Here are some other points that I'd like to make:
  • Of the 65 people reported on, one died of sepsis; obviously, this is the worst adverse effect possible.
  • 34 people experienced adverse effects (65 events in total).  There was no published data on severity of these events.   As an example, the most common adverse event was fever, but there are no notes on how serious or threatening the fever was.  Alopecia was the second most common adverse effect.
  • The earlier in the honeymoon period that a person was treated, the more successful the treatment.
Discussion

There are lots of interesting discussion points in here, and I don't have time or space to go into all of them, but here are a couple:

The researchers believe that a specific type of immune cell, called a CD34+, is critical to success of this technique. Remember that the immune system has many different types of cells, which are often named based on proteins on their outside coating which have these "CD" numbers.  CD34+ is not a cell I have seen specifically "called out" in previous research done in people.  However CD34+ cells are found in umbilical cord blood, which has been used in human research, as well as in bone marrow (as in this trial).

The researchers did measure the long term health of the immune system after treatment, and their summary was "Immune system recovery was rapid and complete".  So they found no evidence of long term weakness in the immune system after this treatment.

What is the future direction of this work?  The researchers discuss two paths for future development of a safer cure based on this work.  The first path is to improve the treatment, by using less immunosuppression at the start, and stronger drugs to prevent infections during treatment.  There are many different immunosuppressive drugs in use, and it may be that a safer drug (or drug combination) can be used in the future.  Similarly, there are many drugs designed to prevent infection by bacteria, viruses, etc.  and it may be that there is a better combination of these drugs available. The second path, is to make the treatment more effective, possibly by increasing the number of CD34+ cells infused back into the patient.

Is this treatment a cure?  That depends on your view of safety.  With a death rate of 1 in 65, I think few people would consider this a cure.  However, if you assume that someone with type-1 diabetes lives (on average) 5 years less than someone without, then in an actuarial (purely mathematical) sense, this treatment does extend average life. This is comparing shaving a few years off of many people's lives vs. cutting a few lives very short.  While this might be a mathematically viable comparison, I don't think it's how most people really think, and certainly not in making decisions about their children.  But of course, research is fueled by hope for the future: what it will grow into, not limited to what it is right now.

Previous Blogging: http://cureresearch4type1diabetes.blogspot.com/search/label/Burt
Abstract: http://diabetes.diabetesjournals.org/content/63/9/3041?etoc

I want to thank the authors of the paper, who provided me with a copy so that I could blog on it.
Normally, this paper is behind a pay wall.

Joshua Levy 
http://cureresearch4type1diabetes.blogspot.com 
publicjoshualevy at gmail dot com 
All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions. My daughter has type-1 diabetes and participates in clinical trials, which might be discussed here. My blog contains a more complete non-conflict of interest statement. Thanks to everyone who helps with the blog.

Saturday, November 29, 2014

Will That Clinic Cure You (Or Your Kid)?

One thing that I am thankful for, is the relative lack of quacks and charlatans in the world of type-1 diabetes.  Sure, we have a few researchers who say "cured in 5 years", and a plague of reporters and bloggers always looking forward to amplify whatever fool thing they say.  But that is very different from the outright fraudsters who are attracted to some other diseases.  We get fewer of those.  This posting describes how to look at doctors and clinics which claim to cure/treat type-1 diabetes and decide for yourself if they are worth your money, time and energy. Although it is targeted specifically at far away clinics (especially stem cell clinics). Most of what I write here will apply very well to other treatments "too good to be true".

Far Away Clinic X Says They Can Cure Type-1 Diabetes! 
Have You Heard Of Them?

Every now and then I get a question about some clinic or doctor who claims to be able to cure type-1 diabetes.  When I get these emails, if I have time, I look into the clinic or doctor.  They are mostly the same, they take stem cells from a person's bone marrow, and then reinject them back into the person.  Although some of them inject other stuff.

The rest of this blog contains four different ways to evaluate a clinic or doctor who claims to cure type-1 diabetes:
  1. Five questions to ask.
  2. Common excuses for not having data.
  3. Danger signs.
  4. How much evidence of safety and effectiveness do they have, and how much do you need?
Five Questions To Ask

Actually, before asking any questions, search the web.  What do the patients say about the clinic? Especially, what do the people who were cured of type-1 diabetes say about the clinic?  Obviously, any clinic that can cure type-1 diabetes is going to have scores of happy customers posting to every internet forum you can imagine.  (Not just one or two, but swarms of them.)  So start by reading posting on the various type-1 forums.  How many of their customers have posted happy results on www.childrenwithdiabetes.com?  How about tudiabetes.org?

I don't know about you, but if my daughter was cured, you couldn't stop me from posting everywhere about it!  I would go out of my way to help by talking to reporters, potential patients, venture capitalists, anyone…..  Nothing would make me happier than to make the discoverer of a cure for type-1 diabetes rich.

Clearly, it is easy to post fake reviews and postings in the web, so happy customer testimonials need to be researched.  (Do they reply to email?  Did they post somewhere besides the clinics' own web page?  Did they post on type-1 forums prior to their cure?)  But if you find nothing, then they obviously haven't cured anyone, or very few people.  

After that, here are the five questions that I would ask of any person or any clinic who says they can cure type-1 diabetes:
  1. Where is your data?  I'll describe how to use this data in the next section.  But if you ask this question, and get excuses rather than data, then it's clear they have nothing.  Remember, everyone who does not have data, will certainly have excuses.   Whatever the excuses, ignore them, but do look at the data they provide.  
  2. Who have you cured?  This is pretty obvious, but in the cases I've seen, the person or clinic has claimed to be able to cure people for a long time, yet doesn't have a bunch of cured people available.  In one case, the guy claimed to have cured over 10,000 people in the last 20 years, yet not one of them had ever posted to a forum or spoken to a reporter.  In another case, a clinic claimed to have used their cure for 15 years, yet again: no forum posts, no interviews with the media, no discussions with potential new patients, no one available. 
  3. What insurance do you take? / What country's medical plans send their type-1 patients to you to be cured?  This might strike you as silly questions, since none of these guys are ever covered by insurance.  But think about it: your insurance company spends thousands of dollars every year treating your type-1 diabetes.  They are going to continue to spend that money for years, maybe decades.  If someone could cure type-1 diabetes, even for $20,000, your insurance company would be overjoyed to pay for it.  Indeed, they would likely force you to go get cured, so they could avoid paying out all the money they do now.  So this is a serious question. Taking it a step further, there are many European countries which have "single payer", or have some form of public health insurance.  In those countries, the minute someone is diagnosed with type-1, the  public health insurance knows they are going to have to pay over $100,000 over that person's life.  In those countries, they would save vast amounts of money by chartering a jet, and shipping all their type-1 patients to this clinic to be cured.  Even if the country were in Scandinavia, and the clinic in Mexico.  So why don't they?
  4. How many type-1 diabetics work for you?  They're all cured, right?  Many people with type-1 diabetes end up working in clinics for people with type-1 diabetes.  So an obvious question is, do you employ any type-1 diabetics, and have you cured them?  After all, type-1 diabetics would flock to employment at a clinic that really could cure type-1 diabetes, both to cure themselves and to cure others. 
  5. What did you do before?  In a certain sense, I don't care what someone did before they cured type-1 diabetes.  If their previous job was sitting under a bridge and eating goats, that's fine with me, as long as they have peer-reviewed data showing that they cured type-1 diabetes. However, in cases where they don't have data, or it is not peer reviewed, then I think it is worthwhile to look into what they have done before.  For example, what if a guy's previous job was "the founder of the 'Essene Order of Light', an offshoot of a New Age religion based upon modern interpretations of the Essenes, an ancient Jewish sect?" (This quote comes from the man's self bio.)  Does that make you nervous? Should it?  And don't laugh about this example, it is a real guy, Dr. Gabriel Cousens, who really claims to be able to cure type-1 diabetes.  
Common Excuses For Not Having Data

Remember, when you ask for data, and the clinic gives you excuses for not having data, my advice is not to consider if the excuses are good or not, because it just doesn't matter.  If they don't have the data, then they don't have the data.  Having an excuse is never a replacement for missing information. But with that in mind, the following excuses are common:

Privacy is a common excuse which you should ignore, for two separate reasons: first of all, you don't want to know people's names, you want to know how they did, so you are not asking for personally identifying information; second, if this clinic has cured people, those people should be overjoyed and excited about others being told about their successes.  Think about it: if a clinic cured your child, and the clinic asked if they could write up your experience as a case study, and even have you talk to future patients, you would say "yes" in a heartbeat, right?  You would want to tell others about this cure.

Another excuse, is that "no one will publish my results showing a cure".  If you get that, say, "No problem!  I'll take a look at your manuscript, I don't care if it is published or not!"  And see what happens.  Obviously, a peer reviewed article would be better, but if they don't have a manuscript, they never even tried to get it published.

A third excuse is "no one will pay for a study to show my treatment works!".  Tell them, that's fine, but you'd still like a summary of how many of their patients were cured, and for how long. No complex study, just the basic data.  And if they don't keep that, what does that say about their follow up with their existing customers?

Danger Signs

In general, I focus on peer-reviewed evidence of effectiveness and safety; the kind that comes from clinical studies.  However, when looking at treatments for my daughter, I don't ignore danger signs associated with fraud.

No matter how much or how little data a clinic has to support their cure, these signs can provide a separate warning that you are getting into trouble.  None of these prove that the clinic or doctor in question is a quack, but I've found that they are suggestive that the treatment is shaky:
  1. Do they use the same treatment to treat different diseases?  Many of these clinics (especially the stem cell clinics) treat all diseases the same.  In some cases the treatment is absolutely identical, treating lung cancer, the exact same way as heart attacks, as type-1 diabetes, as eye problems, etc.  In other cases, the treatment is identical, except that the injection is in a different place. Ask yourself: does that make sense?  Cancers are a large group of related diseases, and they are treated very differently.  So does it make sense for these guys not only to treat all cancers the same, but heart attacks and autoimmune diseases, as well?  For me, it does not.
  2. Any clinic run by, or associated with, any doctor who has lost his license somewhere else.  (If they can cure type-1 diabetes, there is no reason for them to associate with anyone even slightly "shady".) 
  3. Associating their treatment with other, different treatments that are in the news. 
  4. Associating their research with reputable organizations (often Universities), which are actually doing different research.  
For points 3 and 4: Some of the more sophisticated clinics have links on their web pages to studies that supposedly support their ability to cure people. When I have tracked down these studies, I often find that they share only a buzzword or two with whatever the clinic is doing.  So if their marketing literature uses the term "stem cells" then they will have a link to some academic research, which also uses the same term, but otherwise is completely different from what they are doing.

How much evidence of safety and effectiveness do they have, and how much do you need?

The critical question, that you need to answer before you think about a specific clinic or treatment, is how much evidence do you need?  Not just for that one clinic or that one treatment, but for all of them.  For example, the FDA generally requires four clinical trials before they will approve a new treatment.  But that's them, and you are free to choose a different level of evidence, if you want. Maybe you are OK with only two clinical trials?  Or three?  Maybe you want four clinical trials, and two years worth of real world experience, before you will use a new treatment.  These are all reasonable answers to the question.  There is no one universal answer.

Once you have your answer, and you've considered it calmly, and grown comfortable with it.  Then, you need to apply it to these clinics.  In my experience, they have almost no strong evidence that their treatments work.  So even if you have quite low standards (just two peer reviewed papers showing results, for example), they usually can not even make that low bar.  Even if your requirement is "they don't need any published papers at all, I just want to talk to five people who they have cured, one of who I find myself", my guess is that you will not be able to find them.

My experience has been that these clinics are very strong in providing reasons why they have never published papers, why they don't even have the (unpublished) data you want.  Very strong in describing why the FDA, the AMA, the ADA, and everyone else is against them.  But they are very weak in terms of data to support you giving them thousands (sometimes tens of thousands) of dollars. At the end of the day, these kinds of excuses don't even start to suggest that they are actually curing anything.

Finally, I would be very careful about clinics that claim to cure type-1 diabetes, but only provide evidence that they are "helping" type-1 diabetes.  Often these clinics will provide personal testimony from people who say things like "my son's type-1 got much better after the treatment" or "he stopped having lows (or highs or big spikes after meals) after the treatment".  If this is the kind of improvement they advertise, then personal testimonials are the absolute worst way to document it. This is the kind of results where you need to see average BG numbers, or A1c improvements or other hard data that things are getting better.  One of the good things about type-1 as a disease, is that a cure is obvious.  No one can scam a cure.  But "improvements" are easy to scam, so that is what is claimed, then data points are even more important.  (And in reality, if they claim the treatment results in better control, how can they possibly claim that if they don't have specific data showing it?)

In Conclusion

Quack doctors and clinics will always have a good story. They tell you what you most want to hear, and so can be the siren song of hope. Selling cures to people with incurable diseases is a lucrative market for them. So I hope that when you see such cures available, you will ask the questions I discuss here, and think about the data you get in response.


Joshua Levy
http://cureresearch4type1diabetes.blogspot.com
publicjoshualevy at gmail dot com 
All the views expressed here are those of Joshua Levy, and nothing here is official JDRF, JDCA, or Tidepool news, views, policies or opinions. My daughter has type-1 diabetes and participates in clinical trials, which might be discussed here. My blog contains a more complete non-conflict of interest statement. Thanks to everyone who helps with the blog.

Thursday, November 20, 2014

Extra Reading


JDCA "State of the Cure" Update

Each year the JDCA (Juvenile Diabetes Cure Alliance) puts together a summary of cure research.  As a JDCA fellow I contributed information to this effort, although I did not help write the report.  In my opinion, it's a excellent document, well worth reading.  It's only about 15 pages long.  In addition to scientific information on a cure, it also includes information on money: how it's raised, who spends how much, etc.

http://www.thejdca.org/wp-content/uploads/2014/11/SOTC-2014-Final.pdf

JDRF Slide Show On Prevention

This is a great slide show put together by Jessica Dunne who is the Director of Discovery Research for the Juvenile Diabetes Research Foundation.  It is 12 slides.  In addition to material on possible viral and microbiome ("gut") triggers of type-1, it also includes data on growth in type-1 diagnosis, genetics, and so on.

http://www.tudiabetes.org/forum/attachment/download?id=583967%3AUploadedFile%3A3546968


Joshua Levy
http://cureresearch4type1diabetes.blogspot.com 
publicjoshualevy at gmail dot com 
All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions. My daughter has type-1 diabetes and participates in clinical trials, which might be discussed here. My blog contains a more complete non-conflict of interest statement. Thanks to everyone who helps with the blog.

Saturday, November 15, 2014

Artificial Pancreas Update (Nov 2014)

This is a quick update on several artificial pancreas (AP) projects.  The term "artificial pancreas" refers to using a continuous glucose monitor (CGM) to feed data to a computer, which controls an insulin pump, and in some models, a glucagon pump as well.  Artificial pancreas refers to using existing technology in all these areas, but connecting them together so that a person does not need to worry about counting carbs or blood glucose levels.  It is all done automatically.

Medtronic Starts Two Phase-III Trials 

Medtronic is currently the leader in commercial development of an artificial pancreas.  They have already released CGM/pump combination that automatically shuts down insulin injection if blood glucose levels go too low for too long.  This existing technology is very likely to prevent "dead in bed", and it is the first small step towards an artificial pancreas.

The next step will be what's called "predictive shutoff".  While the existing system will only stop insulin when blood glucose levels have already gone too low for too long, the new system will use knowledge of insulin on board and blood glucose trends to cut off insulin before blood glucose levels drop below acceptable levels.  This is a big step forward in terms of keeping people in healthy blood glucose ranges, and it is also a big regulatory step forward.  It means that software will be making changes based on the expected (future) situation, not the known (past) situation.

Medtronic is starting two studies of this feature.  An American study will use 84 people at several different sites, while an international study will have 100.  The American study specifically says it is phase-III, and I suspect the other one is as well, but it doesn't say that specifically.  This would be great news, because a new device needs two phase-III trials before it can be approved for marketing in the United States, and both of these studies hope to finish by December 2014.  I view these studies as an attempt to get to market with a "step 2" artificial pancreas device as described in the diagram below.

The American study has one contact person:
Julie Sekella (818) 5765171 julie.sekella@medtronic.com

For all these locations (not all of which have started recruiting, yet):
  • AMCR Institute, Inc.  Escondido California
  • Stanford University Department of Pediatric Endocrinology, Palo Alto California (Bruce Buckingham)
  • Barbara Davis Center of Childhood Diabetes, Denver Colorado (Satish Garg)
  • Yale University Diabetes Research Program, New Haven Connecticut
  • Atlanta Diabetes Associates, Atlanta Georgia (Bruce Bode)
  • University of Virgina, Charlottesville Virginia (Stacey Anderson)
  • Rainier Clinical Research, Renton Washington (Ronald Brazg)
The international study has these two locations:
  • Schneider Children's Medical Center of Israel, Contact: Moshe Phillip, PhD + 972 3 9253747 mosheph@post.tau.ac.il
  • University of Ljubljana, Faculty of Medicine, Contact: Tadej Battelino, PhD +386 1 5229235 tadej.battelino@mf.uni-lj.si
Clinical Trial Records:
http://clinicaltrials.gov/ct2/show/NCT02130284
http://clinicaltrials.gov/ct2/show/NCT02179281
News: http://www.marketwatch.com/story/medtronic-begins-pivotal-study-of-first-predictive-low-glucose-management-technology-for-people-with-diabetes-2014-10-14?reflink=MW_news_stmp

There is a third clinical trial, which is described here: http://clinicaltrials.gov/ct2/show/NCT02160184 and which is expected to enroll 12 people and finish Feb 2015.  It's not clear to me if it is testing the same predictive shutoff feature as the other two.  It is being run in Spain.  Contact: Mercedes Rigla, MD, PhD +34-93-745-8412 mrigla@tauli.cat

Two of the three studies described here refer to a commercial model number: 640G.  

MD-Logic Update

MD-Logic refers to another group of researchers working on a different artificial pancreas.  This AP is in Step 3 or 4 in the diagram below.  They recently published new data.  People used their artificial pancreas for 6 weeks (night only) in their regular lives.  So they were "out and about".  This was a cross over trial, meaning each person spent 6 weeks using the closed loop and six weeks not.  Half the group used the closed loop first, and half of them used closed loop second.  The results were all very good:
  • Reduced time spent in hypoglycemia 
  • Increased the percentage of time spent in the target range of 70–140 mg/dL 
  • Time spent in substantial hyperglycemia above 240 mg/dL was reduced by a median of 52.2% 
  • Overnight total insulin doses were lower in the closed-loop nights
  • The average daytime glucose levels after closed-loop operation were reduced by a median of 10 mg/dL
Clinical Trial: http://care.diabetesjournals.org/content/37/11/3025?etoc

Interview with JDRF's Dr. Kowalski

This interview has a lot of interesting information about how JDRF and AP research interact:
https://myglu.org/articles/a-pathway-to-an-artificial-pancreas-an-interview-with-jdrf-s-aaron-kowalski

It includes the JDRF "AP Step/Generations" diagram, which is how they think an AP will be developed over time.  You can read more about these steps here:
http://jdrf.org/research/treat/artificial-pancreas-project/

New Artificial Pancreas Project

Another new artificial pancreas project is getting underway at Rensselaer Polytechnic Institute, which you can read about here:
http://news.rpi.edu/content/2014/10/21/1-million-nih-grant-enables-clinical-trials-artificial-pancreas
http://www.meddeviceonline.com/doc/artificial-pancreas-to-begin-clinical-trials-0001
they have not started human trials yet, but it sounds like they will, soon.

Are They Working Together?

One question I get asked about different groups doing similar research is: are they working together?  And usually, I don't know.  However, in the case of Artificial Pancreas research, I know that the different groups are working together, because in some cases, there is overlap among the researchers.  To give you just two examples:
  • Bruce Buckingham is working on the Medtronic clinical trial, the University of Virginia clinical trials, and the planned Rensselaer clinical trial.  Plus algorithms that he worked on were used in the Cambridge AP work.
  • Moshe Phillip is working on both the Medtronic and the MD-Logic clinical trials.
It's clear that the AP groups are not working "in a vacuum".  They are all aware of each others work.

Direct Comparison (Updated)

The chart below is a comparison of all AP projects which I know about that are either in clinical trials, or about to start them.  Some of these projects are not included in this blog posting, but are described in previous postings: http://cureresearch4type1diabetes.blogspot.com/search/label/Artificial%20Pancreas

Group
FDA
Phase
JDRF
Step
Average BG
Estimated A1c
Size
Adolescents?
Duration
AP Use
Boston University
II
6
138
6.4
53
Yes5 days24 Hours/Day
Cambridge
II
3
146
6.7
17
No
8 days24 Hours/Day
MD-Logic
II
3

24
Yes
90 days
Night Only
Virginia
II
3
135?
13
No
2 days
24 Hours/Day

Medtronic
III
2
Just
Started
184
Yes
2 days
24 Hours/Day

Rensselaer
Not
Started



Joshua Levy 
http://cureresearch4type1diabetes.blogspot.com 
publicjoshualevy at gmail dot com
All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions. My daughter has type-1 diabetes and participates in clinical trials, which might be discussed here. My blog contains a more complete non-conflict of interest statement. Thanks to everyone who helps with the blog.