Tuesday, September 1, 2015

Background Information: "Adverse Events" In Clinical Trials

This blog posting applies to all clinical trials, not just those for type-1 diabetes.

I try to avoid using technical jargon when I describe clinical trials.  I think one of the values of this blog is that I turn technical jargon in to plain English.  (I sometimes joke about providing "researcher to patient simultaneous translation", but it's not really a joke.  It's important.)  However, one technical term that I do use is "adverse event".  "Adverse event" generally means "bad side effect".  Serious adverse event generally means "really bad side effect".  But the truth is more complex than this simplified version, and so I thought I would make a post describing exactly what "adverse event" and "serious adverse event" means, because these terms are defined by the US FDA, and their meaning is the same no matter which clinical trial I'm discussing.

The Basics

The basic definition of "adverse event" and "serious adverse event" comes from the US FDA:
http://www.fda.gov/Safety/MedWatch/HowToReport/ucm053087.htm
for lots more details:
http://www.fda.gov/downloads/Drugs/Guidances/ucm073087.pdf
  • An "adverse event" is any bad effect seen in the study.  The FDA uses the term "undesirable experience".  It does not have to be caused by the treatment!
  • A "serious adverse event" is an adverse event that causes death, hospitalization, persistent or significant disability, or a birth defect.  Or one which requires immediate medical attention to prevent one of these outcomes.
For example, a mild allergic reaction would usually be considered an "adverse event", but if the patient had trouble breathing, that would be a "serious adverse event".

The First Complexity: How Bad Is Serious?

No matter how many rules the FDA makes, and how many documents it publishes, there will always be room for researchers to interpret a specific events as serious or not.  Therefore, there will always be controversies about it.

For example, in one Chronic Fatigue Study there was controversy because several adverse events required patients to go to a clinic (but not a hospital).  Now hospitalization clearly means serious, but the company producing the drug felt that going to a clinic was not a sign of a serious adverse event. When the FDA reviewed the study, they disagreed, and the the larger number of serious adverse events the FDA counted were part of the reason the drug was not approved.

The Second Complexity: Treatment Related Or Not?

In general, researchers are required to track all adverse events, no matter what their cause. The FDA terminology is "associated with" not "caused by". After all, these are experimental treatments and some of the bad side effects might be unexpected. I've seen a trial for an immune system drug, which listed one serious adverse event: a broken arm. Now, I don't think that broken arm had anything to do with the immune treatment being tested.  But it is still a serious adverse event, and must be reported.
A more complex situation is adverse events associated with the disease being treated.  For example, if you are testing a drug for depression, and someone in the study commits suicide, that is clearly a serious adverse event, but is it treatment related?  How would anyone ever know?

This whole area is usually resolved by comparing adverse event rates between the control group and the treated group.  If there are statistically significantly more adverse events in the treated group as compared to the control group, that is the important result.  Arguing that some of these adverse events are not "treatment related" much less important. More adverse events is bad, no matter if the researchers think they are not related to treatment.  But what about those phase-I trials that don't have control groups?  For those trials, arguing about "treatment related" can be important.

The Third Complexity:  Who Decides?

Someone goes through every event and decides if it is serious or not.  The same is true for "treatment related" if that is reported separately. Obviously, this is a human activity and the results will be imperfect, but the exact procedure used can minimize (or maximize) risk of bias.  The two things to look for are blinding and reviewers.

The review can be done "blind" or not "blind".   The reviewer looks at the event, and maybe some data about the person who had the event, but does not know if the person is in the control group or the treated group (or what dose the person got, if multiple doses were tested).  But if the reviewer knows that the event occurred in the control group or the treated group, the risk of bias is more pronounced.  If the study doesn't have a control group, then this review will never be blind.

The reviewing is usually done by the same researchers running the trial. However, it can be done by a different group of doctors, recruited especially for that purpose.  Having a different group lowers the risk of bias, and this is done for some particularly controversial or emotional trials.

Some Discussion and Opinions

Overall, I think we are lucky in the world of type-1 diabetes research, in that the reporting of adverse events is generally not complex or controversial.  Type-1 diabetics are generally pretty healthy, and also the bad complications of type-1 diabetes are generally well understood.  Therefore, there is consensus as to the types of adverse events that are likely related to treatment, and those that are not.

Especially in larger clinical trials, serious adverse events will happen.  So the important thing to look at is: Were there more serious adverse events in the treated group than in the control group?  Also, if multiple different doses were given to different groups of people, do the higher dosed groups see more serious adverse events, or are they randomly spread throughout all the dosing groups?

Since all adverse events must be reported, it is important to consider the impact of different adverse events as compared to the disease being treated.  For example, rashes or mild fevers are common adverse events (not serious ones). Compared to curing type-1 diabetes, these might be well worth it.  On the other hand, in a drug which merely treats type-1, the very same adverse event might cause you to use a different drug.

Because the long term outcomes of type-1 diabetes is relatively well known, it's easy for patients to "trade off" the adverse events seen in testing a cure, to the long term complications of having type-1 diabetes.

One problem in the whole approval process is the issue of very rare side effects, especially those which happen rarely in healthy, untreated people. Take the following situation, you treat 300 basically healthy, basically young, people with a drug. One of them has a stroke. That's a serious side effect. But it is something that happens -- although very rarely -- in young people who are not taking the drug. With 300 people you may not have the statistical power to know if it is a statistically significant event. Are you going to delay availability and require a larger (and very expensive) study just to eliminate the statistical chance that the drug causes stroke? Or maybe approve the drug, but require a strong (ie. "black box") warning about stroke? Or just decide that it was random bad luck, and approve the drug?
(The situation is much worse with diseases like type-2 diabetes.  Was that stroke caused by type-2 diabetes, or the drug given to treat the type-2 diabetes?)

In a sense, the FDA cannot win in these cases, because no matter which outcome they choose, some people will want the other one.  So if the drug is delayed, some patients (and the company involved) will scream loudly about delaying needed treatments and creating unnecessary hurdles to drug approval.  On the other hand, if the drug is approved, another group of patients (and consumer advocates) will yell about approving dangerous drugs so big pharma can profit.  If the drug is given to 10,000 and one of them has a stroke (by chance? or because of the drug?) then recriminations will be deafening.


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.

Wednesday, August 19, 2015

Research In The News (August)

This blog posting contains bits and pieces of news on type-1 diabetes research aimed at a cure.

The Phase-II Trial of Secukinumab Was Terminated

The phase-II clinical trial of Secukinumab was canceled in June 2014. I have not seen any public notification about why it was canceled. Apparently five people were dosed before it stopped, but I have no idea if any results will be published or not.  This trial was being run by Novartis.

You can read my previous blogging on this trial here:
http://cureresearch4type1diabetes.blogspot.com/2014/05/secukinumab-and-ustekinumab-each-start.html

Reporting: http://webcache.googleusercontent.com/search?q=cache:-Iu_s9VcSmwJ:adisinsight.springer.com/drugs/800023920+&cd=1&hl=en&ct=clnk&gl=us
Clinical Trial Record: https://clinicaltrials.gov/ct2/show/NCT02044848


Phase-II Trial of BCG By Faustman Starts Recruiting

I made a big announcement when Dr. Faustman announced she was ready to start her phase-II trial. However it took over a year to actually start recruiting patients.  The blog I wrote previously is still accurate (except as described below), so If you want to know what is going on with BCG, I'd start out by reading my previous blog:
http://cureresearch4type1diabetes.blogspot.com/2014/04/dr-faustman-starts-phase-ii-trial-for.html
and then consider the following updates in the last year:

First the good news: it will include 150 patients, rather than 120 as before.

Second, the bad news: the delay means the study will complete in 2023 rather than 2022 as before (which means publication in 2024 is a reasonable goal).

Third, a change in primary outcome.  The study as I read it now, is going to have A1c measurement as it's primary end point, and C-peptide measurement as a secondary end point.  Previously, I had thought that both would be primary end points, but I might have just misread the clinical trial registration.

However, no matter which is primary and which is secondary, the important end point is the C-peptide numbers, not the A1c numbers.  For cure research, C-peptide is a much better measure of success than A1c.  C-peptide is what the FDA requires for cures, and that is what measures how much insulin your body is creating itself. A1c, on the other hand, is a good measure for type-1 treatments.  So in this case, in 2024, when we are looking at the results, it will be the C-peptide results that matter.

I don't see that there are any other major changes from a year ago: no change to dosing regimen and no change to duration.

Press Release: http://www.eurekalert.org/pub_releases/2015-06/mgh-mgh060315.phpClinical Trials Record: http://clinicaltrials.gov/ct2/show/NCT02081326

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.

Sunday, July 19, 2015

Artificial Pancreas Updates From ADA (July 2015)


In my opinion, artificial pancreas (AP) technology was the single most important technology of the American Diabetes Association Scientific Sessions this year.  There were many papers, posters, and presentations on artificial pancreases and related technologies (such as continuous glucose monitoring, stable glucagon, etc.)  Nothing generated more Twitter buzz.

This blog posting attempts to summarize a little of the research presented.  There was way too much for me to cover it all, and so this posting gives light coverage to the most important news.

My overall summary is that we are no longer talking about if there will be an AP.  The question is: when there will be an AP, and how many APs, and how many different types of technology they will use.  I continue to be heartened by:
(a) the progress made by AP research projects over the last few months (and years)
(b) the large number of new companies entering the field
(c) the product roadmap announced by Medtronic as they move their existing partial AP to a full AP.

The AP world is more and more driven by commercial considerations, rather than research considerations, and that is a strong signal that we are close to general availability.  (Close meaning years, but not too many of them.)

This tweet summarizes my thoughts, as well:
“Closing the loop is no longer a mystery; it’s not a puzzle. We just have to do it.” 
https://twitter.com/eliotmbrenner/status/607536971192377344

Second Bi-Hormonal Artificial Pancreas In Development

I recently found out about a second bihormonal AP  (in addition to Dr.  Ed Damiano's).  These researchers are in The Netherlands, and you can read more about it here:

http://www.inredadiabetic.nl/diabetes-product-ontwikkeling/
http://www.inredadiabetic.nl/us/history/
http://www.inredadiabetic.nl/news/

It's a little hard for me to figure out exactly where they are, and I have not found any articles in scientific journals.  However, it appears that earlier this year they ran a two day test on one person, and got quite good results.  The average BG was 125.  Based on that they are hoping to run two clinical trials (called APPEL 4 and APPEL 5) later this year.  They hope those trials will used as the basis for European "CE" approval.

Maybe a Third?

They haven't started recruiting yet, but this looks like a phase-II trial for yet a third bi-hormonal artificial pancreas.  I'll blog more fully if they start recruiting:

https://clinicaltrials.gov/ct2/show/NCT02379299

Back To Ed Damiano's Bi-Hormonal Artificial Pancreas

Not from ADA, but from another conference, comes this summary of Ed Damino's current status:
http://www.medpagetoday.com/MeetingCoverage/AACE/51551?xid=nl_mpt_DHE_2015-05-16&eun=g118127d0r

But if you want a summary in 140 characters, here it is, from
https://twitter.com/DiabetesMine/status/607298177952321537:
Damiano says #BionicPancreas showing ave BGs of 135-142, which would equate to 6.5% A1C.
[What's not to like!]

Plus there was this good news tweet:
From https://twitter.com/InsulinNation/status/607300794875002882:
Ed Damiano says there is room temperature stable glucagon that stays good for up to a year. Needs FDA approval.

Medtronic's 670G

The Medtronic 670G, as announced, will be an "all but meals" style, single hormone artificial pancreas, available in the United States in April 2017.  As far as I know it is the most powerful AP with a clear commercial delivery date.  For comparison, the 640G is already available in Europe, but does not prevent "highs," only "lows".

diaTribe interviewed a patient who has used the 670G as part of a clinical trial:
http://diatribe.org/medtronic-minimed-670g-hybrid-closed-loop-exclusive-interview-17-year-old-trial-participant

This is Medtronic's press release summary of results from a 640G study, a 670G study, and some other research they presented at ADA:
http://finance.yahoo.com/news/medtronic-accelerates-path-artificial-pancreas-140201655.html
The current plan is for the 640G to be available next year, and the 670G the year after.

This news resulted in the following tweets (and many more, of course):
https://twitter.com/DiabetesMine/status/607197166193508353
https://twitter.com/DiabetesMine/status/607198339600392192

More General AP News

The following, more cautionary tweets report on other aspects of AP research:

From https://twitter.com/InsulinNation/status/607284169622880256:
During artificial pancreas study, the AP couldn't be used 1 in 3 nights because of tech issues (sensors) or family/health issues.[But I don't know which AP this tweet is about!]

From https://twitter.com/DiabetesMine/status/607284048931770368:
CDE Laurel Messer: Still enough tech issues exist with CGM sensors to impact hoe [sic, should be "how"] closed loop is used in kids and young adults.
From https://twitter.com/InsulinNation/status/607278840193400832:
Predictive pump technology significantly reduced nighttime lows in kids in almost 1000 night study. [But again: I don't know what AP this refers to!]

The following link goes to a summary of one of the ADA sessions:
http://www.saluteh24.com/il_weblog_di_antonio/2015/06/artificial-pancreas-moving-toward-pediatric-use-2015ada-meeting-in-boston.html

Personal testimonial (with graph) of how well an AP works, but I don't know which one!  Anyone recognize the screen?
https://twitter.com/DiabeticSisters/status/607709090278699008

Bigfoot Explodes Big  (In a Good Way!)

Bigfoot is a one year old company.   They had a very successful ADA and generated a lot of "buzz", which this tweet tries to summarize.
From https://twitter.com/diaTribeNews/status/604309757093011456:
@BigfootBiomed acquires Asante pumps! Goal to enter pivotal trial of full #artificialpancreas system late 2016

A "pivotal" trial is industry-speak for a phase-III clinical trial.  What they are saying is that they hope to start phase-III trials of an AP next year.  That would put them shoulder to shoulder with Medtronic and front running bihormonal research projects.  Even if they are overly optimistic, and they actually start those tests in 2017, they are still not that far away from a commercial AP.

But even more promising (to me) is that Bigfoot feels like a tech start up, not a medical device company. It feels like Silicon Valley rather than Washington D.C.  I can't tell if that's a marketing strategy or the truth, but if you look at the founders, look at the tactics (reuse the failed carcass of another project), and the strategy: it really does look like the way things happen "out here".

When a company like that can successfully create an AP, it means that APs are technology gizmos, and not medical devices, and technology products can improve much more quickly than medical products.  I'm sure the FDA will have something to say about it, but even if Bigfoot is just a 20% step in the direction of Silicon Valley, that's going to "light a fire underneath" some medical device companies.

The following link goes to one diaTribe story, but that story has links to other stories, and you can get the whole saga of how big they've grown, how quickly, and how important that might be:
http://diatribe.org/bigfoot-biomedical-acquires-asante-snap-pump-technology

TypeZero: Yet Another New Company Focused On A Single Hormone AP 

And if that were not enough, TypeZero Technologies is yet another new company trying to create a single hormone AP "from scratch".  DiabetesMine has a summary article:
http://www.healthline.com/diabetesmine/typezero-tech-closed-loop-commercialization

This is based on AP research done at the University of Virginia which I have reported on before.

Comparison

There was some debate at ADA about which was better: single hormone artificial pancreases, or bihormonal artificial pancreases.  My first reaction to this debate was this: who cares?  Either one is so much better than what we have now, let the people who like insulin only APs develop those, and let the people who like insulin and glucagon APs develop those, and let the market decide, or maybe let the market decide that there is room for more than one AP technology.  I mean some people have cable while others have satellite, why not the same with APs?  Have we learned nothing from the death of communism?  Let the market decide, as fed by the strongest proponents of each system.

My second reaction to this debate was that it can never be resolved by research. The data we have now is pretty clear: single hormone APs result in average BG numbers about 10 points higher than dual hormone APs  (for example mid 130s vs mid 140s).  However, dual hormone APs are more complex to manufacture, more complex to operate, and involve the tiny risk of long term, very low dose glucagon (and that risk is unknown, and will remain unknown for years).  So some people are going to say dual hormone is 10 points better than single hormone, end of story.  But others will say, mucking about with refilling two reservoirs is just not worth 10 points.  And neither of these opinions is right or wrong, they are just different.  And always will be.

However, even if research cannot answer a question, it can still inform the discussion, and there have been some papers directly comparing the two systems. The following tweet is one summary, but the links to the abstracts below contain more data.

From https://twitter.com/sarhoward/status/608301471529107457:
Haidar: Both single and dual hormone artificial pancreases better than pump for BG control at night, dual better for reducing hypos

http://www.thelancet.com/journals/landia/article/PIIS2213-8587(15)00141-2/abstract
http://www.thelancet.com/journals/landia/article/PIIS2213-8587(14)70226-8/abstract


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, July 4, 2015

News from ADA 2015

The American Diabetes Association's annual conference is the largest scientific gathering covering diabetes in the United States.  Even though most of the conference is aimed at type-2 diabetes, the part covering type-1 diabetes is still overwhelming.  About 18,500 people attended this year.

I was not able to go this year (it was in Boston), so I tried an experiment.  I closely followed tweets and news coverage of the convention.  I thought of myself as a wire service and the tweeters/bloggers/reporters at the conference as my freelancers.  I was reading about 1000 tweets a day from the following sources: #2015ADA, #ADA2015, @diaTribeNews, @DiabetesMine, @sarhoward, @AmyDBMine, and @kellyclose.

I'm going to summarize these in two postings.  This posting has four sections: an overview, research in people aimed at a cure, research which has cured mice, and non-cure related research. The next posting will cover artificial pancreas research. There was a lot.

ADA includes a sea of expert opinions, but also the results of many experiments.  So it is especially important to remember these words by Robert H. Mathies  (Often incorrectly attributed to von Braun):

"One experiment is worth a thousand expert opinions"

Overview

You can read the abstract to every poster session at the link below, and most of them have a PDF of the poster itself:
http://ada.apprisor.org/epsSearchADA.cfm
Although the posters are easy to search, I cannot set up a link to one once I find it.  So I have put in the poster number (like 1234-P  or 42-LB).  Go to the link above and search for the number to find the abstract and the poster itself, when it's on line.

The following search page can get you to abstracts for many presentations, but I found it very hard to use:
http://www.abstractsonline.com/pp8/#!/3699
http://app.core-apps.com/tristar_ada15

The link below is a summary of the conference by Insulin Nation.  Some of it is reporter-insider snark, but other points are quite good.  The useful and the useless are mixed together:
http://insulinnation.com/living/random-observations-from-the-ada-scientific-sessions/
P.S. The answer to 41 is "brown fat".

The link below is someone else's summary of the conference.  I completely disagree with the headline, but the section on type-1 research is a good summary.  You'll notice that only one of the possible cures they mention are in human trials now.  (Unless you consider AP or transplantation to be cures.)
http://www.bioworld.com/content/hope-seen-type-1-diabetes-fix-obesity-still-clouds-type-2-outlook

Below is a link to Sarah Howard's summary.  She follows possible environmental causes for both types of diabetes, so she focuses on different parts of the conference than I would:
https://ourhealthandenvironment.wordpress.com/2015/06/12/an-environmental-perspective-of-the-american-diabetes-associations-75th-scientific-sessions/

A big theme of the conference seemed to be treating patients rather than numbers, and generally emphasizing holistic care, and looking at more complex (and realistic) measures of health, than single numbers.  For me, this was typified by the following tweet which I saw repeated several times:  "A three-month average cannot tell the full story."  I think the tweet originated with @kellyclose (diaTribe), but I'm not sure.

Research On Potential Cures In Human Trials

I expect to blog on each of these trials in the coming months.

Fastuman Starts a Phase-II Trial Off BCG
Here's the press release:
http://www.eurekalert.org/pub_releases/2015-06/mgh-mgh060315.php
https://twitter.com/BostonBiotechRL/status/607653887676456960

Obviously, this is big news, and I'll blog about it in the next few months. But in the meantime, you can read my last blog on her BCG research:
http://cureresearch4type1diabetes.blogspot.com/2014/04/dr-faustman-starts-phase-ii-trial-for.html
The new news is that the trial is actually recruiting patients now.  Any updated details will be in my new blog.

ViaCyte's Phase-I Trial is 1/10th Enrolled
JDRF sent out this update on ViaCyte's Phase-I clinical trial:
There are as many as 4 people in SoCal currently testing @ViaCyte's experimental devices. That's progress.
https://twitter.com/JDRF/status/606910609695735808
The trial plans to enroll 40 people, so it sounds like they are 1/10th of the way there (depending on exactly what "as many as" really means).

1102-P: Immune Modulation of Stem Cell Educator Therapy in Caucasian Type 1 Diabetic Subjects
This poster contained information from the Phase-II trial of the Stem Cell Educator currently running in Spain.  I will blog more on this later, but for me, this poster had a "split personality".  On the one hand it was reporting on good changes to the immune system in people who got the treatment.  More good immune cells; less bad ones.  It looks like good news: the Educator is changing the immune system for the better.   On the other hand, there is none of the patient-focused data that would show progress to curing type-1 diabetes.  No data on C-peptide production; no improvements to A1c; no changes reported in insulin use.  (And the phase-I trial did have this kind of data.  So I'm not sure if this poster just focused on the immunology details, and a future paper will include C-peptide data, or if the C-peptide data in this second trial was not worth reporting.)

1099-P and 102-LB: Effect of Cell-Free Mesenchymal Stem Cells Microvesicles (MVs) and Exosomes Therapy on ß-Cell Mass in Type 1 Diabetes Mellitus (T1DM)
As far as I can tell, these two posters were identical, except that the LB poster only listed one author, and included the clinical trial registration number.
Patients were given stem cells (source not described), and compared to a control group.  Results were good:  HbA1c (6.67 ± 0.321 at 12 weeks vs. 8.245 ± 0.72 at baseline), fasting C-peptide levels (1.095 ± 0.215 at 12 weeks vs. 0.245 ± 0.069 at baseline) and C-peptide response following a 75-g oral glucose tolerance test (1.817 ± 0.27 at 12 weeks vs. 0.504 ± 0.065 at baseline).   To me, this looks like it is well worth a follow up.

Transplantation Work
So far with Edmonton protocol of islet Tx, 58% insulin free (need immunosupression), 92% have C-peptide after 7 years.  But those people will need to take immunosuppressives for the rest of their life.
https://twitter.com/KellyRawlings/status/607996263599079424

Cured in Mice

Random quote from Richard Asher: "despair is best treated with hope not dope"
https://twitter.com/GoDiabetesMD/status/607974101349765121

Poster 1812-P:
A new peptide (small protein like chemical), called KGYY15 is a honeymoon cure of type-1 diabetes in NOD mice.

Poster 1804-P:
Amylin Induces CD4+CD25+Foxp3+ Regulatory T Cells
Amalyin is a hormone given to type-2 diabetics, but there is some research to show that it would also help type-1 diabetics maintain better BG and A1C numbers.  This poster reports that it also increases the number of a specific type of helpful T cell.  This work is related to human trials, because at least two groups are "growing out" CD4+CD25+ T cells in the hopes that they will be a honeymoon cure to type-1 diabetes. Obviously, if Amylin has the same effect in people as these researchers found in mice, and if the researchers "growing out" these cells in people get a good result, that's good all around.

Using Th17 to prevent type-1 diabetes in mice:
http://www.sciencedaily.com/releases/2015/06/150607214213.htm

Poster 1818-P: Local Expression of CCL21 in Pancreatic Islets Prevents Autoimmune Diabetes in Mice and Is Associated with Beta Cell Antigen-Expressing Lymphoid Stromal Cells
The poster was not on line, but the abstract was.  CCL21 (another small protein) prevented type-1 diabetes in NOD mice.

Poster 1826-P:
Prevention or Early Cure of Type 1 Diabetes by Intranasal Administration of Gliadin in NOD Mice
The poster was not on line, but the abstract was.

Poster 218-LB:
Nasal Administration of Novel Insulin Degrading Enzyme Inhibitor Ameliorates Autoimmunity in [NOD mice]
The poster was not on line, but the abstract was.

For those keeping track, that is six mouse cures presented at one scientific meeting.  For me, the interesting point will be: how many eventually get into human trials.  One?  None?  Only time will tell.

Non-Cure Research, But Interesting To Me

FDA Bullshit
This tweet really angered me:
Stayce Beck of @US_FDA calls out companies for not including kids in pediatric studies, says it's opposite of what agency wants.
https://twitter.com/DiabetesMine/status/607291226597883904
This is completely two-faced, as far as I'm concerned.  Every researcher I interact with wants to have more kids involved in their studies.  Especially for honeymoon research, there are just so many more kids around.  But they can't because the FDA has specific regulations which prevent it!  It's the FDA who is creating and enforcing unreasonable limitations, and to turn around and "blame the victim" is scummy.  And the FDA's policies on kids in research does victimize researchers (as well as children) because it really slows down research and at the same time limits approved options for treating kids.

(I don't think I've ever sworn on this blog before, but this quote -- if true, and if really said by an FDA employee -- really deserves it.   I'm proud to say:  I call bullshit on that!)

Type-1 vs. LADA
There were several posters and papers which reported on differences between people diagnosed with type-1 as kids, and those diagnosed with it as adults.  Some researchers consider these to be the same disease with slightly different natural histories (sort of like chickenpox vs. shingles) while others consider these two to be two different diseases (with different causes or "etiologies"). All of the following posters described differences in early onset type-1 diabetes and late onset type-1 diabetes:
Poster 1801-P: Heterogeneity in Type 1 Diabetics Is Defined by Contrasting C-Peptide Declines, Autoreactive T Cell Burdens, and Metabolomic Differences
Poster 1819-P: IGRP-specific CD4+ T Cell Response Is Distinct between Adult-Onset and Juvenile-Onset Type 1 Diabetes Patients
Poster 212-LB: Anti-paralemmin 2 Antibody as a Novel Antibody for Latent Autoimmune Diabetes in Adults
Poster 1723-P: Determinants and Prognosis of Early- vs. Late-Onset Islet Autoimmunity

Poster 1737-P:
Ecological Study between the Incidence of Type 1 Diabetes and Geochemical Data in Sardinia: Negative Correlation with Zinc and Copper
Sardina has a high rate of type-1 diabetes, and the rate is not the same throughout the island, so these researchers tried to correlate various heavy metals in the environment to the higher type-1 rates in the same areas.  Higher levels of Zinc and Copper were found to protect people from type-1 (ie. higher levels of these metals correlated with lower levels of type-1), and no correlation was found for the rest of the metals they researched.  Here are the metals they checked: As, Be, Cd, Co, Cr, Cu, Mn, Ni, Pb, Sb, Se, Sn, Th, Tl, U, V, Zn.
https://twitter.com/sarhoward/status/607251283796443136

1732-P:
Unexpected Stability of Type 1 Diabetes Incidence in a U.S. Cohort, 1994-2010
Basically, they found a type-1 rate of about 1 in a 1000 (lower than expected) and found that this number was going up before 2002, but going down after that.  That's not the common wisdom.  Most researchers think the type-1 rate is steadily going up.

For the opposite viewpoint: 1735-P:
The Incidence of Type 1 Diabetes Mellitus in Romanian Children Aged 0-14 Years Increased Constantly
(No poster, but a very nice graph in the abstract.)  This is the opposite finding as the previous poster, but this is the conventional wisdom about what is happening.  The two posters covered different geographical areas.

978-P:
Dance-501 Inhaled Human Insulin
Research results from another inhaled insulin.  Phase-I trial, 24 people, type-2 diabetics.  Affrezza might have competition someday, and that can only be good, in terms of more choices for type-1s.

Big claim by Dr. Dandona: “Predict w/ this 3x therapy (insulin, GLP-1, SGLT-2) we can get at least 50% of #T1D patients [below] 6% A1c"
If he is right (and that is a big "if"!) this will be a big change in the treatment of type-1 patients. Right now, insulin-only treatment is normal, and A1Cs are rarely this low.  GLP-1 is widely used in type-2, but not widely used in type-1.  In my opinion, the results of the GLP-1 in type-1 studies that we do have, show some improvement, but not a lot. SGLT-2 is even farther away from type-1 use, as there is even less research.  But again, in my opinion, the improvements that have been seen are real (in early testing) but not dramatic.  However, this doctor thinks that by combining these two treatments, we can lower A1c between 1 and 2 points;  that would be great, if it were true, and if type-1s were willing and it was safe to take both drugs for the rest of their lives.
https://twitter.com/diaTribeNews/status/607664169408733184

In large Dexcom-funded analysis, CGM users had a 42% lower hospital admission rate and 17% lower ER ad. rate over non-CGM users.
https://twitter.com/InsulinNation/status/607544997785817088

“Preprandial Oral Insulin (ORMD-0801) Reduces Rapid-Acting Insulin Requirements and Fasting Glucose Levels in T1DM Patients”
https://twitter.com/CureT1Diabetes/status/607670142785323008

Some things are more scary than others:
Studies of diabetes blogs don't show discussion of complications but more near term issues like nighttime hypoglycemia
https://twitter.com/joyclee/status/607166577407098881

If you got all the way down here, you deserve a laugh:
http://www.healthline.com/diabetesmine/sunday-funnies-2015a#6
which came from this tweet:
https://twitter.com/DiabetesMine/status/607535486995800064

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.

Tuesday, May 26, 2015

Mesenchymal Stromal Cell Results From a Phase-I Trial


Mesenchymal Stromal Cells (MSC) are the stem cells in your bone marrow.  Stems cells can grow into beta cells, and some researchers think they can modulate the immune system (they generate one or more chemicals that cause the immune system to stop attacking beta cells).  So it's possible that stem cells might resolve both cure issues at once.  They might be able to regenerate beta cells and stop the autoimmune attack.  That is what these researchers hope.

Results From a Phase-I Trial

These researchers, at Uppsala University Hospital in Sweden, ran a phase-I trial, randomized and with a control group, but not blinded.  There were 10 people in the treated group, and 10 in the control group.  MSCs were harvested from a patient, treated externally, and then put back in that same patient.  No immunosuppression was used, and I don't think the people were ever hospitalized (the work was done in a clinic).  Data was collected on insulin usage, A1c, fasting C-peptide, and post meal C-peptide, among other measures.

Fasting C-peptide measures how much insulin your body is generating as background. It's measured while fasting, usually first thing in the morning.  This is your natural basal insulin. Post meal C-peptide measures how much insulin your body is generating in response to carbohydrates.  It's measured after eating a meal with a known carbohydrate content. This is a body's natural insulin bolus.

My summary of the results are as follows. In all cases the paper is comparing data measured 10 weeks after the treatment (which the paper considers starting or baseline data) to data measured 1 year after treatment (which the paper considers resulting data):
  1. Fasting C-peptide, A1c, and insulin usage did not significantly change for either group, and there was no significant differences between the groups.
  2. Post meal C-peptide levels for the untreated group dropped about 12%.  Dropping is bad, but it's also normal during the honeymoon phase.  In the treated group, C-peptide numbers rose 5-10%, and that represents improvement.  The difference between the two groups was statistically significant.
  3. There were no safety issues.
Discussion and Opinions

Confirming that the procedure was safe is a good thing, of course, and is the official goal of a phase-I trial.  But this is a procedure that's been done for decades to treat other diseases (especially cancer), so no surprise that it is safe.

I was a little surprised at how consistent the insulin usage, A1c numbers, and fasting C-peptide numbers were.  I assumed that A1c would still be high from diagnosis and would drop, and that insulin usage would rise to the end of the honeymoon, and that fasting C-peptide would drop.  None of that happened during the course of the honeymoon.

The important results are the post meal C-peptides.  For this data, higher numbers are good, because they mean the body is generating more of it's own insulin.  In untreated people those numbers dropped about 15%, which is normal for the first year after diagnosis.  The treated people saw a rise in their C-peptide.  There is no doubt that is good news, but it did not have an impact on the treated people. Specifically, they were still injecting the same amount of insulin, and their A1Cs did not improve.  So it's a small effect.

My memory is that I've seen this level of result several times, for several different drugs, over the last two years or so.  I think I was much more excited about them in the past.  Part of my lack of excitement is that the treatments with these results that I saw a few years ago have not progressed. They don't give better results in more recent studies.  That might be because the research is taking longer than expected, or it might be that getting a small result is much easier than getting a useful (to patients) result.  But in any case: I haven't seen forward progress in other treatments with similar initial results, so I've become less excited about these kinds of results, in general.

So in general, these results go in my "good start, but more is needed" category of results.

This study was published on line Sept-2014 and on paper in Jan-2015:
http://diabetes.diabetesjournals.org/content/early/2014/09/05/db14-0656?papetoc
http://diabetes.diabetesjournals.org/content/64/2/587?etoc

Clinical trial record: https://clinicaltrials.gov/ct2/show/NCT01068951

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.

Friday, May 8, 2015

Artificial Pancreas Update (May 2015)

I have decided, for 2015 at least, to do quarterly updates for Artificial Pancreas research. The area is moving forward so quickly that I think that quarterly updates are warranted.

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. Most people do not consider this a cure, but I follow AP research because some people do consider it a cure.  There is no doubt that such technology would be a huge step forward in treatment, and would largely prevent "dead in bed" due to low blood glucose events.

An earlier version of this blog had the wrong dates for future Medtronic product releases.  I'm sorry about that.  This posting has the correct dates.  Thanks to Tamar Sofer-Geri for finding the mistake.

Artificial Pancreas Update for April 2015

The JDRF uses a 6 step model to describe milestones on the way to the fully featured artificial pancreas that we all want.  You can read about those milestones here: http://jdrf.org/research/treat/artificial-pancreas-project/.
So when I refer to "step 1" and "step 4" and so on in this blog, I'm referring to the steps described by JDRF.

Corporate News from Medtronic

Back in January, Medtronic made the following product announcements:
  • The 640G (predictive low glucose suspend) will ship in Europe in April 2015.
  • The 640G will ship in the United States in April 2016.
  • The 670G will ship in the United States in April 2017.
  • The 670G will ship in Europe in April 2018.
News (from Close Concerns / diaTribe): https://www.closeconcerns.com/knowledgebase/r/ce9abf26

There are three pieces of good news included in those predictions.

First, the 640G is a step 2 Artificial Pancreas, so it will predict and avoid low blood glucose events.

Second, the 670G (depending on exactly how it turns out) could be a step 3 or 4 device.  That means it will predict and avoid both low BGs and high BGs, but not cover meals automatically.

Third, it means that Medtronics believes that the FDA's previous approval delays will stop:

  • There was a 2.5 year delay (from European approval to US approval) for the 530G.
  • Medtronics expects a 1 year delay for the 640G.
  • Medtronics expects a 1 year advantage (US before Europe) for the 670G.

I hope they are right about this!  FDA's delays in earlier AP approvals are one of the major reasons AP development has been slow, and European availability is ahead of us. If the FDA is able to fix this problem over the next few years, that is a huge piece of good news for all AP companies and ultimately, all AP users.

MD-Logic Goes Commercial

MD-Logic is one of the artificial pancreas projects which has been in phase-II clinical trials.  I previously blogged on it in Nov-2014: http://cureresearch4type1diabetes.blogspot.com/2014/11/artificial-pancreas-update.html
In the past, it has been a research project, but a company called DreaMed Diabetes was founded to commercialize it, and they recently signed an agreement with Medtronic.  According to diaTribe:
http://diatribe.org/medtronic-signs-exclusive-agreement-use-glucositter-artificial-pancreas-software-future-insulin
Medtronic plans to use this technology in their artificial pancreases after the 670G.  The 670G will be a step 4 AP (automatic except for meals), while the MD-Logic based follow on will be a step 5 AP (automatic including meals).

Also, MD-Logic's blood glucose control algorithm got a "CE" mark in Europe (which is their "approval to sell" symbol).  You can read about it here:
http://www.diabetesincontrol.com/articles/diabetes-news/17774-artificial-pancreas-software-algorithm-receives-approval-in-europe-
However, I'm not sure what that means from a practical point of view.  You cannot use an algorithm by itself.  It has to be part of a piece of software or hardware, and right now no one is selling any product which uses the algorithm.  Maybe this CE mark will speed Medtronic's approval in Europe when the time comes?

Artificial Pancreas News From Tandem (makers of t:slim)

I slogged through a Tandem analyst's call in Feburary, which you can read here:
http://seekingalpha.com/article/2946926-tandems-tndm-ceo-kim-blickenstaff-on-q4-2014-results-earnings-call-transcript?part=single

There are only a few paragraphs on AP research, and my rough translation of them is this:

Tandem is currently experimenting internally, and not on people, with both predictive low glucose suspend (step 2 AP) and predictive high glucose dosing (step 3 AP).  In the second half of 2015 they will start the paperwork to run a clinical trial testing predictive low glucose suspend.  Based on discussions with the FDA at that time, they will have  better idea of how many clinical trials will be required for approval (and therefore how long it will take).  Also they will have a better idea about testing both the predictive low suspend and high dosing at the same time, or release one and then the other.

Bihormonal AP Update from CarbDM's Diabetes Summit

I attended CarbDM's "Diabetes Summit" in Silicon Valley last month.  It was wonderful, even though I could not stay to the end.  Listening to the morning speakers was very informative, but in this blog I'm going to limit myself to discussing  Dr. Ed Damiano's talk.

Dr. Damiano is working on a bihormonal (insulin and glucagon) AP, called the "Bionic Pancreas". The key piece of information from his talk was that they will finish the current round of phase-II trials on April 27th (that's the last day of data collection).   Another round of studies is planned for the second half of 2015.  For next year, the plan is to create a device that can be sold and spend the rest of 2016 and 2017 testing it.

Dr Damiano reported on results from several clinical trials (adults and children who use the AP under different circumstances).  For all these studies, the numbers were great (in my opinion).  They averaged in the low 140s or high 130s in different trials.

There were some other interesting tidbits: the daily dose of glucagon used by people on this bihormonal AP was between 1% and 3% of the dose used in a single "rescue" injection, so a relatively small amount.   Also, the amount of insulin used by people on the AP was about the same as people in the control group.  So it's clear that the bihormonal AP is using insulin more efficiently, not just using more insulin.

CarbDM's: http://carbdm.org/
The Diabetes Summit: http://carbdm.org/summit/

International Conference on Advanced Technologies & Treatments for Diabetes (ATTD 2015) 

This was a conference held in Feburary in Europe that had dozens of papers, many of which covered artificial pancreas research, continuous glucose monitoring techniques, and related areas.

You can see all of their posters here:
http://dasterminal.com/posters/attd2015/
Abstracts for a huge number of papers are here:
http://online.liebertpub.com/doi/full/10.1089/dia.2015.1525



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.

Sunday, April 19, 2015

ATG and GCSF Combination Starts a Phase-II Trial


ATG is Anti-Thymocyte Globulin, a biological agent used to lower immune reactions.
GCSF is Granulocyte Colony-Stimulating Factor, a biological agent which causes bone marrow to generate more stem cells and more immune cells, and put them into the blood stream.  It is sometimes called G-CSF, and the exact product being used is Neulasta.

So the two of them together could make an effective combination therapy against type-1 diabetes. ATG would lower the autoimmune attack, and GCSF would help the body regrow beta cells.  At least, that is the hope. I wrote a more detailed blog entry on this combination four years ago, which you can read here:
http://cureresearch4type1diabetes.blogspot.com/2010/08/atg-gcsf-starts-phase-i-clinical-trial.html

ATG and GCSF Combination Starts a Phase-II Trial

This is a three armed study.  Each group will have at least 28 people.  The first will get ATG.  The second will get ATG and GCSF.  The third will get a placebo.  The ATG will be given twice, one day apart.  The GCSF will be given six times, two weeks apart. They started recruiting in December 2014, and hope to finish collecting their data in October 2016.  The primary outcome (the most important result they will measure) is C-peptide generation after a meal as measured a year after treatment.  There are no secondary outcomes listed, however I've been told they will track A1c, insulin usage, low BG, adverse effects, and infection rates as secondary outcomes.

They are recruiting in at least six different locations, all over the United States.  Although it's not listed on the clinical trial site, Stanford is recruiting for this trial, and they are planning on adding UCSF soon as well.  The list (with contact information) is in the Clinical Trial Record below. Patients must be between 12 and 46, and have been diagnosed within a 100 days,so this is a honeymoon trial.

Recruiting Site: http://www.diabetestrialnet.org/ATG-GCSF/index.htm
Clinical Trial Record: https://clinicaltrials.gov/ct2/show/NCT02215200
Press Release: http://jdrf.org/2015/01/unlocking-a-combination-therapy-for-new-onset-t1d/
Wikipedia: http://en.wikipedia.org/wiki/Anti-thymocyte_globulin http://en.wikipedia.org/wiki/Granulocyte_colony-stimulating_factor

Funding for this trial comes from several US government agencies, JDRF, ADA, Helmsley, and two commercial companies: Sanofi and Amgen.

Discussion About Previous Results

For me, the most important question in a phase-II trial is: "What happened in the phase-I trial?"  If there was a phase-I trial.  For this treatment, there was and it included a placebo group.  The results were good, but not great, from the point of view of curing type-1 diabetes.  Over the years of the trial, the placebo group had lower C-peptide levels (meaning they lost the ability to make their own insulin). This is what would be expected during the years after diagnosis.  The treated group's C-peptide levels stayed about the same.

Obviously, an optimist will look at those results, and say "they stopped the loss, this is good, and the earlier we can use this, the better it will be".  A pessimist would say "they had type-1 when the trial started; they had it when it was over; there was no real improvement".

My blog on their previous results is here:
http://cureresearch4type1diabetes.blogspot.com/2014/07/ada-2014-type-1-diabetes-cure-research_14.html

And here is the most important graph from those results, you can see that treated people stayed the same (dark line at top) while untreated people got worse (lighter line below):

The full paper is here: http://www.jci.org/articles/view/78492.
Thanks to the The Journal of Clinical Investigation for making the whole paper available on line.

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.