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.

Friday, April 10, 2015

Kickstarting Type-1 Diabetes Research

Kickstarter is a web site which "crowdsources" funding for creative projects. This is called "crowdfunding". In my opinion is is an important part of a creative explosion made possible by the world wide web. If someone wants to write a book, they can run a Kickstarter to fund printing it, before they spend the time writing it. They could promise people who give $20 a copy of the book, and promise people who give $40 an autographed copy of the book, and allow people who give $200 to name a minor character in the book. That sort of thing. It opens up whole new areas of creativity, by lowering the financial risk to creative people.

You can go to kickstarter.com and search for "diabetes" to see projects which have something to do with diabetes.  Kickstarter is not the only site that does this kind of crowdfunding.  Gofundme.com and indiegogo.com are similar.

Kickstarting Type-1 Diabetes Research

This blog entry is about The Diabetes Research Connection: https://www.thediabetesresearchconnection.org/

This web site is trying to take the ideas which worked so well for Kickstarter, and apply them to funding of type-1 diabetes research projects.  They've got six projects on their web site right now, so you can see how it works.  Of the six projects, one is fully funded, and one other is a sort of "internal project" to fund the web site itself.  The other projects are in process.  Projects must be completed in a year, and are limited to $60,000, so I doubt these guys are going to fund any human trials. However, all research needs to start somewhere.

Discussion and Opinion

There is no doubt in my mind, that the reason some people don't like giving money to large, impersonal organizations (like JDRF) is that they don't have any connection to where the money ends up.  If I give $1000 to JDRF, they end up giving that money to 300 different research projects.  I can read about the highlights of JDRF funding in general, but I don't feel a personal connection to any of it.  That really bothers some people.  (I'm just using JDRF as an example here, most large charities work this way.  Discussion of "earmarking" is below.)

This system is very much the opposite.  I know exactly where my $1000 goes, and get updates from the researcher, and see exactly what gets published and so on.  When I donate, I automatically become part of a community of people who care about that specific research project; there is a social aspect to it.

There is also a "middle of the road" option. For many charities, including JDRF, you can gain that personal connection by "earmarking" your donation to a specific research project or specific research area, but that requires a little extra work, and does not have the social aspects that The Diabetes Connection has. The Diabetes Connection has forums for each specific research project; JDRF has fewer opportunities for interaction, and they are for the charity as a whole, not specific research projects.

I certainly am not going to argue that one system is better than another; for one thing, I think different people will be attracted to different systems.  I like the idea of different models of charitable giving completing with each other to see which works best, and also available for different people who like different ways of donating money.

But it is also important to remember the risks.   The Diabetes Research Connection has not yet been reviewed by CharityNavigator.org, and doesn't have a track record to evaluate (either from a research point of view or a financial point of view).   Finally, the whole idea of pushing funding decisions down to the individual contributor has some large risks.  Charity organizations, especially the larger well established ones, have resources and processes to evaluate research proposals. Individual contributors rarely do.

I want to thank Brian Braxton for first bringing this to my attention.

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, March 15, 2015

Tocilizumab (Actemra) Starts a Phase-II Trial

Tocilizumab (brand name: Actemra, often shortened to TCZ) blocks the action of IL-6 which is a part of the immune system. It has been approved in the USA since 2010 for use against Rheumatoid Arthritis, which, like type-1 diabetes, is an autoimmune disease.  The hope is that since it works on one autoimmune disease, it will work on another.  Usually the drug is given as an IV drip (which requires a clinic visit), but recently a subcutaneous injection was approved.  Subcutaneous injections are the same type of injection as used for insulin.

Tocilizumab Starts a Phase-II Trial

The trial is straightforward.  It is placebo controlled, double blind.  Of 108 patients in the trial, 2/3s will get the treatment and 1/3 will get the placebo.  The drug is given via IV once a month for a total of seven treatments.  The last data will be collected 2 years after the first treatment.  Researchers will gather data on C-peptide production, A1c numbers, and insulin usage.  This study is being funded by the National Institute of Allergy and Infectious Diseases (NIAID) and done in cooperation with Immune Tolerance Network (ITN), and the Diabetes TrialNet.  They are recruiting honeymoon diabetes (within 100 days of diagnosis), and expect to have ten different sites all over the US.  They hope to have results by August 2018.

The interesting part, at least to me, is how they are handling recruiting children.  They have the standard problem of recruiting honeymoon type-1 diabetics:  The FDA often requires a trial in adults before you can run a trial in children.  Of course, this is a particularly silly requirement for a drug (like Tocilizumab) which has already been approved for use in children.  In order to get around this restriction, the researchers organized their trial in the following way: The first 30 patients will all be adults.  After those adults have been treated for 12 weeks, the accumulated safety data will be reviewed, and (hopefully) the rest of the trial will be open to people of all ages.  But the downside is the delay caused by limiting recruitment to adults for about 30 out of 108 patients.  Finding adults within 100 days of diagnosis is a lot slower than finding children.

This clinical trial is currently recruiting in two locations:
Benaroya Research Institute -- Seattle, Washington, United States, 98101
    Contact: Marli McCulloch Olson    206-342-6943    marli@benaroyaresearch.org
Sanford Research -- Sioux Falls, South Dakota, USA
    Contact: Angela Vanveldhuizen    605-312-1395    angela.vanveldhuizen@sanfordhealth.org
Indiana University, Riley Hospital -- Indianapolis, IN, USA
    Contact: Bonnie Jagielo  317-278-8879  bjagielo@iu.edu

However, they are planning on adding many more sites, including these in California:
University of California San Francisco -- San Francisco, California, USA -- Rebecca Wesch 415-476-5984 weschr@peds.ucsf.edu
Stanford University  -- Stanford, California, USA -- Trudy Esrey 650-498-4450 tesrey@stanford.edu

Many more are listed in the clinical trial record.  The web site is below.

Study Web Page: http://www.extendstudy.org/
One Site's Page: https://www.benaroyaresearch.org/our-research/diabetes-clinical-research/find-study/extend-study
Clinical Trial Record: https://clinicaltrials.gov/ct2/show/NCT02293837
Wikipedia: http://en.wikipedia.org/wiki/Tocilizumab
Effect on Type-2 Diabetes: http://ard.bmj.com/content/70/6/1164.extract
(Case study were type-2 diabetics had improved A1c numbers.  Researchers assumed this was due to Tocilizumab's anti-inflammatory properties.)

Tocilizumab's safety profile is pretty good.  This study:
http://arthritis-research.com/content/13/5/r141
looked at serious adverse events and "plain old" adverse events in 8 different clinical trials run for Tocilizumab's rheumatoid arthritis approval. Five of them were phase-III trials.  You can look at the details, but basically serious adverse effects where the same in placebo, low dose and high dose.  For "plain old" adverse effects, high dose was about 10% higher than placebo, and low dose in between the two.

If Tocilizumab does prove effective, there are several other drugs available which work by blocking IL-6, and presumably they would be worth testing as well: Sarilumab, Olokizumab, and Elsilimomab are examples.

Extra Bits and Pieces

I have not found a "cured in mice" type experiment for Tocilizumab, but it has been tested in human tissue samples.  There are some mouse studies from the 1990s showing that IL-6 does effect the development of autoimmune diabetes in NOD mice.

Clinical development for this drug took about 13 years until it became available in the US, and it was first created about 25 years before commercial availability.

In 2011, the FDA approved Tocilizumab for use in children as young as two years old.

If Tocilizumab does prove effective, there are several other drugs available which work by blocking IL-6, and presumably they would be worth testing as well: Sarilumab, Olokizumab, and Elsilimomab are examples.

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, March 8, 2015

Smart Insulin (MK-2640) Starts Clinical Trials

This is a blog posting that I've been waiting four years to write: the start of clinical trials for "Smart Insulin".

First, some general background on "Smart Insulin". The idea here is simple: create a chemical that holds insulin and only releases that insulin when the sugar level in the surrounding region is high. You would not have to measure blood sugar levels or match insulin to food. Instead you would just take this "self-dosing" insulin compound and it would release insulin as needed based on what you ate or did not eat.

"Smart Insulin" was the name of the first strong contender in the field, which was developed by Dr. Zion first at MIT and then at Smart Cells, which was later bought by Merck.  The term is also used generically, to refer to any "self dosing" or "Glucose Responsive Insulin"  (although I'm sure Merck's trademark lawyers would not approve).  No other self dosing insulin is in human trials, but SIA-II, Ins-PBA-F, and Sensulin, are being developed, and those are just the ones that I know about.  Smart Insulin had been tested in mice when it was sold to Merck (in 2010) and so a lot people, myself included, thought it would be in clinical trials quickly.  Obviously, the "quick" part did not happen, but the clinical trial part has started.

Smart Insulin (MK-2640) Starts A Clinical Trial

But the big news is that Smart Insulin has started clinical (human) trials.  In fact, the trial started months ago, in November 2014.   I missed it, mostly because Merck changed the drug's name from "Smart Insulin" to "L-490" to "MK-2640".   The clinical trial was under the name MK-2640, and I missed it.  Luckily Mike Hoskin at DiabetesMine publicized the name change.  You should read his blog for some general background, but notice that MK-2640 (the smart insulin I discuss here) is the second part of the posting:  http://www.healthline.com/diabetesmine/more-brains-smart-insulin

The trial itself has a fairly complex design.  It's two trials combined into one.  Part 1 is a group of 7 different "panels" (dosing regimens) given to healthy people.  Part 2 is a comparison of regular insulin to MK-2640 in people who have had type-1 diabetes for at least a year.  All of this involves 58 people and is expected to be done by July 2015.  Unfortunately, I cannot tell how many people are doing what, so I don't know if each of the 58 people are doing each dosing regimen, or if the 58 people are divided up between the different doses.  Most of the data they are collecting is "pharmacokinetic" meaning they are measuring how much of the drug is available in the body at any given time.  How quickly it "washes out" of the body and so on.  They will also be looking for adverse events and also patient drop outs caused by adverse events.  For a drug like "smart insulin" where variable dosing is critical to its success, focusing on pharmacokinetics makes a lot of sense to me.

The study is recruiting in Chula Vista, California, USA. Call their toll free number: 1-888-577-8839.

Clinical Trial Record: https://clinicaltrials.gov/ct2/show/NCT02269735
ClinicAnnouncement of Merck buying Smart Cells: http://www.merck.com/licensing/our-partnership/SmartCells-partnership.html

Discussion

My summary is simple: in a few short months, we are going to know a lot more about how "Smart Insulin" works in people, than we know now.

One very good thing about "Smart Insulin", especially when developed by a big pharma company like Merck, is that it can move through the approval process much faster than the other drugs I cover. One of the repeating themes of this blog is that it will take a cure at least 10 years to go through the FDA's approval process, and more years are likely.  That's not rocket science, it is simple math.  The FDA requires three phases, the first phase usually takes a year to recruit the patients and a year to gather the data.  The second and third phases also take a year to recruit the patients, and two years to gather the data, and then there is a year or two for marketing approval, and we are at (2+3+3+2) 10 years.  That assumes that every phase starts the moment the previous phase ends.  In real life there are often months or years of delay between each phase, so in real life these drugs take longer to get approved.

But that is for drugs aimed at curing type-1 diabetes.  For a new insulin, most studies only collect data for three months.  Also, recruiting people is much easier, both because they are adults and because they already are taking insulin, so you're just asking them to take a different insulin.  It's not as scary as something that changes your immune system.   Bottom line is that the phase-I trial is expected to be done in 8 months (recruiting and data collection).  I would expect phase-II and phase-III trials to also be sped up, as compared to cure trials.  The downside is that insulins usually have more than 4 clinical trials before approval, and usually a couple of them are longer than 3 months. But still, I would expect a quicker testing cycle for a new insulin than for a potential cure.

This is a treatment where some people are going to think of it as a cure, and others are going to think of it as a treatment.  That's not an argument I want to spend time on.  I will cover Smart Insulin (at least this first trial) because some people do consider it a cure.  If it is highly effective, then more people might consider it a cure.  Of course, if it doesn't work well or has limitations in how it can be used, then fewer people will consider it a cure.  But I'm happy to cover it for a clinical trial or two.

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, March 1, 2015

Verapamil Starts a Phase-II Trial

Soundtrack is "I'm Bad, I'm Nationwide" by ZZ Top:
http://grooveshark.com/#!/s/I+m+Bad+I+m+Nationwide/3OTEOT

Verapamil Starts a Phase-II Trial

Verapamil is a drug which has been used in the US since 1982 for high blood pressure, migraines, and heart problems.  It also lowers levels of a protein called TXNIP.  The researchers running this trial believe this is important because they believe TXNIP kills beta cells as part of the onset of type-1 diabetes.  So giving Verapamil should lower TXNIP which should improve beta cell survival, and stop type-1 diabetes.  In addition TXNIP is known to lower inflammation, and that might have an effect on type-1 diabetes as well. TXNIP worked in mice trials (but see discussion below).

Drs. Anath Shalev and Fernando Ovalle at the University of Alabama at Birmingham have started a clinical trial. They are enrolling 52 adult, honeymoon type-1 diabetics; half will be treated, half are a (double blind) placebo control group. Patients will get Verapamil for a year, at the same doses that it is commonly prescribed.  The primary end point is C-peptide levels after a meal. The researchers will also track several other outcomes: insulin usage, A1Cs, TXNIP, beta cell markers, glucose generation, and two measures of BG stability.  They expect to finish in July 2017, which breaks down to about 1 1/2 years to recruit all the patients, and 1 year to run the trial.

This study is funded by JDRF, and is being conducted at The University of Alabama at Birmingham. Contact information is:
Tiffany H Grimes, RN    205-934-4112    tdgrimes@uab.edu
Kentress Davison    205-934-4112    kdavison@uab.edu  

News: http://www.medpagetoday.com/Blogs/DiabetesDiscovery/49622
News: http://www.uab.edu/medicine/diabetes/new-clinical-trial
News: http://www.uab.edu/news/innovation/item/5508
Clinical Trial Record: https://clinicaltrials.gov/ct2/show/NCT02372253
Mouse study: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3314354/
Wikipedia: http://en.wikipedia.org/wiki/Verapamil

Discussion and Opinions

There is a lot to like about this trial.  Using an already approved drug means they don't need to do a phase-I trial; they can start out with a larger group.  It also means if they report good results, off label use becomes a possibility, and could result in much faster availability.

I particularly like the list of outcomes these researchers will measure.  C-peptide (their primary outcome) is the surrogate end point recommended by the FDA for type-1 cures.  But they are also watching insulin usage, A1C numbers, and BG stability, which are of practical importance to people with type-1.  Finally, they are tracking several biochemical changes which should help them understand what is happening "on the inside".

On the downside, they are only recruiting adults.  That's unfortunate, because it will take them much longer to find 52 honeymooning adults, than 52 honeymooning children.  (I know that sentence only makes sense in the world of type-1 diabetes.)  Since the drug is already approved, it's too bad they could not include the people who are most likely to be in the honeymoon phase.  But Verapamil is typically prescribed for high blood pressure or angina, so I suspect there is not much experience giving it to children.

My Opinions About Those Mice....

These researchers have succeeded in preventing type-1 diabetes in mice, by treating during the mouse honeymoon.  But I don't put much stock in mice tests, because there have been so many treatments that have led nowhere in people.  Hundreds of cures in mice and (so far) no cures in people. However, the mice used in these tests were STZ mice, which I'm particularly nervous about. Basically, the researchers took healthy mice and injected them with a toxin (streptozotocin) which killed their beta cells.  These are are referred to as STZ-mice.  They are commonly used as an animal model of type-1 diabetes, however they do not have autoimmune diabetes.  In comparison NOD-mice, also used as an animal model of type-1 diabetes, do have autoimmune diabetes.

In my opinion, STZ-mice are fine for testing new insulins and pumps, and also for doing tests related to long term complications.  However, I don't think they are good models for testing cures, because they lack the ongoing autoimmune beta cell destruction which is the hallmark of real type-1 diabetes.

The danger is that even if Verapamil does cause the body to grow more beta cells, they will be destroyed by the autoimmune attack, and patients will not see any improvement.  This treatment could be combined with something that stops the autoimmune attack, and the combination might be a cure, but testing Verapamil alone is unlikely to give good results.  The researchers understand this; the interview with Dr. Anath Shalev makes that clear.  Her hope is that by carefully measuring BGs (using a CGM) and C-peptides, she will see a small improvement, which will have good health effects (even if it is not a cure).   My blog posting "The Value of a Few Beta Cells" discusses this point:
http://cureresearch4type1diabetes.blogspot.com/2013/10/the-value-of-few-beta-cells.html
Also, a small improvement could provide the justification for a combination trial (Verapamil and an immune modulator/suppressor), and such a combination could be a cure in the future.

But in a certain sense, even discussing the mouse research is a waste of time, once the human trials have started.  Only the human trial results will matter moving forward.

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, February 8, 2015

HPV Vaccination and Type-1 Diabetes


There are 14+ studies showing that vaccines do not increase the chance of getting type-1 diabetes, and I've posted that list in the past. However, most of those studies were done before HPV vaccines were developed, so this posting focuses on HPV vaccines.

This posting covers the two HPV vaccines in common use in the US: Cervarix (made by GlaxoSmithKline) and Gardasil (made by Merck).  A vast amount of background information on HPV and these vaccines is available on Wikipedia:
Including HPV prevalence, death rates, etc.

Studies on HPV Vaccines and Type-1 Diabetes

It is important to remember that these vaccines are typically given to girls (and increasingly boys) at about 10-14 years old.  This is "prime time" for type-1 diabetes diagnosis as well.  So we should all expect stories that talk about someone who got an HPV vaccine and then came down with type-1 diabetes a few weeks later.  Occasionally, we'll even hear about stories where the person was diagnosed with type-1 diabetes the day of the vaccine, or maybe just a day or two later.  Because of blind bad-luck, and the relative number of people given the vaccine and diagnosed at the same time, you will see a few that overlap.

But the important question is this: do people who get HPV vaccines get type-1 diabetes at a higher rate, than those who don't?

The Huge Gardasil Study

A very large study was published in 2012, which looked at Gardasil and autoimmune diseases. It covered 190,000 people, and was done by an insurance company. Type-1 diabetes was one of the diseases they looked for specifically.

Here is the summary from the news coverage (bolding added):
They found no increase in any of 16 autoimmune disorders in the vaccinated population compared to a matched population of non-vaccinated girls and women. The 16 autoimmune disorders they looked for were:  "... immune thrombocytopenia, autoimmune hemolytic anemia, systemic lupus erythematosus, rheumatoid arthritis, juvenile rheumatoid arthritis, type 1 diabetes, Hashimoto's disease, Graves' disease, multiple sclerosis, acute disseminated encephalomyelitis, other demyelinating diseases of the central nervous system, vaccine-associated demyelination, Guillain-Barr syndrome, neuromyelitis optica, optic neuritis and uveitis."
I know some people are afraid that the same drug companies that sell the vaccine will also fund the studies showing they are safe. Having an insurance company run the study is much better. They are the people who pay for the vaccine, and they are the people who pay for any adverse side effects of the vaccine, so they are the best people to evaluate safety. Plus, they have the records to do it well. Not just anyone can review 190,000 patient records!

News: http://www.medicalnewstoday.com/articles/240897.php
Abstract: http://www.ncbi.nlm.nih.gov/pubmed/21973261

Large Cervarix Study

This was also a large study, about 18,000 people.  Type-1 diagnosis was specifically tracked as part of the trial's safety protocol, and the people were followed for 4 years.
In the Phase III trial, no differences were observed in the overall safety profile of the vaccine when administered to women aged 15–25 years with or without evidence of prior HPV-16/18 infection. [r3] 
Clinical Trial Record: http://clinicaltrials.gov/ct2/show/NCT00122681

Don't underestimate the size (and therefore the power) of these studies.  Larger studies make it possible to detect smaller effects, and an 18,000 person study could detect even a very slight rise in the chance of a disease (and a 190,000 person study, even more so).  For comparison, phase-III studies, the largest required before a new drug is approved, are usually around 300 people for potential cures for type-1 diabetes. Obviously, both the Cervarix and Gardasil studies described above are vastly larger than that.  It's not a direct comparison, because phase-III studies are done on people who have type-1 diabetes already, while these were done on the general population.  Never the less, these are very large, powerful studies, and much larger than commonly used in testing potential type-1 diabetes cures.

Other Studies

You'll notice that there are no studies listed here that found HPV vaccines to cause higher rates of type-1.  That's because I could not find even one such study.  I looked for such a study in two ways. First, I looked for the Clinical Trials site which is run by the FDA and is required for all studies that are used for drug approval in the US.  Second I looked at "Google Scholar" which is Google's specialized academic paper search engine.  

In total, there were 60 Cervarix and 113 Gardasil studies listed on the FDA's clinical trial registry, and none of those found an increase in type-1 diabetes based on HPV vaccination.  Obviously, I did not read 170+ studies.  I did look through their titles, and then skimmed the abstracts of the ones that looked promising, and then read the abstract (or occasionally the whole paper) if the abstract looked like it contained applicable data.  I was not able to find one paper that suggested a higher rate of type-1 diabetes in people who got HPV vaccines as compared to people who did not.

This is a summary of information available in 2008 in this document:
Here is their data:
No increased risk of [new onset autoimmune diseases] was observed in the HPV-16/18 vaccine group compared with any of the control groups in any age group. ... The overall incidence of these events was low and within the range expected in the general population.  An integrated analysis [ie. review of many different studies] of over 68,000 subjects who received AS04-adjuvanted vaccines or controls demonstrated a low rate of autoimmune disorders (~0.5%), with no evidence of an increase in relative risk associated with AS04-adjuvanted vaccines. [r1]
New onset of autoimmune diseases (NOADs). ... No differences were seen in the frequency of NOADs between study groups in any age group during any follow-up period and no apparent clusters of events were detected . [r1]
In vaccinated girls aged 10–14 years, no withdrawals due to adverse events and no vaccine-related SAEs [serious adverse events] were reported over 24 months of follow-up after the first vaccine dose. [r2]

Common Complaints and Worries about HPV Vaccine Safety

A common worry that I hear is "these vaccines are not tested enough to know they are safe".


If this is an issue for you, ask yourself how many times a vaccine should be tested; in how many different clinical trials?   The FDA's answer to this question is "at least 4".  For the FDA, 4 clinical trials are the minimum level of testing (and not just for vaccines, for all new drugs).  As I said before Cervarix has already been tested in 60 separate clinical trials, and Gardasil in 113 trials.  Even if you would prefer a safety margin of 2x or 3x more trials than the FDA requires, these vaccines are way above that.

I sometimes hear people say "HPV vaccination has been associated with [bad effect X]..." 

Of course.   Every day, 100s of girls are given the HPV vaccination.  Just based on chance, some of those people are going to get the flu, get a bad grade, be diagnosed with type-1 diabetes, or be hit by a car, that very day!  (Or maybe the next week.)  With the large number of vaccinations given, even very rare events (like heart attacks and strokes in the young) are going to happen from time to time. That's what statistics are all about.

You will hear people say "I heard about person X, and they got rare cancer the week after an HPV vaccination".  They sure did.  If you vaccinate a million people a year, then some very rare things are going to happen.  In the case of HPV vaccines, there are two separate groups of people who will endlessly repeat any vague badness they can associate with HPV vaccination.  (One group is the anti-vaxxers, who object to all vaccines, and the other group is ultra conservatives, who object to vaccines against sexually transmitted diseases.)

A second issue is VAERS.  VAERS is a public database of medical events seen after vaccinations. Anyone at all can add events to VAERS.  They are not limited to entering effects on their own patients, and can enter cases where they don't know important facts.  There is no quality control or required fact checking.  VAERS was set up to find very rare side effects.  The hope was that if something very unusual happened, it would be stored in the database, and if it happened again, it could be investigated.  Unfortunately, the database is subject to manipulation, and in any case does not imply causation.  The following is a true story:

When HPV was first being used, I read in both Catholic and anti-vaccine web sites about HPV causing a girl's death.  They referred to VAERS reports.  I was able to find the report, and it went like this [4]:
VAERS ID 279592  2007-05-24
Administered by: OTH     Purchased by: OTH
Symptoms: Death Thrombosis
Information has been received from a licensed visiting nurse via a nurse practitioner. The nurse practitioner was told by a friend that a female patient was vaccinated with Gardasil and two weeks after developed a blood clot. Subsequently the patient died. The cause of death was from the blood clot. The reporting licensed visiting nurse considered the blood clot to be immediately life-threatening and disabling. Additional information has been requested. [There was no additional information included.]
In this case, the report was not made by anyone who actually knew the subject.  Nor even by someone who knew someone who knew the subject.  The licensed visiting nurse then filed a VAERS adverse effect report, although she did not include the name of the patient (she did not know it), nor the vaccine dose, nor the date of the vaccination or death.  In the legal world, this would be hearsay twice over.  In the scientific world this is too vague to be useful.  Indeed, it's not clear the event actually happened at all.  There is no required fact checking of VAERS data, .

If you'd like to read more about VAERS and HPV data, you can look here:
http://www.cdc.gov/vaccinesafety/Vaccines/HPV/jama.html

But do we really know about HPV Vaccine safety, when children are getting so many other vaccinations?  What if a combination causes a problem?

It's the idea that since vaccines are tested one at a time, combinations of vaccines are not tested and might be dangerous.  It's wrong, because vaccines are not tested one at a time.  They are tested "on top" (or in addition to) a normal vaccination schedule.  So the testing covers the situation where all the vaccines are given.

When phase-III trials are run for a new vaccine, they are comparing a normal vaccine schedule plus the new vaccine, to a normal vaccine schedule. (As they should.) But if the new vaccine caused a bad interaction with the existing schedule, then it would certainly turn up in the clinical trial. Similarly, if there was some problem with the total number of vaccines, then again that would show up in the testing for HPV.

But HPV Vaccination is new, so how can long term problems be known?

I think there are two good answers to this worry.  The first is simple: HPV is generally given to pre-teens and teenagers.   Type-1 diabetes is most commonly diagnosed just slightly later: in teenagers. Therefore, it makes sense that if there was a problem, it would show up in terms of higher type-1 diabetes rates within a few years (as the pre-teens who were vaccinated became teenagers who were diagnosed).  That hasn't happened.  Gardasil has been in use for over 8 years, and Cervarix for over 5 years, so it has now been enough time so vaccinated people would have progressed into the prime years for type-1 diagnosis.

If HPV caused or contributed to type-1 diabetes, we would see three strong signals: First when some girls started to be vaccinated, there should have been a "bump" in type-1 diagnosis.  There wasn't. Diagnosis continued to steadily grow at the same rate it has for decades.  Second, when the vaccine was officially recommended for girls, then again there should have been a corresponding "bump" in diagnosis for girls. This would have been particularly obvious, because it would have been in girls and not in boys. But it didn't happen. Third, when HPV was recommended for boys, then there would have been a corresponding "bump" a few years later.  Just in boys, so obvious to spot.  Again, it did not happen.

Bottom line: HPV has been in use long enough so that if it caused or contributed to type-1 diabetes, it would have been obvious (three times over), already.

A second answer to this worry, is to ask the person if Acai berries (or whatever the current health fad) have been tested "long enough"?  Has the person reviewed the long term safety tests for Vitamin-D supplements?  Organic food? A low fat diet?  The fact is that almost nothing in our lives is systematically tested for long periods of time.  If you think about it, you would need to run the test for a person's whole life to really be sure, and the results would only help the next generation, and only if nothing in the world had changed over those years to effect the results.  In short, "not tested long enough" is a bar nothing can reach, and one that is applied selectively to the things the worrier doesn't like.

More Information

SNOPES, which is a great general resource for "internet scare stories" has a good write up on Gardasil:
http://www.snopes.com/medical/drugs/gardasil.asp

More References

[r1] Descamps D, Hardt K, Spiessens B, Izurieta P, Dubin G. Safety of human papillomavirus (HPV)-16/18 AS04 adjuvanted vaccine for cervical cancer prevention: integrated summary of 11 clinical trials. Presented at: 26th Annual Meeting of the European Society for Paediatric Infectious Diseases. Graz, Austria, 13–17 May 2008.
http://www.tandfonline.com/doi/pdf/10.4161/hv.5.5.7211

[r2] Schwarz TF, Descamps D. Long-term safety and immunogenicity of an AS04 adjuvanted cervical cancer vaccine in girls aged 10–14 years. Presented at: 26th Annual Meeting of the European Society for Paediatric Infectious Diseases. Graz, Austria, 13–17 May 2008.

[r3] Cruickshank M, Teixeira J, Gall S et al.; on behalf of the PATRICIA Study Group. Efficacy and safety of GSK's HPV vaccine in women initially seropositive or seronegative for HPV-16/18 in a Phase III trial. Presented at: EUROGIN: New Strategies of Cervical Cancer Prevention – the Reality of HPV Vaccines. Monte Carlo, Monaco, 4–6 October 2007 (Abstract SS1–2).

[r4] These examples are from anti-vaccine web sites:
http://www.whale.to/vaccine/vaers_gardasil.html

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 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.