New Resource: Next Expected Milestone

I have the first draft of a new on-line resource for tracking research aimed at curing type-1 diabetes.  It is not in a "polished" form as yet.  I'm releasing it now partly because I think it will be very helpful, and partly so you can give me feedback on it.

I call it the Next Expected Milestone page.  It's permanent home is here:
http://cureresearch4type1diabetes.blogspot.com/p/next-expected-milestone.html
But I've included the important part below.

My goal with this page is to make it easy, for each clinical trial, to see what research milestones are expected to be completed in the next month, season, year, etc.   On the one hand, this page can serve as an TLOD ("too long over due") list of research that isn't reporting the expected results.  On the other hand, it can tell you what announcements to especially look for in the next few months.

In the table below, the the important column is the last one.  It contains the next expected milestone the researchers should make.  So "Jun-2011 III Results !" means that in June of 2011, that trial should release their results, and the ! means they have publicly said they will do this.  "April-2012 II Started" means they will start a phase-II trial in April 2012, and so on.  Red dates are long over due.  Orange dates are slightly over due. and BoldGreen dates are coming up in the next few months.  All the columns in the table, and all the abbreviations and acronyms, are described in a section below the table.

Name          Id/Developer           Notes            Date Last Milestone        Date Next Milestone

Lisofylline   DiaKine                Inflam           May-2009 I Started         Dec-2009 I Complete

BCG           Faustman               Estab Comm       Jun-2010 I GotData         Oct-2010 I Results

Anakinra      NCT00645840            Inflam (Kineret) Jun-2010 I Completed       Dec-2010 I Results
Exsulin       Exsulin                Beta             Sep-2009 II Started        Nov-2010 II Complete

Atorvastatin  NCT00529191            (Lipitor)        Feb-2010 II Enrolled       Feb-2011 GotData

Etanercept    NCT00730392            (ENBREL)         Apr-2009 I Results         Apr-2011 II Start

GAD65*        NCT00723411 - EU                        Nov-2009 III Enrolled      Jun-2011 III Results!
Dendritics    NCT00445913            Estab            Feb-2011 I Enrolled[*]     Jun-2011 Results
Liraglutide   Hvidovre Univ Hosp     Estab            Jan-2011 II Complete       Jul-2011 II Results

AAT           Kamada                 Inflam           Mar-2011 I Paperwork       Aug-2011 I Starts

Anakinra      AIDA                   Inflam (Kineret) Jan-2009 I Starts          Sep-2011 I Complete 

BHT-3021      NCT00453375            Estab            Nov-2010 I Enrolled        Oct-2011 I Complete?

Xoma 52       Xoma Corp              Estab Inflam     Jul-2010 II Enrolled       Oct-2011 II Results
GAD65         NCT00751842 DIAPREVENT                  Nov-2010 III Enrolled     Oct-2011 III Complete 
DiaPep227*    DIA-AID1 NCT00615264                    Sep-2009 III Enrolled      Dec-2011 III Complete

Rituximab     Pescovitz at Indiana                    Dec-2009 II Publication?   Dec-2011 III Start?

Cord Blood    Haller                                  Mar-2009 II Started        Mar-2012 II Complete?
PROCHYMAL     Osiris                                  Jan-2010 II Enrolled       Apr-2012 II Results
Pioglitazone  NCT00545857                             Oct-2009 I HalfEnrolled    Jun-2012 I Complete
GCSF          NCT01102699            Estab            May-2010 I Started         Jun-2012 I Complete 
IBC-VS01      NCT00057499 Orban                       Jun-2010 I Published       Jun-2012 II Start

GAD65 [1]     NCT00837759            Estab            Jan-2011 II Enrolled       Oct-2012 II Complete 
GAD           NCT00529399                             Apr-2010 II Enrolled       Dec-2012 II Complete 
Sitagliptin   Garg                   Estab            Feb-2011 I Results         Feb-2013 II Start
GCSF          Haller                                  Apr-2008 I Start           Apr-2013 I Complete
ATG GCSF      Haller                 Estab            Apr-2010 I Started ?Aug    Apr-2013 I Complete
AAT           NCT01319331            Estab Inflam     Mar-2011 I Started         Sep-2013 II Complete 

Abatacept     Orban at Joslin                         Feb-2008 II Started        Sep-2013 Results
Proleukin Rapamune  NCT00525889      Estab            Nov-2010 I Enrolled        Sep-2013 I Complete?

NI-0401       NovImmune                               Aug-2010 II Started        Aug-2013 II Results ?
Rituximab     NCT01280682                             July-2010 II Started       Dec-2013 II Completed
DiaPep 277    DIA-AID2 NCT01103284                    May-2010 III Started       Mar-2014 III Complete
AAT*          RETAIN-1 NCT01183468   Inflam           Oct-2010 II FirstDose      Nov-2014 II Complete
Canakinumab   TrialNet               Inflam           Mar-2011 I Enrolled        Dec-2014 I Complete 
ATG           START NCT00515099                       Aug-2007 II Started        June-2015 II Results

Poly Tregs    Gitelman               Estab            Jan-2011 I Started         2016 I Results

[1] Combo trial including GAD65, lansoprazole, and sitagliptin

Understanding The Table

Each line is a separate clinical trial (so drugs/treatments with more than one trial active may have more than one line). 

Name

The most common name of the drug or treatment.  Only one is included.  For drugs that have trade names and generic names, I usually use the generic name if there is space for it.  A * means this is the leading (farthest along) clinical trial for this drug or treatment in type-1 diabetes,  for treatments with many studies going on at the same time.

Id/Developer
Should be an identifying number or trial name, or both.  However, I started out putting the name of the researcher here, and I'm only slowly replacing that with the US government's clinical trial number, or a similar number from another governmental organization.  Developer is the organization creating the treatment or testing it.  Only one is included.

Notes

Here are the notations in this field:

• Appr: Drug or treatment already approved in the US or EU or both.
  
• Beta: Drug or treatment aimed at increasing beta cell mass or efficiency.
• Comm: A commonly used drug, so widely prescribed or not prescription at all.
• Estab: A trial on established (non-honeymoon) type-1 diabetics.  Generally over 1 year.
• Inflam: A drug or treatment based on preventing or lowering inflammation.
• Prev: A trial aimed at preventing type-1, not curing it.
• Treat: A drug aimed at treating type-1, not curing it. 
• (...): A trade name of the drug in the trial, these drugs are usually "Appr".

Milestone Columns
The last two columns in the table are both milestones, and are very similar.  Here are the types of milestones listed in these columns: 

• Paperwork: Filed the paperwork required to start a trial.  Usually either the clinical trial record, or the IND application, if in the USA.
  
• Start: Started trying to enrolling patients in the trial.  Recruitment has started.
  
• First Dose: The first patient actually enrolled and dosed.
  
• Enrolled: Finished enrolling patients in the trial.  Trial is full.
  
• Complete: The completion date from the clinical trial record.
  
• GotData: Finished gathering data.
  
• Results:  Important results published in some form (paper, symposia, abstract,etc.)
  
• Published: Important Results published in a peer reviewed journal.

Also, these marks are used in both milestone columns:

• "I", "II", and "III" refers to phases of clinical trials, and trials which the researchers consider phase-IV, are considered phase-II here.
• A "?" means I need to recheck that date.
• A "!" means the researcher or organization has publicly listed that date.

 
Last Milestone 
This column contains the date and content of this research's last milestone.

Next Milestone 
This column contains the date and content of this research's next expected milestone.

Joshua Levy
All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions.
Blog: http://cureresearch4type1diabetes.blogspot.com
To Get as Email Join here: http://groups.google.com/group/type-1-diabetes-clinical-trials-news

Possible Cures for Type-1 in the News (March)

The first two lines of research discussed below involve treating inflammation, so here is a quick introduction to treating inflammation as a cure for type-1 diabetes:  Everyone knows that type-1 diabetics have a lot of inflammation in their pancreas and especially around their beta cells. Most researchers believe that inflammation is a result of the body's immune attack on it's own cells. That is, the underlying immune problem causes inflammation and also causes beta cells to die (which causes the symptoms of type-1 diabetes):

            /---> causes --> beta cells to die    

Autoimmunity

            \---> causes --> inflammation

However, some researchers believe that the underlying immune problem causes inflammation, and that this inflammation kills the beta cells, which then causes the symptoms of type-1:

Autoimmunity -causes-> inflammation -causes-> beta cells to die

The difference is that, in the second model, if you stop the inflammation you can stop the symptoms of type-1 diabetes (the high BG numbers and the low numbers). And that is a big difference. But this second model is still a minority opinion. 

OmniBio Starts a Phase-I Trial on Established Type-1 Diabetics and Expands their Honeymoon Phase-I Trial

Alpha-1 Antitrypsin (AAT) is an anti-inflammatory drug, which the body makes naturally, and which is already FDA approved for people who have a rare condition where a person don't make enough of it on their own. OmniBio had already started a phase-I trial for honeymoon diabetics, however they are now expanding in two important ways:

First, they are starting up a non-honeymoon phase-I clinical trial.  Obviously, this is very important to the majority of type-1 diabetics who have had the disease for a long time: 

The initiation of a late stage Type 1 diabetes trial.  Proposed Trial Site:  University of Basel, University Hospital-Basel, Basel, Switzerland.  Principal Investigator, Dr. Marc Donath, Professor of Endocrinology, Head of Clinic of Endocrinology, Diabetes & Metabolism.

Second, they are expanding their Honeymoon phase-I trial to 50 patients.  At that size, it really more of a phase-II trial.  Here is that part of the announcement:

The trial ... has seen improvement in the condition of the first enrolled patients.  Based on observations of the first enrolled patients..., Omni Bio intends to expand the patient enrollment to 50 patients, which may involve obtaining a second trial site.

That sounds like great news, but I'm very interesting in exactly what those results where.  (This is a case where "details matter" and a vague statement of improvement is not good enough by itself.)  Hopefully these guys will publish some details, soon.

Press release: http://www.prnewswire.com/news-releases/omni-bio-pharmaceutical-intends-to-expand-type-1-diabetes-trial-to-50-patients-117053528.html
clinical trials: http://www.clinicaltrials.gov/ct2/show/NCT01183468   http://www.clinicaltrials.gov/ct2/show/NCT01183455

Thanks to Cameron Donahue (who works with OmniBio) for providing some of the information used here.

Kamada Starts Paperwork for a Phase-I Trial of AAT

Kamada is a different pharmaceutical company that makes AAT.  They currently make an FDA and EMEA approved formulation which is used for people who naturally don't produced enough AAT of their own.  They are also working on an inhaled version of AAT, since the current product is intravenous, but that is still in clinical trials.  They are planning to test a different brand name of AAT (Glassia®), than Omni's (Aralast NP), but I don't think that is important.

The trial they are planning includes 24 people and will be completed around December 2012.  There will be no control (or "placebo") group, but three groups will each get different Glassia doses.  The primary outcome for this study is general safety, and the secondary outcomes are efficacy as measured by injected insulin and A1c numbers.  (There is also a mention of testing for "Pancreatic beta cell function" which I hope means C-peptide measurements, but the paperwork is not specific.)

This clinical trial is being done at two sites in Israel: Schneider Children's Medical Center (Petach Tikva) and Assaf Haroffeh Medical Center (Zerifin).  Contact is Mariana Rachmiel and her phone number is +972-8-9542007.

clinical trial: http://www.clinicaltrials.gov/ct2/show/NCT01304537
corporate site: http://www.kamada.com/

Personal Opinions on the Impact of this Research on Dr. Faustman's Research

The Alpha-1 Antitrypsin (AAT) research described above may also have huge impact on Dr. Faustman's research.  It could provide strong evidence that her theory is right or wrong.  Dr. Faustman's theory is that BCG will cause the body to generate more TNF which in turn will kill the autoreactive ("bad") T-cells and result in the body generating more of it's own insulin.   She announced that her phase-I trial had finished almost a year ago, but has not published results as yet.  (A very bad sign in itself.)  However, taking AAT lowers the amount of TNF in a person.  This is the opposite of BCG.  Especially for a honeymoon diabetic, this means that if Dr. Faustman's theory is correct, then giving AAT will cause a shorter honeymoon, and will generally result in a quicker onset and the body to generate less insulin.

So, if AAT results in a longer, stronger honeymoon, that suggests that Dr. Faustman's theory is wrong, even if she never publishes the results of her own clinical trail.  Conversely, if AAT results in a shorter, weaker honeymoon, that supports her theory. Again, independent of her own results.

Teplizumab Starts Phase-II to Prevent Type 1 Diabetes


Teplizumab was being developed by MacroGenics until late last year, when it failed it's phase-III clinical trials for honeymoon type 1 diabetics.  It is similar to Tolerx's Otelixizumab which also failed it's phase-III clinical trials.  Both target a specific type of cell in the immune system, called a CD3.  However, months before the phase-III trial failed, the paperwork had started on a clinical trial to give this drug to people at high risk for type-1 diabetes, but who had not yet come down with the disease.  These patients would be identified by having two or more auto-antibodies, a first degree relative with type-1, and already having an abnormal glucose tolerance test.  The idea would be to give these guys Teplizumab to see if it prevented or delayed or lessened the impact of type-1 diabetes.  TrialNet is moving forward with this clinical trial. 


It is easier to have a good effect on type-1 diabetics during the honeymoon phase than later on, after the disease is long established, so it makes sense that it should be easier still to prevent type-1 entirely than to treat it in the honeymoon phase.  So even though this drug did not improve honeymoon diabetics, there is still hope that it might still prevent the disease.


The study will enroll about 170 people, from many different clinical sites all over the US (for the locals: UCSF and Stanford are recruiting, but nothing in Sacramento).  Results in January 2016 if all goes according to plan.  Since the drug has already been through phase-I and II trials for honeymooners, they can start off at phase-II for their prevention trial.  If you're interested there is a recruiting web site and a lot of contact information in the clinical trial record (links below).

News: http://www.popsci.com/science/article/2011-03/experimental-drug-may-prevent-diabetes
Recruiting web site: http://www.diabetestrialnet.org/studies/ACD3.htm
Clinical Trial: http://www.clinicaltrials.gov/ct2/show/NCT01030861
Note that the news article uses the term "Body Reboot" in it's title.  I think this is a poor choice of words.  The drug being tested does not reboot anything (in my opinion).  I think the term "reboot" is properly used to describe the cure being researched by Burt (and collaborators) in Brazil and Snarski in Poland.

(If this had been nearer to Halloween or nearer to April 1st, my lead paragraph would have been something like this:  

Zombie Drug, Left for Dead, Walks Again!  

Teplizumab which was last seen buried in a shallow grave, after having failed phase-III testing in honeymoon diabetics, has risen from the grave and is shambling towards a different use: preventing type-1 diabetes when given to at-risk people who have not yet been diagnosed with the disease.  It was heard mumbling to itself "Hungry for Ceeee Deeee Threees.  Must have Ceeee Deeeee Threees.  Give meeeee Ceee Deeee Threeees......  :-)

A Little Commentary


In addition to seeing if Teplizumab can prevent or minimize type-1 diabetes, this trial will also have a synergistic effect with TrialNet’s Natural History Study trial.  That trial tests relatives of type-1 diabetics for antibodies to help gather pre-diagnosis data on the disease.  I know some people don't participate, because even if they turn up positive for one or more antibodies, nothing can be done.  And they'd rather not know, if nothing can be done.  But now, something can be done: they can enroll in this Teplizumab trial, and maybe (emphasis on "maybe") get a benefit if the trial is successful.  So I think the very existence of this Teplizumab trial will help populate the Natural History Study trial.  And if you have not participated in  TrialNet’s Natural History Study, because you didn't think you could use what you learned, well now maybe you can.

Also, this trial simply could not be run without something like TrialNet’s Natural History Study trial.  The Teplizumab study is dependent on identifying a large group of people who don't yet have type-1, but have a high chance of having the initial onset in the next few years.  That's exactly the type of data that the Natural History Study produces.  Without a trial like Natural History Study it is almost impossible to even test a type-1 preventative drug, because you would need to give it to thousands of people, to even see even 10 or 20 people who would eventually become type-1 diabetic.  By starting with the Natural History Study data, you can run reasonably sized preventative trials, like the 170 for this one.

So this trial helps TrialNet’s Natural History Study, and TrialNet’s Natural History Study helps this trial.  I would expect that as we get more and more data from the Natural History Study these sorts of follow on, prevention studies will be come easier and easy to run (and cheaper), and therefor more common. 

Obviously, this trial is not research aimed at curing type-1 diabetes; it is aimed at preventing it.  So I'm not sure I will continue to follow this in the future.   I do include honeymoon trials.  Should I include prevention trials? 

Non-Type-1 Diabetes News (Learning from Other's Mistakes)
One of the major points I try to make in this blog, is that you can not make your medical decisions based on one study.  No matter how good, how important, how famous, or how much you like the results.  You must look at the whole area of research, and especially follow up studies, before you make a decision.  The Chronic Fatigue Syndrome community is learning this lesson the hard way, as a purported connection between a retrovirus (XMRV) and their disease is coming apart in a very painful and political way:

Editorial: http://newsblogs.chicagotribune.com/tribnation/2011/03/xmrv-chronic-fatigue-syndrome-and-a-fuller-picture-of-their-dubious-connections.html
News: http://www.chicagotribune.com/health/ct-met-chronic-fatigue-xmrv-20110317,0,6116823.story

This quote is from the editorial:

Our story today is about the danger of putting too much stock in one study and forgetting that scientific knowledge is hard won, proven over time, and borne out through many, many studies -- not just one.

Reminder About The Blog
There three ways you can help with this blog:
First, tell other people about it!  Heartfelt testimonials are the best advertising.
Second, tell me about any clinical trials you know about that are not already covered here.
Third, ask me questions that you have.  This tells me what I'm not explaining well, and where I need to put more information into my posts.

Joshua Levy
All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions. 
Blog: http://cureresearch4type1diabetes.blogspot.com
To Get as Email Join here: http://groups.google.com/group/type-1-diabetes-clinical-trials-news
Old Web: http://joshualevy.pbworks.com/DiabetesCureReadyForHumanTrials

Tolerx's Otelixizumab Fails in Phase-III Trial

Otelixizumab (Tolerx / GlaxoSmithKline) Fails Phase-III Trial

The official quote is "did not meet the primary efficacy endpoint".  Basically, the the people who got the drug did not do better than those who did not, in the the most important  measurement of success.  The primary endpoint for this experiment was C-peptide generation, which is a marker for natural insulin production.  Basically, they were hoping that giving this drug would help honeymoon type-1 diabetics generate more of their own insulin, but it did not.

In terms of actions: they have stopped enrollment in their second phase-III trial (DEFEND-2), which shows that they think that there is little to no hope of moving forward with this drug at this time.

So that is about as dead as a phase-III trial can get.  

Press release: http://classic.cnbc.com/id/42028160
Tolerx blog: http://tolerx.com/index.php?page=greenchair&entry=committed-to-the-promise-of-our-normalization-immunotherapy-platform
DEFEND-1: http://www.clinicaltrials.gov/ct2/show/NCT00678886
DEFEND-2: http://www.clinicaltrials.gov/ct2/show/NCT01123083

A Little Discussion

This is not completely unexpected, because there was another similar drug (Teplizumab), which was also an anti-CD3 monoclonal antibody which was also in phase-III clinical trials and just a few months ago, it failed as well.   And for the same reason: did not cure/improve people.  Neither trial had any safety problems.

There is still one anti-CD3 monoclonal antibody out there.  It is NI-0401 by NovImmune, and is in phase-II clinical trials.  Unfortunately, I've never been able to find results for their phase-I study, so I don't hold out much hope.  If you know anything about NovImmune's NI-0401 results, or where they were published, then please tell me.

Previous blogging on Teplizumab:
http://cureresearch4type1diabetes.blogspot.com/search/label/Teplizumab
Previous blogging on NI-0401:
http://cureresearch4type1diabetes.blogspot.com/search/label/NI-0401

So where are we now?

Years ago, there was only one treatment in phase-III trials: DiaPep277.  Last year, there were four.  Since then, two have failed and none have entered, so we are down to two: GAD65 and DiaPep277.  GAD65 is expected to announce their first phase-III results in the next 3 months, but DiaPep277 results are much farther away.

The official musical accompaniment for this blog entry is "River of No Return" from The Jeff Healey Band's album "See the Light".  
      It's a cold hard lesson, that you're gonna learn, on the river of no return....

Joshua Levy
All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions.
Blog: http://cureresearch4type1diabetes.blogspot.com To Get as Email Join here: http://groups.google.com/group/type-1-diabetes-clinical-trials-news
Web: http://joshualevy.pbworks.com/DiabetesCureReadyForHumanTrials