SIPPET Study: Relevance to the Developing World

As the Annual Congress of the World Federation of Hemophilia concluded in Orlando, Florida I want to shift your attention to and comment on the significance of the SIPPET study to the developing world.

It is fair to say that a majority of the persons with a bleeding disorder live in the developing world and a majority in this group is yet to be diagnosed.  This is a very powerful statement and it is true.  The findings of the SIPPET study (SIPPET) have a whole different meaning to the developing world.  Let us revisit some of the premise of the SIPPET first, focusing on keywords used. Subjects in SIPPET were 'PUPs' (previously untreated patients) who were 'Toddlers' (<6 years old).

In the developing world PUPs and Toddlers are not mutually exclusive. I mean PUPs are not always Toddlers.

What was the definition of PUPs in SIPPET?  PUPs were defined as: "no previous treatment with any factor VIII concentrate, no treatment or minimal treatment (<5 times) with blood components (whole blood, fresh-frozen plasma, packed red cells, platelets, or cryoprecipitate), no treatment with investigational drugs, and a negative test for factor VIII inhibitors at the central laboratory."

By this definition a majority of the diagnosed bleeders in the developing world are PUPs.  This is due to the cost and chronic scarcity of purified (plasma or recombinant) factor in the developing world.  For example, I was a PUP until 29 years of age (in India) until I received my first dose of monoclonal antibody affinity-purified Factor VIII which I received in the US.  There are many PUPs in the developing world.  Some younger, some older.  These PUPs are not 'toddlers'.  Once again this is among the diagnosed bleeders.  In the undiagnosed population, ALL ARE PUPS irrespective of age!!
It is important to follow the adult PUP population in the developing world and chart their genetics and inhibitor development- a 'SIPPET' in adult PUPs.  Are the findings in this population are similar to those on toddlers?


Personal stories
I have previously written about my life in India with hemophilia.  After studying the SIPPET paper and knowing that by definition I was a PUP and on recombinant Factor why I did not develop an inhibitor (thankfully!)?  Here are my thoughts.  Yes, as a PUP, I started on purified plasma-derived Factor VIII.  Recombinant FVIII was not available in the early '90s.  After 4-5 years on this I switched to recombinant Factor in the mid-90s.  I do not have an inhibitor to FVIII as of today.


In the case of another Indian I know; he was diagnosed at the age of 25 and had received minimal treatment for hemophilia until he came to the US at 27.  By SIPPET definition he is a PUP. He started on Recombinant FVIII.  A Factor VIII recovery study showed the recovery was poor. Inhibitor analysis led to him being diagnosed with an inhibitor.


I am by no means suggesting any pattern of inhibitor development depending on treatment with plasma-derived or recombinant FVIII.  These anecdotes goes to validate that inhibitors can develop in PUPs of any age. The cost of treating and the consequences of not diagnosing and therefore not treating an inhibitor in bleeding disorders is too high to leave SIPPET to toddlers alone. A SIPPET-like study in PUP adults is warranted.

SIPPET Study: Relevance to the Developing World

As the Annual Congress of the World Federation of Hemophilia concluded in Orlando, Florida I want to shift your attention to and comment on the significance of the SIPPET study to the developing world.

It is fair to say that a majority of the persons with a bleeding disorder live in the developing world and a majority in this group is yet to be diagnosed.  This is a very powerful statement and it is true.  The findings of the SIPPET study (SIPPET) have a whole different meaning to the developing world.  Let us revisit some of the premise of the SIPPET first, focusing on keywords used. Subjects in SIPPET were 'PUPs' (previously untreated patients) who were 'Toddlers' (<6 years old).

In the developing world PUPs and Toddlers are not mutually exclusive. I mean PUPs are not always Toddlers.

What was the definition of PUPs in SIPPET?  PUPs were defined as: "no previous treatment with any factor VIII concentrate, no treatment or minimal treatment (<5 times) with blood components (whole blood, fresh-frozen plasma, packed red cells, platelets, or cryoprecipitate), no treatment with investigational drugs, and a negative test for factor VIII inhibitors at the central laboratory."

By this definition a majority of the diagnosed bleeders in the developing world are PUPs.  This is due to the cost and chronic scarcity of purified (plasma or recombinant) factor in the developing world.  For example, I was a PUP until 29 years of age (in India) until I received my first dose of monoclonal antibody affinity-purified Factor VIII which I received in the US.  There are many PUPs in the developing world.  Some younger, some older.  These PUPs are not 'toddlers'.  Once again this is among the diagnosed bleeders.  In the undiagnosed population, ALL ARE PUPS irrespective of age!!
It is important to follow the adult PUP population in the developing world and chart their genetics and inhibitor development- a 'SIPPET' in adult PUPs.  Are the findings in this population are similar to those on toddlers?


Personal stories
I have previously written about my life in India with hemophilia.  After studying the SIPPET paper and knowing that by definition I was a PUP and on recombinant Factor why I did not develop an inhibitor (thankfully!)?  Here are my thoughts.  Yes, as a PUP, I started on purified plasma-derived Factor VIII.  Recombinant FVIII was not available in the early '90s.  After 4-5 years on this I switched to recombinant Factor in the mid-90s.  I do not have an inhibitor to FVIII as of today.


In the case of another Indian I know; he was diagnosed at the age of 25 and had received minimal treatment for hemophilia until he came to the US at 27.  By SIPPET definition he is a PUP. He started on Recombinant FVIII.  A Factor VIII recovery study showed the recovery was poor. Inhibitor analysis led to him being diagnosed with an inhibitor.


I am by no means suggesting any pattern of inhibitor development depending on treatment with plasma-derived or recombinant FVIII.  These anecdotes goes to validate that inhibitors can develop in PUPs of any age. The cost of treating and the consequences of not diagnosing and therefore not treating an inhibitor in bleeding disorders is too high to leave SIPPET to toddlers alone. A SIPPET-like study in PUP adults is warranted.

SIPPET The Buzz and MASAC recommendations

What does SIPPET mean to the Hemophilia community?

Sippet was a term more commonly used in the 18th century, whose mention has waned today.  The word 'sippet' refers to a small piece of bread or toast used in a soup or sauce as a garnish.  In modern times its known as a crouton.  But that's not what it means to the hemophilia community. Here its been a buzz word for the past 7 months.  It's an international study comparing inhibitor development in PUPs (previously untreated patients) treated with plasma-derived (pD) or recombinant (Re) Factor VIII.  In a previous post on the SIPPET study I have simplified the study and its results.

The aforementioned buzz started when an abstract on the SIPPET study was presented at the ASH (American Society of Hematology) meeting in early Dec 2015.  The abstract was released in advance of this meeting, in Nov 2105, and both NHF and HFA released a statement on their websites.   Things were quiet over the holidays.  I, a patient with Hemophilia A on recombinant FVIII, heard the word SIPPET for the first time in Feb 2016.  Not much more information was available than just the term, and that there was a higher incidence of inhibitors in recombinant FVIII treated patients.  So I asked around.  The only additional information I got was the study was conducted primarily in Asia and Africa. Hence, the results are less relevant to us in the US.  I have never had an inhibitor and so I remained satisfied with that answer.

My next encounter with SIPPET was in Laurie Kelley's PEN magazine article "The SIPPET Bombshell".  This was a well-written article with a lot of detail of the clinical trial, the strategy, the results and shortcomings.  Note that the article was published in May 2016 and so was likely written in March or April.  Why this is important is that the SIPPET specific information available was only the abstract at ASH.  There were some important questions raised by Paul Clement, the author of the PEN article.

Paul asked:  The results are from an abstract and have not been peer-reviewed and published.  Are the results relevant?  The study was funded by plasma-derived product manufacturers.  Is there a conflict of interest?  Is the sample size large enough to come to a conclusion? Why was long-acting factor not used? How will MASAC respond to these results? These are very relevant questions based on what was known at the time the article was written.  Well, the peer-reviewed paper on SIPPET was published in The New England Journal of Medicine (N Engl J Med 2016; 374:2054-2064 May 26, 2016). 

Me being a researcher in the past helped understand the study some and look at the data, the population studied, other parameters, the results and conclusions more closely.  I knew that NEJM was a top caliber journal (Impact Factor 59) to publish in and the manuscript would have gone through a thorough peer-review.  On the product manufacturers' conflict of interest question, the authors of SIPPET have provided full disclosure statements of all conflicts.  Its obvious that all research studies need funding from one or more sources.  At times its a private foundation, sometimes its a state or federally funded agency ( such as the NIH in the USA).

Patients from India ( ~40), Egypt (~38), Iran (~16), USA (9), Italy (5) and other countries (in smaller numbers) were included.  This answered one question- yes, the study was done not only in Asia and Africa.  Yes, the number studied was small.  My thoughts on this are, if the peer-reviewers had found the sample small they would have commented on this and sent the manuscript back for a greater enrollment or outright rejected the paper.  Sample size is very important in any clinical trial.

To explain the statistical modeling I recruited a good friend.  He designs clinical trials for a large pharmaceutical and has a PhD in Pharmacy.  He would know about the technical appropriateness of the SIPPET study and interpret the results for me.  According to him since the difference between the plasma-derived vs. recombinant population was so significant and the variability in the data was within acceptable limits (lots of statistical jargon simplified) the population studied would be sufficient.  I expect the peer-reviewers held similar views.  On why long-acting Factor was not tested, the answer is quite simple:  It was not available when the study started in 2010.

On, are the long-awaited MASAC recommendations, based on the SIPPET study, in? Patrick James Lynch did an interview with Dr. Glenn Pierce.  Dr. Pierce sits on the board of MASAC.  Patrick, a hemophiliac with a tolerized inhibitor himself, questioned Dr. Pierce on why/how inhibitors form in 20-30% of the patients.  He asked Dr. Pierce on the SIPPET study but did not press him because the interview was conducted soon after the NEJM paper appeared and too early to comment.

Good news, readers!  MASAC released their recommendations ( # 243) today- June 28, 2016.  I will offer my take on it in my next post.  Meanwhile here is Patrick Lynch's interpretation of the MASAC recommendations.

SIPPET Study simplified

The Study
SIPPET is an acronym for 'Study on Inhibitors in Plasma-Product Exposed Toddlers'.  The SIPPET study, published in The New England Journal of Medicine (NEJM), is a clinical trial conducted on male toddlers under age 6 diagnosed with Factor VIII deficiency with anti-coagulant activity of < 1IU/dl and no inhibitors. The principal investigators were based in Milan, Italy, however this study was conducted (between 2010-2015) in 5 countries (India, Egypt, Iran, USA, other).  Prior to this study participants had received either no treatment or minimal treatment with blood products (whole blood, FFP, packed red cells, platelets or cryoprecipitate). 

The Products
The Factor products used in this study varied based on what was licensed for use in the country.  One plasma-derived (Pd) and 1 recombinant (Re) product was used in each country.  Patients were randomly assigned to one or the other product. The Pd products used were:  Alphanate and Fanhdi (Grifols), Emoclot (Kedrion Biopharma), and Factane (LFB Biomedicaments ). The Re products were: Recombinate and Advate (Baxalta), Kogenate FS (Bayer AG) and ReFacto AF (Pfizer).

The Study Design
The investigators had determined, based on some statistical analyses, that a sample size of 300 would be sufficient, accounting for a 10% dropout rate.  The steering committee overseeing the trial decided to terminate the trial in May 2015.  This was done in response to announcement by the World Federation of Hemophilia to consider not using Kogenate FS, for newly diagnosed patients with Hemophilia A, when other, safer, clotting-factor concentrates are available. This was due to higher risk of inhibitors.  I assume this put some limits on conducting the trial in certain countries, possibly due to product licensing issues.


Even though they did start with 303 patients assessed for eligibility, 264 were randomized to receive either Pd or Re Factor VIII. A further pared down patient number- 125 in the Pd group and 126 in the Re group were analyzed. The investigators then characterized these patients based on country, age at first treatment, type of mutation, mutation status (null, not-null), family history of hemophilia, family history of inhibitor development, race or ethnic group, previous treatment, type of treatment (on-demand, standard prophylaxis, modified 'once weekly' prophylaxis and brand of Factor VII used. They have further monitored the inhibitor development characteristics based on type of inhibitor ( all, titer- high/low/peak, persistent/transient) and time of development based on exposure days. A data was analyzed for their statistically differences between the two patient groups.


The Results and Interpretations
The results from the analysis of regression models, have lead the authors of this study to conclude that the rate of inhibitor development was 87% higher with recombinant factor VIII than with plasma-derived factor VIII.  In the editorial, in the same issue of NEJM, Donna DiMichele MD wrote:

"these data must now be integrated globally into the multifactorial decision-making processes underlying product selection for at-risk children with severe hemophilia A. The results are scientifically compelling. Endocytosis, clearance, and antigen presentation are affected by factor VIII protein glycosylation and von Willebrand factor association. That both glycosylation and association with von Willebrand factor are altered by recombinant technology lends immunologic plausibility to the implication that the product source plays a role in inhibitor generation and provides valuable mechanistic insight into the conundrum of factor VIII immunogenicity."



The following is my interpretation of this quote: The results from this study are compelling. the recommendation is to select the product source carefully before starting to treat at-risk (for inhibitors) children with severe Hemophilia A.  Dr. DiMichele refers to an article based on which she surmises that the source of the Factor (in this case Recombinant vs. plasma-derived) could make a difference in the immune response developed to Factor.  The chemical structure of recombinant Factor is different from that in plasma-derived. Further, von Willebrand factor is missing in the recombinant product.  These chemical differences in the Factor VIII structure may lead the inhibitor development noted in the SIPPET study.

The Study Author's Disclosure
To address potential conflicts of interest, the authors have disclosed that Grifols, Kedrion Biopharma and LFB have provided grants to the Angelo Bianchi Bonomi Foundation.  This Foundation is the primary funding agency for this study.  However, they had no input in the trial design; protocol preparation; patient recruitment; data collection, handling, and interpretation; or writing of this publication. The full disclosure by corresponding author, Dr. Peyvandi is available for review here.


Coming soon
What does this study result mean to the patient or the caregiver?  Has this trial answered any question conclusively or has it opened up new ones?  Whom can you look to for answers?