The SIPPET Study & MASAC’s Recommendation: What Does It Means For Me?

The SIPPET Study & MASAC’s Recommendation: What Does It Means For Me?

By Patrick James Lynch

Disclaimer

I am not a doctor or a medical professional. I am, among other things, a writer with severe hemophilia A and a tolerized inhibitor. Following the article I wrote in January summarizing the SIPPET abstract, the National Hemophilia Foundation (NHF) engaged me to write a patient-facing article summarizing NHF’s Medical and Scientific Advisory Council’s (MASAC) recommendation in response to SIPPET’s publication. 

In agreeing to do so, my goal was to help patients and families understand MASAC’s recommendations related to the SIPPET study on inhibitor formation, and to empower their decision making in choices about care.

To improve my understanding of the issues at hand, I was invited to be a guest listener on MASAC’s conference calls discussing SIPPET and was copied on the ensuing emails with draft after draft of what is now a completed recommendation. I hope this article helps provide some clarity on what is admittedly a complicated set of study results. To that end, the article is written in my language, not in dense medical-ese. 

Once again, I am not a medical professional, and any decision about you or your child’s medical care should be made by you, your family, and your child in conversation with your usual healthcare team. 

Opening

One of the many challenges that come with a hemophilia diagnosis is that you sorta kinda have to become something of a medical expert. And an insurance expert. And a packing expert (factor can fill a suitcase in no time!). 

It’s an unfortunate reality of having a rare, chronic disorder: there are many needs and few who understand. To further complicate matters, each individual’s unique biology expresses hemophilia differently. For example, my brother and I were born two-and-a-half-years apart, both diagnosed with severe hemophilia A. Growing up, I experienced many breakthrough bleeds, developed target joints, and acquired an inhibitor. My brother bled rarely, had one pseudo target joint, and never developed an inhibitor. 

Variances like this are why patients and caregivers in the bleeding disorders community are encouraged to be educated, proactive, and to create individual care plans tailored to each person’s unique needs. This feels important to emphasize, given that over the past 30 years, significant progress in the prevention of inhibitors has been challenged by, among other things, the complexities of the human immune system and the uniqueness of each individual human body. Such individuality makes blanket treatment plans inappropriate and requires individual patients/families to educate themselves and weigh all considerations before making a decision.

What Is SIPPET?

The much anticipated SIPPET (or “SIPPET study,” as it’s commonly referred to), which is an acronym for Survey of Inhibitors in Plasma-Products-Exposed Toddlers, was published on Friday May 26th, 2016, in the New England Journal of Medicine (1), a prestigious peer-reviewed medical journal. 

The study’s aim was to investigate if there was a correlation between inhibitor formation and the clotting factor product class (which I’ll explain more specifically later) used by participating, previously untreated patients (PUPs) with severe hemophilia A. Data was collected from 251 children with severe hemophilia A, age 6 or younger, across 42 participating sites from 14 countries in Africa, Asia, Europe, North America, and South America.

SIPPET’s Construction, In Broad Terms.

Taking place from 2010-2014, SIPPET was a prospective, randomized, controlled trial, and it’s worth taking a moment to explain what that means. 

A prospective study is a study designed and constructed before any of the subjects developed the outcomes of interest (2)-- in this case, the outcome of interest being the formation of an inhibitor by a PUP. SIPPET being a prospective study is noteworthy, as many studies on inhibitor formation are retrospective, making it challenging to gather clear, accurate information on care regimens, treatment history, and other factors relevant to inhibitor formation (3). 

A randomized, controlled trial means that participating PUPs were randomly selected to receive their specific treatment regimen (4). In this case, participating PUPs were randomly selected to receive either various types of plasma-derived products containing von Willebrand factor or various types of recombinant products. 

SIPPET’s Results, In Broad Terms.

In total, 251 PUPs completed the study. 126 PUPs received a recombinant FVIII product (rFVIII) and 125 PUPs received plasma-derived FVIII containing von Willebrand factor (pdFVIII/VWF). 

It’s important to recognize that this study compared classes of product (i.e., recombinant and plasma-derived). In other words, SIPPET did not compare any specific product from one company to a specific product from another company. 

Furthermore, the study involved only certain recombinant products, not all, and only certain plasma-derived products that contain von Willebrand Factor. I’ll extrapolate on the significance of these details later.

The results:

Of the 125 PUPs with severe hemophilia A treated with pdFVIII/VWF, the total number to develop an inhibitor was 29 (26.8%). A high-titer inhibitor developed in 20 of those PUPS (18.6% of total patients).

Of the 126 PUPs with severe hemophilia A treated with rFVIII, the total number to develop an inhibitor was 47 (44.5%). A high-titer inhibitor developed in 30 of those PUPS (28.4% of total patients).

Note: Inhibitors are measured in titers, and more specifically in what are called Bethesda Units (BU). Inhibitors are broadly classified as either Low Titer (less than 5 BUs, low strength inhibitor; patients can sometimes still be treated with factor products; low titer inhibitors sometimes resolve on their own) and High Titer (greater than 5BUs, strong inhibitor, patients receive no benefit from factor products; do not resolve on their own) (5).

To use MASAC’s language, PUPs taking rFVIII products showed a “significant increase in inhibitor development,” and these figures have rightfully sparked a debate as to what this means for our community (7). 

As the leading medical and scientific council for the bleeding disorders community, MASAC’s recommendation in response to SIPPET has been greatly anticipated, and as of June 28th, 2016, it is now available. If you haven’t already, I’d highly recommend taking a few minutes to read MASAC recommendation on SIPPET (Survey of Inhibitors in Plasma-Product-Exposed Toddlers), Document # 243.

What Does This Mean For Me?

For starters, it’s worth remembering the participants in- and the target audience for- this study: previously untreated patients, or PUPs. Remember that the “T” in SIPPET stands for “toddlers” and that this study was investigating the rate of inhibitor formation specifically in PUPs with severe hemophilia A. 

If a patient has received more than 4-5 doses of factor, he is considered to be a previously treated patient (PTP). Once a patient has been exposed to a recombinant factor product for 50 days (Exposure Days, or EDs), his risk of developing an inhibitor is less than 1% (6). Therefore, one of MASAC’s recommendations is that PTPs with more than 50 EDs, “consider remaining on their current product” (7).

Now, for rarely treated patients (between zero and 50 EDs) and parents of rarely treated patients, MASAC has made the following recommendation:

"Individuals with more than zero and fewer than 50 exposure days should consider staying on their current recombinant FVIII product, since the differences between SIPPET and numerous other studies (8 & 9) may not warrant switching patients who already initiated a treatment regimen" (7).

The language used here assumes said individuals are taking a recombinant product already. This is attributed to MASAC’s 2000 recommendation that recombinant products be viewed as the, “treatment of choice” (10). 

Given the results of SIPPET, this recommendation may strike some who were hoping for a more sweeping response as surprising, but there are a few points worth emphasizing that I believe support this recommendation:

1.  As stated in the quotation, other studies investigating inhibitor formation do not necessarily support SIPPET’s findings. I have come to learn that treaters, scientists, and researchers tend not to make broad statements or recommendations about science and medicine without heavily supported data. SIPPET’s data is not heavily supported by other studies on inhibitor formation.

2.  We know that patient ethnicity is one relative component in determining a patient’s risk for developing an inhibitor. Most patients in SIPPET were from Egypt, India, and Iran, but to date, most data on inhibitors has come from studies on Caucasians. We don’t yet have enough data to understand how to relatively compare across these populations.

3.  Both the pdFVIII/VWF and rFVIII products used in SIPPET do not necessarily reflect products available or commonly used in the United States:

a)  Currently, third-generation rFVIII and long-lasting factor products are used by the majority of U.S. patients. Only 16% of SIPPET patients who were treated with rFVIII (8% of total participants) used one of these products.

b)  Currently, Alphanate, Humate P, and Koate DVI are the three pdFVIII/VWF products licensed in the U.S. Only 7% of SIPPET patients who were treated with pdFVIII/VWF (3.5% of total participants) used Alphanate. None used Humate P. None used Koate DVI.

During my conversation with Dr. Steven Pipe (Medical Director for University of Michigan’s Hemophilia and Coagulations Disorders Program and Chair of MASAC) in preparation for the article I wrote on SIPPET in January, he raised excellent hypothetical questions that gave me a window into the clinician's thought process, and the questions are pertinent to both points 2 and 3 above:

“Is the population of patients in this study really the same as patients I look after in my patient population? And can I really extrapolate from the observations of this study to the patient that I have in front of me in my clinic today?” 

Understanding Dr. Pipes’s perspective and considering the above information about SIPPET’s patient population and specific product choices, it becomes all the more clear why it’s difficult for MASAC or any advising body to make a broad recommendation on the treatment of PUPs based on SIPPET’s data. Similarly, these complications further emphasize why we, as the patient population, must extrapolate data from various studies of interest to make decisions about our own individual treatment, in consultation with our healthcare team. 

Now to look at MASAC’s other recommendation specifically pertaining to PUPS:

"Newly diagnosed individuals and their caregivers should consider the new data from the SIPPET study in the context of all the accumulated data on inhibitor formation in PUPs and the pathogen safety risk/benefit of the two product classes and consider the following options:

a.  Initiate therapy with a pdFVIII/VWF product in all PUPs.

b.  Initiate therapy with a rFVIII product as previously recommended by MASAC (10).

c.  Initiate therapy with a newer rFVIII product.

MASAC lays out the various therapy options for the treatment of PUPs, and does so without urging patients toward one treatment or another, despite having previously recommended that all PUPS initiate treatment on a rFVIII product. 

In my opinion, this is quite significant, as it indicates that MASAC understands that while the data here does not satisfy MASAC’s requirements for a demonstrative shift in its recommendations, the data does elicit enough concern that PUPs and their caregivers should consider all available data and treatment options. 

Also worth noting is that MASAC’s recommendation encourages participation in data collection on the treatment choices and associated outcomes for PUPs. Given that the overall rate of inhibitor formation in people with severe hemophilia A is somewhere between 20-30%, an unacceptably high number, more data collection enables more data to be studied in the ongoing effort to learn more about inhibitor formation.

Finally, community members must keep in mind that, while improvement to donor selection and blood screening practices have vastly improved in the last 30+ years, transfusion-related infections with known viruses continue to occur (11). MASAC’s recommendation references that, "some pathogens such as parvovirus B19 are less susceptible to heat and solve-detergent inactivation methods, are small enough to pass through nanofiltration devices, and therefore are surrogate markers for future viruses of very small size (7)." This cannot be ignored when a patient is considering a plasma-derived product.

What Do I Do Next?

NHF often refers to the patient-base as consumers. Honestly, I didn’t care for this moniker at first, preferring the less-capitalistic title of patient, but having spent time reflecting on NHF’s word choice, I’ve come to appreciate the title of consumer: it suggests that there is a marketplace, and that it’s the responsibility of the marketplace to meet my consumer needs. The ability or inability of entities in the marketplace to meet my consumer needs will determine whether or not each entity is ultimately viable. That’s an empowering position to be in.

Growing emphasis on individualized care in the United States healthcare system is a wonderful thing, but for us patients- or “consumers” it means that we must be active in our self-education, advocacy, and care plan development. Gone are the more passive days wherein patients would await the supreme word of their doctor to determine the course of their health. Today healthcare is a conversation, and treatment is tailored to the individual. 

One of the Hemophilia Federation of America’s core messages is, “Ask Questions. Be Involved. Take Action.” If you are the caregiver of a PUP, it’s in your best interest to read all available information on inhibitor formation and product safety. Come up with a list of questions. Take those questions to your healthcare team and together, discuss what options are available to you, weighing all the various, often complex, considerations.

Hemophilia isn’t an easy diagnosis to manage, and inhibitors are even more challenging, but as a community we are fortunate to have an abundance of educational resources and organizational support. You are never alone in this community and should not hesitate to contact leadership at your local chapter for additional support or guidances.

Additional Resources

Currently, the article on SIPPET is available for a fee, but there are various articles available for free that breakdown and analyze the information. Familiarize yourself with them all. Here are just a few:

  1. MASAC Recommendation on SIPPET (Survey of Inhibitors in Plasma-Product-Exposed Toddlers). MASAC Document #243, National Hemophilia Foundation, 2016, Accessed June 28, 2016, https://www.hemophilia.org/Researchers-Healthcare-Providers/Medical-and-Scientific-Advisory-Council-MASAC/MASAC-Recommendations/MASAC-Recommendation-On-SIPPET-Survey-of-Inhibitors-in-Plasma-Product-Exposed-Toddlers.
  2. “SIPPET Study Results Published in NEJM,” National Hemophilia Foundation, May 26, 2016, https://www.hemophilia.org/Newsroom/Medical-News/SIPPET-Study-Results-Published-in-NEJM
  3. “Update #3: SIPPET Study Released,” Hemophilia Federation of America, June 14, 2016, http://www.hemophiliafed.org/news-stories/2016/06/update-3-sippet-study-released/
  4. Paul Clement, “The SIPPET Bombshell,” PEN, May, 2016, http://www.kelleycom.com/pen/2016_05_PENrev.pdf

References

  1. Flora Peyvandi, et al.,"A Randomized Trial of Factor VIII and Neutralizing Antibodies in Hemophilia A — NEJM," New England Journal of Medicine, Accessed June 17, 2016, http://www.nejm.org/doi/full/10.1056/NEJMoa1516437. 
  2. Wayne W. LaMorte, "Prospective Versus Retrospective Cohort Studies," Boston Univeristy College of Public Health, Accessed June 17, 2016, http://sphweb.bumc.bu.edu/otlt/MPH-Modules/EP/EP713_CohortStudies/EP713_CohortStudies2.html
  3. K. Gomez, R. Klamroth, et al., “Key Issues in Inhibitor Management in Patients with Haemophilia,” Blood Transfusion, 12 (Suppl 1), 2014, http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3934290/.
  4. "Definition of Randomized Controlled Trial," MedicineNet, Accessed June 17, 2016, http://www.medicinenet.com/script/main/art.asp?articlekey=39532
  5. "Inhibitors - Hemophilia Federation of America," Hemophilia Federation of America Inhibitors Comments, Accessed June 17, 2016, http://www.hemophiliafed.org/bleeding-disorders/inhibitors/
  6. Samantha C. Gouw, et al., "Treatment-related Risk Factors of Inhibitor Development in Previously Untreated Patients with Hemophilia A: The CANAL Cohort Study," Blood, 2007, Accessed June 17, 2016. http://www.bloodjournal.org/content/109/11/4648?sso-checked=true. 
  7. MASAC Recommendation on SIPPET (Survey of Inhibitors in Plasma-Product-Exposed Toddlers). MASAC Document #243, National Hemophilia Foundation, 2016, Accessed June 28, 2016, https://www.hemophilia.org/Researchers-Healthcare-Providers/Medical-and-Scientific-Advisory-Council-MASAC/MASAC-Recommendations/MASAC-Recommendation-On-SIPPET-Survey-of-Inhibitors-in-Plasma-Product-Exposed-Toddlers.
  8. Gouw, et al., “Treatment-related Risk Factors” 
  9. Samantha C. Gouw, et al., “Factor VIII Products and Inhibitor Development in Severe Hemophilia A,” The New England Journal of Medicine, January 17, 2013,  http://www.nejm.org/doi/pdf/10.1056/NEJMoa1208024
  10. MASAC Recommendation Regarding the Use of Recombinant Clotting Factor Replacement Therapy. MASAC Document #169, National Hemophilia Foundation, 2000, Accessed June 17, 2016, https://www.hemophilia.org/Researchers-Healthcare-Providers/Medical-and-Scientific-Advisory-Council-MASAC/MASAC-Recommendations/MASAC-Recommendation-Regarding-the-Use-of-Recombinant-Clotting-Factor-Replacement-Therapy
  11. "Blood Safety," Centers for Disease Control and Prevention, 2015, Accessed June 17, 2016, https://www.cdc.gov/ncbddd/hemophilia/bloodsafety.html

About the Author

Patrick James Lynch is the CEO and Co-Founder of the award winning digital content agency Believe Limited, through which he has developed popular community programs such as the inspiring speaker series “Powering Through,” the teen empowerment program “The Impact Awards,” the stop-motion animation series about a girl with VWD “Helping Hany,” the doc-series on WFH’s Humanitarian Aid Program “Treatment for All,” and the sensational comedic web series “Stop The Bleeding!” He is the 2013 Recipient of HFA’s Terry Lamb Award & the 2014 Recipient of NHF’s Loras Goedken Award. Patrick lives with severe hemophilia A dedicates his work to the memory of his little brother Adam. @pjlynch.