SIPPET Study Results Published in NEJM

Horizons in Hemophilia, Summer, 2016

The detailed findings of the much anticipated SIPPET (Survey of Inhibitors in Plasma-Products Exposed Toddlers) study were published May 26. The study, “A Randomized Trial of Factor VIII and Neutralizing Antibodies in Hemophilia A,” appeared in The New England Journal of Medicine. The lead investigator was Flora Peyvandi, MD, University of Milan.

Peyvandi and fellow investigators found that previously-untreated patients (PUPs) had a significantly higher incidence of inhibitors when treated with recombinant factor VIII (rFVIII) than those treated with plasma-derived factor VIII (pdFVIII) containing von Willebrand factor (VWF). Developing an inhibitor to treatment remains the most prominent and challenging complication for clinicians, occurring in approximately 30 percent of hemophilia patients globally.

In December 2015, a preview of the SIPPET findings presented during the American Society of Hematology’s annual conference raised considerable interest among patients, providers and industry. While earlier studies assessed the overall risk of inhibitor development in patients with hemophilia, the SIPPET study is the first large-scale international trial to randomize patients prospectively for the immunogenicity of pdFVIII vs. rFVIII usage.   

SIPPET was a prospective randomized study, which took place between January 2010 and December 2014, and collected data on 251 children (less than 6 years of age with severe hemophilia A) from 42 sites in 14 countries in Africa, North and South America, Asia and Europe. The authors reported that rFVIII was associated with an 87 percent higher incidence than pdFVIII. Half of the patients were randomly assigned to receive either pdFVIII or rFVIII. The authors reported an overall inhibitor incidence rate of 26.8 percent.

Source: New England Journal of Medicine, original article, published May 26, 2016

The National Hemophilia Foundation’s Medical and Scientific Advisory Council (MASAC) reviewed the study and issued Recommendation #243 (see below).

To read the full MASAC review of the SIPPET study, click here. 

MASAC Recommendations

Based on currently available evidence, MASAC makes the following recommendations:

1. Individuals with greater than 50 exposure days to any recombinant product (i.e. Previously Treated Patients or PTPs) should consider remaining on their current product, since multiple clinical studies have shown that their risk for inhibitor development with any FVIII product is markedly diminished after 50 EDs.
2. Individuals with more than zero and less than 50 exposure days should consider staying on their current recombinant FVIII product, since the differences between SIPPET and numerous other studies may not warrant switching patients who have already initiated a treatment regimen.
3. 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:
   • Initiate therapy with a pdFVIII/VWF product in all PUPs.
   • Initiate therapy with a rFVIII product as previously recommended by MASAC (6).
   • Initiate therapy with a newer rFVIII product.
4. Regardless of which option is chosen, all PUPs should be enrolled in the ATHN data collection system or a clinical trial to assess outcomes.
5. For all classes of treatment products, the risk for inhibitor formation in PUPs is unacceptably high. All efforts by government, HTCs, patient advocates, and industry should be directed at reducing the risk of inhibitor formation.