The SIPPET Study Answers an Important Question

Researchers have taken an important step toward understanding inhibitor development. Results from a randomized, controlled trial, called the SIPPET study, demonstrated that previously untreated patients with severe hemophilia A treated with recombinant factor VIII (FVIII) have a higher risk of developing inhibitors compared to patients treated with plasma-derived FVIII containing von Willebrand factor (VWF).1

THE ROAD TO SIPPET: A HISTORICAL PERSPECTIVE

Over the years, medical research has tried to answer an important question: Does the source of FVIII product used in replacement therapy impact the likelihood of inhibitor development? Studies have reported varying rates of inhibitor development with 2 types of FVIII products, plasma-derived and recombinant.1-4

2003
Wight & Paisley
Systematic review of 50 published studies2

Researchers Wight and Paisley reviewed the best evidence that was available in the published literature in 2003. Within the 50 studies, a subset of 13 examined inhibitor incidence in 801 previously untreated patients who received a single FVIII product, and found that plasma-derived FVIII had a lower cumulative risk of inhibitors vs recombinant FVIII.

 
2006
CANAL Study
Retrospective observational study of 316 patients3

CANAL stands for Concerted Action on Neutralizing Antibodies in severe hemophilia A. It was a retrospective cohort study that included 316 previously untreated patients with severe hemophilia A. CANAL concluded that the risk of inhibitor development was slightly lower with plasma-derived products compared with recombinant products. But the difference was not statistically significant.

2013
RODIN Study
Prospective observational study of 574 patients4

RODIN stands for Research of Determinants of Inhibitor Development. It was a prospective observational study that included 574 previously untreated patients born between 2000 and 2010. Results showed no difference in the risk of developing inhibitors with plasma-derived FVIII vs recombinant FVIII. However, RODIN was not a randomized trial, and only 15% of the patients received plasma-derived FVIII.

THE QUESTION REMAINED UNANSWERED1

Experiments showed that plasma-derived FVIII products containing VWF may help reduce the risk of inhibitor development, but the observational studies that preceded SIPPET could not confirm this. These studies were uncontrolled, meaning that other risk factors and influences possibly biased the results, rendering them inconclusive. The SIPPET study was necessary to demonstrate if there was a difference in inhibitor development between recombinant FVIII and plasma-derived FVIII containing VWF in previously untreated patients.

 

SIPPET STUDY RESULTS1

The study demonstrated a significantly higher incidence of inhibitors with recombinant FVIII vs plasma-derived FVIII containing VWF. The rate of inhibitor development with recombinant FVIII was nearly double that with plasma-derived FVIII/VWF (HR=1.87, 95% CI:1.17-2.96). The authors concluded that these results may have implications on how physicians plan treatment in previously untreated patients with hemophilia A.

Cumulative incidence of inhibitor development1

Plasma-derived FVIII
125 patients
Recombinant FVIII
126 patients

Previously untreated patients with inhibitors

Recombinant FVIII had an 87% higher rate of inhibitor development than plasma-derived FVIII/VWF. (Cox regression HR=1.87, 95% CI: 1.17-2.96)1

SIPPET STUDY DESIGN1

SIPPET is an international, multicenter, prospective, randomized, open-label study designed to examine the incidence of inhibitor formation in 2 groups of previously untreated patients. Patients were randomized 1:1 to be treated with either plasma-derived FVIII containing VWF or recombinant FVIII.

*An exposure day was defined as a calendar day with 1 or more infusion of FVIII.

Reference

  1. Peyvandi F, Mannucci PM, Garagiola I, et al. A randomized trial of factor VIII and neutralizing antibodies in hemophilia A. N Engl J Med. 2016; 374(21):2054-2064.

SIPPET STUDY DESIGN1

SIPPET is an international, multicenter, prospective, randomized, open-label study designed to examine the incidence of inhibitor formation in 2 groups of previously untreated patients. Patients were randomized 1:1 to be treated with either plasma-derived FVIII containing VWF or recombinant FVIII.

*An exposure day was defined as a calendar day with 1 or more infusion of FVIII.

REFERENCE

  1. Peyvandi F, Mannucci PM, Garagiola I, et al. A randomized trial of factor VIII and neutralizing antibodies in hemophilia A. N Engl J Med. 2016; 374(21):2054-2064.

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REFERENCES

  1. Peyvandi F, Mannucci PM, Garagiola I, et al. A randomized trial of factor VIII and neutralizing antibodies in hemophilia A. N Engl J Med. 2016;374(21):2054-2064.
  2. Wight J, Paisley S. The epidemiology of inhibitors in haemophilia A: a systematic review. Haemophilia. 2003;9:418-435.
  3. Gouw SC, van der Bom JG, Auerswald G, Ettinghausen CE, Tedgård U, van den Berg HM for the CANAL Study Group. Recombinant versus plasma-derived factor VIII products and the development of inhibitors in previously untreated patients with severe hemophilia A: the CANAL cohort study. Blood. 2007;109(11):4648-4654.
  4. Gouw SC, van der Bom JG, Ljung R, et al, for; the PedNet and RODIN Study Group. Factor VIII products and inhibitor development in severe hemophilia A. New Engl J Med. 2013;368(3):231-239.
  5. National Hemophilia Foundation. MASAC Update on SIPPET. National Hemophilia Foundation website. https://www.hemophilia.org/Newsroom/NHF-Community-News/MASAC-Update-on-SIPPET. Published March 9, 2016. Accessed May 25, 2016.