SIPPET Slowly: This One's HOT!

Inhibitor Development in Previously Untreated Patients or Minimally Blood Component-Treated Patients With Severe Hemophilia A When Exposed to von Willebrand Factor-Containing Factor VIII (vWF/FVIII) Concentrates and to Recombinant Factor VIII Concentrates: an International, Multicenter, Prospective, Controlled, Randomized, Open-Label, Clinical Trial (The SIPPET Trial)

This independent study is sponsored by Fondazione Angelo Bianchi Bonomi.

NCT01064284

77 centers: 32 in nine European countries, 14 in three Asian countries, six in two African countries, 15 in the United States, 10 in four Latin American countries

300 patients (129 randomized to date)

This is a prospective trial designed to compare inhibitor incidence in previously untreated patients or minimally blood-component-treated patients with hemophilia exposed to plasma-derived vWF/FVIII or recombinant FVIII products. Eligibility criteria are as follows: male sex, age <6 years, severe hemophilia A (FVIII:C <1%) without evidence of an inhibitor, previously untreated or minimally treated (<5 exposure days) with blood components only.

Patients are randomized to receive exclusively a single FVIII product (plasma-derived or recombinant), and they are then followed until they reach one of the following three endpoints: inhibitor development, 50 days of exposure to the FVIII product, or three years from enrollment. The primary endpoint is the proportion of patients who develop antifactor VIII antibodies based on analysis performed following every three to four exposure days or every three months, whichever occurs first. Patients on prophylactic therapy will be tested every two weeks. The following secondary objectives are aimed at identifying risk factors for inhibitor development: age at first treatment; bleeding severity; surgery; treatment intensity; treatment regimen; vaccination history; concurrent infections; complications of venous access; delivery type; breastfeeding; FVIII gene defect; FVIII antigen concentration; HLA type, IL-10.G (promoter region microsatellite); TNF-α concentration; and CTLA-4 polymorphisms.

The most challenging complication of hemophilia A is inadequate control of bleeding due to development of antibodies against FVIII. An unresolved issue is whether plasma-derived and recombinant FVIII products are associated with different risks of inhibitor development. A systematic review of published studies was uninformative because the analyzed trials differed in designs, case definitions, treatment regimens, patients’ characteristics, FVIII inhibitors assays, sample size, and duration of follow-up (Iorio A et al. J Thromb Haemost.2010;8:1256-1265). The SIPPET trial is the first prospective, randomized study aimed at establishing whether recombinant and plasma-derived products confer a different relative risk of developing factor VIII antibodies.

Development of anti-factor VIII antibodies greatly complicates management of patients with hemophilia A, as treatment outcome using bypass agents, such as recombinant factor VIIa or factor IX complexes, is unpredictable and expensive. Eradication of inhibitors by inducing immune tolerance using scheduled FVIII infusions is effective in ~70 percent of patients, but the process is demanding and costly. The SIPPET study is aimed at determining if the incidence of antibody development is influenced by the source of replacement product. How the findings will influence practice ultimately will depend on the magnitude of differences (if observed) and perhaps the willingness of patients to put aside concerns about safety if the plasma-derived product proves superior. Any randomized trial that involves a rare disease is a monumental undertaking, but the SIPPET trial, which involves patients and investigators in 19 countries on four continents, is particularly noteworthy.