The international immune tolerance study: a multicenter prospective randomized trial in progress

It was with great interest that we readMannucci’s commentary on the need for randomized trials in hemophilia [1]. The international immune tolerance induction (I-ITI) study, initiated in July 2002, is the only prospective randomized multicenter trial of immune tolerance therapy (ITI). A previously published retrospective meta-analysis of the International [2] and North American [3] ITI registries suggested that outcome was independent of dosing regimen in good-risk high titer inhibitor patients with severe hemophilia A (sHA) [historical peak titer ‡ 5 Bethesda Units (BU) mL and £ 200 BU mL; and starting titer of < 10 BU mL] [4]. The I-ITI trial was designed to test this hypothesis by randomizing 150 good-risk pediatric sHA patients aged < 8 years with inhibitors present for < 12 months (criterion recently extended to < 24 months) to receive either high(200 IU kg day) or low-dose (50 IU kg thrice weekly) factor (F) VIII. Success is defined by a negative inhibitor titer [< 0.6 BU mL; < 0.3 BU mL (Nijmegen method)], and normal FVIII recovery (‡ 66% of expected) and half-life (‡ 6 h). Subjects use the FVIII product of their physician’s choice. Randomization is computerized and uses the method of minimization to balance treatment arms for product type and starting inhibitor titer. Data are collected electronically, analyzed centrally, and adjudicated prospectively by an independent Data Safety Monitoring Committee (DSMC). The randomization code will not be broken until the study concludes. However, with more than a third of the targeted recruitment completed as of January 2006, we wish to share some interesting preliminary observations with the international hemophilia community. Eighty centers in 21 countries fromNorth America, Western Europe, Oceana and Asia have recruited 54 subjects into the study to date. Forty-five of these subjects, whose titers have declined to< 10BU, have been randomized so far at amedian age of 25 months (range: 13–80). These subjects have required a median of 5 months (range: 0–12) from diagnosis for their titers to decline to < 10 BU mL. Importantly, the early concern that allowing for this decline in inhibitor titer would result in a considerable delay in ITI initiation has not yet been warranted. So far, 36 subjects are undergoing or have undergone tolerance with recombinant FVIII; eight are receiving plasma-derived product. Median peak historical and starting titers for the entire randomized cohort are currently 21.0 (range: 7–175) and 5.0 (range: 0.6–9.4) BU mL, respectively. Notably, recruits have so far come from the whole range of inhibitor titers prescribed by the protocol. Themedian peak titer on ITI at this time in the study is 3.1 (0.6–2093) BU mL. The randomized group has been on ITI for a median of 20.5 months (range: 1–33). Twenty-eight (62%) have achieved a negative titer after a median of 6 months (range: 1–18) on therapy. Twenty-three (50%) now have a normal FVIII recovery following a median of 7.5 months of ITI (range: 2–25). To date, 14 (31%) have become tolerant after a median of 12 months (range: 5–25) of Correspondence: Donna DiMichele, New York Weill Cornell Center, 525 East 68th Street, P695 New York, NY 10021, USA. Tel. : +1 212 746 3418; fax: +1 212 746 8986; e-mail: dmdimich@med.cornell. edu