Diary Observational Study in Hemophilia (DOSE): Evaluation of Enrolled Population and Overall Diary Data Capture in Congenital Hemophilia Patients with Alloantibody Inhibitors.
Authors: Young Guy , Shapiro Amy D. , Valentino Leonard A. , Kessler Craig M. , Cooper David L. 
Published: October 2019

Abstract
Abstract 3484
Poster Board III-421

Introduction
Treatment of bleeding episodes in patients with congenital hemophilia (CH) can be complicated by the development of alloantibodies (inhibitors). This results in “difficult to control” bleeding episodes, which could lead to significant joint disease and decreased quality of life (QoL). As the site of treatment has moved from the hemophilia treatment center (HTC) and hospital to the home setting, the correlation between prescribed care and the way patients and their families manage their disease at home and the effects on daily life deserves attention. This analysis reports the overall results of the recently completed DOSE study.

Methods
Patients with congenital hemophilia with inhibitors (CHwI) with 4+ bleeding episodes in the prior 3 months who were prescribed rFVIIa (NovoSeven, Bagsvaerd, Denmark) as their first line or recommended therapy for bleeding episodes including breakthrough bleeds on prophylaxis were eligible for the study. The patients or their caregivers captured all bleed treatments, daily activities, QoL [EQ-5D, health and pain visual analog scales (VAS)], family anxiety/stress, and activity changes over a period of at least 90 days or until they captured 4 bleeds. Patients or caregivers recorded data in primary paper diaries with optional internet-based data entry. Participating sites completed registration forms with demographics, hemophilia history, and descriptions of currently prescribed care.

Results
There were 51 patients enrolled in this study from 18 participating sites. Mean age was 22.6 years (median 16.1), with 27.5% less than age 11, 19.6% ages 11-18, and 39.2% over age 18. The majority were white (70.6%). Mean (SD) weight was 72.4 (43.8) kg (median 61.0 kg). Nearly half (49%) had a central venous access device. The patients were diagnosed with hemophilia A (84.3%) or hemophilia B (15.7%) with inhibitors, with current severity of illnesses described as severe (76.5%) or moderate/severe (19.6%) in most patients. Mean (SD) age at diagnosis was 0.5 (0.7) years (range 0-4 years). Mean (SD) age at first bleed was 0.6 (0.9) years (range 0-6 years). Most subjects had a history of joint bleeds, with muscle, mucosal, and head bleeds also reported. Mean (SD) number of bleeds in the past year was 17.6 (15.4) with mean number of severe bleeds reported as 5.9 (9.2). There were 45.1% reported to have ever had immune tolerance. First line therapy for joint bleeds was rFVIIa in 94.1% with a mean (median) initial dose of 152.2 mcg/kg (120.0), with 33% prescribed 250-270 mcg/kg. Initial dosing for muscle and other bleeds was similar. From the enrolled population, at least 38 patients have completed paper or electronic diaries of 22-180 days duration (median 96 days). There were over 3705 total diary days captured, including 174 bleeding events and 421 bleed treatment days. On average, bleed days accounted for 7.6% of diary days (range 0-68.6%). Of the 174 bleeds, 100 were joint bleeds including 37 target joint bleeds, 19 were muscle bleeds, 4 were mouth/gum bleeds, 2 were in the brain, 1 was in the nose and 1 was in/on the skin, 31 were other. There were instances of two types of bleeds reported during the same episode. Bleed duration was reported as 2.6 (3.0) days (range 1-26).

Conclusions
DOSE represents the first large-scale diary study in the small population of patients with congenital hemophilia with high responding inhibitors. In this preliminary analysis of the data, there are several unexpected and previously unpublished results: 1) there is a surprisingly large number of patients with central venous access particularly when considering the mean age of the group, 2) less than half of the patients have undergone immune tolerance despite the fact that the participating centers are all established Hemophilia Treatment Centers, 3) a significant proportion of patients use doses of 250-270 mcg/kg. We expect further detailed analysis to provide valuable data and insight from which hypotheses can be generated for future studies of this rare patient population.

Disclosures:
Young: Novo Nordisk Inc.: Consultancy, Speakers Bureau. Off Label Use: This abstract describes dosing of rFVIIa that is higher than that in the package insert. Shapiro:Novo Nordisk Inc.: Consultancy, Speakers Bureau. Valentino:Novo Nordisk Inc.: Consultancy, Research Funding. Kessler:Novo Nordisk Inc.: Consultancy. Cooper:Novo Nordisk Inc.: Employment.