Factor VIII Dosing and Preventive Efficacy in Obese Patients with Hemophilia (BMI ≥30 kg/m²) – a Post-Hoc Sub-Analysis of the guardian™ Trials

Introduction & Objectives: Given the longer life expectancy for people with hemophilia today, an increase in diseases such as obesity (defined as body mass index [BMI] ≥30 kg/m²) (Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults – The Evidence Report. National Institutes of Health. Obes Res 1998;6 Suppl 2:51S–209S), diabetes, and cardiovascular disease poses an increasing challenge to their care. Obesity may be of special relevance in hemophilia, both in terms of dosing as well as in impact on general health, yet little is known and published on this topic. Factor (F) VIII dosing is based on body weight (BW) and it has been shown that in vivo recovery increases with BMI due to a decrease in volume of distribution (Blanchette VS, et al. J Thromb Haemost 2008;6:1319–1326). Consequently, dosing based on ideal BW instead of actual BW has been suggested (Hanley MJ, et al. Clin Pharmacokinet 2010;49:71–87; Henrard S, et al. Haematologica 2013;98:1481–1486). In addition to negative effects on general health, obesity can also affect joint health. Intuitively, an increased BMI can have a deleterious effect on joints and aggravate arthropathy, which could theoretically be reflected in higher annualized bleeding rates (ABRs). However, published data are scarce, and conflicting or inconclusive. We performed a post hoc analysis of prevalence, dosing, and outcomes recorded in obese patients in clinical trials of turoctocog alfa (NovoEight^®), a new B-domain–truncated recombinant FVIII product.

Materials & Methods: Previously treated patients with severe hemophilia A without FVIII inhibitors participated in the phase 3a guardian™1 trial (Lentz SR, et al. Haemophilia 2013;19:691–697), and most continued in the extension trial, guardian™2, which is currently ongoing. Adult patients with BW >120 kg were not eligible (in guardian™1), but there were otherwise no restrictions regarding BMI. Prophylactic treatment with turoctocog alfa was given every other day or 3 times weekly. All patients started with an actual body–weight based dose of 20 IU/kg, which could be increased at the investigator’s discretion. Dosing based on ideal BW was not used. Patients who participated in either guardian™1 or guardian™2 and who were ≥18 years old at entry to the latest of the 2 studies (i.e., at entry to guardian™2 unless the patient only participated in guardian™1) were included in this analysis. Data were included up to 30 June 2013.

Results: Mean age at the time of enrollment in the guardian™2 trial was 32 years for obese and 31 years for non-obese patients. Mean duration of observation was 2.23 years per patient for obese and 2.16 years for non-obese patients. Twenty-two of 137 patients (16.1%) had a BMI of ≥30 kg/m² at some point during the observation period. Of these, 13 patients were from the US (comprising 46% of the total adult US patient cohort), which is approximately double the percentage reported in data compiled by the Centers for Disease Control and Prevention in 2005 (Report on the Universal Data Collection Program. 2005;7[1]:30–39).

Mean turoctocog alfa dose/kg BW used for prevention per administration was 25.9 IU/kg in obese and 28.3 IU/kg in non-obese patients (p=0.20). The mean annualized consumption of turoctocog alfa was 4154 IU/kg/year in obese and 4393 IU/kg/year in non-obese patients (p=0.39). The estimated mean ABR was 3.28 and 3.85 bleeds/patient/year in the obese and non-obese patients, respectively (p=0.57).

Conclusions: In the guardian™ clinical trial population examined in this analysis, 16.1% of the total and 46% of US patients were obese, thus highlighting the importance of this co-morbidity in modern hemophilia care. Dosing was similar for both non-obese and obese patients, which was expected given the setting of relatively rigid (and body-weight based) dosing in these trials. Importantly, no statistically significant difference in ABR between obese and non-obese patients was found in the guardian™ trials. These findings could be related to the small subgroup population size and exclusion of patients with BW >120 kg. Given the high prevalence of obesity and its potential effect on pharmacokinetic parameters, joint health, and overall health status, more research is needed on this topic.