Health‐related quality of life and health status in persons with haemophilia A with inhibitors: A prospective, multicentre, non‐interventional study (NIS)

Introduction Real‐world data (RWD) on health‐related outcomes in persons with haemophilia A (PwHA) provide insights into patient needs and can guide clinical study design. A global, prospective, non‐interventional study (NIS; NCT02476942) collected detailed RWD on bleeding outcomes, health‐related quality of life (HRQoL) and health status in PwHA treated per local routine clinical practice. Aim To report HRQoL and health status in the adult/adolescent PwHA with inhibitors cohort in the NIS. Methods This cohort enrolled PwHA aged ≥12 years with high‐titre factor VIII inhibitor history. Participants remained on their usual treatment (no protocol‐specified interventions). Health‐related outcomes: Haemophilia Quality of Life Questionnaire for Adults (Haem‐A‐QoL), Haemophilia‐specific Quality of Life Questionnaire for Children Short Form (Haemo‐QoL SF), EuroQol 5‐Dimensions 5‐Levels (EQ‐5D‐5L) index utility score (IUS) and visual analogue scale (EQ‐VAS). Results One hundred three participants were enrolled on episodic (n = 75) or prophylactic treatment (n = 28); median (range) age, 31 (12‐75) years; median (range) observation time, 26 (4‐70) weeks. Haem‐A‐QoL scores indicated impairments in HRQoL aspects; comparable between episodic/prophylactic regimens and relatively consistent over time. Haemo‐QoL SF scores with both regimens varied over time, and appeared poorer with episodic than prophylactic treatment. IUS and EQ‐VAS were comparable between regimens, stable over time and lower on bleeding days. Mean proportions of missed work and school days were 16% and 23%, respectively; mean (standard deviation) number of days hospitalized was 3.2 (8.8) (comparable between groups). Conclusions These RWD demonstrate that PwHA with inhibitors have impaired HRQoL, despite standard treatment, and that more effective treatment options are needed.


| INTRODUC TI ON
Haemophilia A, characterized by coagulation factor VIII (FVIII) deficiency, is the most prevalent form of haemophilia. 1 Persons with haemophilia A (PwHA) are at high risk of frequent and prolonged bleeding 2 and related sequelae. This may lead to poor quality of life and can affect emotional, social and physical components of patients' well-being and function. [3][4][5][6] The current standard of care for PwHA is intravenous FVIII replacement therapy, which leads to the development of anti-FVIII alloantibodies (inhibitors) in up to 30% of previously untreated PwHA, 7 reducing treatment effects, limiting treatment options and leading to increased risk of morbidity and mortality. 8,9 Standard therapeutic options for PwHA with inhibitors include immune tolerance induction (ITI), which attempts to eradicate inhibitors, and bypassing agents (BPAs) to prevent or treat bleeding. 10 Prophylaxis with BPAs is especially burdensome, requiring infusions every other day. 11,12 Consequently, the majority of PwHA with inhibitors receive episodic BPA treatment. 13 The efficacy of BPAs in the treatment or prevention of bleeding has been shown to be suboptimal. 8,14,15 Validated disease-specific measures are available for assessment of health-related quality of life (HRQoL) in children, adolescents and adults with haemophilia, [16][17][18] but HRQoL and health status outcomes data are limited for PwHA with inhibitors. Moreover, until recently, 19,20 most studies assessing HRQoL had been conducted as part of interventional clinical trials, primarily in PwHA without inhibitors. 21,22 Consequently, additional real-world data (RWD) assessments are needed to determine HRQoL and overall health status in PwHA with inhibitors receiving routine clinical care.
An international non-interventional study (NIS) was conducted to prospectively collect detailed RWD in PwHA, with and without inhibitors, treated according to local routine clinical practice. As long as they met respective eligibility criteria, participants from this cohort who were compliant with requirements of the NIS (ie, completed the Bleed and Medication Questionnaire on a regular basis) could start rolling over into the phase III HAVEN 1 study of emicizumab (HEMLIBRA ® ; F. Hoffmann-La Roche, Basel, Switzerland), as soon as it was opened for enrolment at their treatment centre (ie, before week 25). Emicizumab is a subcutaneously administered recombinant humanized bispecific monoclonal antibody recently approved in several countries for prophylaxis in PwHA with inhibitors of all ages. 23 Bleeding events and safety outcomes recently reported for PwHA with inhibitors aged ≥12 years in the NIS showed that bleeding rates remained high and compliance with activated prothrombin complex concentrate (aPCC) prophylaxis was suboptimal, with 40% of participants exhibiting low compliance to their prophylactic dosing frequency (administered prescribed number of doses <60% of study weeks). 24 Participants did not treat ~40% of bleeds during the study, further supporting the need for more treatment options to decrease the burden of disease and treatment. 24 The objective of this analysis was to characterize disease-specific HRQoL, overall health status and the effect of bleeding on health status in PwHA with inhibitors aged ≥12 years.

| Study setting
The NIS design has previously been described. 24

| Study participants
In cohort A, eligible participants with congenital haemophilia A (any severity) were aged ≥12 years; had a documented history of hightitre FVIII inhibitors (≥5 Bethesda units/mL); documented episodic or prophylactic treatment for bleeds for ≥6 months prior to enrolment; and had experienced ≥6 bleeds on episodic treatment or ≥2 bleeds on prophylaxis in the prior 6 months. Participants receiving ITI with FVIII were ineligible.

| Study design
The target participant number for each treatment type (episodic or prophylactic) enrolled into each cohort was estimated based on the approximate number of participants initially planned for the interventional emicizumab phase III pivotal study (NCT02622321). 26 Participants remained in the NIS for ~6 months before being enrolled in the interventional study. The NIS was closed once all participants had switched to the interventional study or completed the NIS. Participants' usual care was continued throughout the study, with no protocol-specified interventions.

| HRQoL
HRQoL data were collected in adults using the Haemophilia Quality of Life Questionnaire for Adults (Haem-A-QoL), and in adolescents using the Haemophilia-specific Quality of Life Questionnaire for Children Short Form (Haemo-QoL SF).
The "View of Yourself," "Friends," "Sports & School," and "Dealing with Haemophilia" domains were reverse-scored. All scores were transformed to a 0-100 scale, with higher scores reflecting greater impairment.

| Health status
Health status was assessed in all participants using the EuroQol 5-Dimensions 5-Level (EQ-5D-5L) questionnaire, 31,32 a reliable and valid tool for assessing health status in PwHA with and without inhibitors. 19,33 The five dimensions of the EQ-5D-5L assess "Mobility," "Self-care," "Usual activities," "Pain/discomfort" and "Anxiety/depression," each with five levels of severity, ranging from "no problems" to "extreme problems" on the day of questionnaire completion. 32,34 The five dimensions were combined into an index utility score (IUS) using the UK "crosswalk" value set; scores range from −0.594 (extreme problems on all dimensions) to 1 (no problems on all dimensions). 35 Participants rated their general health using the EQ visual analogue scale (EQ-VAS), in which 0 and 100 are the worst and best imaginable health status, respectively. The EQ-5D-5L and EQ-VAS were completed on regularly scheduled reporting days and on days when bleeding occurred.

| Hospitalizations
Hospitalizations during the study period were recorded in the serious adverse events page of the electronic case report forms (eCRFs) by investigators every 4 weeks.

| Data collection and analysis
Clinicians collected demographic data and medical histories from participants' medical records onto the eCRFs.
All other outcomes, except hospitalizations (described above), were recorded by participants using an electronic handheld device provided at enrolment. Participants completed all HRQoL and health status questionnaires on a 4-weekly basis for ~6 months. Patients completed an additional EQ-5D-5L and EQ-VAS on days when bleeding occurred.
Summary statistics for the HRQoL questionnaires and the EQ-5D-5L IUS and EQ-VAS were calculated at each scheduled assessment; no statistical testing was performed. The analysis of IUS and EQ-VAS when a bleed occurred (unscheduled assessments) versus when no bleed occurred (monthly scheduled assessments) included only participants with at least one scheduled and one unscheduled assessment.
The completion rates for Haem-A-QoL, Haemo-QoL SF and scheduled EQ-5D-5L and EQ-VAS were calculated by dividing the All analyses were regarded as exploratory and descriptive; the study was not designed to make confirmatory claims.

| Study population
Cohort A included 103 PwHA with inhibitors on episodic (n = 75) or prophylactic (n = 28) treatment with a median (range) age of 31 (12-75) years ( Table 1). The median (range) observation time/efficacy period was 25 (4-70) weeks in the episodic group and 27  weeks in the prophylaxis group. 24

| HRQoL and health status
All Haem-A-QoL, Haemo-QoL SF, EQ-5D-5L IUS and EQ-VAS scores, starting with week 1, reflect the HRQoL and health status of participants treated according to local clinical practice; treatment was initiated before enrolment in the NIS and continued according to local standards thereafter.  Figure 1A). The domains with greatest impairments (ie, highest scores on a 0-100 scale) in both groups at week 1 were "Sports & Leisure" and "Future".
TA B L E 1 Participant demographics and treatment regimen "Sports & School" and "Family" in the episodic group and "Sports & School" and "View of Yourself" in the prophylaxis group (Table 3).
Although not tested for statistical significance, mean Haemo-QoL SF domain and total scores suggest that adolescents receiving episodic treatment may have poorer HRQoL than those receiving prophylaxis (Table 3; Figure 1B).

| D ISCUSS I ON
This prospective NIS collected detailed RWD on bleeding and health-related outcomes in PwHA with inhibitors aged ≥12 years (cohort A) treated according to local routine clinical practice. The results presented here show these individuals experienced impairments (indicated by higher scores in the Haem-A-QoL and Haemo-QoL SF, respectively) in HRQoL despite standard treatment, with mean scores in the majority of HRQoL domains in adults and adolescents indicative of impairments reported, on average, to occur "sometimes" to "often." These health-related outcomes may result from a combination of poor bleed control and treatment burden. Bleeding outcomes for this NIS cohort have been published, 24 and showed that annualized bleeding rates (95% CI) for all bleeds and treated bleeds, respectively, were high with both episodic (33 [27][28][29][30][31][32][33][34][35][36][37][38][39]; 19 [15-23]) and prophylactic (25 [18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34]; 15 [11][12][13][14][15][16][17][18][19][20][21]) treatment, and that most bleeds occurred in joints. Participants did not treat ~40% of bleeds, and compliance with prophylactic treatment was low, likely reflecting the high burden associated with standard therapies. 24 In adults, mean Haem-A-QoL scores were similar at each analysis time point. Mean Haemo-QoL SF scores among adolescents  There was no systematic change in EQ-5D-5L IUS or EQ-VAS throughout the study. At week 1, mean EQ-VAS was lower in the prophylaxis than the episodic group, but the scores were comparable at most other time points. Mean EQ-5D-5L IUS scores in PwHA with inhibitors in the present study (0.72 and 0.69 in episodic and prophylaxis groups, respectively) were lower than those reported for PwHA with inhibitors in the US Centers for Disease Control and Prevention Universal Data Collection system (0.75), 36 and those reported in the Pain, Functional Impairment, and Quality of Life study (P-FiQ) (0.78). 6 The results in P-FiQ, however, may have been due to the low percentage (33/381; 8.7%) of subjects with inhibitors enrolled. Consistent with previous studies, 37 health status as measured by the EQ-5D-5L IUS and EQ-VAS in the present study was measurably better in the absence of bleeding than on bleeding days, and this effect was comparable between episodic and prophylaxis groups.
The impact of haemophilia A and associated bleeding events on daily activities in PwHA with inhibitors is not well documented. In the NIS cohort A, the overall mean proportions (95% CI) of missed work or school days were 16% (10%-22%) and 23% (14%-32%), respectively, and were comparable in the episodic and prophylaxis groups. In the Dosing Observation Study in Haemophilia, PwHA with inhibitors receiving BPAs and their caregivers missed many full days (13.5% and 9.3%, respectively) from work/school. 38 Overall, most participants in cohort A were not hospitalized, and the average duration of hospitalization was 3.2 days (median, 0 days).
The limitations of the study included the small number of adolescent participants, potential selectivity of the sample, and participant attrition rate. The latter limitation is reflected in the fact that a number of data sets at each time point were incomplete, particularly later in the study. There are many possible reasons for this, including participant rollover into the phase III HAVEN 1 emicizumab clinical trial.

| CON CLUS ION
These RWD from cohort A of the NIS demonstrate that adolescent and adult PwHA with inhibitors experience substantially impaired health-related outcomes while receiving standard care, revealing an unmet need for more effective treatment options.

ACK N OWLED G EM ENTS
The study was sponsored by F. Hoffmann-La Roche Ltd. Editorial assistance for this manuscript was provided by Sophie Nobes, BSc of Gardiner-Caldwell Communications, Daniella Babu, PhD and Amy Lindsay, PhD of Envision Pharma Group, and was funded by F. who vouch for the completeness and accuracy of the data and analy-