The lived experience of a novel disruptive therapy in a group of men and boys with haemophilia A with inhibitors: Emi & Me

Abstract Background People with haemophilia A and inhibitors (PwHi) suffer more orthopaedic complications, bleeding and pain than those without inhibitors. The advent of emicizumab as a prophylactic treatment has led to a reduction in bleed frequency and a significant improvement in overall quality of life. No research to date has examined the nature of this improvement on treated individuals and their families. Aims The Emi & Me study aims to capture the real‐life experience of using emicizumab for PwHi and their families. Methods Participants were recruited through treatment centres, social media and by word of mouth. Each participant and a family member, if available, took part in a semistructured qualitative interview. All interviews were recorded, transcribed verbatim and analysed thematically. All elements of the study were reviewed by local statutory authorities and informed consent was sought from all participants. Results Fifteen PwHi, mean age 27.2 years (range 8–63 years), most with a family member, participated in a single qualitative interview online (n = 13), by telephone (n = 1) or in person (n = 1). Mean time on emicizumab was 2.26 years (range 1–5 years). Six major themes emerged: bleeds; pain; treatment burden; control; freedom (for both PwHi and family members) and missed potential. Emicizumab prophylaxis has delivered significant improvements in the lives of the participants. Despite these improvements, some participants felt that their pre‐existing physical disabilities and the lack of physiotherapy provision had prevented them achieving similar improvements in their functional ability. Conclusion This study shows that in reducing bleeds, pain and treatment burden, emicizumab had given PwHi greater control over their condition, allowing a sense of freedom they had not experienced with factor VIII or bypassing agent prophylaxis. However, for emicizumab to be truly effective, there is a need to ensure the continued availability and accessibility of robust multidisciplinary support services. Without this, it is unlikely that PwHi will realize the life‐changing potential offered either by emicizumab or any other novel treatment approach. Patient or Public Contribution A patient participant (who did not wish to be included as an author of the paper) was involved in the design of the study protocol and interview guide.


| INTRODUCTION
Prophylactic factor VIII (FVIII) replacement therapy is the standard of care for haemophilia A. It has led to significant decreases in comorbidity and improved overall quality of life for people with haemophilia (PwH). [1][2][3] However, around 30% of those treated develop alloantibodies (or inhibitors) to the infused factor, 4,5 rendering treatment ineffective.
Immune tolerance therapy (ITI) aims to suppress the inhibitor, allowing the reintroduction of prophylaxis. ITI requires the infusion of large doses of FVIII, often twice daily, meaning that individuals need either good venous access (which can be problematic in young children) or a central venous access device. Up to 30% of people with haemophilia and inhibitors (PwHi) never tolerize. Bypassing agents, either FEIBA or activated factor VII (FVIIa), are used to manage breakthrough bleeds in ITI 6 and may be used prophylactically in those with persistent inhibitors. 7,8 These agents have short half-lives (4-7 and 2-3 h, respectively) and are less protective than FVIII prophylaxis. Both ITI and the use of bypassing agents in PwHi are burdensome due to infusion frequency and volume, and preparation and administration time. 9 Emicizumab is a humanized monoclonal antibody that mimics the action of FVIII. It binds to activated factor IX (FIXa) and factor X (FX), normalizing the intrinsic clotting pathway and preventing spontaneous and minor traumatic bleeds. 10 Given subcutaneously, weekly, 2-weekly, or 4-weekly, emicizumab was seen in clinical trials to reduce the annualized bleeding rate (ABR), decrease burden of treatment, and increase the overall quality of life for PwHi, [11][12][13] It has been the standard of care treatment for PwHi in the United Kingdom since 2018.
The Emi & Me study was designed to explore the real-world impact of emicizumab on the lives of PwHi and their families.

| Study design
A qualitative interview study was conducted with PwHi whose treatment had been switched to emicizumab from FVIII, FEIBA or recombinant FVIIa. Interviews were carried out by S. F. and K. K. between 1 August 2020 and 31 January 2021.
The interviews followed an interview guide (see Table 1

| Recruitment and data collection
Participants were recruited through centre referral, advertisements on social media sites, and word-of-mouth referrals. All participants took part in a single 1-h interview conducted by two researchers.
Children were interviewed in the presence of a parent; adults were given the option to be interviewed with a member of their family present. The initial recruitment target was 20 dyad pairs (PwHi and a family member) though recruitment could be discontinued once data saturation was achieved.

| Analysis
Each interviewee was assigned a study number (Emi01-Emi30). All interviews were recorded and transcribed verbatim. Transcripts were thematically analysed by both researchers after each interview using inductive coding (S. F.: NVivo ® for Mac; K. K.: manual coding). After coding each transcript, the researchers met to discuss, review, and refine the emergent codes to enable their exploration in subsequent interviews. On completion and analysis of the final interview, the researchers met to discuss all transcripts, further refine codes and identify themes.

| Ethics
Written informed consent was obtained from all participants; children gave their own written assent, along with consent from a parent. • Why do you treat at that time of day?
• How active are you on a day-to-day basis? Do you do any sports?
• How have you adjusted to less frequent treatment?
• What is it like to do subcutaneous injections?-Who taught you to do them? What was it like?
• How do you record your treatment? (Haemtrack, etc.) Do you do that on paper or using the app?
What impact does emicizumab treatment have on your life?
• Imagine a scale of 1-6, where 1 is no impact and 6 is the highest impact. How much of an impact on your life does your treatment represent? o Now vs. before?
• Is there anything you would like to change about your treatment?
• Have you had any bleeds since using emicizumab?
o If yes, where were they? When did they happen? Do you know what caused them? What action did you take?
• Have you noticed any bruising at your injection site?
What about pain? Do you have any pain now? Again, imagine a scale of 1-6, where 1 is very little pain and 6 is the worst pain. How bad is that pain?
• How has it been over the past month (do you get pain every day, is it joint related, is it haemophilia related)?
• What did you usually do in the past when you experience pain related to your haemophilia?-Is it different now you are on emicizumab?
• How does arthritic pain differ from the pain of a bleed (if applicableprobably not to child participants)?
• Is the pain different on emicizumab?
Have you missed a dose of treatment or been late giving it?
• If you do miss a dose, what do you do about it?
• On balance, how easy is it to remember doses when given once week/ fortnight/month?
How did you feel about switching to emicizumab?
• Do you know how emicizumab works?
• When and how did you first hear about emicizumab?
• Who instigated the notion of switching-was it you or your clinicians?
• How often will you be treating? Why are you having that frequency? Has anyone explained pharmacokinetics? Has your doctor or nurse ever tried to explain PK to you?
No new codes were generated after 13 interviews. Recruitment continued for two further interviews, after which the interviewers agreed that data saturation had been achieved and recruitment should cease.
All participants took part in a single semistructured qualitative interview. Due to coronavirus restrictions, most interviews (n = 13) took place by video conference. One interview was conducted by telephone; one took place face to face (relevant coronavirus guidelines were followed).
Seven participants were known to at least one of the interviewers; none were known to both.  Table 3.

| Bleeding
All participants reported a noticeable decrease in the number of bleeds since starting emicizumab, with nine reporting no bleeds ( Have you heard about any other treatments that might be available in the future?
• Knowing how emicizumab has been for you, would you now want to consider other treatments such as gene therapy if it was available?
• How would you feel about having to go back to your last treatment (FEIBA/NovoSeven prophylaxis/on-demand?) Yeah, it's much better. I don't get any bleeds anymore.

Emi03
Yes, I mean, that head injury that I had a couple of weeks ago, I mean, that bled profusely. I mean, it really did. And I could not believe how quickly it stopped. It was remarkable. I don't think there's much that I could do.

Emi09
No, we haven't had NovoSeven since the trial. I know I've had about maybe one or two bad bleeds, but… one or two, whereas I'd used to have them pretty much weekly.

Emi10
(Emi09) is very good at identifying still if… you know, if he has… say, on Friday he twisted his ankle, he just went over on his ankle in PE, he's good at saying, 'No, it's not a bleed'.

Theme 2: Pain
Emi05 This is the other issue with Hemlibra and treatment for people like us. I personally felt, in these last three or four years, some of the pain I was having was not a bleed, it was arthritic pain. So, each patient has to take their own decision whether you want to infuse or you don't want to infuse.

Emi09
It's not as much pain, it's barely any pain that I would get normally. Maybe once in a while I might get a little tingle, but other than that it's perfect, really.

Emi10
We know he walked around in pain a lot, basically.

Emi11
I'm not great at taking pain relief. I've always been a kind of mind-over-matter type.

Emi18
And it's definitely made a big difference in my level of discomfort with my ankle. I still have some, but that's just part and parcel with… what 23 years' worth of bleeds into a single joint. But it's improved since going onto emi and being able to do the physio.

Emi03
And subcutaneous injection once a week is nothing. It's not an inconvenience at all.

Emi13
It's much easier now with Hemlibra; we used to obviously lug all this other stuff around.
Emi18 I was just absolutely thrilled not to have to use a Hickman line anymore. Nothing could have made me happier than getting rid of that thing. The transition was peculiar; it was very weird to not have to go through a full rigmarole of finding a vein or accessing a Hickman line, and just being able to whip it out of the fridge, stick a needle on, draw it up and then give it. That was very weird to start with-I felt like I hadn't properly treated. But I got used to it much quicker than I was expecting to.

Emi26
I mean, it's amazing in terms of how much less time-consuming it was. As I say, before school, if I was going to work… our mornings were just chaos, really, trying to get all of that done, get the children to school get me to work and everything.

Emi28
Yes, we do his emicizumab injections at night, so normally… whereas before we were doing injections all the time, weren't we, really. They'd take quite a long time to do I feel like there's a lot of flexibility and it's much easier, as it's once every two weeks.

Emi03
Yes, it makes me feel uncomfortable, yes. Because the fact that you can administer medication and sort it out yourself, you feel like, 'Okay, I can live in the forest as long as I have my own medication'. But then, when you know that you know you cannot do that, you're not empowered to do that, you just have to be somewhere where there's a structure or something to go to in case there's a problem. But at the same time, you know that it's very unlikely that it would be a problem, which is good.

Emi18
It's very much controlling my condition to a point that I'm more than happy with it, and the treatments that are more close to an actual, mechanical cure for the haemophilia. while emicizumab had made a tangible difference in that they experienced fewer bleeds and less pain, the potential improvements reported by others (increased mobility, freedom to undertake sports and exercise) were unrealized because they could not access the physiotherapy and social care support that would allow them to achieve this.

| Limitations
This study involved a small, self-selecting sample of participants with ready access to bypassing agents and, as such, may not be representative of the entire population if PwHi or the wider population of PwH, haemophilia care teams and statutory bodies in the future.
The experience of bleeds reported here is based on the recall of individual participants rather than objective evidence. However, it does support the reduction in bleeding rates seen in the registration studies. [11][12][13] Few fathers have participated in studies of this type, and in our study, we interviewed only one father. This is a common problem within haemophilia research and has been highlighted by Khair et al. 28

| CONCLUSION
Bleeding is the cardinal symptom of haemophilia, with or without an inhibitor. Treatments for haemophilia are licensed because they reduce bleeds. However, for patients, it is the impact of bleeds on everyday lives that is important. There is a growing recognition of the need for outcome measures that go beyond regulatory endpoints and which truly reflect patients' experience of haemophilia. Bleeding is the cardinal symptom of haemophilia, with or without an inhibitor.
Treatments for haemophilia are licensed because they reduce bleeds.
However, for patients, it is the impact of bleeds on their everyday lives that is important. There is a growing recognition of the need for outcome measures that go beyond regulatory endpoints and which truly reflect patients' experience of haemophilia and the 'real world' impact of their treatments.
Our study showed that in reducing bleeds, pain and treatment burden, emicizumab had given PwHi greater control over their condition, allowing a sense of freedom they had not experienced with FVIII or bypassing agent prophylaxis.
For these patients, emicizumab now offers the first truly prophylactic treatment. While inhibitor eradication with ITI is likely to remain the treatment approach of choice, it may be that emicizumab will be used with ITI to prevent bleeding.
However, for emicizumab to be truly effective, there is a need to ensure the continued availability and accessibility of robust support services. This means strengthening the multidisciplinary comprehensive care approach that has served haemophilia so well. Without this, it is unlikely that PwHi will realize the life-changing potential offered by either emicizumab or by any other novel treatment approach.