1 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).1-3 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 ITI6 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,11-13 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.

2 MATERIALS AND METHODS 2.1 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) based on a review of the literature and the experience of the study team and a patient representative. Questions addressed the individual's haemophilia and treatment history, decision-making, the process of changing treatment, their understanding of and any concerns about their new treatment and their experience of switching, and thoughts on their own future and that of haemophilia treatment.

Table 1.  Interview guide Questions Prompts Part 1: People with haemophilia What is your name … and how old are you? Can you tell me about your haemophilia—when were you diagnosed? When did you get an inhibitor? What treatment (if any) did you have for the inhibitor? What treatment were you most recently on (before emicizumab)? Can you recall how many bleeds you had in a month on your old treatment? Is that fairly typical for you or abnormal? How are your joints? Do you have any joints that bleed more than others? How did you manage those before and has that changed now? Have you ever had an operation in hospital? What was it for? How do you feel/what is your experience your current treatment? What impact does emicizumab treatment have on your life? o If yes, where were they? When did they happen? Do you know what caused them? What action did you take? 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)?

Have you missed a dose of treatment or been late giving it? How did you feel about switching to emicizumab? What are your hopes/expectations for emicizumab? What are your goals for the next 6 months? Do you have any concerns about it? Have you heard about any other treatments that might be available in the future? Part 2: Dyad partner participants What difference has this medicine made to you/your family? How do you think emicizumab has impacted on you as a family/parent/carer? Can you give me examples of what impact this has made? Who does the injections?—Who taught you to do them? How does it compare with IV injections?—Who did those? Do you have any worries for the future? What advice would you give to others switching to emicizumab (inhibitors and haemophilia only)? 2.2 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.

2.3 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.

2.4 Ethics

Written informed consent was obtained from all participants; children gave their own written assent, along with consent from a parent. All participants received a gift voucher as a ‘thank you’ for the time they gave attending interviews. Ethical approval for all elements of the study was granted by the UK Healthcare Research Authority and Research Ethics Committee (19/LO/1592).

3 RESULTS 3.1 Sample characteristics

Fifteen PwHi (nine children [8–15 years; mean 11.3 years], six adults [23–63 years; mean 51 years]) and 13 family members (10 mothers, 1 father, 2 spouses) participated in the study. Two additional family members (one mother and one spouse) withdrew from the study before interview. Five participants were given emicizumab as part of a registration study; five had started emicizumab during an early access scheme; five received the treatment after UK licensing. The mean time on emicizumab was 2.26 years (range 1–5 years) (for demographics see Table 2).

Table 2. Participant demographics Participant number Age Treatment regimen ABRa (before switch to emicizumab) Time on treatment (whole years) ABRa (post switch to emicizumab) Traumatic Spontaneous Emi01 12–17 2 Weekly 7–12 3 0 0 Emi03 45–54 Weekly 19–24 5 5 0 Emi05 55–64 Weekly >48 4 2 1 Emi07 12–17 2 Weekly 0–6 2 0 0 Emi09 8–11 Weekly >48 3 0 2 Emi11 45–54 Weekly 19–24 2 0 0 Emi12 12–17 2 Weekly 7–12 2 0 1 Emi14 8–11 2 Weekly 0–6 1 0 0 Emi16 12–17 2 Weekly >48 2 0 0 Emi18 18–24 Weekly >48 2 0 0 Emi20 8–11 2 Weekly 7–12 2 2 0 Emi22 55–64 2 Weekly 19–24 1 0 0 Emi23 12–17 2 Weekly 19–24 1 8 0 Emi25 8–11 2 Weekly 19–24 2 0 0 Emi29 55–64 2 Weekly 19–24 2 0 0 Abbreviation: ABR, annualized bleeding rate. aSelf-reported figures and no corroborative evidence of bleed rates was sought.

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.

3.2 Overview of findings

Six major themes emerged: (1) Bleeding; (2) Pain; (3) Treatment burden; (4) Control; (5) Freedom; (6) Missed potential. These are supported with direct quotes, anonymized to study number; further quotes are given in Table 3.

Table 3. Further quotes in support of thematic analysis Theme 1: Bleeds Emi01 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. Theme 3: Burden of treatment 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 Theme 4: Control Emi01 Yeah. Yeah, I do. Yeah, I feel like I have a lot of control and I feel like I can control… more control my body, how I want to take the medication, if I want to take it in slowly or fast. Yeah. And it's more comfortable to do it. 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. Theme 5: Freedom Emi01 And the way it affects me, it stops me from doing some sports. But now it doesn't because I'm on the new treatment. Emi02 Because the first years of his life, I always dedicated… since I graduated, I never had the opportunity to work because of all whatever was going on, up and down with his level, his inhibitor level. So, I was just looking for something that would really work so I can get on with my life, really. Emi03 Now I can do anything I want. Emi08 You forget how your life was like as well. You totally forget about that. It's really odd. Emi18 Before emicizumab, because my degree required several foreign field trips, I would have had to either just not go because it would be too inconvenient, or bring with me I think 45,000 units of FEIBA, which is a pallet of FEIBA, which would be a nightmare to transport and to get through customs anywhere, because it's just vials of white powder so immediately alarm bells start ringing. Theme 6: Missed opportunities Emi11 Somehow, I always imagined that with better treatment might come a rolling back of the years, but the things I've always wanted—things like family, career, travel the world, hobbies, things like that that I used to enjoy—all of these things are still pretty much beyond my grasp. Emi24 He prefers it because it's less injections, but he's not more tolerant to have it. And he will not do it himself either. 3.3 Bleeding

All participants reported a noticeable decrease in the number of bleeds since starting emicizumab, with nine reporting no bleeds (Table 2). Six reported bleeding events, of which three were spontaneous. Of those reporting bleeds (spontaneous or traumatic), three said they had resolved more quickly than expected, and in some cases, no additional treatment with a bypassing agent had been required.

Early on in the trial, I walked into the boot lid of my car and cut my head. And usually scalp bleeds were just terrible; they would bleed and bleed and bleed and would be very difficult to control. But it stopped immediately. (Emi03)

Seven participants reported haemostatic challenges (falls, trips, grazes or surgery) for which bypassing agents had not been required.

If I fall over… like I fell over my bike a few times and I just… it will just be a bruise, that's it. Nothing else. (Emi16)

He's had two biggish injuries that would absolutely have required a lot of factor, that we watched and waited with this bruise and it's come up and then dispersed so much earlier than it ever would. (Emi21)

One mother spoke of her son undergoing a portacath removal:

I remember the surgeon afterwards speaking to me and saying… I think he was the second haemophiliac who he'd removed a port on in someone who was on emicizumab, and he just was saying how… he described the surgery as amazing as it's like there's this… there's no blood. He said it's really weird, you expect someone with haemophilia there's a certain amount of blood and things, and he said it's just incredible how… how little they bleed from it, really. (Emi26)

Three participants reported difficulty in understanding whether an injury would require treatment, or whether they should ‘wait and see’.

I just thought, ‘Oh, I think I might struggle’. And I sometimes do as well—not quite as much now, down the line—but about believing that he wouldn't need treated, that kind of thing. Like, ‘Well, surely that needs something, that was a big one’, or… that kind of thing. (Emi20)

He fell over the other week and he cracked his head, and they were going, ‘Oh…' probably thinking, ‘We'll need to go down’, and they rang the hospital and they just said, ‘Well, keep an eye on him—he should be fine’, and he was. (Emi22)

One interviewee described a period of hypervigilance, a hangover from his pre-emicizumab days, where he was almost overly concerned that he might be about to get a bleed. He gradually became less concerned.

In the early phase of the trial, there were a few occasions when we treated with recombinant VII for what I thought were bleeds. And whether that was because the emicizumab hadn't reached the level it needed to be effective or whether it was just this hypervigilance persisting and not being entirely trusting of the emicizumab… But then there was a clear point when I thought, ‘Let's just see what happens if I don't treat—because what's the worst that can happen is I'll have a bad bleed, which I've had all my life anyway’. (Emi03)

Two participants referred to occasions before starting emicizumab on which they may have taken factor inappropriately, now believing their pain was arthritic rather than a symptom of an acute bleed.

This is the other issue with [emicizumab] 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. (Emi05)

Although her son was experiencing fewer spontaneous bleeds, one mother described continuing trauma-related bleeds. This, combined with his dislike of the injection, meant emicizumab had not significantly improved his quality of life.

He's still bleeding when he's active. So, February to September, he had a bleed every month from falling off his bike, playfighting with his friends, anything really. And I'd say the only reason he's not had a bleed now probably since September is because of Covid restrictions as he's not been going out. He doesn't want to be on Hemlibra. He hates the injection. (Emi24)

Two participants who had been involved in registration studies referred to the risks associated with administering FEIBA as a treatment for bleeding while on emicizumab14 although both felt this was now less of a concern.

3.4 Pain

All six adult PwHi described pain as a constant part of life before emicizumab. Three said the nature of the pain they experienced had changed over the course of their life.

I think as the joints become more damaged, the bleeds become less painful. I can remember as a youngster up to my teens, bleeds would be just indescribably painful. (Emi03)

I have more aches than pains. Because like I say, my joints are wearing out, my bones are wearing out. (Emi22)

Pain relief was also an issue for these participants. Four reported an ambivalent relationship with analgesics and a reluctance to take them, partly due to side effects.

I find that the pain relief, because I've already got the exhaustion, fatigue and that side of things as much as anything, and brain fog, because of all of that, the last thing I want is another medication that's going to dampen down my brain, my thought process or my energy levels anymore. (Emi11)

Two felt they needed to keep them in reserve.

Because I'm so used to pain relief and all that sort of thing, I take [them] when I'm having severe, severe pain. (Emi06)

One said analgesia was of little use.

You can't… you can't medicate against those sorts of pains. (Emi03)

Pain was an issue raised by two mothers. One said her son had complained of constant pain in his ankles even when not in a bleed state.

I remember he just looked up and he said, ‘But my ankles always hurt, mummy’. You know, he just went, ‘They never stop hurting, mummy. They've always hurt’. (Emi10)

Another thought the level of pain experienced by children was under-recognized:

I do wonder if they probably do feel quite a bit of discomfort but don't know that they are; the pain or discomfort is normalized. I wonder about that. I don't know. (Emi08)

Most of those reporting pain said emicizumab had made a difference to the level of pain experienced. For three adults, experiencing fewer bleeds meant a decrease in some pain.

It's improved pain levels in terms of the fact that I'm not getting bleeds, and then I'm not getting recovery periods and stuff like that. (Emi11)

One mother said her child's pain had improved after starting emicizumab.

One of the loveliest days for me—I don't know if (Emi09) would remember this, really—so in that first six months you'd be constantly still going, ‘Any aches and pains? You okay? Does anything hurt? Are you all right?’ and I remember going… I remember saying to him, ‘Is everything okay, anything ache?’ and he went, ‘No, mummy’. And I went, ‘You know how your ankle used to ache?’ and he went, ‘Mummy’, he said, ‘Nothing's hurt for such a long time’. (Emi10)

However, pain remained an issue for one participant due to damage caused by previous bleeds:

Between the arthropathy, contractures and this spasming, yes, it's quite restrictive and it's a quite painful experience. (Emi11)

3.5 Treatment burden

Nine participants (four PwHi, five parents) spoke of the burden of treatment before starting emicizumab.

I always knew that we needed two hours to get out—that was in my head. You know, like if somebody rang up and said, ‘Meet us up…’ I don't know, for example, ‘Meet us up the park, we're going up there in half an hour’, in the morning, say, you got a text message at eight saying, ‘We're going to be at the park at nine’, you knew that you couldn't. You'd have to go… if you hadn't done his medicine, I knew it would have to be definitely a two-hour thing. (Emi10)

To be honest with you, the whole time is a bit of a blur. I think at the time we just went into survival mode, because even now I speak about everything we've been through and it almost feels like it didn't happen. Because it was so time-consuming and the thought of doing that now, I just can't imagine. (Emi26)

Four participants spoke of gaining time in their lives due to shorter administration times.

I felt really happy after a while, because I realised that I didn't have to take it every single day, not take thirty minutes, just take it… And now I can just take five minutes of my time and just take my medication. It's just like a small thing that I need to do once every two weeks (Emi01)

After so long on very awkward and very clunky treatment, this is still… I still can barely believe how effective it is for such a small time commitment and such a small treatment burden. (Emi18)

One mother said her son had gained the confidence to self-treat since starting emicizumab.

So, it's now subcut into his leg and (Emi12) now gives it himself and draws everything up and does the electronic diary, and he's really, really good at it. (Emi13)

There was recognition that while emicizumab had changed the treatment burden, it had ‘not changed the disease’ (Emi08).

All participants were aware of gene therapy as a possible cure for haemophilia, but that it might not be a possibility for them because of their inhibitor and, in the case of children, their age. Two participants said they would not want to have gene therapy even if it were available to them as emicizumab had allowed them to take back control of their condition.

I think it's as close to a cure as I'm prepared to go at the minute. Because it's very much controlling my condition to a point that I'm more than happy with it. (Emi18)

3.6 Control

Eleven participants (six PwHi, five family members) felt emicizumab had given them more flexibility and therefore control over their lives.

It's given me a bit more control, because it's sort of like… well, I'm not going to suffer now as much as I did earlier on in life. I feel a bit more assured, if you know what I mean. I can do something and say, ‘Well, if that doesn't go right, it's not going to hurt’. Well, it will hurt, but it's not going to hurt for two weeks as it normally did. But yes, it's made me… yes, it's good. (Emi22)

And then after maybe ten seconds it's done, and I do that once every two weeks. That's really helpful. (Emi01)

Two mothers described their child's quality of life having been limited by their condition, and that limited treatment options had led them to try what was at the time an experimental medication.

We were kind of desperate at that time […] we were looking for something that worked, because FEIBA was just unpredictable. (Emi02)

It was a leap of faith. But to be honest, our options were very limited at that time, and I just feel very, very lucky. (Emi13)

This sense of limited options and lack of control had also impacted the wider family. Eight participants (four mothers, two spouses, two PwHi) spoke of disruption to the lives of family members.

Because the first years of his life, I always dedicated… since I graduated, I never had the opportunity to work because of all whatever was going on. (Emi02)

It had a huge effect on the whole family. I became (Emi12)'s… I gave up my job, I became (Emi12)'s carer. (Emi13)

Five PwHi reported that family life had often revolved around their haemophilia.

We never used to plan our holiday with the girls. Eight out of ten times I'd have a bleed on that day, so the choice was should we continue with the holiday—and then if you continue with the holiday, you're bleeding. So, it's not just myself. And they don't enjoy the holiday. (Emi06)

For me it had a big impact, but for my sister it's had a pretty big impact as well. I think probably, even into adulthood, that impact has kind of left psychological marks. I think there's this element of feeling like you come second to… (Emi11)

3.7 Freedom

Eleven participants (seven PwHi, four family members) said emicizumab had given a sense of freedom—something few had experienced previously. PwHi were now able to undertake activities, both sporting and travel-related, without fear of having a bleed.

I can go out with my friends, go on my bike when I want to. (Emi16)

There is nothing now that I can't do that I would have wanted to normally. Because I wouldn't be… I wouldn't get into boxing or play rugby, but that's because I don't like those things now, not because I'm not allowed to do them. (Emi18)

For family members, freedom included the ability to return to a career.

When he first went on emicizumab I took a new job that involved me going up to Scotland for a couple of days once a month, and I was able to do that, which… I hadn't been able to leave him. It's not something someone else can pick up, putting a needle in a vein and mixing up all that stuff. It's quite an involved process; you can't just write it on a piece of paper and ask someone else to do it. So, yes, it enabled me to take a job and allowed me to be [away] overnight. (Emi08)

Four participants (two PwHi, two family members) spoke of the whole family gaining a new sense of freedom.

You can plan much further ahead. I mean, our planning was, ‘Right, what are we doing tomorrow? Because I haven't got a bleed today’. Now, I can plan… well, we'll go on holiday in August, and with relative certainty know that you could. (Emi29)

So, I could quite happily do whatever I want; I don't have to think about if there's going to be anyone around for him. If I wanted to just go away for a week or two weeks, absolutely no question. (Emi04)

One father spoke of the change in himself as a parent since his son started emicizumab.

I was just constantly worried whenever there was a party or anything like that. And when he was out and about I was watching him like a hawk. I became Mr Health-and-Safety about everything. And now, like you say… I never really thought he'd be able to play football or anything. He probably told you […] he's obsessed with it now. (Emi28)