Delphi panel to understand the real-world occurrence and management of ofatumumab injection-related reactions among healthcare providers of people with relapsing multiple sclerosis

Abstract

Background

People with relapsing forms of multiple sclerosis (PwRMS) treated with ofatumumab, a fully human anti-CD20 monoclonal antibody, can experience local/systemic injection-related reactions (IRRs). However, data on the occurrence and management of local/systemic IRRs in real-world clinical settings are limited.

Objective

This study aimed to better understand clinicians’ perspectives regarding occurrence and management of local/systemic IRRs among PwRMS treated with ofatumumab in clinical practice.

Methods

A panel of US-based neurologists and advanced practice providers experienced with ofatumumab therapy in PwRMS participated in a three-round online modified Delphi study. In round 1, participants completed a demographics survey and Delphi questionnaire on IRR management. In round 2, they attended a live webinar to obtain feedback on round 1 results. In round 3, they reviewed round 1 and 2 feedback and provided their final responses.

Results

Forty participants (neurologists, n = 31; nurse practitioners, n = 5; and physician assistants, n = 4) completed all three rounds. Participants strongly agreed that local/systemic IRRs, regardless of severity, were unlikely with ofatumumab. Pre-/post-treatment of systemic IRRs was not uniformly required.

Conclusion

This study gives health care providers insight into the potential occurrence and management of IRRs with ofatumumab in the clinical practice setting.

Introduction

Ofatumumab is the first B-cell–depleting therapy that can be self-administered once monthly at home via an autoinjector pen. ¹ Ofatumumab is a fully humanized, high-affinity, and highly potent anti-CD20 monoclonal antibody that demonstrated superior efficacy and a similar safety profile to teriflunomide in the phase 3 ASCLEPIOS I/II trials (NCT02792218 and NCT02792231, respectively).^2,3

In ASCLEPIOS I/II, people with relapsing forms of multiple sclerosis (PwRMS) who received of atumumab had a slightly greater incidence of local (10.9%) and systemic injection-related reactions (IRRs) versus participants on teriflunomide who received placebo injections (ofatumumab: 10.9% and 20.2%; teriflunomide: 5.6% and 15.0%, respectively). Systemic reactions occurred within 24 hours after injection. ³ Reported systemic IRRs, such as headache and flushing, were mostly mild to moderate in severity, occurred at first dose, and did not require treatment. ³ Pre-medication with steroids, acetaminophen, or antihistamines was optional and provided limited benefit against systemic IRRs. ³

PwRMS who experience IRRs may be less adherent to their prescribed therapy.^4–6 Although systemic IRRs with ofatumumab were described in clinical trials, ³ their occurrence and management in the real-world setting is unclear. Therefore, it is important to understand IRRs within a real-world setting and identify whether pre- and/or post-administration of medications or implementation of other non-pharmacologic strategies may be warranted to mitigate their impact.

This Delphi panel study aimed to identify IRRs observed by health care providers (HCPs) when treating PwRMS using ofatumumab in real-world clinical practice. It also examined if and when HCPs use or recommend pre-treatment (preventive) and/or post-treatment (rescue) medications to manage these IRRs. Furthermore, this study identified HCP consensus around the preferred treatment approach and/or regimen when pre- and/or post-treatment interventions may be warranted to manage ofatumumab IRRs.

Materials and methods

Delphi panel implementation

A modified Delphi consensus-building approach was employed, consisting of three Delphi rounds conducted online between April (round 1) and September (round 3) 2023. This approach was based on the RAND/UCLA Appropriateness Method. ⁷ An online approach was employed because of its logistical advantages, and it can avoid potential bias among participants as they are able to view and respond to de-identified feedback while remaining anonymous. Data were collected in a double-blinded manner; the sponsor did not have access to participants’ identifiable information, and the participants were not provided information regarding the study sponsor. Details of panelist inclusion/exclusion criteria, recruitment process, and survey development are provided in Supplementary Materials.

Data collection

During round 1 (initial assessment), participants completed the two-part Delphi survey which included a 10-item questionnaire containing demographic and expertise-specific questions along with the Delphi questionnaire, which included 17 questions categorized into 4 sections according to various ofatumumab IRR areas.

For round 2 (feedback), participants attended a virtual live webinar to anonymously provide feedback on round 1 results. Participants shared their viewpoints in response to follow-up questions using the online chat. A moderator guide was developed by the research team, which included clinical experts, to review key findings of the round 1 Delphi questionnaire and facilitate round 2 discussions. This involved presenting findings lacking consensus and posing follow-up questions to understand the lack of consensus.

During round 3 (reassessment), participants reviewed round 1 results, including their original response(s) to each Delphi question, and round 2 feedback before providing their final response. The durations of rounds 1 and 3 were approximately 3 weeks, whereas round 2 was roughly 2 hours.

Analyses

Participants’ characteristics, including relevant demographics and collective expertise in neurology, were summarized descriptively.

For categorical measures such as ranks, results are presented as frequency (number of cases [N]) and percentage (%) for each response option. For continuous variables, such as likelihood or parameter estimates, findings are presented using means and medians. In addition, standard deviations, interquartile ranges (IQRs), and minimum and maximum values were considered to understand levels of agreement and disagreement for each area of uncertainty. Individual responses were linked across rounds to gauge whether group discussion led to a consensus among participants.

For likelihood/proportion questions, consensus was deemed to be met if IQRs (75th–25th percentiles) around the median (0–100) responses were <25. Threshold median values for level of likelihood were <25 for unlikely, 25–75 for moderately likely, and >75 for likely. In likelihood questions, participants were offered “I don’t see this injection-related reaction” and “I don’t know” answer options for use in instances where participants had not observed a given side effect among PwRMS or could not answer a question based on their experience, respectively. These responses were not included in the results calculation because not observing an IRR was not considered equivalent to a 0% chance of occurrence. For ranking questions, consensus was deemed met if >75% of respondents ranked an option among the top two in round 3.

Results

Delphi participants

Of 75 experts invited to round 1, 64 agreed to participate and 56 completed round 1 and were subsequently invited to round 2 (Figure 1). Of the 56 experts invited to round 2, 45 were available to attend a live webinar whereas 8 showed continued interest in participation but were unable to join the scheduled sessions and were provided an offline, recorded version of the webinar. Of these, one provided responses. Of the 53 experts invited to round 3 (the 45 round 2 webinar attendees and the 8 with continued interest in participation), 40 participants, including 4 of the 7 who did not complete round 2, completed round 3 and were included in the final analyses (neurologists, n = 31; nurse practitioners, n = 5; and physician assistants, n = 4).

Figure 1.

Delphi round flow chart. ^aOf the 56 experts invited to round 2, 45 were able to attend the live webinar; a further 8 showed continued interest in participation but were unable to join the scheduled sessions and were therefore provided with an offline version of the webinar. Of these, one provided their responses. Advanced practice providers include nurse practitioners and physician's assistants.

The majority of participants were male (55.0%), White (62.5%), and had ≥10 years of clinical practice experience (72.5%) (Table 1). All participants treated ≥6 PwRMS with ofatumumab; 40% of participants treated between 6 and 10 PwRMS with ofatumumab, 22.5% treated between 11 and 25 PwRMS, and 37.5% treated >25 PwRMS.

Table 1.

Participant characteristics.

Characteristic, n (%)	Participants (N = 40)
Sex
Male	22 (55.0)
Female	16 (40.0)
Prefer not to answer	2 (5.0)
Age, years
20–29	1 (2.5)
30–39	11 (27.5)
40–49	9 (22.5)
50–59	11 (27.5)
60–69	7 (17.5)
≥70	1 (2.5)
Race
Asian	5 (12.5)
Black or African American	2 (5.0)
Native Hawaiian or other Pacific Islander	1 (2.5)
White	25 (62.5)
≥2 races	2 (5.0)
Prefer not to answer	5 (12.5)
Ethnicity
Hispanic or Latino	2 (5.0)
Not Hispanic of Latino	31 (77.5)
Prefer not to answer	7 (17.5)
Current role
Neurologist	31 (77.5)
Nurse practitioner	5 (12.5)
Physician assistant	4 (10.0)
Experience in clinical practice, years
<10	11 (27.5)
10–19	11 (27.5)
20–29	15 (37.5)
30–39	2 (5.0)
≥40	1 (2.5)
Primary clinical practice setting
University hospital or university affiliated clinic	13 (32.5)
Private medical practice	12 (30.0)
Specialty group practice	9 (22.5)
Multi-specialty group practice	5 (12.5)
Hospital or clinical not associated with a university a	1 (2.5)
Time spent providing direct patient care in a clinical setting
>74%	40 (100)
Proportion of people seen with MS, % monthly
1–20	11 (27.5)
21–40	11 (27.5)
41–60	7 (17.5)
61–80	3 (7.5)
81–100	8 (20)
People with MS prescribed ofatumumab, n
6–10	16 (40.0)
11–25	9 (22.5)
26–50	8 (20.0)
51–75	3 (7.5)
>75	4 (10.0)

MS: multiple sclerosis.

^a

Including community health clinics.

Delphi round 3 results

Detailed responses for each Delphi questionnaire item are presented in Supplementary Tables S1–S3, and key areas of consensus and uncertainty are summarized in Figure 2.

Figure 2.

Key areas of consensus and uncertainty by ofatumumab IRR area. H: hour; IRR: injection-related reaction; PwRMS: people with relapsing multiple sclerosis.

Section 1: Likelihood of IRRs (local and systemic) among PwRMS

Participants agreed local ofatumumab IRRs were highly unlikely, regardless of severity levels (questions 1–3; Figure 3) and that among the small number of local IRRs observed in clinical practice, none were severe. Participants also agreed systemic ofatumumab IRRs were highly unlikely (questions 4–6; Figure 3). The proportion of participants who did not observe any of the possible systemic IRRs in clinical practice ranged from 17.5% for mild systemic IRRs to 55% for severe. Participants agreed it is highly unlikely to see the following (questions 7–9):

Mild systemic IRRs at first, second, or subsequent doses immediately after injection (30 minutes) and >24 hours after injection

Any moderate or severe systemic IRRs across first, second, and subsequent dose time frames (immediately after injection, delayed but within 24 hours of injection, and >24 hours after injection)

Figure 3.

Likelihood of local/system ofatumumab IRRs. ^aData are presented for participants who indicated that they had observed local/systemic IRRs following OMB administration. Data are not shown for participants who answered “not seen” or “don’t know.” ^bReached consensus (IQR, 75th–25th percentile, around median responses were <25 out of 100). ^cMedian likelihood toward 0 means highly unlikely and toward 100 means highly likely. Threshold median values for the level of likelihood were <25 for unlikely, 25–75 for moderately likely, and >75 for likely. IQR: interquartile range; IRR: injection-related reaction; OMB: ofatumumab; Q: question; RMS: relapsing multiple sclerosis.

Section 2: Systemic IRR treatment options and management for PwRMS

Participants were most likely to recommend acetaminophen/paracetamol to manage systemic IRRs (question 10). The most common challenges to managing systemic ofatumumab IRRs in clinical practice were (question 11; Supplementary Figure S1):

Lack of communication with patients/patients not reporting IRRs

Lack of knowledge/ability to predict likelihood or severity of individual patient IRR risk

Section 3: Systemic IRR prevention management—pre-treatment decision-making for PwRMS

Participants agreed prior adverse reactions were a top factor when considering pre-treatment for potential systemic IRRs and, on average, ranked it highest priority (question 12; Supplementary Figure S2). Participants were highly unlikely to recommend (questions 13–14):

Pre-treatment for systemic IRRs for the first five doses of ofatumumab, regardless of patient factors of interest

Any pre-treatment options for systemic IRRs and highly agreed they would be unlikely to recommend heat at the first, second, and third dose, as well as time of day of injection at the first dose only

When asked about timing recommendations for pre-treatment of systemic ofatumumab IRRs (question 15), participants highly agreed they were highly unlikely to recommend any pre-treatment options for systemic IRRs, regardless of time point (day/evening before injection, morning of injection, day before and morning of injection, immediately before injection, 30–60 minutes before injection, and 60–120 minutes before injection).

Section 4: Systemic IRR rescue management—post-treatment decision-making for PwRMS

Most participants ranked severity and type of side effect in the top five most important factors when deciding whether to post-treat systemic IRRs, although consensus was not achieved for any ranked factors (Supplementary Figure S3, question 16). Participants were highly unlikely to recommend any post-treatment option for systemic IRRs at first and/or second dose, reaching consensus around heat and time of day of injection at all dose options (first dose only, at first and second dose, at first, second, and third dose, all doses) (question 17). Additionally, at first, second, and third doses, as well as all doses, participants highly agreed it was highly unlikely they would recommend antihistamines post-treatment. Participants agreed they were highly unlikely to recommend any post-treatment option across systemic IRRs as a one-time therapy but strongly disagreed on recommending any post-treatment options as needed per recommended dosing.

Areas not reaching consensus

Participants did not reach consensus around:

Recommending heat, hydration, ice, and time of day of injection for managing potential IRRs (question 10).

Key barriers to PwRMS effectively managing potential IRRs (question 2.11).

The importance of patient factors to consider for pre-treatment options for potential systemic IRRs in PwRMS starting ofatumumab (question 12).

The importance of patient factors to consider for post-treatment options for potential systemic IRRs in round 3 (question 16).

Participants were extremely unlikely to recommend pre-treatment for systemic IRRs regardless of patient level factor. Consensus around the likelihood of prescribing pre-treatment options to manage systemic IRRs when considering patient factors across doses was observed for most options except patient preferences, prior adverse reactions, and significant number of pre-existing allergies to medications (question 13). Participants only reached consensus against recommending heat at all doses and time of day injection at first dose for pre-treatment for ofatumumab IRRs (question 14). Consensus did not change in any key areas between rounds 1 and 3.

Discussion

This study used a Delphi consensus-building process to examine real-world experiences of US clinicians regarding occurrence and management of IRRs with ofatumumab therapy in PwRMS. Participants reached consensus that it was highly unlikely to see local or systemic IRRs with ofatumumab therapy in PwRMS Although the real-world incidence of IRRs cannot be estimated using the Delphi method, the number of events significant enough to be acknowledged by patients to HCPs appears low. For instance, a recent 3.5-year analysis of the ALITHIOS study focused on adverse events associated with ofatumumab found 11.5% and 24.8% of the overall safety populations had local and systemic IRRs, respectively. ⁸ However, this apparent discrepancy between incidence of IRRs in real-world clinical practice settings and clinical studies/trials may be due to people not actively reporting adverse reactions, particularly if they were mild in severity, to HCPs or HCPs not inquiring about specific IRRs.

In this study, we found that clinician-perceived likelihood of IRRs among PwRMS decreased with increasing IRR severity. This finding aligns with outcomes reported in the ALITHIOS study, in which all local and systemic IRRs documented in PwRMS who recently transitioned to ofatumumab were mild to moderate and non-serious in nature. ⁸ Participants were highly unlikely to recommend pre-treatment for systemic IRRs for the first five doses of ofatumumab. This is in contrast to other currently approved anti-CD20 monoclonal antibody treatments for PwRMS delivered by intravenous infusions, such as ocrelizumab and ublituximab, for which pre-medication with corticosteroids and antihistamines is recommended before each infusion, with many infusion centers also routinely administering pre-treatment with acetaminophen/paracetamol.^9,10

Participants were highly unlikely to recommend any post-treatments for systemic IRRs at first and/or second dose. Some participants reported that, although IRRs were unlikely to occur, they were most likely at first ofatumumab dosing, consistent with observations from ASCLEPIOS I/II. ³ Participants were, however, highly unlikely to recommend pre- and/or post-treatment options.

No agreement was reached on the use of non-pharmacologic treatments for managing IRRs, such as heat, hydration, ice, or timing of injections. Consensus was also not reached on key barriers to effective management of IRRs in ofatumumab-treated PwRMS. Participants indicated that a lack of communication with patients, patients not reporting IRRs, and a lack of knowledge/ability to predict the likelihood or severity of individual IRR risk were the most common barriers to management. Similarly, for considering pre-treatment options of systemic IRRs, consensus was limited, with general agreement lacking except for a few specific factors, such as patient preferences, prior adverse reactions, and pre-existing allergies. The only unanimous decisions were against recommending heat for all doses and adjusting injection timing for the first dose.

Study limitations

Although the Delphi consensus process is a valuable method for gathering expert opinions, the study's limitations should be considered when interpreting the results. The Delphi method aims to reduce the influence of dominant individuals through anonymous responses; however, the iterative nature of the process can still allow for group swaying through more influential voices. Subsequent rounds of questioning may inadvertently lead to a conformity of opinions, influenced by responses in earlier rounds. ¹¹ However, this study's use of a virtual webinar with anonymized participants in round 2 likely mitigated the potential of any dominant individuals having too much influence over the group's responses.

A substantial limitation of the Delphi process is potential homogeneity of the expert panel. Despite efforts to include diverse viewpoints, selection of experts often leans toward those with similar backgrounds or experiences, which can lead to a consensus that reflects a narrower scope of the field than intended.^11,12 Results reported here are based on clinical experience of US-based participating experts and therefore may not represent experiences or perceptions of HCPs practicing outside the US who regularly use ofatumumab in PwRMS. Furthermore, patients were not directly assessed in this study. As such, there is a possibility that HCP perception may not accurately reflect patient experience.

As participants volunteered and were compensated for their participation, the results of this study may have been impacted by self-selection bias. To reduce potential conflicts of interest and minimize biases, data were collected in a double-blinded manner and the study advisors were external to the study sponsor. However, the financial relationship between the study sponsor and study advisors may have introduced potential bias in the way certain questions were framed in the study questionnaire. Although the aforementioned limitations should be considered in the interpretation of this study, they do not mitigate the importance of the study findings.

Conclusions

In this study, the consensus among these experts was that likelihood of local or systemic IRRs occurring with ofatumumab administration in clinical practice is very low. Furthermore, these experts were highly unlikely to recommend use of pre- and/or post-treatment measures for ofatumumab-related IRRs. This study offers valuable insights from clinicians regarding the possible occurrence and management of IRRs with ofatumumab in PwRMS in clinical practice.

Supplemental Material

sj-docx-1-mso-10.1177_20552173251355677 - Supplemental material for Delphi panel to understand the real-world occurrence and management of ofatumumab injection-related reactions among healthcare providers of people with relapsing multiple sclerosis

Supplemental material, sj-docx-1-mso-10.1177_20552173251355677 for Delphi panel to understand the real-world occurrence and management of ofatumumab injection-related reactions among healthcare providers of people with relapsing multiple sclerosis by Shiv Saidha, John Kramer, Brandon Brown, Iris Brewer, Jacquelyn W Chou, Marlon Graf, Rozanne Wilson and Benjamin M Greenberg in Multiple Sclerosis Journal – Experimental, Translational and Clinical

Supplemental Material

sj-docx-2-mso-10.1177_20552173251355677 - Supplemental material for Delphi panel to understand the real-world occurrence and management of ofatumumab injection-related reactions among healthcare providers of people with relapsing multiple sclerosis

Supplemental material, sj-docx-2-mso-10.1177_20552173251355677 for Delphi panel to understand the real-world occurrence and management of ofatumumab injection-related reactions among healthcare providers of people with relapsing multiple sclerosis by Shiv Saidha, John Kramer, Brandon Brown, Iris Brewer, Jacquelyn W Chou, Marlon Graf, Rozanne Wilson and Benjamin M Greenberg in Multiple Sclerosis Journal – Experimental, Translational and Clinical

Supplemental Material

sj-docx-3-mso-10.1177_20552173251355677 - Supplemental material for Delphi panel to understand the real-world occurrence and management of ofatumumab injection-related reactions among healthcare providers of people with relapsing multiple sclerosis

Supplemental material, sj-docx-3-mso-10.1177_20552173251355677 for Delphi panel to understand the real-world occurrence and management of ofatumumab injection-related reactions among healthcare providers of people with relapsing multiple sclerosis by Shiv Saidha, John Kramer, Brandon Brown, Iris Brewer, Jacquelyn W Chou, Marlon Graf, Rozanne Wilson and Benjamin M Greenberg in Multiple Sclerosis Journal – Experimental, Translational and Clinical

Supplemental Material

sj-docx-4-mso-10.1177_20552173251355677 - Supplemental material for Delphi panel to understand the real-world occurrence and management of ofatumumab injection-related reactions among healthcare providers of people with relapsing multiple sclerosis

Supplemental material, sj-docx-4-mso-10.1177_20552173251355677 for Delphi panel to understand the real-world occurrence and management of ofatumumab injection-related reactions among healthcare providers of people with relapsing multiple sclerosis by Shiv Saidha, John Kramer, Brandon Brown, Iris Brewer, Jacquelyn W Chou, Marlon Graf, Rozanne Wilson and Benjamin M Greenberg in Multiple Sclerosis Journal – Experimental, Translational and Clinical

Supplemental Material

sj-docx-5-mso-10.1177_20552173251355677 - Supplemental material for Delphi panel to understand the real-world occurrence and management of ofatumumab injection-related reactions among healthcare providers of people with relapsing multiple sclerosis

Supplemental material, sj-docx-5-mso-10.1177_20552173251355677 for Delphi panel to understand the real-world occurrence and management of ofatumumab injection-related reactions among healthcare providers of people with relapsing multiple sclerosis by Shiv Saidha, John Kramer, Brandon Brown, Iris Brewer, Jacquelyn W Chou, Marlon Graf, Rozanne Wilson and Benjamin M Greenberg in Multiple Sclerosis Journal – Experimental, Translational and Clinical

Supplemental Material

sj-docx-6-mso-10.1177_20552173251355677 - Supplemental material for Delphi panel to understand the real-world occurrence and management of ofatumumab injection-related reactions among healthcare providers of people with relapsing multiple sclerosis

Supplemental material, sj-docx-6-mso-10.1177_20552173251355677 for Delphi panel to understand the real-world occurrence and management of ofatumumab injection-related reactions among healthcare providers of people with relapsing multiple sclerosis by Shiv Saidha, John Kramer, Brandon Brown, Iris Brewer, Jacquelyn W Chou, Marlon Graf, Rozanne Wilson and Benjamin M Greenberg in Multiple Sclerosis Journal – Experimental, Translational and Clinical

Supplemental Material

sj-docx-7-mso-10.1177_20552173251355677 - Supplemental material for Delphi panel to understand the real-world occurrence and management of ofatumumab injection-related reactions among healthcare providers of people with relapsing multiple sclerosis

Supplemental material, sj-docx-7-mso-10.1177_20552173251355677 for Delphi panel to understand the real-world occurrence and management of ofatumumab injection-related reactions among healthcare providers of people with relapsing multiple sclerosis by Shiv Saidha, John Kramer, Brandon Brown, Iris Brewer, Jacquelyn W Chou, Marlon Graf, Rozanne Wilson and Benjamin M Greenberg in Multiple Sclerosis Journal – Experimental, Translational and Clinical