# The PERFUSE study: The experience of patients receiving Adalimumab biosimilar SB5

Yoram Bouhnik, Franck Carbonnel, Mathurin Fumery, Mathurin Flamant, Anne Buisson, Armelle Camoin, Janet Addison

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Yoram Bouhnik, Franck Carbonnel, Mathurin Fumery, Mathurin Flamant, Anne Buisson, et al.. The PERFUSE study: The experience of patients receiving Adalimumab biosimilar SB5. Digestive and Liver Disease, 2023, 55 (12), pp.1658-1666. 10.1016/j.dld.2023.05.025. hal-04131508

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Alimentary Tract

# The PERFUSE study: The experience of patients receiving Adalimumab biosimilar SB5

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Yoram Bouhnik<sup>a,*</sup>, Franck Carbonnel<sup>b</sup>, Mathurin Fumery<sup>c</sup>, Mathurin Flamant<sup>d</sup>, Anne Buisson<sup>e</sup>, Armelle Camoin<sup>f</sup>, Janet Addison<sup>g</sup>

ARTICLE INFO

Article history:

Received 31 January 2023

Accepted 25 May 2023

Available online 10 June 2023

Key words:

Inflammatory bowel disease

Adalimumab

Biosimilars

Patient-reported outcomes

A B S T R A C T

**Background:** SB5 is an EMA-approved adalimumab biosimilar, having demonstrated bioequivalence, equivalent efficacy, and similar safety and immunogenicity to the reference product.

**Aims:** Describe patient training and satisfaction using patient-reported outcome measures (PROMs) and assess their impact on 12-month persistence on SB5.

**Methods:** The observational PERFUSE study included 318 Crohn's disease (CD) patients and 88 ulcerative colitis (UC) patients in 27 sites across France between October 2018 and December 2020. PROMs were collected at 1-month post-baseline using an online questionnaire (ePRO) designed with patient associations. Treatment persistence was collected during routine visits (up to 15 months post-initiation). Results are presented by prior experience with subcutaneous biologics and training in proper use of the injection device.

**Results:** 57.1% (n = 145) and 44.1% (n = 67) of naïve and pre-treated patients, respectively, answered the ePRO. Naïve patients were offered training more often (86.9% vs 31.3% respectively, *p* < 0.05), with disparities between sites. All subgroups' satisfaction scores were high. 12-month persistence on SB5 was significantly higher for respondents than for non-respondents (68.0% [60.9; 74.1] vs 52.3% [44.5; 59.6]; *p* < 0.05) and in patients with a better perception of their illness (OR=1.02, [1.0; 1.05]; *p* < 0.05).

**Conclusions:** Early patient questionnaires may be useful to identify patients at higher risk of treatment discontinuation.

© 2023 The Authors. Published by Elsevier Ltd on behalf of Editrice Gastroenterologica Italiana S.r.l. This is an open access article under the CC BY license ([http://creativecommons.org/licenses/by/4.0/](http://creativecommons.org/licenses/by/4.0/))

# 1. Introduction

The prevalence of Inflammatory Bowel Disease (IBD) has increased worldwide over the past few decades [1–3]. According to estimates using data from the French national healthcare database, there were between 250 000 and 300 000 IBD patients in France in 2017 [4,5].

Conventional IBD treatment relies primarily on symptom control through pharmacotherapy, including aminosalicylates, corticosteroids (CS) and immunomodulators [6]. Since their in-

troduction, biologics, such as specific tumor necrosis factor (TNF) inhibitors, though expensive, have been a significant improvement for patients, enabling greater long-term remission [7]. Historically, the first TNF inhibitor was infliximab (authorised in 1998 by the Food and Drugs Administration [FDA] and 1999 by the European Medicines Agency [EMA]) [8,9]. Since then, several other biologics have been developed, such as adalimumab, approved by the EMA in 2013 for use in IBD [10].

Biosimilars are functionally similar molecules to biologics which represent more affordable alternatives to the reference products [11–15]. Several studies investigating the switch from a reference biologic to a biosimilar, from a biosimilar to another biosimilar or multiple switches demonstrated comparable safety and efficacy to the reference biologic [16–18]. Biosimilars are

<footnote><sup>a</sup> Paris IBD Center, Groupe hospitalier privé Ambroise Paré - Hartmann, 25 Boulevard Victor Hugo, 92200 Neuilly sur Seine, France</footnote>

<footnote><sup>b</sup> Hôpital Bicêtre, AP-HP, 78 Rue du Général Leclerc, 94270 Le Kremlin Bicêtre, France</footnote>

<footnote><sup>c</sup> CHU Amiens, Département de Gastroentérologie, 1 Rond-point du Professeur Christian Cabrol, 80054 Amiens, France</footnote>

<footnote><sup>d</sup> Clinique Jules Verne, Département de Gastroentérologie, 2-4 Route de Paris, 44300 Nantes, France</footnote>

<footnote><sup>e</sup> AFA Crohn RCH, 32 rue de Cambrai, 75019 Paris, France</footnote>

<footnote><sup>f</sup> Biogen France SAS, Gastroenterology & Rhumatologie, Biosimilars, 1 Passerelle des Reflets, 92400 Courbevoie, France</footnote>

<footnote><sup>g</sup> Biogen IDEC, Clinical Research, Biosimilars, Innovation House 70 Norden Road, Maidenhead, Berkshire SL6 4AY, United Kingdom</footnote>

<footnote>* Corresponding author at: Paris IBD Center, Groupe hospitalier privé Ambroise Paré - Hartmann, 25 Boulevard Victor Hugo, 92200 Neuilly sur Seine, France.
E-mail address: yoram.bouhnik@institutdesmici.fr (Y. Bouhnik).</footnote>
therefore a pharmaceutical opportunity that should not be over-
looked. However, consolidating data on their long-term safety and
effectiveness, especially in indications other than the one which
served for the authorization process are welcomed by authorities.
The treatment considered in this study, SB5, is an adalimumab
biosimilar authorised by the EMA in 2017 [19].

The PERFUSE study (NCT03662919) is a long-term observational study of 914 patients with chronic rheumatic diseases and IBD who received SB5 as routine therapy. This study captured both clinical data from routine visits as well as patient reported data using a questionnaire completed on a secure online portal (ePRO). To ensure their relevance and clarity, questions were co-designed with patient associations [20].

This study aims to describe the patient-reported data of the IBD cohort concerning their illness, perception, satisfaction, and confidence regarding the treatment. In France, specific training is recommended for all new users of an injection device, so the frequency and quality of training practices are also evaluated. Patient-reported data will be used to qualify the effects of patient training, and experience at the time of prescription on persistence.

## 2. Methods

### 2.1. Study design

PERFUSE (NCT03662919) is a long-term, non-interventional, multicenter cohort study of patients with gastroenterological and rheumatological Immune-Mediated Inflammatory Diseases (IMIDs) using adalimumab biosimilar SB5.

The primary outcome measure of the PERFUSE study was SB5 treatment persistence from baseline to Month 12, reported by physicians. Secondary outcomes included a description of patients' satisfaction with and confidence using SB5, perception of their interactions with physicians, beliefs about medicine and perception of their illness as well as the effects of these patient-reported outcomes on SB5 treatment persistence. The database extract for this analysis was taken on 04 April 2022.

To be included in the PERFUSE SB5 gastroenterology study, adult patients had to meet all the following criteria: i) 18 years of age or older, ii) a diagnosis of Crohn's Disease (CD) or Ulcerative Colitis (UC), iii) to be able to understand the information provided and complete French language questionnaires, and iv) initiated SB5 treatment between October 2018 and October 2020.

A patient meeting any one of the following criteria was not included in the study: i) SB5 treatment for any other illness than those mentioned above as a primary indication, ii) impossibility of regular on-site check-ups, iii) plans of changing follow-up site during the investigation period, or iv) pregnant or with plans to get pregnant during the investigation period.

### 2.2. Data collection

Data collection methods and outcome measures are summarised in Supplementary Data 1.

Persistence data (i.e., patient continued use of SB5) was collected during routine visits by site staff. Patient-reported outcomes were collected once using an electronic patient questionnaire (ePRO) via a secure study-specific web portal. Patients had one month from SB5 treatment initiation to complete this questionnaire. The ePRO collected the following patient-reported outcome measures (PROMs): patients' satisfaction with and confidence using SB5, perception of their interactions with physicians, beliefs about medicine, and perception of their illness. Each dimension measured by the ePRO was evaluated using validated questionnaires where available. Scores were calculated and analysed using the appropriate methods as described below.

This data was collected from October 2018 to November 2020.

### 2.2.1. Patient persistence on SB5

Twelve-month persistence was defined as the proportion of pa-
tients who were still treated with SB5 at 12 months as reported
by site staff during the 12-month visit. Patient visits included a
baseline visit at inclusion (M0), a 12-month (M12) visit between
12 and 15 months of follow-up and one intermediate visit between
baseline and M12. The numerator was "the number of patients still
treated by SB5" at 12 months and the denominator was the "total
number of included eligible patients".

### 2.2.2. Patient satisfaction and confidence

Ad hoc questions designed in collaboration with patient associations evaluated patient satisfaction and confidence on a scale of 0 (worst) to 10 (best). Higher scores indicated a higher degree of satisfaction or confidence. Such scales are commonly used to evaluate satisfaction, though their lengths vary [21,22].

These scores were used to evaluate the following patient dimensions: satisfaction with the information received on biosimilars, confidence in their ability to use the injection device, satisfaction with the injection device (no distinction was made between syringes and auto-injector pens), and satisfaction with their overall care at the time of prescription.

The exact wording and their translation are provided in Supplementary Data 2.

### 2.2.3. Patient-physician interactions

The Perceived Efficacy in Patient-Physician Interactions questionnaire (PEPPI) was used to evaluate the quality of the dialog between patients and their physicians at the time of prescription. PEPPI scoring is described in Maly et al. (1998) with higher scores indicating higher perceived self-efficacy in patient-physician interactions [23].

### 2.2.4. Patient beliefs about medicine

The Beliefs about Medicines Questionnaire (BMQ) was used to assess patients' beliefs and fears about their treatment and their illness. Fall et al. (2014) describes scoring for the French version of the BMQ, which is composed of 2 sub-scores, the BMQ-specific score compares patients' perceived concerns about their treatment and necessity to take it (negative scores indicate that concerns outweigh necessity) and the BMQ-general score measures patients' perception of the harm and overuse of medication in general (higher scores indicate stronger views that medicines are harmful) [24,25].

### 2.2.5. Patient perception of their illness

The Brief Illness Perception Questionnaire (B-IPQ) was used to determine patients' perception of their illness with low scores denoting a strong negative perception and high scores indicating a strong positive perception. Broadbent et al. (2005) describes scoring of the B-IPQ divided into 8 subscores, which increase linearly with their measured dimension [26]. A higher total score indicates a more positive view of the patient's situation regarding their illness.

## 2.3. Statistical analysis

Only patients who completed the ePRO and reported using SB5 at that time could be analysed in terms of satisfaction and beliefs. The respondent population is subdivided into 2 groups based on whether or not the patient had prior experience with biologic subcutaneous treatments (BSC). BSC refers to any therapy that involves an injection of a biologic such as adalimumab. This distinction is
of particular importance as the expected results for naïve and pre-treated patients are quite different in terms of persistence.

All statistical analyses were performed using SAS software version 9.1 or later (SAS institute Inc. SAS Campus Drive, Cary, North Carolina 27,513, USA). A Shapiro-Wilk test assessed the normality of quantitative variables. Normally distributed quantitative data are reported using the mean value and standard deviation (SD) for each subgroup for whom data was available. Non-normally distributed data are presented using the median value and interquartile range (IQR). Statistical differences between subgroups were computed using an analysis of variance test (ANOVA) or a Mann-Whitney-Wilcoxon test for normally and non-normally distributed variables respectively. Significant differences are shown using 95% confidence intervals (CI) and computed using the *p*-value: *p* < 0.05 is considered statistically significant ('n.s.' for 'not significant' reports no statistical difference between groups).

Persistence was evaluated using a Kaplan Meier (KM) approach and statistically significant differences between subgroups were calculated using a log-rank test and are denoted with a star on graphs.

A univariate correlation analysis using a Cox model was performed to analyze the impact of continuous variables on persistence: results were presented using the odds ratio with a 95% CI and *p*-value.

## 2.4. Ethical considerations

All necessary ethical considerations and measures were taken to ensure the protection of all participants: patients were only eligible for the study if they were able to understand and sign a consent form.

All versions of the study protocol, up to and including its final amendment, were approved by an independent ethics committee

(Comité de Protection des Personnes - CPP) in France, in accordance with French regulations, on April 25th, 2019.

This study is listed on clinicaltrials.gov (identifier NCT03662919) and was approved by the appropriate bodies in terms of quality of the methodology, data security, and scientific merit.

# 3. Results

## 3.1. Included populations and response rates

This study includes 406 gastroenterology patients (88 UC patients and 318 CD patients) monitored in 27 tertiary care sites (both private and public). Baseline characteristics of both respondent and non-respondent populations were similar (Table 1). There were 254 BSC-naïve patients and 152 BSC-pre-treated patients (Supplementary Data 3).

Around half the overall population responded to the questionnaire: this percentage was numerically higher in naïve patients (n = 145; 57.1%) than in pre-treated patients (n = 67; 44.1%). Overall, 1.2% of the included population had not yet started SB5 treatment and were not eligible for analysis. Response rates also varied between sites (IQR=[44.4%; 65.9%]) (Fig. 1A). There was a higher proportion of females than males among the respondent population.

Patient training, satisfaction, patient-physician communication, and belief data were available for all patients who completed the online questionnaire.

## 3.2. Patient training

Of respondent BSC-naïve patients, 86.9% (n = 126/145) reported being offered training on proper use the SB5 injection device and

<table><caption>**Table 1**
Baseline patient characteristics.</caption><thead><tr><th rowspan="2"></th><th colspan="2">BSC Naïve</th><th colspan="2">BSC pre-treated</th><th colspan="2">Total</th></tr><tr><th colspan="2">N = 254 (62.3%)</th><th colspan="2">N = 152 (37.7%)</th><th colspan="2">N = 406</th></tr></thead><tbody><tr><td><strong>ePRO completion, n (%)</strong></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Overall</td><td colspan="2">148 (58.3%)</td><td colspan="2">69 (45.4%)</td><td colspan="2">217 (53.4%)</td></tr><tr><td>SB5 users</td><td colspan="2">145 (57.1%)</td><td colspan="2">67 (44.1%)</td><td colspan="2">212 (52.2%)</td></tr><tr><td></td><td>Respondent</td><td>Non-Respondent</td><td>Respondent</td><td>Non-Respondent</td><td>Respondent</td><td>Non-Respondent</td></tr><tr><td><strong>Age, years, mean (SD)</strong></td><td>38.4 (14.3)</td><td>34.7 (14.9)</td><td>43.9 (12.7)</td><td>38.8 (14.4)</td><td>40.1 (14.0)</td><td>36.5 (14.8)</td></tr><tr><td><strong>Previous biologic treatment, N (%)</strong></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Adalimumab</td><td>0 (0.0%)</td><td>0 (0.0%)</td><td>56 (83.6%)</td><td>66 (79.5%)</td><td>56 (26.4%)</td><td>66 (34.0%)</td></tr><tr><td>Other BSC</td><td>0 (0.0%)</td><td>0 (0.0%)</td><td>11 (16.4%)</td><td>17 (20.5%)</td><td>11 (5.2%)</td><td>17 (8.7%)</td></tr><tr><td><strong>Schema of injection at baseline, N (%)</strong></td><td>1 (0.7%)</td><td>0 (0.0%)</td><td>18 (26.9%)</td><td>17 (20.7%)</td><td>19 (9.0%)</td><td>17 (9.0%)</td></tr><tr><td>40 mg every week</td><td>11 (7.6%)</td><td>2 (1.9%)</td><td>38 (56.7%)</td><td>48 (58.5%)</td><td>49 (23.1%)</td><td>50 (26.6%)</td></tr><tr><td>40 mg every 2 weeks</td><td>0 (0.0%)</td><td>0 (0.0%)</td><td>0 (0.0%)</td><td>0 (0.0%)</td><td>0 (0.0%)</td><td>0 (0.0%)</td></tr><tr><td>80 mg every 2 weeks</td><td>1 (0.7%)</td><td>0 (0.0%)</td><td>0 (0.0%)</td><td>0 (0.0%)</td><td>1 (0.5%)</td><td>0 (0.0%)</td></tr><tr><td>40 mg every 4 weeks</td><td>0 (0.0%)</td><td>0 (0.0%)</td><td>0 (0.0%)</td><td>0 (0.0%)</td><td>0 (0.0%)</td><td>0 (0.0%)</td></tr><tr><td>40 mg every 3 weeks</td><td>6 (4.1%)</td><td>5 (4.7%)</td><td>1 (1.5%)</td><td>2 (2.4%)</td><td>7 (3.3%)</td><td>7 (3.7%)</td></tr><tr><td>80 mg at week 0 followed by 40 mg at week 2</td><td>126 (86.9%)</td><td>99 (93.4%)</td><td>10 (14.9%)</td><td>15 (18.3%)</td><td>136 (64.2%)</td><td>114 (60.6%)</td></tr><tr><td>160 mg at week 0 followed by 80 mg at week 2</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td><strong>Disease duration, years, mean (SD)</strong></td><td>8.3 (9.9)</td><td>5.7 (7.7)</td><td>13.1 (9.8)</td><td>11.1 (7.9)</td><td>9.8 (10.1)</td><td>8.1 (8.2)</td></tr><tr><td><strong>Number of women, n (% of each sub-group)</strong></td><td>81 (55.9%)</td><td>48 (45.3%)</td><td>32 (47.8%)</td><td>33 (39.8%)</td><td>113 (53.3%)</td><td>81 (42.9%)</td></tr><tr><td><strong>BMI, kg/m², mean (SD)</strong></td><td>23.4 (4.4)</td><td>23.0 (4.3)</td><td>26.0 (4.8)</td><td>24.7 (5.7)</td><td>24.2 (4.7)</td><td>23.7 (5.0)</td></tr><tr><td><strong>Level of education of respondents, n (% of each sub-group)*</strong></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>&lt; High School diploma</td><td>9 (6.2%)</td><td></td><td>6 (9.0%)</td><td></td><td>15 (7.1%)</td><td></td></tr><tr><td>High School diploma</td><td>61 (42.1%)</td><td></td><td>31 (46.3%)</td><td></td><td>92 (43.4%)</td><td></td></tr><tr><td>Up to Bachelor's</td><td>41 (28.3%)</td><td></td><td>13 (19.4%)</td><td></td><td>54 (25.5%)</td><td></td></tr><tr><td>More than Bachelor's</td><td>34 (28.4%)</td><td>N/A</td><td>17 (25.4%)</td><td>N/A</td><td>51 (24.1%)</td><td>N/A</td></tr></tbody></table>

<footnote>* Collected in the online questionnaire. As such this data is only available for the respondent population. BSC = Biologic Subcutaneous Treatment; SD = Standard Deviation.</footnote>
<figure><img src="image_3.png" /><figcaption>**Fig. 1.** For all graphs, BSC pre-treated patients are light gray and BSC naïve patients are dark gray. **A.** Distribution of ePRO answer rates per site. Rates were site-dependent, ranging from 0 to 100%. No statistical differences were observed between naïve and pre-treated patients. **B.** Distribution of rates at which training is offered to BSC naïve and BSC pre-treated patients. BSC naïve patients are offered training significantly more often than BSC pre-treated patients (p < 0.01). **C.** Rates at which patients attended training if it was offered (left) and the satisfaction with training length (right). BSC naïve patients attended training significantly more often than BSC pre-treated patients when offered (p < 0.01).</figcaption></figure>

96.8% (n = 122/126) of these patients attended the training session (Figs. 1B and C). Training sessions mostly took place at the hospital (95.0%, n = 116) and some took place at the patient's home (3.3%, n = 4) or elsewhere (1.7%, n = 2). The length of the training session was deemed satisfactory by 92.6% (n = 113/122) of patients (Fig. 1C). Training of naïve patients was site-dependent with sites offering training to 77.4% (SD=36.2, IQR=[33.3; 100]) of their patients on average (Fig. 1B).

Of BSC-pre-treated patients, 31.3% (n = 21/67) reported being offered training on how to properly use the SB5 injection device and 61.9% (n = 13/21) of patients who were offered training attended the training session (Figs. 1B and C). Training sessions all took place at the hospital. The length of the training session was deemed satisfactory by 92.3% (n = 12) of attendees (Fig. 1C). Training of pre-treated patients was site-dependent with sites offering training to 15.1% (SD=27.4, IQR=[0; 28.6]) of their patients on average (Fig. 1B).

Training was offered significantly more frequently to naïve patients than to pre-treated patients (p < 0.05) (Fig. 1B). Neither satisfaction with session length nor distribution of training locations were significantly different between groups. Pre-treated patients'

attendance rates were significantly lower than for naïve patients (p < 0.05) (Fig. 1B).

### 3.3. Patient satisfaction and confidence

Satisfaction with the information received on biosimilars was similar for both naïve and pre-treated patients (8.2 [SD=2.0] vs 8.7 [SD=1.6]; n.s.) as was patients' confidence using the injection device (8.6 [SD=2.2] vs 8.7 [SD=2.6]; n.s.), and satisfaction with overall care at the time of prescription (8.1 [SD=1.7] vs 8.1 [SD=1.4]; n.s.). Satisfaction with the injection device was significantly higher in naïve than in pre-treated patients (8.2 [SD=1.9] vs 6.8 [SD=2.8]; p < 0.01) (Fig. 2A).

Overall (both naïve and pre-treated patients), no statistically significant differences in terms of confidence using the injection device (8.6 [SD=2.1] vs 8.5 [SD=2.7]; n.s.), nor in satisfaction with overall care at the time of prescription (8.3 [SD=1.4] vs 8.0 [SD=2.0]; n.s.) were observed between patients who attended a training session (n = 135) and those who did not (n = 77). Satisfaction with the injection device was significantly higher in pa-
<figure><img src="image_4.png" /><figcaption>**Fig. 2.** Satisfaction and confidence scores for each subgroup. Results are presented using the mean value and symmetrical error bars are the standard deviation. **A.** Satisfaction and confidence scores were all high (scales of 0 to 10). The only statistically significant differences observed were in patients' satisfaction with the injection device: between overall BSC naïve and BSC pre-treated patients, between overall trained and untrained patients, and between BSC naïve trained and untrained patients (all *p* < 0.05) **B.** Perceived efficacy of patient-physician dialog was high overall. No significant differences were observed (scale of 0 to 50).</figcaption></figure>

tients who attended a training session than in those who did not (8.2 [SD=1.8] vs 7.0 [SD=2.8]; *p* < 0.01) (Fig. 2A).

In the naïve population, no statistically significant differences in terms of confidence using the injection device (8.6 [SD=2.1] vs 8.0 [SD=2.8]; n.s.), and satisfaction with overall care at the time of prescription (8.1 [SD=1.5] vs 8.0 [SD=2.9]; n.s.) were observed between patients who attended a training session (n = 122) and those who did not (n = 23). There was a significant difference in terms of satisfaction with the injection device (8.2 [SD=1.8] vs 7.0 [SD=2.8]; *p* < 0.01) (Fig. 2A).

Finally, concerning the pre-treated population, no statistically significant differences in terms of confidence using the injection device (8.2 [SD=2.6] vs 8.8 [SD=2.6]; n.s.), satisfaction with the injection device (7.0 [SD=2.4] vs 6.7 [SD=2.9]; n.s.), or satisfaction with overall care at the time of prescription (7.9 [SD=1.5] vs 8.6 [SD=1.3]; n.s.) were observed between patients who attended a training session (n = 13) and those who did not (n = 54) (Fig. 2A).

### 3.4. Patient-Physician communication

Patient-physician communication was rated similarly highly by both naïve and pre-treated patients (41.2 [SD=7.8] vs 43.5 [SD=6.5]; n.s.). There was no significant difference between patients who attended a training session and those who did not (41.3 [SD=7.0] vs 42.9 [SD=8.2]; n.s.) (Fig. 2B).

### 3.5. Patient beliefs

Though B-IPQ scores were significantly higher in naïve patients than in pre-treated patients (45.7 [SD=10.3] and 40.0 [SD=11.3] respectively; *p* < 0.01), indicating that naïve patients had a significantly better view of their illness than pre-treated patients, scores remain moderate, showing that most patients were generally ambivalent regarding their disease, irrespective of previous experience with BSC treatments (Fig. 3C).

The BMQ specific necessity score (naïve: 9.5 [SD=2.6] vs pre-treated: 9.1 [SD=3.2]; n.s.) was significantly lower than the specific concern score (naïve: 14.5 [SD=3.5] vs pre-treated: [SD=4.1]; n.s.) for both populations (*p* < 0.05) (Fig. 3A). BMQ overall specific score was -5.0 (SD=3.7) and -6.0 (SD=3.7) for naïve and pre-treated patients respectively (n.s.), indicating that patients' concerns about their treatment outweighed the perceived necessity to treat their illness (Fig. 3C).

The BMQ general harm (naïve: 9.5 [SD=2.6] vs pre-treated: 9.1 [SD=2.4]; n.s.) and overuse scores (naïve: 10.6 [SD=2.7] vs pre-treated: 10.3 [SD=2.6]; n.s.) indicated an ambivalent disposition regarding medicines in general (Fig. 3A). Indeed, the BMQ general score was moderate for both naïve and pre-treated patients (20.1 [SD=4.9] vs 19.5 [SD=4.4]; n.s.) (Fig. 3C).
<figure><img src="image_5.png" /><figcaption>**Fig. 3.** Patient belief scores. For all graphs, BSC pre-treated patients are light gray and BSC naïve patients are dark gray. **A.** BMQ scores. The specific concern score was significantly lower than the specific necessity score, indicating patients were sceptical about their treatment (*p* < 0.05). The general score was moderate. No differences were observed between subgroups. **B.** Scatterplot of BMQ scores. Error bars are standard deviation. No significant differences were observed. **C.** BIP-Q scores (scale of 0 to 50). This score was significantly higher for naïve patients than for pre-treated patients.</figcaption></figure>

## 3.6. Correlation of PROMs with persistence

Persistence on SB5 at 12 months was numerically lower for trained than for untrained patients (63.0%, CI=[53.5; 71.1] vs 75.1%, CI=[63.4; 83.5]; n.s.) (Fig. 4A).

However, persistence on SB5 at 12 months was significantly higher in ePRO respondents than in non-respondents (68.0%, CI=[60.9; 74.1] vs 52.3%, CI=[44.5; 59.6]; *p* < 0.05) (Fig. 4B).

A univariate Cox model analysis showed that patients with higher B-IPQ scores were significantly more likely to stop treatment within 12 months of SB5 initiation than those with lower scores (OR=1.02, CI=[1.0; 1.05], *p* < 0.05). This same model also showed that patients who reported better satisfaction with the injection device were numerically less likely to stop treatment within this same period than those with lower satisfaction scores (OR=0.91, CI=[0.83; 1.01], n.s.). Finally, we observed no significant correlation between persistence and PEPPI scores (OR=1.0, CI=[0.97; 1.04], n.s.) or either BMQ general (OR=1.06, CI=[0.99;

<table><caption>**Table 2**
Cox correlation analysis.</caption><thead><tr><th>Score</th><th>N</th><th>OR [95% CI]</th><th>p-value</th></tr></thead><tbody><tr><td>PEPPI score</td><td>212</td><td>1.000 [0.966; 1.036]</td><td>0.9817</td></tr><tr><td>Satisfaction with SB5 device</td><td>212</td><td>0.913 [0.825; 1.010]</td><td>0.0777</td></tr><tr><td>BMQ specific score</td><td>212</td><td>1.058 [0.990; 1.130]</td><td>0.0955</td></tr><tr><td>BMQ general score</td><td>212</td><td>1.042 [0.988; 1.099]</td><td>0.1296</td></tr><tr><td><strong>B-IPQ score</strong></td><td><strong>212</strong></td><td><strong>1.023 [1.000; 1.046]</strong></td><td><strong>0.0464*</strong></td></tr></tbody></table>

1.13], n.s.) or specific scores (OR=1.04, CI=[0.99; 1.10], *p* < 0.05) (Table 2).

## 4. Discussion

This study shows a high degree of satisfaction and confidence in SB5 treatment for BSC-pre-treated and naïve patients. However,

<footnote>* Bold lines indicate a significant correlation B-IPQ = Brief Illness Perception Questionnaire; BMQ = Beliefs about Medicine Questionnaire; PEPPI = Perceived Efficacy of Patient-Physician Interactions.</footnote>
<figure><img src="image_6.png" /><figcaption>**Fig. 4.** Kaplan-Meier survival curves for persistence on SB5. Data shown up to 24 months. Persistence was calculated and compared at 12 months. Asterisks on the curve indicate censored patients and steps indicate a patient who stopped SB5. **A.** Survival curves for trained patients (red) compared with untrained patients (green). No statistical difference is observed. **B.** Survival curves for non-respondents (red) compared with respondents (green). Persistence was significantly higher in respondents than in non-respondents (p < 0.01).</figcaption></figure>

disparities were observed in the two groups. First, while almost all naïve patients were trained on the proper use of the SB5 injection device, most pre-treated patients were not, apparently due to two main factors: pre-treated patients were not offered training, and even when training was offered, pre-treated patients attended the training session significantly less often than naïve patients. Indeed, there seems to be a lack of support during switches, possibly because patients have already been educated for their first subcu-

taneous treatment. Patients and physicians perhaps consider that there is no need for specific training for the device, which is debatable. Regardless, recommendations are that all patients should be adequately informed on any newly prescribed treatment and these results show that application of these recommendations must be improved, especially when switching [27]. Appropriate information provided as part of a multidisciplinary care effort has been shown to significantly improve several aspects of patient experience,
though we did not observe any significant differences in satisfaction [28]. However, satisfaction scores, which were high for all subgroups, may have been influenced by the patients' interpretations of "satisfaction". This could possibly be reduced by using a different satisfaction score, which is less open to interpretation, though this is a well-documented limitation of such measurements [29].

Patient training practices were also site-dependent, suggesting there may be underlying issues preventing patient training in certain sites. Indeed, patient education practices are a concerted effort between site staff involving both physicians and nurses [28,30]. Possibly, the absence of trained personnel, such as nurses trained in patient education or IBD coordination nurses (*Infirmières de Coordination*) in some investigation sites de facto limits their ability to provide patient training and education services, though this warrants further investigation. The lack of trained personnel could be addressed by the creation of digital training platforms providing patients with the necessary information concerning their treatment, either as a stand-alone solution or as a complement to therapeutic education.

Regarding patients' persistence on SB5 treatment, neither training, nor higher patient satisfaction, were found to increase persistence, which appears to contradict previous studies showing that persistence increases with an enhanced communication strategy [31,32]. However, this may be explained by the untrained population being mainly pre-treated patients, generally more persistent than naïve patients. The observed impact of the B-IPQ scores on persistence is likely also a proxy for inclusion status. That said, the fact that ePRO respondents are more persistent than non-respondents does not appear to be tied to inclusion status as the populations are similar and the response rate among pre-treated patients is lower than naïve patients. Thus, early patient questionnaires could potentially be used to inform physician decisions and identify patients at a higher risk of non-persistence. In an oncology study, survival was observed to be better in patients who communicated via email with their physician [33], indicating that certain profiles of patients who are either more technologically inclined or more involved with their treatments may benefit more from them.

This study, while providing insights into the experience and satisfaction of both naïve patients and patients with prior experience using a BSC, presents certain limitations, many of which stem from its observational real-world design [34,35]. Indeed, our design relied on data already being available or routinely collected during the routine visits (M0 and M12) and patients completing an optional questionnaire. This led to paucity of certain data points, notably a low ePRO response rate, a common problem for such studies [36]. Other data, such as quality of life, experience and adverse events under the previous treatment (e.g., injection site burning or discomfort) were not available, making interpretation of satisfaction scores less evident in the pre-treated group. Response rates were also site-dependent (ranging from 0 to 88%), which may have led to a population bias between respondent and non- respondent populations. However, making the ePRO mandatory would have prevented the comparison of the respondent and non- respondent populations' persistence. This design also relied on the accuracy of the patient-reported data, which depends on the properties of the questionnaires included in the ePRO. When available, validated questionnaires were preferred. However, satisfaction was collected using ad hoc questions: while the scale bounds were fixed, linearity remained uncertain and patient interpretations may vary, hindering interpretability and comparability with other studies [29]. Also, while the overall population size lent itself well to statistical analysis, the number of people who did not attend training was relatively small. Similarly, subdividing the population by indication would not have been statistically meaningful. Concerning persistence, the reasons for discontinuation were outside the scope of this analysis, as were safety data such as adverse events and im-

munogenicity. Finally, a multivariate analysis model was not performed as it would not provide further meaningful information than the univariate analysis. Indeed, only one explanatory factor was significant, and the explanatory factors showed signs of multicollinearity.

In conclusion, observed patient training practices indicated a lack of support during switches, with strong disparities between sites. Though this does not appear to impact patient persistence, it highlights the need to provide additional support to sites lacking the necessary resources to provide these services consistently. Switched patients were less interested in training practices, feeling that they had enough knowledge from their previous treatment. This should be investigated and specific support for these people could be considered. Also, early online patient questionnaires may help identify patients at a higher risk of non-persistence who may require closer follow-up. Finally, recent changes in the regulatory landscape in France, with the introduction of a pay-performance model, may change switching practices, warranting further investigation.

## Financial disclosure

The authors acknowledge Sanoïa for data management services, writing and editorial support for this manuscript. Funding for this assistance was provided by Biogen France SAS (Paris, France). This study was funded by Biogen International GmbH (Baar, Switzerland). The authors had full editorial control and provided final approval of all content.

## Acknowledgements

The authors would like to thank:

* All the patients who participated in the study.

* All the investigators who contributed to data collection.

* Sanoïa e-Health services for their work as a CRO providing management, medical writing and editing services for this work.

## Supplementary materials

Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.dld.2023.05.025.

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