Abstract
Introduction
This post hoc analysis of VOLTAIRE-RA compared patient-reported outcomes, including health-related quality of life (HRQoL), in patients with rheumatoid arthritis (RA) before and after treatment with biosimilar adalimumab-adbm or adalimumab reference product.
Methods
HRQoL was assessed by 36-Item Short Form Survey (SF-36) Physical and Mental Component Summary (PCS and MCS, respectively) and domain scores at baseline and weeks 12/24. Results were considered clinically meaningful if improvements were greater than or equal to minimum clinically important differences (MCIDs) of 2.5 for PCS and MCS and 5.0 for domain scores. Comparisons with age- and sex-matched norms and treatment-associated changes in domain scores from baseline were quantified using spydergrams and the health utility SF-6D measure. All comparisons between treatment groups were descriptive in nature.
Results
No differences in PCS scores were reported between treatment groups at baseline or weeks 12/24. MCS scores slightly favored the reference product group at baseline, and differences in scores at weeks 12/24 generally reflected those differences. Improvements in PCS scores greater than or equal to MCID at weeks 12/24 were reported by over 65% of patients in both treatment groups, while over 56% experienced improvements in MCS scores greater than or equal to MCID at weeks 12/24. Similar proportions receiving reference product and adalimumab-adbm reported scores greater than or equal to US age- and sex-matched normative values at week 24: 14–39% versus 15–36%, respectively, compared with baseline (1–17%).
Conclusion
In patients with moderate to severely active RA, adalimumab-adbm and adalimumab reference product were both associated with clinically meaningful improvements in SF-36 PCS, MCS, and domain scores that were highly similar at weeks 12/24. The high proportion of patients reporting scores greater than or equal to normative values in both treatment groups is notable, as this represents a treatment goal that was difficult to achieve in earlier RA trials.
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Trial Registration
VOLTAIRE-RA (ClinicalTrials.gov number, NCT02137226; EudraCT number, 2012-002945-40).
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Why carry out this study? |
Rheumatoid arthritis is commonly associated with symptoms that can negatively impact a patient’s health-related quality of life and predispose them to impaired work productivity and inability to fulfill day-to-day activities. |
This post hoc analysis provides a comprehensive assessment of patient-reported outcomes in the first 24 weeks of the VOLTAIRE-RA trial that compared adalimumab-adbm with adalimumab reference product in patients with rheumatoid arthritis. |
What was learned from the study? |
Both adalimumab-adbm and adalimumab reference product were associated with significant improvements in physical and mental summary scores at 12 and 24 weeks after initiation of treatment. |
The efficacy and safety profiles of adalimumab-adbm translated into clinically meaningful improvements in patient experiences and perceptions that were equivalent and highly similar to those seen with the adalimumab reference product. |
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Introduction
Rheumatoid arthritis (RA) is a chronic, autoimmune, inflammatory disease that can lead to joint destruction, deformity, disability, and a shortened life expectancy [1]. If appropriate long-term treatment is not given, progressive functional impairments can result in reductions in health-related quality of life (HRQoL) [1]. The most commonly reported RA symptoms associated with negative effects on HRQoL include pain, physical function impairments, fatigue, and morning stiffness [2,3,4]. These symptoms also predispose to impaired work productivity and inability to fulfill day-to-day activities [3, 5, 6]. Therefore, contextualizing the overall impact of new treatment options from the patient’s perspective is an important consideration when designing, conducting, and reporting clinical trials [7, 8].
Adalimumab-adbm (Cyltezo®, formerly known as BI 695501; Boehringer Ingelheim International GmbH, Ingelheim am Rhein, Germany) is an approved interchangeable biosimilar to adalimumab reference product (Humira®; AbbVie Inc., North Chicago, IL, USA) in the USA [9, 10]. Adalimumab-adbm and adalimumab reference product have structural similarity and comparable functionality and are pharmacokinetically and clinically bioequivalent [11, 12]. This was further demonstrated in the VOLTAIRE-X trial in patients with chronic plaque psoriasis, where efficacy, safety, and pharmacokinetic outcomes were shown to be highly similar in patients who switched between the reference product and adalimumab-adbm multiple times compared with those who remained on adalimumab reference product throughout [13].
The double-blind, phase 3 randomized controlled trial (RCT) VOLTAIRE-RA demonstrated that adalimumab-adbm and adalimumab reference product had equivalent efficacy and comparable safety and immunogenicity in patients with moderate to severely active RA on background methotrexate [14]. Psychometrically validated patient-reported outcome (PRO) measures of HRQoL were assessed in the VOLTAIRE-RA RCT [14]. In particular, both treatment groups reported comparable improvements in the 36-Item Short Form Survey (SF-36) Physical (PCS) and Mental Component Summary (MCS) scores at weeks 12 and 24, indicative of similar improvements in HRQoL [14].
In view of the importance of patient well-being in the management of RA, this post hoc analysis provides a comprehensive assessment of PROs in the first 24 weeks of VOLTAIRE-RA.
Methods
Study Design and Participants
The full methodology of the international, double-blind, phase 3 RCT VOLTAIRE-RA (ClinicalTrials.gov study number, NCT02137226; EudraCT, 2012-002945-40) has previously been reported [14]. Briefly, consenting patients who enrolled in VOLTAIRE-RA were aged 18–80 years with moderately to severely active RA on stable methotrexate. They received 40 mg of adalimumab-adbm or adalimumab reference product via subcutaneous injection once every 2 weeks for 24 weeks. Patients randomized to adalimumab reference product were re-randomized at week 24 to continue adalimumab reference product or switch to adalimumab-adbm; patients originally randomized to adalimumab-adbm were dummy re-randomized to continue adalimumab-adbm.
The protocol for VOLTAIRE-RA was approved by the applicable independent ethics committee or institutional review board at each participating site, and the trial was performed in accordance with Good Clinical Practice and the Declaration of Helsinki. Written informed consent was obtained from all patients before their participation.
Assessment of PROs
PRO questionnaires were completed at baseline and weeks 12 and 24. HRQoL was assessed by the SF-36 PCS and MCS and domain scores at baseline and weeks 12 and 24, with Patient’s Global Assessment of Disease Activity (PtGA), pain assessment and Health Assessment Questionnaire-Disability Index (HAQ-DI) also assessed at these times. SF-36 aggregates PCS and MCS based on eight domains (physical functioning [PF], role physical [RP], bodily pain [BP], general health [GH], vitality [VT], social functioning [SF], role emotional [RE], and mental health [MH]), measured on a scale of 0 to 100, where higher scores indicate better health [15,16,17,18]. Results were considered clinically meaningful if improvements were greater than or equal to minimum clinically important difference (MCID), where MCID is used to interpret the significance of outcomes from baseline by representing the minimally significant change to PROs: 2.5 for PCS and MCS and 5.0 for individual domains [8, 19]. Normative values for both PCS and MCS are defined as ≥ 50 with a standard deviation (SD) of 10.1 [18, 20]. For SF-36 domains, comparisons with US normative age- and sex-matched values to the protocol population [21], as well as treatment-associated changes from baseline in domain scores, were quantified using spydergrams [21] and the SF-6D health utility measure.
The SF-6D is a single health utility score ranging from 0 (death) to 1.000 (full health) based on mean scores across all eight SF-36 domains, sensitive to change in rheumatic diseases [18, 21,22,23]. It has been validated in RA and other rheumatic diseases, with an MCID of 0.041 [23]. The SF-6D also enables comparisons of baseline and post-treatment changes in HRQoL [24].
PtGA and patient pain were assessed by visual analog scale (VAS) [8, 19, 25]. MCID for PtGA and pain are defined as reductions ≥ 10 mm on a 100-mm VAS [8, 19, 26]. HAQ-DI assessed physical function (MCID is ≥ 0.22 units [8, 19], normative value in RA is defined as ≤ 0.25 [27, 28]).
Statistical Analyses
All patients from the safety set of the VOLTAIRE-RA study (i.e., those who received one or more doses of study drug) were included in this analysis [14]. Questionnaire compliance was calculated at every assessment time point, defined as the number of patients completing one or more questions divided by the total number of patients available at that assessment time point. All comparisons between treatment groups were descriptive in nature without statistical assessments.
Results
Study Population
Patient disposition throughout the study and demographic information has previously been published in full [14]. Data for these analyses were obtained from 645 patients with RA (324 randomized to adalimumab-adbm and 321 to adalimumab reference product). Baseline and at least one post-baseline score for SF-36 were available for 324 patients in the adalimumab-adbm treatment group versus 321 patients who were assigned to reference product.
SF-36
At baseline, the PCS and MCS were low in both treatment groups, more than 1 SD below normative values of 50 (Table 1). No differences in PCS were observed between treatment groups at baseline, although MCS scores slightly favored the reference product group. After 12 and 24 weeks, the extent of the improvements in PCS and MCS scores was similar in both treatment groups, greatly exceeding the MCID (Fig. 1), and approached or were within 1 SD of normative values (Table 1). The approximately 2-point higher mean MCS score favoring the adalimumab reference product group at baseline remained through week 24.
A large proportion of patients in both treatment groups reported clinically meaningful improvements on the SF-36. In the adalimumab-adbm group, 66.4% and 67.6% of patients reported changes in PCS ≥ 2.5 at weeks 12 and 24, respectively, compared with 65.4% and 69.8% in those receiving adalimumab reference product. In the adalimumab-adbm group, 58.6% and 56.4% of patients reported changes in MCS scores ≥ 2.5 at weeks 12 and 24, respectively, compared with 56.3% and 59.1% in those receiving adalimumab reference product.
Low domain scores were reported by VOLTAIRE-RA patients at baseline, particularly in the BP, but also the PF, RP, GH, and VT domains (Table 2). Baseline domain scores were generally higher in the adalimumab reference product group than in adalimumab-adbm; the largest differences were in the RP (Δ3.72) and RE (Δ4.70) domains. Differences in domain scores at weeks 12 (BP, MH, and VT) and 24 (PF and GH) generally reflected those differences evident at baseline, but all differences in domain scores at weeks 12 and 24 were not clinically meaningful (Table 2, Fig. 2).
In addition to providing health economic data, the SF-6D utility score can serve to illustrate the “total change” depicted in each polygon of the spydergrams. Mean SF-6D scores in patients in both treatment groups at baseline were similar and substantially lower than age- and sex-matched norms (Table 3). Differences in SF-6D scores were small at baseline and remained low at weeks 12 and 24.
Responder Analysis
Following treatment with BI 95501, clinically meaningful improvements in SF-36 PCS at weeks 12 and 24 were reported in 66% and 68% of patients, respectively, and in 56% and 59% in SF-36 MCS (Fig. 3). Similar proportions of patients in the adalimumab reference product group had these benefits. The majority of patients reported improvements greater than or equal to MCID in each SF-36 domain, with the greatest improvements reported in BP (Fig. 4).
At baseline, 0–1% and 16–20% of patients had SF-36 PCS and MCS scores, respectively, that exceeded US age- and sex-matched normative values specific to this protocol population (Fig. 5). At week 24, 11% of patients reported scores greater than or equal to normative values in PCS and 29–40% in MCS. At week 24, similar proportions of patients receiving adalimumab-adbm (15–36%) and adalimumab reference product (14–39%) reported scores greater than or equal to normative values.
Similar proportions of patients in both treatment groups reported clinically meaningful improvements in pain (week 12, 68–69%; week 24, 68–70%) and PtGA (week 12, 67–70%; week 24, 70–71%) (Fig. 4). The proportions of patients reporting clinically meaningful improvements in HAQ-DI ranged from 50% to 54% (Fig. 3): 17% of patients in the adalimumab-adbm group and 19% in the adalimumab reference product group had HAQ-DI scores at week 24 greater than or equal to normative values (Fig. 5).
Discussion
VOLTAIRE-RA represents the final step of the biosimilarity assessment for adalimumab-adbm versus adalimumab reference product [14]. In parallel with the equivalent efficacy of adalimumab-adbm and adalimumab reference product in VOLTAIRE-RA [14], substantial benefits were reported across a range of PROs in both treatment groups. Thus, the efficacy and safety profiles of adalimumab-adbm translated into clinically meaningful improvements in patient experience and perception.
Adalimumab-adbm and adalimumab reference product resulted in similar, clinically meaningful improvements in SF-36 PCS, MCS and domain scores at weeks 12 and 24 in patients with moderately to severely active RA. The percentages of patients reporting improvements greater than or equal to MCID in SF-36, PtGA, pain, and HAQ-DI were also high and similar between the treatment groups. In VOLTAIRE-RA, RP, PF, and BP had the lowest mean scores at baseline (similar to other reports in RA [21]) but showed the greatest improvements at week 24.
A comparable proportion of patients reported SF-36 scores greater than or equal to normative values in the adalimumab-adbm and adalimumab reference product groups. The fact that these outcomes are now attainable contrasts with early RCTs in RA. Inspection of the SF-36 domains offers an interesting pattern. The VT domain, which reflects “fatigue” as well as “pep and energy”, was relatively similar in that small percentages of patients in the treatment groups reported scores greater than or equal to norms at baseline (11–12%), yet this domain showed the largest increases at weeks 12 and 24 (range 31–39%). Other large percentage improvements in patients reporting scores greater than or equal to norms were evident across the SF-36 domains, with the exception of RP and GH.
When considering these findings, several factors relating to study design should be noted. The lack of randomization and attrition bias due to study withdrawals could potentially have introduced a selection bias. Although any between-group differences apparent in the data can be accounted for by baseline imbalances, the VOLTAIRE-RA trial was not designed to compare PRO-related characteristics at baseline or prospectively between adalimumab-adbm and adalimumab reference product. Finally, the follow-up period for this study, although comparable to other trials in this indication, was relatively short in comparison to the duration of the disease and may not have captured long-term effects that may be seen in clinical practice. That said, this study did use an active control for the comparator and used validated instruments for the assessments. These findings were also consistent with PRO data from the phase 3 ARMADA study, in which patients with active RA received adalimumab adjunctive to methotrexate (SF-36, 46.9–54.4% vs 68–70%; PtGA VAS, 46.9–54.4% vs 68–70%; pain VAS, 45–50.2% vs 67–70%; and HAQ-DI, 35.5–40.0% vs 50–54% in ARMADA and VOLTAIRE-RA, respectively) [29].
Conclusion
Both adalimumab-adbm and adalimumab reference product were associated with similar clinically meaningful improvements in HRQoL (SF-36 and EQ-5D), PtGA, pain, PF, and health utility measure in patients with moderately to severely active RA at weeks 12 and 24. The high proportion of patients in this trial who reported scores greater than or equal to normative values across both treatment groups is notable, as this represents a treatment goal that was difficult to achieve in earlier RA trials.
Data Availability
To ensure independent interpretation of clinical study results and enable authors to fulfill their role and obligations under the ICMJE criteria, Boehringer Ingelheim grants all external authors access to relevant material, including participant-level clinical study data. In adherence with the Boehringer Ingelheim Policy on Transparency and Publication of Clinical Study Data, scientific and medical researchers can request access to clinical study data after publication of the primary manuscript in a peer-reviewed journal, providing regulatory activities are complete and other criteria are met. Researchers should use the https://vivli.org/ link to request access to study data and visit https://www.mystudywindow.com/ for further information.
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Acknowledgements
This study was supported and funded by Boehringer Ingelheim Pharmaceuticals, Inc. (BIPI). The authors met criteria for authorship as recommended by the International Committee of Medical Journal Editors (ICMJE). The authors did not receive payment related to the development of this manuscript. Boehringer Ingelheim was given the opportunity to review the manuscript for medical and scientific accuracy as well as intellectual property considerations. Andy Shepherd, PhD, of Elevate Scientific Solutions LLC, provided medical writing, editorial support, and formatting support, which were contracted and funded by Boehringer Ingelheim Pharmaceuticals, Inc.
Funding
This study was supported by Boehringer Ingelheim. The Rapid Service Fee was also funded by Boehringer Ingelheim.
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Authors and Affiliations
Contributions
Vibeke Strand: Conceptualization, investigation, methodology, visualization, and data presentation, writing original draft, review, and edit of the manuscript. Shawn Bender: Data curation, formal analysis, review, and edit of the manuscript. Dorothy McCabe: Conceptualization, methodology, writing original draft, review, and edit of the manuscript. All authors have reviewed the final version of this manuscript and approved its publication.
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Conflict of Interest
Vibeke Strand is a consultant for AbbVie, Alpine Immune Sciences, Alumis, Amgen, Aria, AstraZeneca, Atom Bioscience, Bayer, Bioventus, Blackrock, Boehringer Ingelheim Pharmaceuticals, Inc., Bristol Myers Squibb, Celltrion, Chemocentryx, Eli Lilly and Company, Equillium, Ermium, Fortress Biotech, Genentech/Roche, Gilead Sciences, GlaxoSmithKline, Horizon, Inmedix, Janssen, Kiniksa, Merck, MiMedx, Novartis, Pfizer, Rapt, Regeneron, R-Pharma, Samsung, Sandoz, Sanofi, Scipher, Setpoint, Sorrento, Spherix, and Tonix. Shaun Bender is a former employee of Boehringer Ingelheim Pharmaceuticals, Inc. and an employee of Alnylam Pharmaceuticals, Cambridge, MA, USA. Dorothy McCabe is a former employee of Boehringer Ingelheim Pharmaceuticals, Inc.
Ethical Approval
The protocol for VOLTAIRE-RA was approved by the applicable independent ethics committee or institutional review board at each participating site, and the trial was performed in accordance with Good Clinical Practice and the Declaration of Helsinki. Written informed consent was obtained from all patients before their participation.
Additional information
Shaun Bender and Dorothy McCabe were affiliated with Boehringer Ingelheim at the time of analysis.
Prior Presentation: This research was published in part in the supplement to Cohen SB, Alonso-Ruiz A, Klimiuk PA, et al. Ann Rheum Dis. 2018;77(6):914–21.
A Summary of Research for this article was published on https://doi.org/10.1007/s40744-024-00691-0.
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Strand, V., Bender, S. & McCabe, D. Effects of Adalimumab-adbm Versus Adalimumab Reference Product on Patient-Reported Outcomes in Rheumatoid Arthritis: Results from VOLTAIRE-RA. Rheumatol Ther (2024). https://doi.org/10.1007/s40744-024-00687-w
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DOI: https://doi.org/10.1007/s40744-024-00687-w