Systemic Lupus Erythematosus Clinical Trials Research Articles

Model-based meta-analysis using latent variable modeling to set benchmarks for new treatments of systemic lupus erythematosus.

Several investigational agents are under evaluation in systemic lupus erythematosus (SLE) clinical trials but quantitative frameworks to enable comparison of their efficacy to reference benchmark treatments are lacking. To benchmark SLE treatment effects and identify clinically important covariates, we developed a model-based meta-analysis (MBMA) within a latent variable model framework for efficacy end points and SLE composite end point scores (BILAG-based Composite Lupus Assessment and Systemic Lupus Erythematosus Responder Index) using aggregate-level data on approved and investigational therapeutics. SLE trials were searched using PubMed and www.clinicaltrials.gov for treatment name, SLE and clinical trial as search criteria that resulted in four data structures: (1) study and investigational agent, (2) dose and regimen, (3) baseline descriptors, and (4) outcomes. The final dataset consisted of 25 studies and 81 treatment arms evaluating 16 different agents. A previously developed (K Goteti etal. 2022) SLE latent variable model of data from placebo arms (placebo + standard of care treatments) was used to describe aggregate SLE end points over time for the various SLE placebo and treatment arms in a Bayesian MBMA framework. Continuous dose-effect relationships using a maximum effect model were included for anifrolumab, belimumab, CC-220 (iberdomide), epratuzumab, lulizumab pegol, and sifalimumab, whereas the remaining treatments were modeled as discrete dose effects. The final MBMA model was then used to benchmark these compounds with respect to the maximal efficacy on the latent variable compared to the placebo. This MBMA illustrates the application of latent variable models in understanding the trajectories of composite end points in chronic diseases and should enable model-informed development of new investigational agents in SLE.

Towards a novel clinical outcome assessment for systemic lupus erythematosus: first outcomes of an international taskforce.

Systemic lupus erythematosus (SLE) is a disease of high unmet therapeutic need. The challenge of accurately measuring clinically meaningful responses to treatment has hindered progress towards positive outcomes in SLE trials, impeding the approval of potential new therapies. Current primary end points used in SLE trials are based on legacy disease activity measures that were neither specifically designed for the clinical trial context, nor developed according to contemporary recommendations for clinical outcome assessments (COAs), such as that substantial patient input should be incorporated into their design. The Treatment Response Measure for SLE (TRM-SLE) Taskforce is a global collaboration of SLE clinician-academics, patients and patient representatives, industry partners and regulatory experts, established to realize the goal of developing a new COA for SLE clinical trials. The aim of this project is a novel COA designed specifically to measure treatment effects that are clinically meaningful to patients and clinicians, and intended for implementation in a trial end point that supports regulatory approval of novel therapeutic agents in SLE. This Consensus Statement reports the first outcomes of the TRM-SLE project, including a structured process for TRM-SLE development.

Medications impact different aspects of the quality of life of patients with systemic lupus erythematosus

AbstractPurposeIn this real‐world observational study, we analyzed the effects of different drugs on the quality of life (QoL) of patients with systemic lupus erythematosus (SLE).MethodWe identified patients in our prospective SLE Registry who received new medications. We measure QoL with MOS 36‐Item Short‐Form Health Survey (SF‐36), a generic health questionnaire, and SLEQOL, a disease‐specific instrument. We compared the patients' scores before and after initiation of treatment.ResultsWe identified 259 episodes of drug initiation in 193 SLE patients. SLEQOL registered statistically significant changes with intravenous cyclophosphamide (total score and the domains of physical functioning, activities, and self‐image), mycophenolate (total score, treatment, mood, and self‐image) and azathioprine (total score, activities, and mood), but not with cyclosporin A and hydroxychloroquine. Two SF‐36 subscales (general health and physical functioning) showed statistically significant improvement in the patients who received intravenous cyclophosphamide. Both instruments have floor effect. There was weak correlation between changes in the QoL instruments and the patient assessment of disease activity or an objective disease activity index.ConclusionSLEQOL distinguishes the differential effects on QoL of the various drugs. Treatment with intravenous cyclophosphamide and mycophenolate impacted the highest numbers of domains of SLEQOL, followed by azathioprine, cyclosporin A, and hydroxychloroquine. SLEQOL may be a useful outcome measure in SLE clinical trials.

Generation of evidence supporting the content validity of SF-36, FACIT-F, and LupusQoL, and novel patient-reported symptom items for use in patients with systemic lupus erythematosus (SLE) and SLE with lupus nephritis (LN)

ObjectiveSLE and lupus nephritis (LN) have significant impacts on the health-related quality of life of patients living with the condition, which are important to capture from the patient’s perspective using...

Concordance and discordance in SLE clinical trial outcome measures: analysis of three anifrolumab phase 2/3 trials

ObjectivesIn the anifrolumab systemic lupus erythematosus (SLE) trial programme, there was one trial (TULIP-1) in which BILAG-based Composite Lupus Assessment (BICLA) responses favoured anifrolumab over placebo, but the SLE Responder...

T Helper 2-Associated Immunity in the Pathogenesis of Systemic Lupus Erythematosus.

Systemic Lupus Erythematosus (SLE) is a chronic autoimmune disease that mainly affects women in their reproductive years. A complex interaction of environmental and genetic factors leads to the disruption of immune tolerance towards self, causing overt immune activation and production of autoantibodies that attack multiple organs. Kidney damage, termed lupus nephritis, is the leading cause of SLE-related morbidity and mortality. Autoantibodies are central to propagating lupus nephritis through forming immune complexes and triggering complements. Immunoglobulin G (IgG) potently activates complement; therefore, autoantibodies were mainly considered to be of the IgG isotype. However, studies revealed that over 50% of patients produce autoantibodies of the IgE isotype. IgE autoantibodies actively participate in disease pathogenesis as omalizumab treatment, a humanized anti-IgE monoclonal antibody, improved disease severity in an SLE clinical trial. IgE is a hallmark of T helper 2-associated immunity. Thus, T helper 2-associated immunity seems to play a pathogenic role in a subset of SLE patients. This review summarizes human and animal studies that illustrate type 2 immune responses involved during the pathology of SLE.

Clinical meaningfulness of a British Isles Lupus Assessment Group-based Composite Lupus Assessment response in terms of patient-reported outcomes in moderate to severe systemic lupus erythematosus: a post-hoc analysis of the phase 3 TULIP-1 and TULIP-2 trials of anifrolumab

The British Isles Lupus Assessment Group-based Composite Lupus Assessment (BICLA) is a validated global measure of treatment response in systemic lupus erythematosus (SLE) clinical trials but does not include patient-reported outcomes. To evaluate the clinical meaningfulness of a BICLA response from the patient perspective, we aimed to analyse patient-reported outcomes by BICLA responses with anifrolumab or placebo in patients with moderate to severe SLE. We did a post-hoc analysis of pooled data from the phase 3 TULIP-1 (NCT02446912) and TULIP-2 (NCT02446899) trials of anifrolumab, which assessed health-related quality of life using the Short Form 36 Health Survey (SF-36; version 2) and Lupus Quality of Life, fatigue using the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), pain using the Numerical Rating Scale, and disease activity using Patient Global Assessment. Changes from baseline and proportions of patients reporting improvements in patient-reported outcomes greater than or equal to the minimum clinically important differences and scores greater than or equal to the normative values were compared in BICLA responders and non-responders and by treatment group (intravenous anifrolumab 300 mg or placebo). 726 patients were included in the TULIP trials, of whom 366 received placebo (184 patients in TULIP-1 and 182 in TULIP-2) and 360 received anifrolumab 300 mg (180 patients in each trial). The mean patient age was 41·8 years (SD 11·9). 674 (93%) patients were female, 52 (7%) were male, and 479 (66%) were White; 283 (39%) were BICLA responders and 443 (61%) were BICLA non-responders. Compared with non-responders, BICLA responders reported greater mean improvements from baseline at week 52 in Patient Global Assessment, SF-36, Lupus Quality of Life, FACIT-F, and pain Numerical Rating Scale scores (all nominal p<0·0053). Compared with non-responders, a greater proportion of BICLA responders reported improvements greater than or equal to the minimum clinically important difference across all SF-36 domains; eg, Physical Component Summary (165 [60%] of 277 for responders vs 63 [15%] of 416 for non-responders), Mental Component Summary (140 [51%] of 276 vs 59 [15%] of 416), and role physical (184 [70%] of 264 vs 76 [19%] of 398); Lupus Quality of Life domains; eg, physical health (151 [58%] of 262 vs 60 [15%] of 396), and intimate relationships (77 [41%] of 187 vs 33 [11%] of 286), and FACIT-F (155 [56%] of 276 vs 66 [15%] of 439). Similarly, a greater proportion of BICLA responders had scores equal to or greater than the normative values across all SF-36 domains and FACIT-F compared with BICLA non-responders at week 52. Patients who received anifrolumab reported greater numerical improvements in Patient Global Assessment, SF-36, Lupus Quality of Life, FACIT-F, and pain Numerical Rating Scale scores than those who received placebo. BICLA responders reported significant and clinically meaningful improvements in Patient Global Assessment, health-related quality of life, fatigue, and pain compared with BICLA non-responders. More patients with moderate to severe SLE who received anifrolumab were BICLA responders and had improved health-related quality of life, fatigue, and pain than those who received placebo. AstraZeneca.

Increasing Ancestral Diversity in Systemic Lupus Erythematosus Clinical Studies.

Non-White people are more likely to develop systemic lupus erythematosus (SLE) yet are underrepresented in SLE clinical trials. The efficacy and safety of drugs may be influenced by ancestry, and ancestrally diverse study populations are necessary to optimize treatments across the full spectrum of patients. However, barriers to entry into clinical trials are amplified in non-White populations. To address these issues, a conference was held in Bethesda, Maryland, from October 15-16, 2019, entitled "Increasing Ancestral Diversity in Systemic Lupus Erythematosus Clinical Studies: Overcoming the Barriers." Conference participants included people with lupus, lupus physicians, lupus clinical trialists, treatment developers from biotechnology, social scientists, patient advocacy groups, and US government representatives (The Office of Minority Health, Centers for Disease Control and Prevention, National Institutes of Health, and the Food and Drug Administration). For all these groups, the organizers of the conference purposefully included people of non-White ancestry. Decreased participation of non-White SLE patients in clinical research was evaluated through historical, societal, experiential, and pragmatic perspectives, and several interventional programs to increase non-White patient participation in SLE and non-SLE research were described and discussed. The presentations and discussions highlighted the need for changes at the societal, institutional, research team, referring physician, and patient education levels to achieve equitable ancestral representation in SLE clinical studies.

Clinician-reported outcome measures in lupus trials: a problem worth solving.

Systemic lupus erythematosus (SLE) remains a disease of high unmet clinical need. Because of substantial patient heterogeneity, the execution of clinical trials that successfully determine the efficacy of novel therapeutics compared with placebo is a continuous challenge. Clinician-reported outcome measures of treatment response used in SLE trials have evolved from the use of individual disease activity indices, including the SLE Disease Activity Index (SLEDAI) and British Isles Lupus Assessment Group (BILAG), to composite responder definitions such as the SLE Responder Index (SRI) and BILAG-Based Composite Lupus Assessment (BICLA), which are based on these indices. However, these approaches have notable drawbacks and defining the optimal clinical trial outcome measure for SLE remains a research goal. In this Viewpoint, we explore the strengths and limitations of existing indices and composite assessments, illustrating features which should be investigated in future analysis of trial data. Further, we provide a platform from which to advance new approaches to endpoint design, which is crucial to improve the interpretability and success of subsequent clinical trials in SLE.

Psychometric Analysis from EMBODY1 and 2 Clinical Trials to Help Select Suitable Fatigue PRO Scales for Future Systemic Lupus Erythematosus Studies.

IntroductionFatigue is one of the most important symptoms reported by patients with systemic lupus erythematosus (SLE) and a key concept of interest in SLE clinical trials. Despite this, fatigue remains poorly understood and sub-optimally measured by existing patient-reported outcome (PRO) instruments and scales. Here, we psychometrically evaluated the measurement properties of three PRO scales that purport to measure fatigue, using data from two SLE clinical trials.MethodsData were pooled from two completed phase 3 SLE trials: EMBODY1 (NCT01262365) and EMBODY2 (NCT01261793). FACIT-F, SF-36 Vitality and LupusQoL Fatigue data were selected for post hoc Rasch Measurement Theory psychometric analysis in two stages: (1) scale-to-sample targeting, thresholds for item response options, item fit statistics, and reliability; and (2) proposal and evaluation of pooled fatigue items based on the best-performing items. Responsiveness analyses on group-level (two effect size [ES] calculations and relative efficiency) and individual level (within person statistically significant difference), were conducted to compare original scales and pooled item sets.ResultsScale-to-sample targeting was good for FACIT-F, but suboptimal for SF-36 Vitality and LupusQoL Fatigue. Thresholds for item response options were ordered for all three scales. Item misfit was found in all three scales (FACIT-F 10/13; SF-36 Vitality 4/4; LupusQoL Fatigue 1/4). Reliability statistics were good for FACIT-F (0.93) and LupusQoL Fatigue (0.80) but low for SF-36 Vitality (0.53). The pooled fatigue items improved some psychometric properties despite persisting misfit issues (2/10) and were more sensitive in detecting change at week 24 compared with un-pooled data (ES 0.41 vs. 0.26–0.25).ConclusionsFACIT-F, SF-36 Vitality, and LupusQoL Fatigue were found to have important limitations in the EMBODY1 and EMBODY2 SLE clinical trials. Findings from pooled fatigue items support the need for further research to improve conceptual underpinnings of fatigue PROs and make them fit for purpose for drug development.

Psychometric properties of FACIT-Fatigue in systemic lupus erythematosus: a pooled analysis of three phase 3 randomised, double-blind, parallel-group controlled studies (BLISS-SC, BLISS-52, BLISS-76)

BackgroundFatigue is a key symptom in patients with systemic lupus erythematosus (SLE), and regulatory bodies recommend its assessment in clinical trials of SLE therapies.MethodsThis post hoc pooled analysis of the three BeLimumab In Subjects with Systemic lupus erythematosus (BLISS) Phase 3 randomised, double-blind, parallel-group controlled trials evaluated the measurement properties of the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue. Patients (N = 2520) completed the FACIT-Fatigue every 4 weeks from baseline until the end of each study period. Internal consistency, test–retest reliability, convergent validity, and ability to detect changes in SLE were evaluated for the FACIT-Fatigue.ResultsThe FACIT-Fatigue showed good internal consistency reliability (Cronbach’s alpha > 0.90), very good test–retest reliability (0.76 ≤ intraclass correlation coefficient ≤ 0.92), and moderate-strong convergent validity (0.49 ≤ |r| ≤ 0.86) against scale and summary measure scores from the Short Form 36 Health Survey Version 2. Correlations between FACIT-Fatigue and British Isles Lupus Assessment Group (BILAG) General/Musculoskeletal scores (0.24 ≤ |r| ≤ 0.43) supported convergent validity. Correlations between FACIT-Fatigue and the Safety of Estrogens in Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) scores and SLE annualised flare rate were weak but in the expected direction (ranging from − 0.02 to − 0.25). Known-groups validity testing showed that the FACIT-Fatigue can significantly discriminate between patient groups with differing scores for SELENA-SLEDAI, BILAG (General and Musculoskeletal) ratings, and Physician’s Global Assessment (PGA). Patients showing improvement in PGA and meeting the BILAG responder criteria had significantly higher mean improvement in FACIT-Fatigue scores than those without improvements in either measure (Week 52 mean score difference [95% confidence interval]: − 4.0 [− 5.0, − 3.0] and −2.2 [−3.1, −1.2], respectively; both p < 0.0001). The range of important (i.e. meaningful) change in FACIT-Fatigue, based on multiple anchors, was 3–6 points.ConclusionsThe FACIT-Fatigue demonstrated adequate psychometric properties in patients with SLE. The body of evidence from the three BLISS trials (both pooled and individually) supports the FACIT-Fatigue as a reliable and valid measure of SLE-related fatigue in clinical trials.Clinical trial identifiersBLISS-SC (NCT01484496), BLISS-52 (NCT00424476), and BLISS-76 (NCT00410384).

PSY45 PATIENT-REPORTED OUTCOMES USED IN CLINICAL TRIALS OF SYSTEMIC LUPUS ERYTHEMATOSUS: A REVIEW OF SUITABILITY FOR FDA LABELLING CLAIMS

This review sought to identify patient-reported outcome (PRO) instruments that have been used in clinical trials of systemic lupus erythematosus (SLE) and examine their suitability for FDA labelling claims, based on proximity of the concept they measure to symptoms of SLE and evidence of content validity in SLE patients. A search was conducted on clinicaltrials.gov to identify PROs used as primary and/or secondary endpoints in SLE clinical trials. A literature review of identified PROs was then conducted, examining their structure, the concept they measure and evidence of content validity as per FDA standards, including involvement of SLE patients in instrument development. 49 different PRO instruments, used across 129 trials, were identified. The majority (39) measured multi-dimensional constructs or distal concepts of disease, including health-related quality of life (HRQOL), impacts on mental function (depression, anxiety, stress, anger), cognition, physical activity, sleep, social functioning and work performance, as well as self-management/efficacy, coping strategies and global impression of change. 10 identified PROs measured proximal concepts/symptoms of disease, namely fatigue and pain. Out of all 49 instruments that were identified, only 4 PROs, all HRQOL instruments, were SLE-specific and three of those, the LupusQoL, LupusPro and SLEQOL, had satisfactory evidence of content validity. A further review of these three instruments revealed that only LupusQOL contained domains that measure well-defined and proximal concepts/symptoms of disease, namely pain and fatigue. Despite a considerable number of PROs that have been used in SLE clinical trials, only three instruments had satisfactory evidence of content validity in SLE patients in line with FDA standards. Only one of these instruments, the LupusOOL, contains domains measuring proximal concepts/symptoms of disease (pain and fatigue) that could be considered suitable for inclusion in endpoint models in SLE drug development with intended PRO-based labelling claims in the US.

Lupus Low Disease Activity State (LLDAS) discriminates responders in the BLISS-52 and BLISS-76 phase III trials of belimumab in systemic lupus erythematosus

ObjectiveWe evaluated the discriminant capacity of the Lupus Low Disease Activity State (LLDAS) in post-hoc analysis of data from the BLISS-52 and BLISS-76 trials of belimumab in systemic lupus erythematosus...

The development of an end-to-end service solution to support lupus patients and improve their experience in clinical trials

ObjectiveTo develop an end-to-end clinical trial service to improve patient experience during trials, reduce the burden of participating in a trial, and increase trial retention.MethodsA literature search and stakeholder interviews were used to identify current challenges and unmet needs of systemic lupus erythematosus patients and other systemic lupus erythematosus clinical trial stakeholders. The results from the literature search and interviews were used to create a five-phase map describing the current clinical trial experience of all stakeholders. A set of proposed solutions were developed to address the identified unmet needs and challenges. These solutions were presented to trial-experienced patients and study site personnel; any feedback obtained was used to further refine the solutions.ResultsFour site personnel and seven patients from three different systemic lupus erythematosus clinical trial sites were interviewed between September 2015 and December 2015. Key unmet needs and challenges were identified at each stage of the clinical trials. At the screening stage, some patients incorrectly thought they were successfully enrolled into the clinical trial. During enrollment, some patients found it difficult to keep fully informed about the trial and were unable to explain the trial process to loved ones. During the trial, patients struggled to prepare for study visits, felt overwhelmed by the trial process, and wanted someone to talk to for support. Clinical trial site personnel reported current key challenges as: delivering trial information clearly and consistently to patients, setting patient expectations, retaining enrolled patients, and providing non-clinical patient support. To address the needs of patients and site personnel, an end-to-end support service was designed, consisting of nine solutions: My Best Choice, My Eligibility, My Lupus Trial Kit, My Lupus Trial Coach, My Appointment Guide, My Clinic Compass, Our Gratitude, Building a Different Network, and My Next Chapter.ConclusionThe solutions proposed in this qualitative study may help improve the systemic lupus erythematosus clinical trial experience for patients, potentially helping to increase trial recruitment and retention. The solutions proposed here would also promote positive patient-trial personnel relationships, which may help site personnel identify patients at risk of early withdrawal, while ensuring that the time and resources of site personnel are used efficiently.

2008–2018: a decade of recommendations for systemic lupus erythematosus

Recommendations represent a popular way of integrating evidence-based medicine to clinical practice. These systematically developed statements can assist practitioner and patient decisions about appropriate healthcare, facilitate teaching of students and...

Evaluating duration of response to treatment in systemic lupus erythematosus clinical trials

ObjectiveTo evaluate response duration and identify predictors of transitioning into and out of the response state in patients with SLE receiving standard of care (SoC) in 52-week clinical trials.MethodsA multistate...

The innate immune system in human systemic lupus erythematosus.

Although the role of adaptive immune mechanisms, e.g. autoantibody formation and abnormal T-cell activation, has been long noted in the pathogenesis of human systemic lupus erythematosus (SLE), the role of innate immunity has been less well characterized. An intricate interplay between both innate and adaptive immune elements exists in protective anti-infective immunity as well as in detrimental autoimmunity. More recently, it has become clear that the innate immune system in this regard not only starts inflammation cascades in SLE leading to disease flares, but also continues to fuel adaptive immune responses throughout the course of the disease. This is why targeting the innate immune system offers an additional means of treating SLE. First trials assessing the efficacy of anti-type I interferon (IFN) therapy or modulators of pattern recognition receptor (PRR) signalling have been attempted. In this review, we summarize the available evidence on the role of several distinct innate immune elements, especially neutrophils and dendritic cells as well as the IFN system, as well as specific innate PRRs along with their signalling pathways. Finally, we highlight recent clinical trials in SLE addressing one or more of the aforementioned components of the innate immune system.

Patient-reported outcomes in lupus clinical trials with biologics.

Therapeutic advances in systemic lupus erythematosus (SLE) are greatly needed. Despite advances in our knowledge of pathogenesis of the disease and targets, treatment remains a significant challenge. Finding effective and relatively safe medications remains one of the top priorities. SLE significantly impairs quality of life (QoL), and patient-reported outcomes (PROs) measure a unique aspect of the disease not captured by disease activity. Inclusion of PRO measurements is encouraged in SLE clinical trials, as they allow capturing benefits of a proposed intervention in language patients can relate to and in areas deemed pertinent and important to and by patients. Availability of patient-reported and patient-centric clinical trials data may facilitate patients in informed and shared decision making, and allow for comparative cost-effectiveness evaluation for future resource allocation and reimbursements. Herein we review clinical trials with biologic therapies wherein PRO tools were included in the study design.

T-cell-directed therapies in systemic lupus erythematosus.

Drug development for the treatment of systemic lupus erythematosus (SLE) has largely focused on B-cell therapies. A greater understanding of the immunopathogenesis of SLE coupled with advanced bioengineering has allowed for clinical trials centered on other targets for SLE therapy. The authors discuss the benefits and shortcomings of focusing on T-cell-directed therapies in SLE and lupus nephritis clinical trials.

Statistical considerations for stopping systemic lupus erythematosus clinical trials earlier.

Group sequential designs are used to potentially shorten randomized clinical trials and thereby reduce subject burden, improve safety, and save time and resources. Clinical trials comparing treatments for systemic lupus erythematosus (SLE) might adopt such designs if the ordinal outcome scales for SLE, such as the Systemic Lupus Activity Measure and Systemic Lupus Erythematosus Disease Activity Index, were more like continuous outcome scales with interval properties. After describing the basic features of sequential trials and highlighting some major issues in their design, we propose approaches that mitigate these issues. In particular, high-speed computing has accelerated advances in sequential design, making available a variety of designs that can be implemented with minimal technical support. The challenge now is to understand the concepts behind such flexible designs and then to apply them to improve studies of SLE.