Systemic Lupus Erythematosus Clinical Trials Research Articles

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.

Effect of corticosteroid use by dose on the risk of developing organ damage over time in systemic lupus erythematosus—the Hopkins Lupus Cohort

ObjectivesThe impact of corticosteroids on the risk of organ damage in the context of clinical end points endorsed in some systemic lupus erythematosus (SLE) clinical trials is underexplored.MethodsWe analysed data...

Validation of the LupusPRO in Chinese patients from Hong Kong with systemic lupus erythematosus.

LupusPRO is a disease-targeted, patient-reported outcome (PRO) measure that was developed and validated for assessment of quality of life in US patients with systemic lupus erythematosus (SLE). We present results of adapting the LupusPRO into Chinese and testing its psychometric properties in Chinese patients with SLE. LupusPRO was translated into "traditional" Chinese, followed by pretesting among native Cantonese Chinese speakers. The translation version was revised based on the feedback obtained. The Chinese language LupusPRO tool was administered along with a generic PRO tool (the Short Form 36 health survey [SF-36]) to ethnic Chinese SLE patients. At the same time, demographic information, clinical data, disease activity (Safety of Estrogens in Lupus Erythematosus National Assessment [SELENA] version of the Systemic Lupus Erythematosus Disease Activity Index [SLEDAI]), and damage (Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index [SDI]) were obtained. We performed confirmatory factor analysis of the Chinese LupusPRO and evaluated internal consistency reliability, as well as convergent and criterion validity. Among the 463 SLE patients (95% women) with a mean ± SD age of 42.3 ± 13.5 years, the mean ± SD physician global assessment score was 0.48 ± 0.45, the mean ± SD SELENA-SLEDAI score was 2.9 ± 3.0, and the mean ± SD SDI score was 0.7 ± 1.2. Results of factor analysis conformed to the original LupusPRO model with only minor modifications. The reliability of the LupusPRO domains ranged from 0.60-0.94. LupusPRO domains had correlations as expected with the corresponding SF-36 domains. A significant but weak correlation with disease activity was noted for criterion validity as expected. The Chinese language LupusPRO has fair psychometric properties and may be used in SLE clinical trials.

Patient-reported outcome measures for systemic lupus erythematosus clinical trials: a review of content validity, face validity and psychometric performance.

BackgroundDespite overall progress in treatment of autoimmune diseases, patients with systemic lupus erythematosus (SLE) experience many inflammatory symptoms representing an unmet medical need. This study aimed to create a conceptual model of the humanistic and economic burden of SLE, and review the patient-reported outcomes (PROs) used to measure such concepts in SLE clinical trials.MethodsA conceptual model for SLE was developed from structured review of published articles from 2007 to August 2013 identified from literature databases (MEDLINE, EMBASE, PsycINFO, EconLit) plus other sources (PROLabels, FDA/EMA websites, Clinicaltrials.gov). PROs targeting key symptoms/impacts were identified from the literature. They were reviewed in the context of available guidance and assessed for face and content validity and psychometric properties to determine appropriateness for use in SLE trials.ResultsThe conceptual model identified fatigue, pain, cognition, daily activities, emotional well-being, physical/social functioning and work productivity as key SLE concepts. Of the 68 articles reviewed, 38 reported PRO data. From these and the other sources, 15 PROs were selected for review, including SLE-specific health-related quality of life (HRQoL) measures (n = 5), work productivity (n = 1), and generic measures of fatigue (n = 3), pain (n = 2), depression (n = 2) and HRQoL (n = 2). The Functional Assessment of Chronic Illness Therapy - Fatigue Scale (FACIT-Fatigue), Brief Pain Inventory (BPI-SF) and LupusQoL demonstrated the strongest face validity, conceptual coverage and psychometric properties measuring key concepts in the conceptual model. All PROs reviewed, except for three Lupus-specific measures, lacked qualitative SLE patient involvement during development. The Hospital Anxiety and Depression Scale (HADS), Short Form [36 item] Health Survey version 2 (SF-36v2), EuroQoL 5-dimensions (EQ-5D-3L and EQ-5D-5L) and Work Productivity and Activity Impairment Questionnaire: Lupus (WPAI:Lupus) showed suitability for SLE economic models.ConclusionsBased on the identification of key symptoms and impacts of SLE using a scientifically sound conceptual model, we conclude that SLE is a condition associated with high unmet need and considerable burden to patients. This review highlights the availability and need for disease-specific and generic patient-reported measures of relevant domains of disease signs and symptoms, HRQoL and work productivity, providing useful insight for SLE clinical trial design.

AB1054 Lupus Impact Tracker is Responsive to Changes in SELENA-SLEDAI in Lupus

BackgroundPatient reported outcomes (PRO) are important to understand, educate, manage and follow patients with systemic lupus erythematosus (SLE). Lupus Impact Tracker (LIT) is a ten-item tool that was developed from...

THU0440 Lupuspro is Responsive to Changes in Disease Activity over Time

BackgroundPatient reported outcome (PRO) tools are important to understand, educate, manage, and follow patients with systemic lupus erythematosus (SLE). Disease targeted PRO for SLE (LupusPRO) has good reliability and has...

Which outcome measures in SLE clinical trials best reflect medical judgment?

ObjectivesTo compare two measures of systemic lupus erythematosus (SLE) response: the British Isles Lupus Assessment Group (BILAG)-based Composite Lupus Assessment (BICLA) and the Systemic Lupus Responder Index (SRI) against a...

PRM146 - Patient-Reported Outcome Measures for Systemic Lupus Erythematosus Clinical Trials: A Content Validity and Psychometric Performance Review

PRM146 - Patient-Reported Outcome Measures for Systemic Lupus Erythematosus Clinical Trials: A Content Validity and Psychometric Performance Review

Challenges and opportunities in SLE clinical trials

To provide an update on the field of clinical trials in systemic lupus erythematosus (SLE). This review will examine failed and successful clinical trials in SLE in order to draw lessons and determine the optimal ways forward. Over the past decade, many clinical trials in SLE met with limited success, but in the past 2 years several SLE clinical trials have been successful. The two large phase III randomized controlled trials (RCTs) of belimumab achieved their primary endpoints and resulted in food and drug administration and European medicines agency approval of the drug. Characteristics of these trials were, among other things, a very large number of patients (>800 each), compound clinical endpoints, and a flexible design with regards to concomitant medication use. Likewise, large randomized controlled trials with mycophenolate mofetil, although nominally unsuccessful, clearly demonstrated the clinical benefit of this drug in lupus nephritis. Posthoc analyses of several failed trials involving abatacept and rituximab revealed design elements and/or outcomes that might have changed the outcomes of these studies. Many smaller trials have also been reported, in some instances with surprisingly positive results. An improved understanding of specific design features in SLE clinical trials combined with robust outcomes will make it possible more effectively to design and conduct clinical trials in SLE.

PSY61 - Who told you that: Do guidelines for including patient-centered outcome measures in systemic lupus erythematosus clinical trials include patient input?

The importance of patient-centered outcomes (PCO) in drug development is increasingly recognized by health authorities, clinical advisory and patient advocacy bodies. Accordingly, many of these organizations seek to include PCO in their guidelines and recommendations. However, complex disorders present measurement challenges that are difficult to resolve within the scope of a clinical trial (CT). An example is Systemic Lupus Erythematosus (SLE), characterized by myriad clinical indicator, symptom, severity and frequency combinations. SLE patient burden studies demonstrate that, while symptoms differ, the impact is universal. This study evaluates the relationship between recently updated SLE guidances and concepts reported directly by SLE patients. A qualitative study comprised of six SLE patient focus groups (N=43) was conducted to elicit direct patient input on key symptoms and concepts. FDA and EMA guidelines for SLE clinical trials, European League Against Rheumatism (EULAR) CT endpoint recommendations, and the Systemic Lupus International Collaborating Clinics (SLICC) classification system were evaluated for PCO-specific content. Patient-reported outcomes (PRO) concepts from the study were then compared to the PCO content from the guidelines and recommendations. All study subjects (mean age 44.3 years; 91.7% women; 63% diagnosed ≥ 5 years; 91% experienced flare ≤ 3 months; 74% mild/moderate disease) identified fatigue among “most important symptoms” with 98% citing pain and 44% fog/confusion. Regardless of “importance” all subjects deemed other symptoms highly disruptive. EMA and FDA both specify fatigue as a clinical trial endpoint. FDA included “fatigue” based on clinician input, but recommended development of a PRO-based fatigue exploratory endpoint. EULAR, citing challenges of symptom endpoints, suggested general Health-Related Quality of Life. The SLICC didn’t mention PCOs. Patients identified multiple SLE symptoms and impacts, yet guidances didn’t address these issues. Joint efforts between patients, sponsors, regulators and advisory organizations are necessary to implement relevant PCOs, especially in complex disorders.

Belimumab Therapy in Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is a complex heterogeneous disease, posing challenges to clinical trials. As in other autoimmune diseases, B-lymphocytes play a central role in lupus pathogenesis. The finding that selection and survival of B cells are controlled by a variety of signals, including those provided by the longevity factor BAFF (B-cell activating factor), also called BLyS (B-lymphocyte stimulator), led to preclinical trials that revealed that BAFF represents a promising therapeutic target for human lupus. Belimumab is a fully human monoclonal antibody directed against BAFF. Lessons learned from early clinical trials led to improved methods and success of phase III trials, with recruitment of patients with both clinically and serologically active disease, development and use of a novel SLE Responder Index, and progressive and special restrictions on immunosuppressive and corticosteroid use. These studies offer an attractive blueprint to conduct future clinical trials in SLE. The overall steroid-sparing ability and benefits of belimumab on musculoskeletal and mucocutaneous organ systems suggest that it has an impact on the clinical management of SLE patients. Future directions include studies to determine the role of belimumab in early SLE, as well as in renal or CNS involvement.

Targeting the complement system in systemic lupus erythematosus and other diseases

The importance of the complement system in the pathogenesis of systemic lupus erythematosus (SLE) has long been recognized. However, despite an unprecedented amount of SLE clinical trial activities ongoing at this time, complement inhibitors have been omitted from the therapeutic assault on this disease. We review data generated from murine lupus that provide scientific support for the study of human SLE. Also reviewed is the sole study of a complement inhibitor, eculizumab, performed in patients with SLE. We conclude with a review of other inflammatory diseases where ongoing programs might provide the groundwork for the development of complement inhibitors in SLE.

BAFF and innate immunity: new therapeutic targets for systemic lupus erythematosus

Recently, the B cell has emerged as a cornerstone of systemic lupus erythematosus (SLE) pathogenesis. This has been highlighted by studies of the cytokine B-cell-activating factor of the tumour necrosis factor (TNF) family (BAFF), a crucial factor regulating B-cell maturation, survival and function. Overexpression of BAFF in mice leads to the development of an SLE-like disease, independent of T cells but instead relying on innate immunity mechanisms. Moreover, BAFF has been shown to be elevated in the serum of patients suffering from autoimmune conditions, especially SLE, and may correlate with disease activity. These findings challenge the previous notion that T:B-cell collaboration is the sole driver of SLE. In recent years, controlled trials have for the first time tested targeted therapeutics for SLE. However, agents designed to target B cells failed to meet primary endpoints in clinical trials in SLE, suggesting that a more complex role for B cells in SLE awaited elucidation. By contrast, on 9 March 2011, the US Food and Drug Administration approved belimumab, a fully human anti-BAFF monoclonal antibody, as a new B-cell-specific treatment for SLE. This article will review over 10 years of research on the BAFF system, key findings that led to this recent positive clinical outcome and propose a model potentially explaining why this B-cell-specific therapy has yielded positive results in clinical trials. We will also review promising therapies presently in clinical trials targeting innate immunity, which are likely to revolutionize SLE management towards a personalized and targeted therapy approach.

Novel and Emerging Drugs for Systemic Lupus Erythematosus: Mechanism of Action and Therapeutic Activity

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by B cell hyperactivity and defective T-cell function, and several cytokine aberrations, with high titer production of autoantibodies and clinical involvement in multiple organ systems. It can present with a wide variety of symptoms, most commonly involving the skin, joints, kidneys, and blood vessels. Patients with mild SLE can be treated with non-steroidal antiinflammatory drugs and antimalarials. Corticosteroids, azathioprine and cyclophosphamide, remain important for long term management of most patients with active disease. In recent years, significant progress in molecular and cellular biology of SLE has resulted in a better characterization and understanding of the biology and prognosis of this disease. These achievements have provided new opportunities for the development of innovative, more effective, therapies. Novel agents potentially useful in the treatment of patients with SLE include tolerogens, monoclonal antibodies and other agents. Tolerogens are synthetic molecules that can bind and cross-link autoantibodies on reactive B-cell surface, promoting B-cell depletion or inactivity. An anti-DNA antibody based peptide, pCons, might have also therapeutic efficacy in SLE patients who are positive for anti-DNA antibodies. In addition, prasterone, a proprietary synthetic dehydroepiandrosterone product is under investigation for the treatment of SLE. Blockade of TLR9 with specific G-rich DNAoligonucleotids also suppresses lupus activity. Several newer mAbs have been developed and are being evaluated in phase I/II clinical trials. These include newer anti-CD20 mAbs, anti-cytokine therapies, anti-BLys mAbs and anti-C5 mAbs. Most of the new agents which could be potentially useful in the treatment of patients with SLE need further laboratory investigations and clinical trials. In this review, promising new agents, potentially useful in SLE, are presented.

Measuring outcomes in systemic lupus erythematosus clinical trials

The recent approval of the biologic therapy, belimumab, for treatment of systemic lupus erythematosus (SLE) by the US FDA has shifted the developmental landscape of therapeutics for this autoimmune disease. Promising therapies are currently in development for the treatment of SLE, with trials designed to emphasize clinically relevant end points. This article will discuss outcome measures that have been utilized including disease activity indices, definitions of flare, measures of damage, global assessments of disease activity and measures of health-related quality of life. Application of these outcome measures in recent trials are highlighted as illustrative examples. Contributions to the recent success of randomized controlled trials in SLE have included use of evidence-based responder indices, clear definitions of treatment failure, predefined management strategies for use of immunosuppressive agents and corticosteroids, sufficient sample sizes and efforts to identify responsive patient populations. Each completed study in SLE promises to better inform trial design and offer further opportunities for success in a field with a continuing unmet therapeutic need.

Targeted therapies in systemic lupus erythematosus: successes, failures and future

PurposeThe author's goal is to review recent phase III clinical trials in patients with systemic lupus erythematosus (SLE), with emphasis on outcomes and on mechanisms by which the experimental drugs/biological...

Quality-of-Life Measurements in Multiethnic Patients with Systemic Lupus Erythematosus: Cross-Cultural Issues

Although the survival rate for systemic lupus erythematosus (SLE) has improved dramatically during the past 50 years, the quality of life of patients afflicted with this disease remains poor. Currently existent measures of disease activity and damage in SLE do not capture the patient's perspective and health-related quality of life (HRQoL). Most studies in SLE pertaining to HRQoL are from developed Western societies, with only a few from others. These studies have been conducted predominantly in women and using the Medical Outcomes Survey Short Form 36, a generic HRQoL instrument that has been shown not to be sensitive to change in lupus. Existent lupus-specific HRQoL measures have not yet been used in SLE clinical trials. New HRQoL research tools are currently undergoing validation in different countries, languages, and cultural settings, which may help dissect the underlying role of socioeconomic status and specific disease-related features that impact SLE-related quality of life.

Pitfalls and Opportunities in Measuring Patient Outcomes in Lupus

Health outcomes and their measures used as end points in systemic lupus erythematosus (SLE) patient care and clinical trials have been varied and are still evolving. Although significant reductions in morbidity and mortality in SLE have been achieved, the medications approved for SLE have remained the same during the past 50 years. Despite the pressing need, aggressive advocacy in the community, and advances in drug development and testing in SLE, no medications have met US Food and Drug Administration guidelines for a new indication claim approval for SLE. This may be attributable to its multisystemic, remitting, and relapsing nature, and difficulty in identifying useful end points and appropriate tools to measure them. Thus, it is pivotal to identify and validate appropriate global, disease-specific, and perhaps organ-specific health outcomes for clinical research. This article reviews recent physician- and patient-generated health outcomes in SLE.

Prevalence of Flare and Influence of Demographic and Serologic Factors on Flare Risk in Systemic Lupus Erythematosus: A Prospective Study

We determined the prevalence of and risk factors for British Isles Lupus Activity Group (BILAG) flare in patients with systemic lupus erythematosus (SLE). We followed 299 patients for 1 year with the BILAG scores calculated using British Lupus Integrated Prospective System software and confirmed with manual calculation. "A" flares occurred at a rate of 0.254/year, "B" flares 1.637/year, and A or B flares 1.765/year. The most common A flares were renal and mucocutaneous. The most common B flares were hematologic, renal, mucocutaneous, and musculoskeletal. Risk factors for a later A or B flare in the hematological system included: low C3 (p < 0.0001), low C4 (p = 0.0004), and positive anti-double-stranded (ds)DNA (p = 0.003); in the mucocutaneous system: low C3 (p = 0.02) and low C4 (p = 0.0004); and in the renal system: low C3 (p = 0.02) and low C4 (p = 0.02). In a stepwise regression model, only ethnicity (p = 0.02) and low C4 (p = 0.0002) remained as independent predictors of later A or 2B flares. The organ system distribution of A and B flares is very different, with A flares more common in renal and mucocutaneous, and B flares more common in hematologic and renal systems. A or 2B flares are significantly more common in African Americans and in patients with abnormal serologies (low C3, low C4, or high anti-dsDNA). If flare is an outcome in an SLE clinical trial, these factors must be balanced by taking them into account at baseline in terms of randomization, or by statistical adjustment in final analyses.

Frequency and determinants of flare and persistently active disease in systemic lupus erythematosus

Selection of flare as the primary outcome variable in systemic lupus erythematosus (SLE) clinical trials fails to capture patients with persistently active disease (PAD). We sought to elucidate the frequency and determinants of flare and PAD. Prospectively collected data from the Toronto Lupus Cohort were used to determine the incidence of flare and PAD in 2004 and 2005. Flare was defined as an increase in SLE Disease Activity Index 2000 update (SLEDAI-2K) score of >/=4 from the previous visit. PAD was defined as a SLEDAI-2K score of >/=4, excluding serology alone, on >/=2 consecutive visits. Data from 1, 2, and 3 years prior were used to model flare and PAD in 2004. Model properties were tested for prediction of flare and PAD in 2005. One-third of the patients had >/=1 flare, whereas nearly half experienced PAD in a given year. Nearly 60% of the patients had episodes of flare or PAD per year. At least 25% of patients had PAD without achieving the definition of flare. In the best-fitting model, predictors of PAD in 2004 were SLEDAI-2K score at the start of the outcome interval and prior cutaneous or musculoskeletal disease activity. This model gave 79% correct prediction of PAD in 2005. In contrast, flare prediction models performed poorly. Persistent activity is a common disease state in SLE and should be an outcome variable in SLE clinical trials. Our PAD prediction model may aid prognostication and selection of patients for inclusion in clinical trials.