Measuring outcomes in systemic lupus erythematosus clinical trials

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www.expert-reviews.com ISSN 1473-7167© 2011 Expert Reviews Ltd10.1586/ERP.11.38

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with heterogeneous clini-cal manifestations. Available outcome measures used in randomized controlled trials (RCTs) were developed in longitudinal observational studies (LOS) and, as such, may not reflect the more severe patient populations that RCTs may enroll, nor quantify acute responses to thera-peutic interventions. The number of therapies currently under development for treatment of SLE has underscored the importance of deter-mining how best to assess outcomes in RCTs, and consensus remains to be reached among the rheuma tology community on how best to use these outcome measures. Furthermore, it has been challenging to conduct successful trials in SLE because superiority must be shown in a con-trol group of patients receiving standard-of-care therapy with both placebo and active treatment arms superimposed upon background active therapy including immunosuppressive agents and cortico steroids. This article reviews outcome measures and responder indices and how they can best be utilized and interpreted in RCTs in SLE. The distinguishing features of recent successful trials will be highlighted with an emphasis on how these outcome measures have been utilized.

In 1998, an international consensus confer-ence on outcome measures in rheuma tology (OMERACT 4) recommended that core domains be assessed in RCTs and LOS in SLE should include disease activity, health-related quality of life (HRQOL), adverse events and damage [1,2]. The necessity to quantify and track active features of SLE over time has led to the development of disease activity indices, several of which are used in RCTs. A specific component of disease activity, flare, has been defined in a multitude of ways and has triggered efforts to reach a consensus definition among an international group of clinicians and research-ers. HRQOL has been measured by generic and disease-specific instruments as well as fatigue. Patient and physician global assessments (PGAs) contribute important additional insights into therapeutic outcomes. Finally, as patients are living longer with SLE, damage as a direct or indirect result of ongoing disease activity and its treatment has become important to assess. However, OMERACT and others have empha-sized that any individual measure of clinical response in SLE reflects only a portion of what might be termed ‘true outcome’, and that a com-posite responder index could integrate relatively

Vibeke Strand†1 and Alvina D Chu1

1Division of Immunology and Rheumatology, Stanford University School of Medicine, 306 Ramona Road, Portola Valley, CA 94028, USA †Author for correspondence:Tel.: +1 650 529 0150 Fax: +1 650 529 0225 [email protected]

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.

Keywords: disease activity • flare • outcome measure • responder index • systemic lupus erythematosus

Measuring outcomes in systemic lupus erythematosus clinical trialsExpert Rev. Pharmacoeconomics Outcomes Res. 11(4), 455–468 (2011)

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independent measures into a single assessment defining a patient as a responder or nonresponder [2]. Outcome measures used in RCTs are detailed in the following paragraphs (Box 1).

The US FDA held an open meeting of the Arthritis Advisory Panel in February 1999 to discuss recommendations for develop-ment of a guidance document for testing new products for treat-ment of SLE. A draft document was circulated in 2005 and final guidance for trials in SLE and SLE nephritis were issued in 2010. These include definitions for ‘reduction in disease activity’, ‘com-plete clinical response or remission’, ‘reduction in flare/increase in time to flare’, ‘reduction in concomitant corticosteroid use’, and ‘treatment of serious acute manifestations’ [201,202].

Disease activity indicesFour disease activity indices have been developed over the past three decades, all of which have been used in RCTs: Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), including Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA–SLEDAI) and SLEDAI 2K modifications; British

Isles Lupus Assessment Group (BILAG) Index (classic and 2004 modification); Systemic Lupus Activity Measure (SLAM and SLAM-R modification) and European Consensus Lupus Activity Measure (ECLAM) [2]. Each emphasizes different aspects of SLE disease activity and offer spe-cific strengths and weaknesses. Importantly, global and/or organ specific manifestations must be attributed to disease activity and neither an adverse effect on treatment nor permanent damage from disease, which can lead to confusions in scoring and require that training in their use be mandated. Training is used to familiarize the user to the index and ensure proper attribution of scored features to active disease. These indices have been validated in treatment settings based on acceptable inter-observer variability among trained evaluators, cor-relations between patient scores by differ-ent indices, changes in therapy and dem-onstrated sensitivity to changes in disease activity [1,3–13].

Systemic Lupus Erythematosus Disease Activity IndexThe SLEDAI is a global score based on the presence or absence of clinical signs, symp-toms and immunologic laboratory results within 10 days of the evaluation [14]. Disease activity is based on 24 questions, weighted across nine organ systems, combined into a total score. Scores range from 0 to 105, but are generally <20, even with very active dis-ease. It was originally developed by a panel

of rheumatologists with expertise in SLE by consensus process based on LOS. During development, selection of descriptors placed emphasis on disease activity, and manifestations were excluded if they were considered to reflect damage from disease. The SLEDAI has been validated cross-culturally and demonstrated to be repro-ducible and reliable among expert clinicians and trainees, and it can be completed in a few minutes after minimal training, which may contribute to the advantages of using SLEDAI in RCTs [5,6].

The SLEDAI measures disease activity based on features present in specific organ systems and laboratory results. The descriptors are not easily triggered by normal variations in disease activity, thus setting a higher threshold for response. Modeled on clinicians’ global judgment, it was not intended to detect gradations of disease activity within an organ system, nor worsening or partial improve-ment of a specific manifestation. It gives preferential weight to involvement in the CNS and renal organ systems and excludes rare manifestations of disease activity. Therefore, a patient with active and extensive skin disease as a result of SLE may exhibit a lower SLEDAI score compared with one with proteinuria.

Box 1. Systemic lupus erythematosus outcome measures for use in randomized controlled trials.

Disease activity indices

• SLEDAI

• BILAG Index

• Systemic Lupus Activity Measure

• European Consensus Lupus Activity Measure

• Definitions of flare

• Consensus definition by International Flare Consensus Initiative

• Fortin definition of Severe SLE Flare

• Safety of Estrogens in Lupus Erythematosus National Assessment-SLEDAI Flare Index

• BILAG

Health-related quality of life measures

• Medical Outcomes Survey Short Form-36

• Krupp Fatigue Severity Scale

• Functional Assessment of Chronic Illness Therapy-Fatigue Scale

• Lupus QoL Questionnaire

• L-QoL Questionnaire

• SLEQOL Questionnaire

• Lupus-Patient Reported Outcome Questionnaire

Global assessments

• Patient Global Assessment

• Physician Global Assessment

Measures of damage

• Systemic Lupus International Collaborative Clinics/American College of Rheumatology Damage Index

• Definitions of loss of renal function – per Schiffenbauer

• Osteoporosis/fractures due to SLE and/or its treatment

Responder indices

• SLEDAI responder index

• BILAG-based responder index

BILAG: British Isles Lupus Assessment Group; L: Lupus; QOL: Quality of life; SLE: Systemic lupus erythematosus; SLEDAI: Systemic Lupus Erythematosus Disease Activity Index.

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The SELENA–SLEDAI and SLEDAI-2K are modified ver-sions of the original SLEDAI to reflect persistent, active dis-ease in those descriptors that originally recorded only new or recurrent manifestations [15]. The SLEDAI counts such vari-ables as proteinuria, rash, alopecia and mucous membrane lesions as active only at their first occurrence or upon recur-rence, to distinguish active from chronic disease manifestations. By contrast, SLEDAI-2K and SELENA–SLEDAI record organ system involvement as a reflection of ongoing disease activity with improved clarification and attribution for individual items. The SELENA–SLEDAI includes modifications to the original SLEDAI such as addition of scleritis and episcleritis as descriptors of active disease [16,17]. The SLEDAI-2K, originally developed for a 10-day window, has been validated against the original SLEDAI [15]. Both SELENA–SLEDAI and SLEDAI-2K 30 days are based on scoring manifestations over the last 28–30 days for use in RCTs [16–19]. Reductions in SLEDAI of ≥4 points from baseline have been determined to be clinically meaning-ful also defined for SLEDAI-2K and SELENA–SLEDAI [19–23]. Cross-sectional analysis of data collected on the SLEDAI-2K has demonstrated that the most appropriate cut-off scores for active disease were 3 or 4 [24]. A recent longitudinal analysis of SLEDAI-2K data indicated that the SLEDAI-2K is best used as a continuous outcome and with the score of the previous visit included, with 2.64 being the mean difference in the change in SLEDAI-2000 score from the prior score between patients with treatment increase and those without [24]. In addition, a SLEDAI Responder Index 50 measuring improvement in dis-ease manifestations on follow-up visits by ≥50% improvement of SLEDAI-2K scores has been developed and validated in a longitudinal series [25,26].

The SLEDAI and its modifications have been utilized as inclu-sion criteria to establish a threshold of disease activity for eligibil-ity in clinical trials, and as primary end points or components of primary end points in RCTs, including the SELENA trials of hormone replacement therapy and oral contraceptive use [16,17].

British Isles Lupus Assessment Group Disease Activity IndexThe BILAG scores disease involvement within each organ system in detail based on an intent-to-treat principle, thereby defining severity of disease activity for each manifestation [27]. It was devel-oped and validated based on consensus among SLE experts of the likelihood and type of treatment patients would receive according to specific clinical features in eight organ systems. Manifestations within organ systems are categorized into letters that represent need for therapy: ‘A’ reflecting severe disease, requiring increases in prednisone to >20 mg daily and/or addition of immuno-suppressive agents; ‘B’ indicating less active disease, requiring low-dose prednisone and/or symptomatic treatment with NSAIDs and/or antimalarials; ‘C’ reflecting mild disease requiring only symptomatic therapy such as simple analgesics, or stable disease on current therapy; ‘D’ meaning previous organ system involvement without current disease activity; and ‘E’ indicating no prior or no current disease involvement in that organ system [10,27].

British Isles Lupus Assessment Group 2004 was developed as a major revision to the classic BILAG, incorporating changes to the glossary, items and scoring system, making it operationally differ-ent from its predecessor but preserving the principle upon which the index was established, that of the physician’s intention to treat [10,28]. The BILAG-2004 expands the number of organ-based systems to nine by addition of an SLE-related ophthalmologic category, combining previously scattered abdominal and hepatic manifestations into a gastrointestinal category, and redistributing vasculitis into the organ system of involvement [10]. It also rede-fines terms and definitions for neuropsychiatric manifestations of SLE based on American College of Rheumatology nomenclature and case definitions [29]. The revised scoring system allows severe disease manifestations previously categorized as A, that are still active but improving, to be scored as B, thereby reflecting changes in disease activity of more severe manifestations [10].

Updates to classic BILAG and BILAG-2004 indices have incor-porated numerical additive scoring, resulting in a single summary score [28,30]. Global scores are designed to improve statistical anal-ysis, but, owing to changes made during development of BILAG-2004, the numerical coding scheme for classic BILAG cannot be used interchangeably with BILAG-2004. A separate numerical scoring system has been developed for the BILAG-2004 index [28].

The BILAG and BILAG-2004 indices are the only disease activity indices that score features as same, worse, or improved rather than as present or absent. The comprehensive nature of the BILAG allows its discernment of disease activity within spe-cific organ systems, as well as identifying which are improving or worsening, and also provides a global score, similar to other disease activity indices such as SLEDAI [3,28,30]. The FDA guid-ance for the testing of new products for treatment of SLE suggests that BILAG is a preferred index to study reduction in disease activity in RCTs owing to its ability to score patients’ need for therapy, thus defining clinical meaningfulness [201]. Compared with SLEDAI-2K, BILAG-2004 has been demonstrated to bet-ter detect active disease requiring increases in treatment [31]. However, it should be noted that BILAG places emphasis on changes in disease manifestations in specific organ systems rather than physician assessment of disease activity.

Despite the many advantages of BILAG and BILAG-2004, concerns have been raised about the comprehensive nature of the instrument and the ability to train evaluators in multinational trials in its proper use, since its validation was performed by individuals very familiar with BILAG [3,5,12,32]. Efforts to standardize training for use of BILAG are underway, including a project by the Lupus Foundation of America to create a global training course. In trials where BILAG is used to define ‘no deterioration’ in disease activ-ity by the absence of new A or 2B organ system manifestations, computer-assisted scoring has facilitated more efficient and uniform use of BILAG. In those RCTs where BILAG serves as the primary outcome measure or as the major component of response criteria, because of variability in interpretation and scoring, independent for-mal adjudication panels have been established to ensure that disease manifestations were recorded and correctly attributed. This includes verification that physical examination findings and laboratory

Measuring outcomes in systemic lupus erythematosus clinical trials


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results are scored in a uniform fashion and disease worsening or improvement are accurately captured. An adjudication panel was employed in two trials of epratuzumab, an anti-CD22 monoclonal antibody, in which BILAG was used prominently as in the primary end point [33–36]. The complexity of BILAG and BILAG-2004 indi-ces includes rules for recording manifestations to capture more than the presence or absence of active disease. As BILAG is used more frequently in RCTs, it is expected that investigators will become more familiar with its detailed scoring system.

Systemic Lupus Activity Measure Disease Activity IndexSimilar to SLEDAI, the SLAM is a standardized weighted index for the global assessment of SLE activity, based on signs and symp-toms observed in the previous month [7,37]. The SLAM consists of 24 clinical and seven laboratory features graded as active or inactive, with activity scores varying from mild to moderate to severe [7,37]. In the more commonly used SLAM-R, disease activ-ity scores range from a minimum of 0 to a maximum of 81 [37]. Scoring is weighted toward more severe clinical manifestations and includes patient reported symptoms of fatigue. SLAM-R has been the instrument of choice in the Lupus in Minorities: Nature Versus Nurture LOS of a multiethnic cohort of patients with SLE [38,39]. SLAM was first utilized in multicenter, placebo RCTs of dehydroepiandrosterone (DHEA) [40,41].

European Consensus Lupus Activity Measure Disease Activity ScoreThe ECLAM index is a global score comprised of nine clinical and three laboratory manifestations of SLE over the preceding month, with scores ranging from 0 to 10 [42]. PGA is the reference gold standard of disease activity, and the index was developed based on a large cohort of European patients with SLE, whose symptoms and laboratory parameters were determined to best predict disease activity [42]. ECLAM was utilized as a disease activity measure in an open-label trial comparing mycophenolate mofetil with azathioprine [43].

Definitions of flareClinically, a patient is considered to be in a flare when there is an increase in disease activity, but there is no uniform agreement on how best to measure or define the severity of flare in SLE. In RCTs, the FDA recommends that flares be prospectively defined if they are to be included as an end point [201]. Flare definitions have been constructed based on consensus, disease activity indices and LOS. An international effort sponsored by the Lupus Foundation of America was initiated in 2006 to develop a clinically meaningful definition of flare for use in RCTs, LOS and clinical practice [44]. Consensus was reached for the following definition: “A flare is a measurable increase in disease activity in one or more organ systems involving new or worse clinical signs and symptoms and/or labora-tory measurements. It must be considered clinically significant by the assessor and usually there would be at least consideration of a change or increase in treatment” [44]. A proposed instrument is in development to distinguish ‘mild’ from ‘moderate’ and ‘moderate’ from ‘severe’ flares based on organ-specific clinical manifestations

and treatment. ‘Treatment trumps’, in the sense that the intended treatment decision, if higher, overrides the clinical description in each category.

A variety of flare definitions have been utilized in previous RCTs. A major or severe flare, defined by Fortin et al. includes: new or increased use of immunosuppressive therapy; new or increased use of high dose corticosteroids; and hospitalization and/or death due to SLE disease activity – straightforward and typically not requiring adjudication in RCTs [45,46]. Disease activ-ity indices have been adapted as flare instruments, including the SELENA–SLEDAI Flare Index (SFI) and BILAG, defining severe flare as development of new BILAG A, or 2 concurrent Bs, in any organ system, from previous B, C, D or E; and moderate as a new BILAG B, from previous C, D or E [16,17,47]. The SFI was developed as the primary end point in the SELENA RCTs to define mild/moderate versus severe flares [14,15]. Criteria for mild/moderate flares included new or worsened clinical features, increases in SELENA–SLEDAI ≥three points, prednisone use to <0.5 mg/kg/day, and PGA scores of 1.0–2.5 on a 0–3 visual analog scale. A severe flare was defined as a change in SELENA–SLEDAI score to >12, and/or clinical manifestations requiring doubling of prednisone dose or >0.5 mg/kg/day [16,17].

Comparing populations enrolled in RCTs and LOS, there are remarkably similar proportions of major or severe flares over 12 months regardless of the flare definition used (TaBle 1). Consistently, 5–10% of flares have been defined as severe either by SFI or BILAG A category [16,17,47,48]. Severe flares are increased in subjects with a history of renal disease, for example, 38% in placebo across both abetimus trials, and 23–27% in those with per-sistently active disease enrolled in the SELENA RCTs [16,17,23,49,50]. In the Phase III RCTs with belimumab, severe flares ranged from 23 to 27% in the control groups, in a population with moderate-to-severe active SLE [51,52]. Comparison among BILAG-2004 and SELENA flare index definitions of severe flares have showed good agreement but less consistency for mild/moderate flares [53]. Consensus is still required regarding how best to differentiate mild from moderate flares.

In trial populations, time to severe flare can be a sensitive statis-tical analysis and can be used as a supportive measure of clinical meaningfulness. However, outstanding issues include difficul-ties in differentiating new organ manifestations from worsening within an organ system, distinguishing between small increases in disease activity that fall between predefined thresholds of mild, moderate and severe flare, and differentiating persistent disease activity from flare [44].

Health-related quality of lifeHealth-related quality of life refers to the physical, psychologic, mental and social aspects of health and impact of disease, which are influenced by life experiences and expectations specific to each patient [54]. Generic HRQOL measures and fatigue scales have been utilized in RCTs and LOS (Box 1) [3]. HRQOL has been rec-ommended as an important domain for assessment in RCTs in SLE, and has been demonstrated to distinguish between active and control treatment groups and between doses of active therapy [55].

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A widely used generic measure, the Medical Outcomes Survey Short Form-36 (SF-36), has best reflected the impact of SLE on HRQOL in LOS and frequently has been the only patient reported outcome in RCTs [56–62]. It includes eight domains: physical func-tioning, role physical, bodily pain, general health perceptions, vital-ity (VT; which includes fatigue, energy and vigor), social func-tioning, role emotional and mental-health impact, combined into physical component summary scores (PCS) and mental component summary scores (MCS). The PCS score positively weights the four ‘physical’ domain scores: physical functioning, role physical, bodily pain and general health perceptions, as well as VT, and negatively weights the remaining three; MCS positively weights the four ‘men-tal’ domains: VT, social functioning, role emotional and mental health impact, and negatively the four physical domains. As such, PCS and MCS scores measure different ‘concepts’ but are not fully independent of each other. As a generic measure, SF-36 has been well validated in SLE and is frequently utilized as the only patient reported outcome measure in RCTs [55,63,64]. Values for minimum clinically important differences (MCID) from RCTs in SLE are consistent with those in other rheumatic diseases, 5–10 points in domains and 2.5–5.0 in summary scores, and for ‘no deterioration,’ for example, stabilization and/or improvement, do not exceed -2.5 and -0.8 for domain and summary scores, respectively, indicating that patients perceive worsening sooner than improvement [64,65]. On an individual basis, these definitions may be used to define subjects reporting clinically meaningful improvement and may also be correlated with answers to the transition question: ‘compared with a year ago, how is your general health today?’

Other patient-reported measures used in SLE include those for fatigue and for physical function. Two measures of fatigue, Krupp Fatigue Severity Scale and Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue scale, have been utilized in

RCTs. Responders in the belimumab Phase III RCTs reported significant improvements in FACIT and VT domains as well as rating themselves ‘somewhat better’ to ‘very much better’ on the transition question of SF-36 [66]. Good correlations (>0.60) were demonstrated between FACIT and VT domains of SF-36, sup-porting the utility of this generic measure of multidimensional function in SLE.

Measures of physical function, including Health Assessment Questionnaire (HAQ) and Arthritis Impact Measurement Scale, have been used less frequently in SLE. The HAQ has been vali-dated in SLE and, like SF-36, does not correlate closely with measures of disease activity, indicating that it reflects different domains of disease impact [67,68]. The MCID for HAQ has been shown to be consistent with that of patients with rheumatoid arthritis, although Burckhardt and colleagues found it to be a less responsive instrument in SLE [69,70].

Several disease-specific questionnaires have been developed to measure HRQOL in SLE with the intention of designing an instrument with enhanced responsiveness and content validity for SLE compared with generic instruments. The LupusQoL was designed based on semi-structured interviews of SLE patients in the UK and has demonstrated good internal consistency, test–retest reliability and concurrent validity with the generic SF-36 [71,72]. Weakly correlated with disease activity and dam-age indices, LupusQoL provides additional information on the impact of SLE on a patient [72]. This instrument has been adapted and validated for assessment of patients with SLE in the USA (LupusQoL-US) as well as in other languages [73,203]. Another disease specific HRQOL instrument, L-QoL, was developed from patient interviews and validated in the UK, and is based on the concept that gains in HRQOL are derived from the ability and capacity of individuals to satisfy their needs [74].

Table 1. Rates of severe systemic lupus erythematosus flares over 12 months: data from randomized controlled trials and longitudinal observational studies.

Study Flare definition Sample size (n)

Severe or major flare rates in control groups

Ref.

Kalunian et al.: anti-CD40 ligand mAb RCT

SELENA–SLEDAI Flare Index 94 10% severe flares [48]

Gordon et al.: LOS BILAG 250 10.4% severe ‘A’ flares [47]

Buyon et al.: hormone replacement therapy RCT

SELENA–SLEDAI Flare Index 351 4.9–8.1% severe flares [17]

Petri et al.: oral contraceptive RCT SELENA–SLEDAI Flare Index 183 8.4–8.7% severe flares [16]

Sanchez-Guerrero et al.: oral contraceptive RCT

Change in SLEDAI 162 3.0–9.0% severe flares [101]

Cardiel et al.: abetimus sodium RCT ‘Fortin definition’ of severe flare 230 298

42% major flare (with renal disease)31% major flare (with renal disease)

[49]

Navarra et al. and Van Vollenhoven et al.: belimumab RCTs

SELENA–SLEDAI Flare Index SFI 865819

23.0% severe flare (moderate-to-severe active SLE)26.5% severe flare (moderate-to-severe active SLE)

[51,52]

BILAG: British Isles Lupus Assessment Group; LOS: Longitudinal observational study; mAb: Monoclonal antibody; RCT: Randomized controlled trial; SELENA: Safety of Estrogen in Lupus Erythematosus National Assessment; SFI: SELENA Flare Index; SLEDAI: Systemic Lupus Erythematosus Disease Activity Index. Adapted and updated from [23].



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The Systemic Lupus Erythematosus Quality of Life question-naire (SLEQOL) consists of items considered by rheumatology professionals to be important determinants of HRQOL in SLE patients [75]. It has less concurrent validity than SF-36 and its sensitivity to change remains to be validated. The Lupus-specific Patient Reported Outcome measure (Lupus-PRO) developed in the USA, includes ten domains of HRQOL as well as four con-sidered to reflect ‘non-HRQOL’ including desires/goals, coping, social support and medical care [76]. It is undergoing validation to be used as a patient-reported instrument for use in day to day practice. These disease-specific HRQOL measures still require validation in RCTs, as well as across geographic and culturally diverse populations, particularly because RCTs in SLE must be large and therefore multinational.

Patient global assessments & PGAsPatient global assessments and PGAs offer unique perspectives to outcomes in SLE [3]. PGAs are included as components of the SLE responder index (SRI) utilized in Phase III RCTs with belimumab and the BILAG based responder index used in the Phase IIb EMBLEM™ trial with epratuzumab [34,51,52,77,78]. The SFI also includes PGAs for determination of flare [16,17].

Patient global assessments of disease activity and wellbeing are important components that should not be excluded from RCTs. These assessments are different from multidimensional HRQOL, but are supported by improvements in the transition question of SF-36 [79].

Patients’ perceptions of illness severity have been shown to be associated with psychosocial stressors, and may not correlate with physician assessments determined in the context of disease activity and damage, such as asymptomatic renal disease and/or CNS manifestations [80,81]. Patient global asessments have been included in multiple RCTs [34,40,49,82,83]. Of interest, patient global asessments and PGAs correlated closely in the epratu-zumab ALLEVIATE RCTs, perhaps, in part, owing to rapid improvements in disease activity [82].

Measures of damage Although there has been decreased mortality in SLE due to improvements in diagnosis and treatment, ongoing disease activ-ity has led to irreversible damage resulting in organ dysfunction and comorbidites [84]. Even in those patients whose disease is well controlled, risks for adverse effects from medications and sequelae from longstanding SLE, such as premature cardio vascular disease, remain [84]. To reflect damage from either SLE, medication side effects, or comorbid conditions, the Systemic Lupus International Collaborating Clinics (SLICC) developed and validated the SLICC/American College of Rheumatology Damage index (SDI) [85–88]. The SDI measures organ system damage owing to SLE or its treatment that has been present for ≥6 months, and is designed to identify irreversible damage. A total of 12 organs are assessed with up to six components in each, summed up to a maximum of 47 points. The use of the SDI in RCTs should be considered for stratification at baseline to identify patients with a poorer prognosis, and may be a component of outcome when

defining no worsening of disease in any organ system. Other measures of damage include various organ-specific definitions of worsening and/or loss of function, common in RCTs of SLE nephritis [89]. A RCT with DHEA similarly quantified damage owing to osteopenia/osteoporosis as owing to both SLE and its treatment with corticosteroids [90].

Composite responder indicesResponder indices define those who have improved or responded compared with those who have not. The Response Index for Lupus Erythematosus, developed by consensus process, is an example of a responder index that defines specific improvements in organ system manifestations as ‘response’ and has been utilized in a Phase II RCT evaluating an anti-CD40 ligand monoclonal antibody [48,91,92]. The Response Index for Lupus Erythematosus is not a composite index that combines different measures, but rather has a clear definition of ‘improvement’ based on consensus definition of response by organ system.

Composite indices have been developed to define responders versus nonresponders to therapy in recent RCTs but predominantly concentrate on assessing disease activity (TaBle 2). In general, com-posite responder indices that are composed of measures that are not closely correlated have increased the ability to distinguish differ-ences between treatment groups, thus decreasing sample size deter-minations. This is especially important given the heterogeneity of SLE and the need for multicenter, multinational trials.

Responder indices in RCTs generally first require that patients are not ‘treatment failures,’ with parameters predefined specifi-cally in each study that constitute a treatment failure. This defini-tion may include not having received new or increased use of pro-hibited medications or not having discontinued treatment owing to an adverse event. This is an important part of protocol design as it allows patients to leave the protocol when medically indicated, but still be ‘counted’ in the statistical analysis as a treatment fail-ure. It is also important in trials that concentrate predominantly on single organ system manifestations such as nephritis, to ensure that worsening in other organ systems does not occur.

The first use of a composite responder index in an RCT was developed in collaboration with the FDA and evaluated DHEA for symptomatic benefit. First, a responder could not be a treatment failure based on predefined organ specific manifestations or dam-age, or discontinue therapy owing to an adverse event. In addition, a responder had to demonstrate improvement in either SLEDAI or SLAM without deterioration in the other, and improvement in either patient global assessment or Krupp Fatigue Severity Scale score without deterioration in the other [41]. Other composite responder indices have since been developed in an evidence-based fashion based on data mining from Phase II RCTs evaluating belimumab and epratuzumab.

The SRI is a composite index developed from analyzing the 71.5% seropositive population in the Phase II RCT of belim-umab [77]. An SRI response was defined as no increased or new use of prohibited medications or early dropout and a ≥4-point reduction in SELENA–SLEDAI score, no new BILAG A or 2B domain scores, and no deterioration from baseline in PGA

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by ≥0.3 points. Evidence-based development and validation of the SRI from Phase II data and its subsequent application to two successful Phase III trials, BLISS-52 and BLISS-76, one for ‘validation’ and the other for confirmation, demonstrates the utility of developing a responder index for RCTs that is specific to the performance of the therapy [51,52]. The SF-36 and FACIT-Fatigue instruments were considered supportive, in secondary analyses [66].

A composite responder index was designed by analyzing the two aborted studies of epratuzumab, SL0003 and SL0004, or ‘ALLEVIATE A and B’. The primary end point was a composite responder index defined as no ‘treatment failure’ and reduction of all baseline BILAG As to B/C/D and Bs to C/D in all body systems, no BILAG worsening in other organ systems, and no deterioration in SLEDAI or PGA [34,35]. This responder index will be utilized in upcoming Phase III trials.

Expert commentaryThe BLISS-76 and BLISS-52 studies conducted with belimumab met the primary end point defined by SRI in the 10 mg treat-ment groups and constitute replicate trials considered pivotal for labeling for treatment of SLE. Clinically meaningful and statisti-cally significant improvements were also demonstrated for two epratuzumab dose groups using a combined responder index in the Phase IIb EMBLEM trial at 12 weeks, despite small num-bers and short duration. To date, these three multicenter RCTs have successfully differentiated results from previous failed trials in SLE. Important components of trial designs that contributed to their positive outcomes, described below, should help inform subsequent RCTs in SLE.

Evidence-based composite responder indicesBoth belimumab and epratuzumab trials utilized evidence-based composite responder indices based on data from previous trials, validated and confirmed in subsequent RCT(s). The SRI utilized SELENA–SLEDAI scores to determine global improvement, BILAG scores to ensure no significant worsening in individual organ systems, and PGAs to establish that improvements in dis-ease activity were not achieved at the expense of the patient’s overall condition [51,77]. The prominent use of SELENA–SLEDAI in this study enabled consistency in the definitions of disease activity and that used for f lare. However, improvement in SELENA–SLEDAI required that a manifestation switch from present to absent. Gradations in disease activity and flare from one visit to another were captured by BILAG, emphasizing the utility of multiple outcome measures in a study to measure improvement.

The EMBLEM study with epratuzumab also used BILAG, SLEDAI and PGAs in the responder index, but was primarily BILAG-based. Important to the success of this outcome measure, every BILAG determination was independently adjudicated by a monitoring committee.

Use of these composite indices acknowledges the limitations of any single disease activity index and the utility of using one to measure improvement and another to ensure that ‘no dete-rioration’ has occurred. They emphasize disease activity and do not include measures of damage; and include PGAs but not patient-reported outcomes.

However, FDA and European League Against Rheumatism guidances recommend that HRQOL be measured in trials of SLE [2,93,201]. SF-36 was not incorporated into the SRI but uti-lized instead as a secondary supportive ana lysis in BLISS-76

Table 2. Responder indices utilized in randomized controlled trials.

Responder index Trials Method of derivation

‘Responder’ definition Ref.

Responder index for DHEA DHEA RCTs US FDA sponsor consensus

No treatment failureImprovement in SLEDAI or SLAM without deterioration in the otherImprovement in patient global assessment or KFSS without deterioration in the other

[41,83]

Response index for lupus erythematosus

aCD154 (CD40 ligand) RCT

Delphi process Complete response based on resolution of abnormal signs in specific organ systems including renal, neurologic, mucocutaneous and musculoskeletalPartial response based on decreased features of disease within an organ system, but not full resolution

[48]

SLE responder index Belimumab Phase III RCTs

Phase II data mining

No new or increased use of prohibited medications or early dropout≥4-point reduction in SELENA–SLEDAINo new BILAG As or 2 BsNo PGA deterioration from baseline ≥0.3 points

[51,52,77]

Responder index for epratuzumab

Epratuzumab Phase IIB RCT

Phase II data mining

No treatment failureReduction of all baseline BILAG As and BsNo BILAG worsening in other organ systemsNo deterioration in SLEDAI or PGA

[34,35]

BILAG: British Isles Lupus Assessment Group; DHEA: Dehydroepiandrosterone; KFSS: Krupp Fatigue Severity Scale; PGA: Physician global assessment; RCT: Randomized controlled trial; SELENA: Safety of Estrogen in Lupus Erythematosus National Assessment; SLAM: Systemic Lupus Activity Measure; SLE: Systemic lupus erythematosus; SLEDAI: Systemic Lupus Erythematosus Disease Activity Index.



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and BLISS-52 studies [66]. In a combined ana lysis of both tri-als, responders by SRI reported statistically significant improve-ments, well exceeding MCID in SF-36 scores, including fatigue/VT [51,66]. These data demonstrate that patient-reported outcomes lend another dimension to treatment response, indi-cating improvements are perceptible to patients, and clinically meaningful. Ideally, a responder index would therefore include not only disease activity measures, account for flares from baseline to end point and PGAs, but also patient-reported HRQOL to better capture all aspects of treatment response.

Efforts are being made to develop responder indices based on individual systems of the body. In order to help standardize defi-nitions of renal response in clinical trials, an SLE renal response index was developed by the members of the SLICC group [94]. Though it still requires further validation in RCTs, it serves as a step toward a consensus definition of renal response. Use of such a renal response index would contribute valuable renal-specific information that cannot be captured by global measurements. However, since the vast majority of patients with lupus nephritis have disease involvement in other organ systems, systemic disease activity would need to be measured in parallel.

Predefinition of ‘treatment failure’To determine response to therapy it is crucial to clearly define ‘treatment failures’. The BLISS studies defined treatment failures as patients with new or increased use of prohibited high dose cor-ticosteroids and/or immunosuppressive therapies (including SLE flare) and/or early discontinuations due to treatment-associated adverse events [51,52]. Treatment failures in the EMBLEM study were defined as patients who required new or increased immuno-suppressives, antimalarials, or corticosteroids above baseline or tapering level at any point following randomization or those with hospitalizations or serious adverse events due to SLE and/or its treat-ment [34]. In these trials, treatment failures were considered nonre-sponders; patients were allowed to exit the protocol and receive any necessary therapy, having met a statistical end point for ana lysis. Thus, parameters for ‘treatment failure’ should be well defined at study initiation, both for safety of the patient and adherence to protocol design.

Predefined concomitant medications, including corticosteroidsThe use of concomitant therapy can confound results of an RCT for a variety of reasons. As was well illustrated in the rituximab tri-als, it is not possible to distinguish improvement of disease activity owing to investigational therapy compared with corticosteroids. Thus, doses and types of allowed background therapies should be predefined with limited or no medication changes during the course of the study to maximize the ability to distinguish active treatment from standard of care. Corticosteroid use in particu-lar has been an important differentiating factor between suc-cessful and failed RCTs in SLE. In the rituximab and abatacept RCTs, initial high doses of corticosteroids were required followed by a prolonged tapering regimen [95,96]. It was not possible to distinguish active from background therapy in either trial.

In the Phase II belimumab RCT, changes in background therapy, both immunosuppressive agents and corticosteroids, were allowed throughout 12 months treatment; a trend in fewer increases in doses and more tapering with active treatment was evident [78]. In the Phase III belimumab RCTs, adjustments to background immunosuppressives were allowed only through week 16, and cortico steroids through week 24, with tapering at the investigator’s discretion over weeks 44–52 [51,52]. Later in BLISS-76, adjustments in background therapy were allowed over weeks 52–64, again with tapering during weeks 68–76. This flex-ibility probably confounded the ability to distinguish active from control therapy, as well as determining when onset of efficacy with belimumab was evident. Nonetheless, more subjects receiving active therapy were able to taper corticosteroids to ≤7.5 mg/day and fewer had increases in doses than those receiving placebo plus standard of care.

In the ALLEVIATE epratuzumab trials, corticosteroid doses initiated at enrollment could be tapered as early as clinically indi-cated, on or after week 4, at the investigator’s discretion with a goal for achieving doses of 7.5–10 mg prednisone equivalent at weeks 12 or 24, without a predefined tapering regimen. A similar regi-men was allowed in the subsequent EMBLEM trial although only 2.7–12.8% of patients were receiving >30 mg/day of prednisone equivalent despite moderate-to-severe active SLE [34].

Taken together, these trials have demonstrated that maintenance of stable background therapy with early initiation of an individual-ized corticosteroid taper can more readily differentiate active treat-ment from background therapy. Corticosteroid tapers should be individualized as soon as possible at the discretion of the investiga-tor with a predefined ‘goal’ to achieve, generally ≤7.5 mg/day, con-sidered a ‘physiologic’ dose. A prolonged tapering regimen should not be mandated. Allowances must be made for limited increases of corticosteroid doses for mild flares of ≤14–28 days in duration, as well as stress coverage by mineralocorticoids as indicated.

Patient populationAs a result of the heterogeneity of this disease and its variable course, previous RCTs in SLE have demonstrated the importance of defining an adequate sample size and recruiting patients most likely to respond to the therapy. Post-hoc ana lysis of the failed Phase II study with belimumab revealed that the 71.5% sero positive patients had higher B-lymphocyte stimulator/B-cell-activating fac-tor levels and disease activity, more of whom had renal involve-ment, and lower complement levels [78]. This example underscores the utility of biomarker analyses to select a potentially responsive patient population.

Recruiting large numbers of patients that meet entry criteria poses a challenge to the conduct of RCTs in SLE. The Phase III BLISS studies randomized 865 and 819 seropositive patients, large sample sizes to account for multicenter variability, heterogeneity of the disease and clear differences in geographies and utilization of background therapy [51,52]. It would be ideal if pilot studies with new therapies could be performed in smaller numbers of patients to determine an early signal of efficacy before enroll-ing hundreds of patients in large RCTs. In studies focused on

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improving or reducing flares in SLE, one consideration would be to select patients likely to flare by biomarker analysis, in whom a new therapy can be evaluated over a shorter period of time [97]. This population of patients could be used in a proof-of-concept study in which the new therapy is ‘screened’ for preliminary effi-cacy with a defined follow-up period to determine efficacy in clinical trials [97].

Similarly, the EMBLEM Phase II study with epratuzumab recruited patients who were actively in SLE flare to determine a dose range that successfully met the primary end point [34]. While the treatment proved to be efficacious over the short 12-week trial, it remains to be seen if this is an adequate strategy to determine the dose and dosing regimen for treatment of SLE over 52 weeks in a larger number of patients.

Five-year viewThe recent FDA approval of belimumab is the first specifically labeled for treatment of SLE in over 50 years [204,205]. Success of the belimumab trials has provided an important ‘benchmark’ for

subsequent approvals for new therapies in SLE. Indeed, a growing number are currently in Phase II and III RCTs, many of which are biologic agents that target inflammatory pathways in SLE (TaBle 3). Data from these trials will further inform the utility and performance of individual outcome measures in SLE. It is anticipated that responder indices specifically derived from data from previous trials with individual agents will be used more frequently. Disease-specific instruments offer promise for assess-ing HRQOL in addition to the generic SF-36 and hopefully one or more will emerge as cross-culturally and geographically vali-dated. Particular attention must be paid to appropriate utiliza-tion of treatment failure definitions and use of responder indices. Importantly, one size does not fit all, both in terms of trial design and responder definitions.

The approval of belimumab for treatment of SLE is a landmark. Nonetheless, members deliberated over points that bear consider-ation in upcoming RCTs. Outcome measures attempt to reflect a clinically meaningful change, but there has not been consensus as to what threshold of improvement is clinically meaningful,

Table 3. Primary outcome measures for selected ongoing and completed randomized controlled trials in systemic lupus erythematosus.

Name Mechanism Development stage

Primary outcome measure

Completed RCTs

Belimumab Inhibits soluble BLyS/BAFF Phase III SRI

Epratuzumab Binds CD22 receptor Phase II Responder index using BILAG

Ongoing RCTs

Blisibimod (A-623) Inhibits membrane and soluble BLyS/BAFF Phase II SRI

LY2127399 Inhibits membrane and soluble BLyS/BAFF Phase III SRI

Atacicept Inhibits BLyS/BAFF and a proliferation-inducing ligand

Phase II/III New flare defined by BILAG A or B

Epratuzumab Inhibits CD22 receptor Phase III Responder index using BILAG

AMG-557 Anti-B7RP: inhibits B7RP-1/ICOS-1 interaction Phase I Safety features

Ocrelizumab – now discontinued

Inhibits CD20 Phase III Major/partial/no clinical responses by BILAG

SBI-087 Inhibits CD20 Phase II Not available

Sifalimumab (MEDI-545)

Inhibits IFN-a Phase II Safety features,responders

Rontalizumab RG7415 Inhibits IFN-a Phase II Responders

CNTO-136 Inhibits IL-6 Phase II Proteinuria

PF-04236921 Inhibits IL-6 Phase II Not available

Lupuzor (CEP-33457) CD4 T-cell modulator Phase III SRI

Paquinimod (ABR-215757)

Immunomodulator Phase III Disease activity,biomarkers

Edratide Immunomodulator Phase II Not available

Bortezomib Proteosome: targets long-lived plasma cells Phase I Not available

BAFF: B-cell-activating factor; BILAG: British Isles Lupus Assessment Group; BLyS: B-lymphocyte stimulator; PF: Physical functioning; RCT: Randomized controlled trial; RP: Role physical; SRI: Systemic lupus erythematosus responder index.Data taken from [206].



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nor whether patient reported outcomes should be included in definitions of response, as in other rheumatic diseases [77,98,99]. Responder indices or reduction in number of or prolonged time to flares must be shown to be clinically meaningful, either by reduc-tions in corticosteroid doses, ‘steroid sparing’, or improvements in patient-reported outcomes.

Until now, RCTs in SLE have been conducted as superiority trials comparing the new therapy to placebo, both superimposed upon standard-of-care. With FDA approval of belimumab for treatment for SLE, the question becomes whether a non inferiority trial using it as an active comparator will become a preferred design. This will require use of more sensitive outcome mea-sures that can better distinguish between active therapies. The induction Phase of the ALMS trial well illustrates the challenges in demonstrating superiority of one treatment to another: that mycophenolate mofetil was not statistically better than cyclo-phosphamide but in MAINTAIN was superior to azathioprine for maintenance therapy [100]. In the setting of noninferiority trials, development of responder indices which more sensitively detect treatment differences will be crucial.

This landscape of active drug development for treatment of SLE promises to offer new opportunities for successful development and validation of outcome measures and for improved trial design in SLE.

Financial & competing interests disclosureVibeke Strand and Alvina D Chu have received no remuneration for prepa-ration of this manuscript. Vibeke Strand serves as a consultant and has participated in advisory boards for: Amgen, Anthera, Astra Zeneca, BMS, Centocor, Genentech/Roche, HGS, Idera, Lilly, Medimmune, Merck Serono, NovoNordisk, Orbimed, Pfizer, Rigel, Sanofi-Aventis and UCB. She is not on any speakers bureaus and holds no stock in these companies. Vibeke Strand is a member of the clinical faculty at Stanford University, serving as Clinical Professor, Adjunct, Division of Immunology and Rheumatology. Alvina D Chu is a full-time employee at Anthera Pharmaceuticals, Inc. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• It has been challenging to conduct successful trials in systemic lupus erythematosus (SLE) because superiority must be shown to a control group of patients receiving standard-of-care therapy.

• Systemic Lupus Erythematosus Disease Activity Index, British Isles Lupus Assessment Group, Systemic Lupus Erythematosus Activity Measure and European Consensus Lupus Activity Measurement-based disease activity measures emphasize different aspects of SLE activity and each has its own strengths and weaknesses.

• An international effort sponsored by the Lupus Foundation of America has developed a consensus definition of flare that is clinically meaningful for use in randomized controlled trials, longitudinal observational studies and clinical practice.

• Patient-reported outcome measures such as Short Form-36 and patient global assessment lend another meaningful dimension to treatment response.

• Successful randomized controlled trials have utilized evidence-based responder indices developed from Phase II data which were then validated in Phase III trials.

• Control of concomitant corticosteroid, immunosuppressive regimens and other background therapies, and definitions of treatment failures should be predefined.

• The future success of therapeutics in SLE will rely on not only effective mechanistic targets, but also appropriate use of outcome measures of disease activity, health-related quality of life and damage.

ReferencesPapers of special note have been highlighted as:• of interest•• of considerable interest

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products for treatment (2010) www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatory Information/Guidances/UCM072063.pdf

202 US Department of Health and Human Services FDA, Center for Drug Evaluation and Research, Center for Biologics Evaluation and Research, Center for Devices and Radiological Health. Guidance for Industry: lupus nephritis caused by systemic lupus erythematosus – developing medical products for treatment (2010) www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatory Information/Guidances/UCM216280.pdf

203 Corporate Translations website for LupusQoL translation www.corptransinc.com

204 US FDA News Release. FDA approves Benlysta to treat lupus (2011) www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm246489.htm

205 US FDA. Benlysta label for prescribing information (2011) www.accessdata.fda.gov/drugsatfda_docs/label/2011/125370s0000lbl.pdf

206 ClinicalTrials.gov www.ClinicalTrials.gov

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Documents

Measuring outcomes in systemic lupus erythematosus clinical trials