Background/Purpose:

Recent SLE RCTs were examined and compared to rheumatoid arthritis (RA) RCT to suggest modifications to SLE RCTs that could improve the future success of SLE trials. 

Methods:

RA and SLE biologics RCTs published between 2005 and July 2013 were identified using PubMed. Inclusion criteria, study design, outcome measures, sample size calculations, baseline characteristics, steroid use and results were compared.

Results: Twenty-two RA RCTs and eight SLE RCTs were included. RA RCTs used composite scores (ACR response or DAS28). SLE RCTs used SLEDAI, BILAG, SLAM, SRI and BICLA. RA trials were larger (543 vs. 376 participants). RA measurements of response included patient reported outcomes, SLE trials did not. Concomitant corticosteroid use was stable in 100% of RA trials while all SLE RCTs allowed tapering. RA trials were mostly in methotrexate or DMARD inadequate responders whereas SLE trials allowed for the presence or absence immunosuppressives within all trials. Positive trials were found in 100% of RA RCTs and 25% of SLE RCTs. Table shows suggestions to improve SLE trials. 

Conclusion:

The potential insensitivity of SLE disease activity index (SLEDAI) to partial improvements may result in type II errors in SLE RCTs, whereas many BILAG flares were recorded with a significant number not considered as important flares by the physician (nonspecificity). Varying concomitant pharmacotherapy, especially corticosteroid use, in SLE may blunt observed treatment effects. Steroid dose must be accounted for within SLE trials. Sample size calculations in SLE may be unrealistic in some SLE trials. Moving forward, clinical relevance in treatment could be considered by proportional responses similar to ACR20 such as in SLE inflammatory arthritis trials or per cent improvement for skin studies in SLE and/or time to improvement of active urinary sediment in nephritis studies and/or reduction of steroids. SLE trial experts may need to reassess what outcomes and what minimal degree of change should be necessary to consider a treatment effective.

Suggestions of Outcomes in SLE trials:  Points to Consider

Organ specific trials in SLE
Inflammatory arthritis	If arthritis is being studied, the SJC and TJC should be the primary outcome and patients with fibromyalgia may need to be excluded.
Rash	If rash is the being studied, MD and patient global assessment of SLE rash and the CLASI (Cutaneous Lupus Erythematosus Disease Area and Severity Index) may be considered as outcomes.
Renal	In renal SLE, head to head comparisons of standard of care vs. the new treatment or add on to standard of care can be done with active urinary sediment (red blood cell [RBC] casts, total protein/day) and creatinine as the outcomes as well as time to normalizing urinary sediment. WBCs in the urine are not part of lupus nephritis and should not be included as an outcome (unless interstitial nephritis is being studied). Likewise, urinary RBCs may not be due to lupus nephritis. Many patients will do well on standard of care treatment so longer outcomes such as creatiniine, 24hr proteinuria at one and two years may be needed Time to achieving a certain renal outcome, steroid sparing effect and safety may be the important outcomes
Flares as an outcome	Flares in SLE patients within trials are frequent and a minimally important flare should be defined as relevant to the drug under study. A flare may need different defintions with a sensitivity analysis – such as MD reported major flare, a major increase in prednisone or a change in SLEDAI by at least 2 or 4 points
Steroid sparing effects of treatment	A primary outcome could be a steroid sparing effect of a drug where steroids are not strictly mandated in their use and tapering but a suggested protocol of steroid tapering is given and only those with a certain minimum dose of steroids are allowed into the trial.
Head to head trial with active new comparator	The speed of improvement, ability to taper steroids and/or safety may be the primary outcomes or a non-inferiority design.

 

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/a-comparison-of-rheumatoid-arthritis-and-systemic-lupus-erythematosus-trial-design-ways-to-improve-positive-trials-in-systemic-lupus-erythematosus/