About one-third of patients with systemic lupus erythematosus treated with placebo and standard of care in randomized controlled trials with biologics achieved their respective primary endpoints, findings that could inform future trial design, researchers reported November 10 at the annual meeting of the American College of Rheumatology in Atlanta.
“Rates of response to placebo plus standard of care are unexpectedly high in most research clinical trials, hindering the development of new biologic drugs for lupus,” said Konstantinos Tselios, M.D., Ph.D., a clinical research fellow at the University Health Network, University of Toronto in Canada, who presented the findings.
Dr. Tselios and colleagues conducted a pooled analysis of 12 phase 2/3 RCTs of biologics in 7940 patients with non-renal non-psychiatric SLE 48 to 52 weeks after randomization. The 2621 placebo group participants had a mean age of 39.7 ± 12.2 years and a mean disease duration of 6.5 ± 6.8 years. Their baseline SLE Disease Activity Index 2000 (SLEDAI-2K) was 10.3 ± 3.7.
In addition to placebo, they received standard of care such as glucocorticosteroids (in 86.4%), antimalarials (68.1%), and immunosuppressives (44.9%). Patients in active trial arms had no significant differences in SLE features or treatment compared with placebo plus standard of care groups.
Participants in the placebo plus standard of caregroups had a mean reduction in SLEDAI-2K of 4.05 (range 3.3-4.8) and of 19.9 (range 11.7-23.8) in Physician Global Assessment (PGA, 0-100 scale). The actual difference in efficacy between the placebo and the active arms combined was 9% on average, while most studies were designed with an expected difference of 12% to 20%, said Tselios.
Multiple factors probably contribute to high placebo plus standard of careresponse rates, he said, including the heterogenous nature of lupus itself, patient and outcome selection, and study design.
“The response to placebo was particularly high for the most commonly used endpoint (the SRI-4), reaching 40%, whereas it was lower for more stringent end-points,” Tselios said. “These findings make clear that the bar set by the SOC treatment (and the placebo effect) is really high for any new biologic drug in development. This bar could have been even higher if one considers the relatively low rates of concomitant antimalarial and immunosuppressive use.”
With regard to future trials, he noted that enrollment of a homogeneous patient group should become a priority.
“This should apply not only to seemingly similar manifestations (eg, mucocutaneous disease) but extend further to the categories of cutaneous lupus and/or their severity,” he said. “Patient randomization should consider the timing of the current flare and the duration of the concomitant treatment. Finally, the application of different endpoints may offer a clear differentiation between the active and the placebo arms.”
If clinical trial design for biologics in SLE remains unchanged, Dr. Tselios added, sample sizes may need to be doubled or tripled to prove superiority to placebo plus standard of care.
Dr. Tsleios spoke with Rheumatology Network at length about the challenges of studying biologics in SLE.
Q: How can the high clinical heterogeneity of SLE affect rates of response to active agents and to placebo?
A: The clinical heterogeneity of SLE reflects the differences in the underlying pathogenetic mechanisms, making it unlikely for a certain biologic to suppress autoimmune inflammation in all cases. Even within the context of a single organ involvement, for example, the skin, different pathogenetic pathways will lead to expression of distinct clinical phenotypes, ie, acute or subacute or discoid lesions.
Detailed information on skin disease type are lacking for the patients enrolled in the lupus RCTs. Furthermore, topical treatments, particularly topical glucocorticosteroids and calcineurin inhibitors, which are not regularly monitored in RCTs, have been moderately beneficial for acute and subacute cutaneous lupus. In the same line, spontaneous remissions have been reported for cutaneous lupus.
Q: How might other features of SLE have influenced response rates in the current pooled analysis?
A: Most of the enrolled patients were in late phases of the disease. This may have had a significant impact on the fluctuations of disease activity since it has been shown that disease severity subsides considerably over time. Consequently, minor musculoskeletal and mucocutaneous flares may be more easily controlled with SOC treatment in newly diagnosed patients, whereas that would be more difficult for patients with disease that is persistently active for many months or even years.
Q: What other factors in this analysis could be driving the high rate of response to placebo plus standard of care?
A: The timing of the randomization of each patient is not known and this may affect the outcomes. For example, a patient who developed a disease flare a few months before randomization would have been prescribed corticosteroids and immunosuppressives and eventually respond in a short period after baseline, apparently due to the effect of the standard of care therapy, and not the active drug or placebo.
Treatment with mycophenolate mofetil led to resolution of the initial non-renal clinical manifestation in more than 50% of the patients after 6 months, whereas it was accompanied by a significant (approximately 33%) reduction of the concomitant prednisone dose. On the contrary, patients who developed a flare shortly before randomization would depend more on the active drug, given that new corticosteroids and/or immunosuppressives were not allowed in the majority of the RCTs.
If the aforementioned factors—the nature and extent of the cutaneous involvement, phase of the disease, timing of flare, time spent on standard of care therapy before randomization—that are usually not reported in the RCTs are in favor of the placebo arms, this would offer an advantage to these patients and inflate the placebo response.
Q: Why are currently used endpoints for lupus RCTs problematic?
A: The most commonly used outcome (SRI-4) applies to a reduction of 4 points in SLEDAI-2K, ie, no new activity from any other organ system and no deterioration in the Physician’s Global Assessment.
Given that most of the enrolled patients have active musculoskeletal or mucocutaneous disease or both, an SRI-4 can be achieved only through complete resolution of the occasional manifestation such as arthritis or complete resolution of two mucocutaneous manifestations, for example, inflammatory rash and alopecia, or one cutaneous manifestation and one immunologic marker.
Proportionally, this would apply to an “ACR100,” a target that may be unrealistic not only because of the level of response but also because of its potential heterogeneity, which is in contrast to the purely articular ACR20. In this context, other endpoints such as the SLEDAI-2K Responder Index-50, which considers the severity of the initial manifestation and requires a 50% improvement, may be more relevant.
“Abstract 940 - Response to Placebo in Randomized Clinical Trials with Biologics in Non-renal, Non-neuropsychiatric Systemic Lupus Erythematosus: A Systematic Review and Pooled Analysis,” Konstantinos Tselios, MD, PhD, 4:30 p.m., Sunday, Nov 10. American College of Rheumatology 2019 annual meeting, Atlanta.