Solving Catch 22 in Failed SLE Drug Trials: Don't Treat Control Group?


ACR 2013: Stymied by high response rates in the "usual care" comparison arm of new-drug trials, lupus researchers are testing a bold idea: Carefully withdraw treatment from the control group.

Lupus experts have suspected that proposed new treatments for systemic lupus erythematosus (SLE) are set up to fail: In clinical trials, even the modest success of standard lupus treatments used in the comparison group set the bar for statistically significant improvement impossibly high.

Of course, it's unethical not to give standard treatment to the control group. Or is it? Researchers have been testing the feasibility of simply stopping treatment for the control group in clinical trials of SLE, and they find it has promise.

Kenneth Kalunian MD of the University of Californa San Diego School of Medicine presented data that document the problem. At the 2013 annual meeting of the American College of Rheumatology in San Diego this week, Kalunian described results from a study specifically designed to assess the impact of "background medications" on SLE clinical trials: the Lupus Foundation of America Collective Data Analysis Initiative, which compiled data from 933 patients in six investigational drug trials to look at results for those in the "standard of care" or control arm.

The analysis confirmed high response rates in the standard-care group, ranging from 38% to 52% in trials of patients with lupus nephritis, which may well explain the failure of new drugs to thrive in clinical trials. In non-nephritis trials, Kalunian said, the overall response rate was 45% at week 12, with no significant difference between background drugs used. By week 24, the control-group response rate was still 33%.

One interesting insight from the trial:  Patients on mycophenylate mofetil were most likely to experience flares. 

A study aptly nicknamed BOLD (Biomarkers of Lupus Disease) tested the safety of a trial design intended to address the background medication problem. o-sponsored by Pfizer and the Oklahoma Medical Research Foundation (OMRF), it eliminated immunosuppressant medication in 41 of 102 SLE patients with active but non-organ-threatening disease as judged by disease activity  measures and joint counts. Joan Merrill MD of the OMRF presented the latest results.

The 41 patients in the no-treatment group received a short course of intramuscular depomedrol followed by withdrawal of their immunosuppressant medication. The remaining 62 patients merely donated blood for analysis. The study protocol called for further steroid injections in case of flare, and for careful followup with serial biomarker testing until flare occurred.

All but one patient in the drug-withdrawal group flared within six months, but flares resolved within six weeks after repeat steroid injections, Merrill said. The only adverse event, a bleeding ulcer, resolved with treatment. Furthermore, a novel genetic test created by Pfizer that defines a interferon signature correlating with certain autoantibodies and circulating levels of B-lymphocyte stimulator (BLyS) and interleukin 23 (IL23) suggests the possibility of identifying patients more likely to flare and less suitable for drug withdrawal.

"This supports an ethical trial design with immediate disease amelioration at baseline," she concluded, "and by using discriminatory techniques to identify meaningful differences with immediate treatment for returning disease activity, we might reduce the confusing results of clinical trials."

Completely withdrawing medications is also often successful in ordinary practice, to judge from results at the University of Toronto lupus clinic, presented by Zahi Touma MD with the title "Do We Know How and When to Taper and Stop Immunosuppressants in Lupus Patients?". The study assessed 179 patients in a cohort of 1678 treated at the clinic between 1987 and 2012 who were able to taper their medications to some degree, reducing prednisone to or below 7.5 mg/day or tapering immunosuppressant doses by at least 25%.

Among the 103 patients who tapered their medications only partially, 53% had at least one flare (defined as any increase in SLEDAI score or change in management) during the follow-up period. But 191 patients were able to discontinue medications entirely, and of these 75% succeeded with no flares whatever during a mean of 3.3 years followup. The risk of flares decreased with increasing time since drug withdrawal.

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