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‘Excess serious adverse events’ halt trial for kidney disease treatment

Researchers terminated a trial that assessed the effectiveness of methylprednisolone in patients with IgA nephropathy at risk of progression due to serious adverse events, according to research recently published in JAMA.

“Global guidelines currently suggest a 6-month course of corticosteroids for individuals

with urinary protein excretion persistently above 1g/d and an estimated glomerular filtration rate (eGFR) greater than 50 mL/min/1.73 m² after at least 3 months of appropriate supportive care,” Jicheng Lv, MD, of the department of medicine at Peking University First Hospital in Beijing and colleagues wrote. “However, it is acknowledged that this weak recommendation is based on low-quality evidence.”

To advance knowledge of this therapy, Lv and colleagues randomly assigned 262 patients to receive methylprednisolone or placebo. Patients had IgA nephropathy and an eGFR of 20 mL/min per 1.73 m² to 120 mL/min per 1.73 m² after at least 3 months of BP control with renin-angiotensin system blockade. The treatment group, comprising 136 patients, received 0.6 mg/kg per day oral methylprednisolone up to a maximum of 48 mg per day, the remaining 126 patients received placebo. Patients received instructions to take the medications for 6 months, but researchers scaled back the dose amount over time.

Researchers wrote that the original mean follow-up was intended to be 5 years, and include 750 participants, but recruitment was stopped after a median of 2.1 years due to “excess serious adverse events.”

Twenty participants in the treatment group experienced infections, gastrointestinal complications, bone disorders and other serious adverse events compared with four participants in the placebo group who experienced the same adverse events except the bone disorders (risk difference = 11.5%; 95% CI, 4.8%-18.2%). There were also two deaths.

“The nearly 5 times higher risk of [severe adverse events] is a particularly important finding, given that many previous corticosteroid trials in IgA nephropathy have collected and reported adverse effects inconsistently,” Lv and colleagues wrote.

Researchers also noted that the primary composite renal outcome occurred in eight participants in the methylprednisolone group and 20 in the placebo group (HR = 0.37; 95% CI, 0.17-0.85). Further, only 14 participants reached end stage kidney disease, with no clear difference among participants.

“Although the results are consistent with potential benefit, definitive conclusions about treatment benefit cannot be made, owing to early termination of the trial,” Lv and colleagues wrote, adding that previous studies mirror and contrast the findings that were discovered before the trial stopped.

In a related editorial, Michelle M. O’Shaughnessy MB, BCh, MS and Richard A. Lafayette, MD, both of Stanford University, suggested a course of action until medical science can come up with a more definitive form of therapy for kidney disease can be found.

“...An onus is on physicians to effectively translate the adverse event findings from [this] trial to their patients with IgA nephropathy,” they wrote.

“Borrowing from guidelines developed for corticosteroid prescribing for patients with rheumatic diseases, embarking on this course of therapy in patients with IgA nephropathy should involve a careful assessment of expected risks and benefits, counseling patients about these potential outcomes, and close monitoring for the development of adverse events if this treatment course is pursued.” – by Janel Miller

Disclosure: Lv reports receiving grant funding from Pfizer. Lafayette reports serving as a consultant for Alexion Inc. and Mallinckrodt Inc. and receiving research support from NIH, Roche Inc. Mallinckrodt Inc. and Rigel Pharmaceuticals Inc. O’Shaughnessy reports no relevant disclosures. Please see the study for a full list of the other study authors relevant financial disclosures.