Mycophenolate Mofetil Trial in Patients with IgA Nephropathy Ended Early

Worldwide, the most common type of idiopathic glomerulonephritis is immunoglobulin A nephropathy (IgAN), creating a need for effective strategies for the treatment of patients with this condition to prevent kidney function decline. In some patient populations, effective treatments include corticosteroids, angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers, and omega-3 fatty acids. Previous studies have demonstrated varying results of treatment with mycophenolate mofetil (MMF): two studies from China showed MMF to be an effective therapy, whereas two other trials (one from Belgium and one from the United States) showed no MMF-related benefit.

Ronald J. Hogg, MD, and colleagues recently conducted a trial designed to test the hypothesis that treatment with MMF would result in significant improvement in proteinuria in children, adolescents, and adults with IgAN. They reported results of the double-blind, placebo-controlled, randomized controlled trial in the American Journal of Kidney Diseases [2015;66(5):783-791].

The researchers restricted the randomization phase of the trial to patients who had persistent proteinuria following a 3-month course of lisinopril (or losartan) and Omacor®, a highly purified omega-3 fatty acid. This was done to avoid exposing patients to an immunosuppressive regimen if they were able to respond well to nonimmunosuppressive medications.

The primary outcome was change in proteinuria after 6 and 12 months of treatment with MMF and at 12 months following the treatment period. Study participants were from 30 centers in the United States and Canada. Participants were 52 children, adolescents, and adults 7 to 70 years of age. Inclusion criteria were urine protein-creatinine ratio (UPCR) ≥0.6 g/g (males) or ≥0.8 g/g (females) and estimated glomerular filtration rate (eGFR) ≥50 mL/min/1.73 m2 (≥40 mL/min/1.73 m2 if receiving ACE inhibitor). Mean age was 32 years, 62% of participants were white, and 73% were male.

Lisinopril (or losartan) plus a highly purified omega-3 fatty acid (Omacor) was given to 94 patients for 3 months; 58 patients with persistent UPCR ≥0.06 g/g (males) and ≥0.8 g/g (females) were eligible for the trial. Of those, 52 were randomly assigned to receive MMF (n=25) (at a target dose of 25-36 mg/k/d) or placebo (n=27) in addition to lisinopril/losartan plus Omacor. Six patients were not randomly assigned because the trial was terminated.

At the time of termination, 44 patients (22 in each arm) had completed 6 months of the study drugs. Of those, 28 (13 MMF, 15 placebo) had completed 12 months of the study drugs and 17 (7 MMF, 10 placebo) had completed the entire trial.

Treatment with MMF did not result in a significant change in mean UPCR after 6 and 12 months of treatment. Confidence intervals for mean estimates overlap across groups and do not allow for determination of clinical benefit of MMF.

No patient in either group experienced compete remission after 6 or 12 months of treatment. Only one patient in each group had a UPCR <0.3 g/g after 12 months. In five of 22 patients treated with MMF, UPCR decreased by ≥50% (partial remission) and in three of 22 patients given placebo after 6 months of their respective study drug.

Thirteen patients treated with MMF completed 12 months of treatment, including four of the five who had a partial remission at 6 months. After 12 months, remission was maintained in only two of the four who completed 12 months of treatment. None of the other nine patients treated with MMF achieved partial remission, making the rate of partial remission at the end of treatment (either 6 or 12 months), in the group treated with MMF 14% (3 of 22).

In the placebo group, 15 patients completed 12 months of the study, including three who had a partial remission at 6 months. In two of those three patients, partial remission persisted at 12 months. None of the other 12 patients in the placebo group who completed 6 or 12 months had a complete or partial remission, making the partial remission rate at 6 or 12 months 9% (2 of 22).

In the MMF group, the decrease in eGFR was greater than that in the placebo group (P=.03). However, this difference was not seen in the 28  patients who continued receiving the study drugs for 12 months or the 17 patients who completed the trial.

MMF was well tolerated and adverse events did not occur more frequently in the group receiving MMF than in the placebo group, with the exception of nausea.

Study limitations cited by the authors were the short follow-up period and the low patient enrollment.

“In conclusion, results from this multicenter randomized controlled trial showed that MMF did not decrease proteinuria significantly in patients with IgAN who had UPCRs ≥0.6 g/g (males) or ≥0.8 g/g (females) after 3 months’ treatment with an ACE inhibitor/angiotensin receptor blocker plus omega-3 fatty acid. However, the trial was not sufficiently  long in duration to permit an evaluation of the extent to which MMF might afford protection from progressive deterioration of GFR,” the researchers said.

Takeaway Points

  1. Researchers recently conducted a randomized controlled trial to test the hypothesis that treatment with MMF would result in significant improvement in proteinuria in patients with IgAN.
  2. The trial was terminated early; at trial termination, only 44 patients had completed 6 months of study drugs (22 in the MMF arm and 22 in the placebo arm); 28 had completed 12 months of the study dugs (13 MMF, 15 placebo).
  3. There was no significant improvement in patients with IgAN who had persistent proteinuria after treatment with MMF for 6 or 12 months.