Clinical trial of focal segmental glomerulosclerosis in children and young adults

Abstract

This NIH-funded multicenter randomized study of focal segmental glomerulosclerosis (FSGS) treatment compared the efficacy of a 12-month course of cyclosporine to a combination of oral pulse dexamethasone and mycophenolate mofetil in children and adults with steroid-resistant primary FSGS. Of the 192 patients enrolled, 138 were randomized to cyclosporine (72) or to mycophenolate/dexamethasone (66). The primary analysis compared the levels of an ordinal variable measuring remission during the first year. The odds ratio (0.59) for achieving at least a partial remission with mycophenolate/dexamethasone compared to cyclosporine was not significant. Partial or complete remission was achieved in 22 mycophenolate/dexamethasone- and 33 cyclosporine-treated patients at 12 months. The main secondary outcome, preservation of remission for 26 weeks following cessation of treatment, was not significantly different between these two therapies. During the entire 78 weeks of study, 8 patients treated with cyclosporine and 7 with mycophenolate/dexamethasone died or developed kidney failure. Thus, our study did not find a difference in rates of proteinuria remission following 12 months of cyclosporine compared to mycophenolate/dexamethasone in patients with steroid-resistant FSGS. However, the small sample size might have prevented detection of a moderate treatment effect.

Trial registration: ClinicalTrials.gov NCT00135811.

Figure 1. Summary of randomized subject disposition

Treatment failure was declared if a subject either met a final outcome status of no remission (failure to achieve at least a partial remission by week (Wk) 26 (category 5 and 6) or failure to achieve a partial or complete remission by week 52) or reached a protocol-defined study stop point. *2 missing week-52 visits were assigned treatment failure outcome and are included in the 6 week-52 treatment failures. CSA, cyclosporine; DEX, dexamethasone; ESKD, end-stage kidney disease; MMF, mycophenolate mofetil.

Figure 2. Subgroup analyses for the primary outcome, proteinuria remission by 52 weeks, and main secondary outcome, sustained remission between 52 and 78 weeks

Shown are odds ratios and 95% confidence limits comparing the odds of a primary outcome score of ≥3 (left) and of a main secondary outcome score of ≥3 (right) between the MMF/DEX and CSA interventions for prespecified subgroups. CSA, cyclosporine; DEX, dexamethasone; eGFR, estimated glomerular filtration rate; MMF, mycophenolate mofetil; Up/c, urine protein/creatinine.

Figure 3. Change in proteinuria and eGFR over time

(a) Ratio of week 26:week 0 Up/c. Dark gray represents the CSA arm and light gray represents the MMF/DEX arm. Shown are box plots (indicating 5th, 25th, 50th, 75th, and 95th percentiles) of the ratio of follow-up to baseline Up/c values. (b) Ratio of week 26:week 0 eGFR. Dark gray represents the CSA arm and light gray represents the MMF/DEX arm. Shown are box plots (indicating 5th, 25th, 50th, 75th, and 95th percentiles) of the ratio of follow-up to baseline eGFR values. CSA, cyclosporine; DEX, dexamethasone; eGFR, estimated glomerular filtration rate; MMF, mycophenolate mofetil; Up/c, urine protein/creatinine.

Figure 4. FSGS CT outcome based on longitudinal control of proteinuria

(a) Ordinal classification of FSGS CT proteinuria primary outcome. Category 1: patients who achieved a complete remission by week 26 that was sustained to week 52; category 2: patients who achieved a partial remission at week 26 and then a complete remission at week 52; category 3: patients who achieved a partial remission by week 26 that was sustained to week 52; category 4: patients who achieved a partial remission at week 26 and then had recurrence of proteinuria before week 52; category 5: patients who achieved a partial remission before week 26 and then had a recurrence of proteinuria before week 26; category 6: patients who never had a Up/c reduction of >50% and an absolute value below 2 g/g. (b) Ordinal classification of FSGS CT main secondary outcome: sustainable remission of proteinuria. Participants with a primary outcome level 4 to 6 were assigned level 5. If the primary outcome was level ≤3, the main secondary outcome was assigned to levels 1, 2, 3, or 4 as follows: Level 4 was assigned if the participant failed to maintain at least a partial remission from week 52 through week 78. Participants who maintained at least a partial remission from week 52 through week 78 were assigned to level 3 if they had a partial remission at week 78, to level 2 if they had a complete remission at week 78 but had at least one Up/c between 0.2 and 2.0 between weeks 52 and 78, and to level 1 if they maintained a complete remission from week 52 through week 78. FSGS CT, focal segmental glomerulosclerosis Clinical Trial; Up/c, urine protein/creatinine.