|Year : 2020 | Volume
| Issue : 2 | Page : 43-48
Daily levamisole versus mycophenolate mofetil in patients with frequently relapsing or steroid-dependent nephrotic syndrome: An open-label non-inferiority randomized controlled trial
Jyotsana Singh, Kamran Afzal, Shaad Abqari
Department of Pediatrics, Jawaharlal Nehru Medical College, AMU, Aligarh, Uttar Pradesh, India
|Date of Submission||06-Mar-2020|
|Date of Decision||20-Mar-2020|
|Date of Acceptance||08-Jul-2020|
|Date of Web Publication||31-Dec-2020|
Department of Pediatrics, Jawaharlal Nehru Medical College, AMU, Aligarh - 202 002, Uttar Pradesh
Source of Support: None, Conflict of Interest: None
Introduction: The therapy of choice for children with frequently relapsing and/or steroid-dependent nephrotic syndrome (FRNS/SDNS), who are unable to maintain remission with tapering doses of prednisolone, is unclear. Aim: The aim of the study was to examine the non-inferiority of daily levamisole versus mycophenolate mofetil (MMF) in preventing relapses in FRNS/SDNS over a 1-year period. Methods: Children with FRNS/SDNS, 1:1 were randomized to receive either daily levamisole at 2.5 mg/kg/day or MMF 1000 mg/m2. Patients on non-corticosteroid immunosuppression, late steroid resistance, secondary nephrotic syndrome, or non-minimal change disease were excluded. Primary objective was to compare the percentage reduction in relapse frequency at 1 year between the groups. Secondary objectives were safety (side effects), time to first relapse, proportion of patients free of relapse, cumulative steroid dose used, and failure of trial medication (CTRI/2018/07/015143). Results: Baseline characteristics were similar in groups (n = 21 each) except for age at enrolment, which was 120 months in MMF group and 60 months in the group receiving levamisole (P = 0.02). Relapse frequency decreased by 65% and 56% in the levamisole and MMF groups, respectively (mean difference: 9.1; 95% confidence interval, -16.9 to–35.2;], P = 0.48). Secondary outcomes did not differ between the groups. Prednisolone could be discontinued in 8 and 6 patients, while 6 and 5 patients were in sustained remission in the levamisole and MMF groups, respectively. There was one treatment failure in MMF group. Conclusion: Daily levamisole is not inferior to MMF in preventing relapses in children with FRNS/SDNS without significant adverse effects.
Keywords: Levamisole, minimal change disease, mycophenolate mofetil
|How to cite this article:|
Singh J, Afzal K, Abqari S. Daily levamisole versus mycophenolate mofetil in patients with frequently relapsing or steroid-dependent nephrotic syndrome: An open-label non-inferiority randomized controlled trial. Asian J Pediatr Nephrol 2020;3:43-8
|How to cite this URL:|
Singh J, Afzal K, Abqari S. Daily levamisole versus mycophenolate mofetil in patients with frequently relapsing or steroid-dependent nephrotic syndrome: An open-label non-inferiority randomized controlled trial. Asian J Pediatr Nephrol [serial online] 2020 [cited 2021 Jan 24];3:43-8. Available from: https://www.ajpn-online.org/text.asp?2020/3/2/43/305896
| Introduction|| |
Steroid-sensitive nephrotic syndrome (SSNS) is the predominant disease type in childhood, in which most children achieve remission with corticosteroid therapy. However, 80% of such children subsequently develop frequent relapses or steroid dependence, requiring further courses of steroids. Patients requiring long-term steroid therapy are treated with steroid-sparing agents to minimize corticosteroid adverse effects, but evidence to guide the choice for the best steroid-sparing agent is limited. SSNS tends to improve with age, with majority achieving normal renal functions by adolescence.
There are limited comparative studies to inform selection of an alternative agent to steroids. In developing countries like India, where it is available, levamisole is often the first steroid-sparing agent used because of its relative safety and low cost compared to other agents., Recent studies have indicated efficacy of daily versus alternate-day levamisole treatment in children with frequent relapses of nephrotic syndrome.,,.Mycophenolate mofetil (MMF) is also an effective and safe alternative agent and is considered by some to be second only to calcineurin inhibitors in children with frequent relapses or steroid dependence. MMF is often used by clinicians in cases that fail on alternate-day levamisole therapy. Thus, MMF is considered a superior drug even though evidence for the same is lacking. We therefore decided to check the noninferiority of daily levamisole compared to MMF.
| Methods|| |
This parallel-arm, open-label non-inferiority trial was conducted in the outpatient clinic of a single center in north India. Following ethical approval and trial registration (CTRI/2018/07/015143), patients with frequently relapsing and/or steroid-dependent nephrotic syndrome (FRNS/SDNS) between 2 and 14 years of age with at least 6-month follow-up record at this center were considered for enrolment if they met any of the following criteria: (i) =2 relapses in 6 months while on therapy with levamisole on alternate days and prednisolone on alternate days in tapering doses; (ii) prednisolone threshold to maintain remission >0.7 mg/kg on alternate days; (iii) significant steroid toxicity (Cushingoid habitus with hypertension, cataract, or glaucoma); (iv) an episode of serious life-threatening infection. Exclusion criteria were onset of nephrotic syndrome at <1 or >10 years old; prior use of alternative agents other than levamisole on alternate days; secondary nephrotic syndrome; histopathology other than minimal change disease; late steroid resistance; residing >100 km away; or unwilling to follow-up.
Randomization and intervention
Randomization was done in blocks of four, with sequence generated using a computer program and maintained by a colleague not directly involved in this trial. Allocation to either of two interventions was concealed in sequentially numbered sealed opaque envelopes that were opened at randomization. One group received levamisole (Decaris™) in a dose of 2.5 mg/kg once daily, and the other group was dispensed MMF as enteric-coated tablets (Mycofit™) to an approximate dose of 1000 mg/m2 (range: 850–1100 mg/m2) in two divided doses, for 1 year. Prednisolone was continued in a dose of 0.25–0.5 mg/kg on alternate days along with calcium carbonate (250–500 mg) and vitamin D (400 IU) given daily to both groups of patients. Patients without relapse for 6 months or longer, while on prednisolone at <0.5 mg/kg on alternate days, were considered for prednisolone discontinuation.
The primary study objective was to compare the percentage reduction in relapse frequency at 1 year in between the groups. Treatment side effects, change in relapse frequency, proportion of patients who were relapse-free, cumulative steroid dose used, and failure of the trial medication in either group were the secondary study variables. FRNS was considered if ≥2 relapses occurred in the initial 6 months or ≥3 in 12 months. Treatment failure was considered if >2 relapses occurred in the first 6 months or >3 relapses in 12 months. Late steroid resistance, significant steroid toxicity, serious relapse-associated complication, or unacceptable drug-associated adverse effects were also considered as treatment failure. Trial medication was discontinued in such patients and alternative agent was used.
Treatment of relapses
Treatment of relapse was initiated after treatment of any triggering infection. Prednisolone was given in a dose of 2 mg/kg/day until urine protein was trace or nil for 3 consecutive days. After achieving remission, the dose was reduced to a single morning dose of 1.5 mg/kg given on alternate days for 4 weeks and thereafter tapered.,
Follow-up and monitoring
The patients and their parents were educated about monitoring urine protein at home using dipstick and maintaining a diary to record the same. The patients were asked to follow-up at this hospital every 3 months to record relapse frequency, cumulative steroids used, infection episodes, and adverse effect of drugs. Record was also made of any unscheduled visits, e.g., for relapses or infections. The patients were asked to bring back empty wrappers of medicines on each visit, to ensure treatment compliance; therapy adherence was also reinforced telephonically. Height, weight, and blood pressure were monitored at each visit. Eye evaluation for cataract and glaucoma was done at enrolment and once in 6 months. Blood was tested for complete blood counts, liver enzymes, urea, creatinine, and cholesterol every 3 months as per the Indian Society of Pediatric Nephrology guidelines. Patients who missed scheduled appointments were contacted telephonically or by mail to ensure compliance with the study protocol.
The study was planned to demonstrate the non-inferiority of daily levamisole over MMF. Both drugs were expected to produce decline in relapse frequency; we considered 20% difference in the reduction of relapse frequencies between the two drugs to be of no clinical significance. Given that the true reduction in relapse frequency using MMF in children with FRNS/SDNS is approximately 75% and that with the use of daily levamisole is 56%, with a standard deviation of the difference in relapse reduction of 25% (from our pilot data), the required sample size with equal allocation to achieve an 80% power at α of 0.05 was 18 cases per group. To allow for an attrition rate of 10%, 21 patients were enrolled in each treatment arm.
Data was analyzed both on intention-to-treat basis and per protocol basis. Intention-to-treat analysis included all patients who were randomized, with efficacy analyses performed using the last observation carried forward. Categorical data were compared using Chi-square statistics, while continuous variables were compared using independent sample t-tests; nonparametric tests were used for variables with nonnormal distribution. Within-group changes in relapse frequencies were compared using repeated-measure one-way analysis of variance test. Age was used as a covariate to calculate adjusted values for continuous variable. Logistic regression was used to adjust the discrete variables for age. The Kaplan–Meier method with the log-rank test was used to compare the time from randomization to first relapse or frequent relapses. Significance was considered at a P < 0.05. All statistical analysis was done using IBM SPSS Statistics for Windows, Version 22.0. Armonk, NY: IBM Corp.
| Results|| |
Of 42 patients (59.5% boys) with SDNS/FRNS enrolled into the study during April 2018 to October 2018, 21 each were randomized to receive daily levamisole (FRNS = 9, SDNS = 12) and MMF (FRNS = 11, SDNS = 10) [Table 1]. Median (interquartile range) age at the onset of nephrotic syndrome was 39 (24, 60) months, while the age at enrolment was 105.5 (49.5, 132) months. Baseline characteristics were similar in both groups except for age at enrolment, 120 months in MMF versus 60 months in the levamisole group [P = 0.02; [Table 1]]. All analysis was adjusted for age. All patients were followed for 1-year period; there was no loss to follow-up [Figure 1]. One patient receiving MMF showed treatment failure at 4 months of follow-up.
|Figure 1: Flow of patients in the study. AD on alternate days; FRNS frequently relapsing nephrotic syndrome; MCNS minimal change nephrotic syndrome; MMF mycophenolate mofetil; SDNS steroid dependent nephrotic syndrome|
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Pretreatment annualized relapse frequency were similar for both drugs (4 [2, 4] each; P = 0.79). Reduction in relapse frequency was similar for levamisole and MMF groups [65.1% vs. 56%; [Table 2]]. Mean difference in the reduction of relapses between groups was 9.1 (-16.9, 35.2; P = 0.48). The difference remained insignificant as per the protocol analysis. No relapses were observed during the 1-year trial period, in 6 (28.6%) and 5 (23.8%) patients in the levamisole and MMF groups, respectively, (P = 0.73) [Supplementary Table 1]. Median time to first relapse was comparable in the groups receiving levamisole (5 [3, 8] months) and MMF group (6 [3, 10] months) [P = 0.89; [Figure 2]].
|Figure 2: Kaplan–Meier survival estimates for (a) time to first relapse and (b) time to frequent relapses, in patients treated with levamisole (blue line) or mycophenolate mofetil (red line). The median time to first relapse was similar for patients treated with mycophenolate mofetil and levamisole (5.0 vs. 6.0 months; log rank P = 0.65). At 12 months, 14.3% of the patients receiving levamisole and 15% of the patients receiving mycophenolate mofetil showed frequent relapses (P = 0.97)|
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|Table 2: Outcomes, including laboratory and anthropometric parameters, at the end of follow-up|
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There was no significant difference in the percentage of patients with frequent relapses, in the levamisole and MMF groups (14.3% vs. 15%; P = 0.97). Treatment with trial medication was discontinued at 4 months due to frequent relapses in one patient on MMF; he was switched to tacrolimus. There was 49.4% reduction in steroid dose in the levamisole group and 56.8% reduction in the MMF group. Steroids were discontinued in 14 (33.3%) patients, i.e., 8 and 6 in levamisole and MMF groups, respectively (P = 0.32).
At enrolment, steroid adverse effects were noted in 22 patients including Cushingoid habitus (n = 15), hypertension (n = 4), cataract and glaucoma (n = 2), and cataract alone (n = 1). No patient in either group developed any adverse effects related to the intervention drug during the study period. All corticosteroid-related adverse effects had resolved at study completion, except for residual cataract in one patient.
In the levamisole group, 12 patients had 1–2 episodes of infection during the study period, for which one required admission (peritonitis), while five patients had respiratory tract infection and six had acute gastroenteritis [Supplementary Table 2]. In the MMF group, 11 patients had 1–2 episodes of infection during 1-year period, out of which one patient required admission due to peritonitis, while four patients had acute gastroenteritis, and six other had upper respiratory tract infection. One patient in each group developed transient leukopenia (total leukocyte count = 4100), at 3 and 9 months, respectively [Supplementary Table 3].
At enrolment, height standard deviation score between -2 and -3 was noted in 10 patients, 5 in each intervention group, while severe short stature (score ≥-3) was noted in four patients, two in each group. At study completion, nine patients had scores between -2 and -3 (including 6 patients with moderate and 3 with severe short stature at enrolment). One patient in the MMF group continued to have scores ≥-3 at the end of study.
| Discussion|| |
In this study on 42 SDNS/FRNS children, we observed no statistically significant difference in the percentage reduction in relapse frequency at 1-year follow-up with either intervention. The difference in percent reduction of relapse frequency was 9.1% (95%CI: -16.9% to 35.2%) in favor of daily levamisole. Thus the margin of 20% for noninferiority of daily levamisole was met. As many as 10 patients who had previously continued to relapse on alternate-day levamisole responded favorably to a switch to daily levamisole therapy (n = 4) or MMF treatment (n = 6). One patient where medication was discontinued and therapy was changed to tacrolimus responded to the changed medication. Abeyagunawardena et al., in a previous prospective pilot study, demonstrated lower relapse frequency with the use of daily levamisole. Similar to our results, in a study by Ekambaram et al., the relapse rate before and after daily levamisole was 2.4 ± 0.5 and 1.3 ± 0.7, respectively, a reduction in the relapse frequency of almost 45.8%.
MMF is known to be effective in children with FRNS/SDNS and is considered to be inferior only to calcineurin inhibitors by some authors.,, Bagga et al. noted a decline in the relapse rate by 4.6 episodes per year during the treatment with MMF. In another study from the same center, MMF was shown to be useful in children with SDNS/FRNS with decline in relapse rates by 62%. However, in the only previous study comparing the two drugs, alternate-day levamisole was compared with MMF in an open-label randomized trial in children with FRNS/SDNS; similar efficacy of the two treatments was reported.
Mean reduction in steroid dose in the current study was 49.4% and 56.8% in the levamisole and MMF groups, respectively. Mean reduction of 40.4% was found with MMF in a study by Afzal et al. During the study period, we were able to stop steroids completely in 14 children (33.33%); 8 and 6 children from levamisole and MMF groups, respectively. In a study by Bagga et al., prednisolone therapy was discontinued in 42% patients, while in other study, prednisolone was discontinued in 12% patients. Treatment failure was seen in one patient who continued to have frequent relapses while on MMF. This case responded to a switch to use of tacrolimus.
None of the patients in the study showed any intervention drug-related side effects. Levamisole is known to produce vasculitis with extended use. We did not encounter this adverse effect possibly due to shorter period of use of this drug. Three patients had ocular complications of steroid at the time of enrolment. During the course of treatment, there was resolution of eye changes in these patients. Four other patients were on antihypertensives at the beginning of study which could be discontinued in all patients during the trial.
This study was limited by biases inherent in its unblinded design. Patients in the MMF group were inadvertently older. Laboratory tests were repeated at 3-monthly intervals for reasons of feasibility. Despite this, levamisole was shown to be noninferior to MMF endorsing our hypothesis. Further, the period of pretreatment follow-up data was limited to 6 months, raising possibilities of seasonal differences in pretrial relapse frequency. However, since both groups received recruitments throughout the year, this limitation is unlikely to have affected the results. Moreover, both FRNS and SDNS were treated as a homogenous disease while it is becoming clear by recent reports that this may not be the case. Levamisole seems to be a preferred option in the early phase of SSNS, especially when patients are not yet steroid dependent. The distribution was similar in both intervention groups in this study, obviating possible modifying effects of SDNS-FRNS on the study outcome. Despite the limitations, the strength of this study lies in the prospective data collection.
| Conclusion|| |
Our study results establish the noninferiority of daily levamisole over MMF in terms of reduction in relapse frequency as well as in the proportion of patients who could be taken off steroids. Since a recently published trial has shown equivalent efficacy of MMF and alternate-day levamisole treatment, it would be prudent to re-evaluate whether daily levamisole therapy has advantage over its alternate-day dosing in a randomized blinded study design that closely monitors for adverse effects.
What is already known?
Levamisole, administered on alternate days, and MMF are effective steroid-sparing agents in children with SDNS/FRNS.
What this study adds?
Levamisole, administered daily, is not inferior to MMF for preventing relapses in children with SDNS/FRNS.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]
[Table 1], [Table 2]