Mycophenolate mofetil (MMF) has emerged as a new therapeutic option in steroid-dependent nephrotic syndrome (SDNS). We conducted a phase II Bayesian trial of MMF in children with SDNS. Phase II trials, usually single-arm studies, investigate the effect of new treatments. Standard Fleming's procedure relies on observed results (relapse rate during the trial), whereas Bayesian approach combines observed results with prior information (expected relapse rate according to prior studies and clinical experience). All patients were required to have received prior alkylating-agent treatment. Sixty-seven percent of them had also received levamisole. Patients received MMF (1,200 mg/m(2)/day) and prednisone according to a defined schedule [reduction of alternate-day (e.o.d) dose to 50% of pre-MMF dose at 3 months, 25% at 6 months]. Twenty-four children (median age 6.0 years, 2.8-14.4) entered the study and 23 completed it. Bayesian analysis showed that adding four patients would not change significance of results, allowing stopping inclusions. Four patients relapsed during the first 6 months (estimated probability 17.6%, 95% credibility interval: 5.4-35.0%) and two at months 8 and 11.5. In the 19 patients free of relapse during the first 6 months, median (Q1-Q3) prednisone maintenance dose decreased from 25 (10-44) to 9 (7.5-11.2) mg/m(2) e.o.d (p < 0.001) and cumulative dose from 459 (382-689) to 264 (196-306) mg/m(2)/month (p < 0.001) before and on MMF respectively. Pre-MMF patient characteristics and MMF pharmacokinetics did not differ between patients with or without relapse. MMF reduces relapse rate and steroid dose in children with SDNS and should be proposed before cyclosporine and cyclophosphamide.
"The use of Bayesian statistics within the applied medical literature is growing, especially in the remits of early phase trials, data monitoring, and adaptive randomisation techniques , ; and towards the other end of the evidence hierarchy, Bayesian methods are increasingly being used within evidence synthesis , . However, use of Bayesian methods within the evaluation of large-scale definitive trials is more limited –. "
[Show abstract][Hide abstract] ABSTRACT: Medication errors are an important source of potentially preventable morbidity and mortality. The PINCER study, a cluster randomised controlled trial, is one of the world's first experimental studies aiming to reduce the risk of such medication related potential for harm in general practice. Bayesian analyses can improve the clinical interpretability of trial findings.
Experts were asked to complete a questionnaire to elicit opinions of the likely effectiveness of the intervention for the key outcomes of interest--three important primary care medication errors. These were averaged to generate collective prior distributions, which were then combined with trial data to generate bayesian posterior distributions. The trial data were analysed in two ways: firstly replicating the trial reported cohort analysis acknowledging pairing of observations, but excluding non-paired observations; and secondly as cross-sectional data, with no exclusions, but without acknowledgement of the pairing. Frequentist and bayesian analyses were compared.
Bayesian evaluations suggest that the intervention is able to reduce the likelihood of one of the medication errors by about 50 (estimated to be between 20% and 70%). However, for the other two main outcomes considered, the evidence that the intervention is able to reduce the likelihood of prescription errors is less conclusive.
Clinicians are interested in what trial results mean to them, as opposed to what trial results suggest for future experiments. This analysis suggests that the PINCER intervention is strongly effective in reducing the likelihood of one of the important errors; not necessarily effective in reducing the other errors. Depending on the clinical importance of the respective errors, careful consideration should be given before implementation, and refinement targeted at the other errors may be something to consider.
PLoS ONE 06/2012; 7(6):e38306. DOI:10.1371/journal.pone.0038306 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background:
Mycophenolate mofetil (MMF) is used as a steroid-sparing agent in pediatric nephrotic syndrome (NS). However, data about its long-term efficacy and safety is limited.
We report the long-term outcome of MMF therapy in 46 NS patients who remained steroid dependent (SD) despite previous treatment with levamisole and cyclophosphamide.
After 1 year of MMF initiation, 32 (70 %) patients had reduced steroid requirement: 12 with decreased threshold dose and 20 were able to stop steroids. At follow-up of mean 3.56 (standard deviation + 1.76) years, 25 (54 %) children required no further alternative immunosuppression (IS), having infrequent or no relapses, of which 14 stopped MMF after a mean 2.4 (standard deviation + 0.9) years; 11 are continuing on MMF for a median of 2.25 years (range 1.33-7.75 years). One patient had a psoriasis flare, and MMF was stopped. No other patient required permanent drug withdrawal due to side effects. The outcome of patients who did not require further alternate IS was significantly better than those who did, with 56 % vs. 10.5 %, respectively, being off regular medications at last follow-up.
We conclude that MMF therapy is safe in the long term and allows >50 % of severe SDNS patients to avoid further toxic IS.
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