Aim: The overall aim of this study is to assess the efficacy and safety of Levamisole in African children with idiopathic nephrotic syndrome.
- to determine the proportion of children on Levamisole who sustain remission more than 6 months post initiation.
- to determine the proportion of children on Levamisole with more than 2 relapses within 6 months.
- to compare remission and relapse rates between patients on Levamisole and those on other immunosuppressive drugs,
- to determine the proportion of children with idiopatic nephrotic syndrome on Levamisole who sustained remission within 6 months.
- Sub-group analysis of effect of gender and duration of illness on duration of remission and frequency of relapses.
- Subgroup analysis that will include:
Meta-regression of age and dosage of Levamisole on duration of remission and frequency of relapses.
- Children with frequent relapses
- Children who are steroid dependent
- Children resistant to steroid treatment
Design: A systematic review and meta-analysis will be conducted on screened and eligible clinical trials, randomized control trials, and quasi-randomized studies done on African children living in Africa who have idiopathic nephrotic syndrome and have been treated with levamisole. The study will cover all available data from 1969 (when levamisole was first commercially manufactured) to date 2020.
Inclusion criteria are:
- Interventional studies including clinical trials, randomized control trials and quasi-randomized studies,
- study must be conducted on African children,
- studies must have Levamisole as drug for comparison,
- studies must have remission and / or relapse rate as measurable outcome,
- studies must be published or retrievable in the English language and
- studies must be available in electronic databases.
Exclusion criteria are:
- All narrative studies, including letters to editors, reviews, commentaries and editorials,
- All non-interventional studies including observational studies,
- All interventional studies not done in Africa,
- Duplicates of same studies,
- Studies with no measurable outcomes and
- Studies that are not retrievable in the English language
This review will be reported in line with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA 2015 Statement).
Research Questions: The following review questions will be addressed:
- Does levamisole sustain remission for 6-12 months in African children with Idiopathic Nephrotic syndrome?
- Is the rate of relapse reduced within 6-12 months in African children with Idiopathic Nephrotic Syndrome treated with levamisole?
- Is levamisole at a clinical dose of 2.5 mg per kg per day safe in African children with Idiopathic Nephrotic Syndrome?
- Do age, gender, duration of illness, and the dose of levamisole moderate the duration of remission and frequency of relapses in African children with Idiopathic Nephrotic Syndrome?
The PICOS is as follows
Participants: African children below 18 years, already diagnosed with idiopathic nephrotic syndrome and have received steroid treatment.
Intervention: Treatment with Levamisole.
Comparator: Treatment with steroids: prednisolone or other immunosuppressive agents: cyclosporine, cyclophosphamide, Mycophenolate mofetil, Rituximab, Tacrolimus and Chlorambucil
Outcomes: a: proportion of children on levamisole with remission within 6 months post initiation, b) proportion of children on other immunosuppressants with remission within 6 months post initiation, c) proportion of children on levamisole with relapses within 6 months post initiation, d) proportion of children on other immunosuppressants with relapses within 6 months post initiation, e) proportion of children on levamisole with sustained remission beyond 6 months post initiation; f) proportion of children on levamisole without remission within 6 months post initiation and g) number of adverse events in children treated with levamisole.
Effect Size: Relative Risk (RR). Other comparable effect sizes in very similar study designs will be converted to RR using the Comprehensive Meta-analysis Software CMA version 3 (BioStat, USA).
The search will employ sensitive topic-based strategies designed for each database. The following databases will be searched: PubMed, AJOL, Google Scholar, CINAHL, EMBASE, Cochrane Library, Web of Science, Scopus, ClinicalTrials.gov and Research Gate. Only randomized control trials and clinical trials retrievable in English language will be included. The time frame is 1969 to 2020.
The search strategy will include MeSH terms, text words, and entry terms. The search strategies to be used in the databases are shown in Table 1:
Studies will be searched using the search strategy. There are four levels of data screening in this study: a) level 1 is based on study design: only randomized clinical trials and clinical trials conducted in Africa will be extracted from the literature. All observational studies and comments will be excluded; b) level 2: selected studies will first be screened by titles and abstracts using entry terms, keywords, and meSh terms;c) level 3: selected studies will be further screened by full-text reading using the same strategy; d) level 4: snowballing of literature from included studies.
Thirteen reviewers are involved in this study. A pair of reviewers will independently screen studies from each database. Conflicts will be resolved by a third independent reviewer. The review is without blinding. All searched, screened, and retrieved items will be exported to the bibliographic software, Endnote version 9. After screening, data will be exported to Microsoft Excel. All relevant studies that meet the inclusion criteria and are exported to Microsoft Excel will also have full texts retrieved and read to enable snowballing search on references. Authors of eligible articles with missing data will be contacted via email address and telephone.
b. Selection process:
Two independent reviewers will screen full texts of all eligible RCTs, and control trials identified from our databases and snowballed articles and conflicts will be resolved by a third researcher on the team to confirm whether each study meets our eligibility criteria.
c. Data collection process
De-duplication of the studies will then be done in the EndNote version 9. Eligible studies will be exported into Microsoft Excel. The following data will be extracted from each study: a) First author's surname and year of publication, b) effect size (RR, measuring remission rate and relapse rate within 6 months post initiation; no remission beyond 6 months post initiation), c) sample size, d) mean age, e) gender, f) the dose of Levamisole, g) duration of illness, h) frequency of relapses and i) number of adverse events
Data from Excel will be exported to CMA Software for meta-analysis.
Risk of bias
The Cochrane Risk of Bias tool which considers sequence generation, allocation concealment, and blinding and other aspects of bias will be used to assess the study risk of bias. The overall rating of risk of bias for each study will be the lowest rating for any of the criteria (e.g. if any domain is scored high risk of bias, the study will be considered high risk of bias). Any discrepancies between reviewers for any of the above steps will be discussed by the reviewers until consensus is achieved. Pedro scale of quality scoring will also be applied.
We will also contact authors of primary publications, collaborators and/or sponsors of clinical trials for missing outcome data or unclear information.
- Reporting of study: whether remission rate or relapse rate/relapse reduction rate as reported will be done at the outcome level and effect sizes converted for uniformity eventually.
- Heterogeneity will be assessed at the study level using Q statistic and its p value, I2 and Tau squared.
- Publication bias will be assessed at the study level using funnel plot.
- Statement of study location will be done.
- Studies that passed the methodological quality assessment using the Cochrane Risk of Bias tool will be included for data synthesis. The results will be presented in tabular format in addition to a narrative synthesis.
- The following shall be included into the meta-analysis:
- Reported proportion of relapse or remission within 6-12 months of initiation of therapy and sample size by individual studies. The effect size is RR. This is the primary outcome measure. This variable must be present for a study to be included.
- Reported sub-group analysis of moderating effects of age, gender, duration of illness and dosage of Levamisole on duration of remission and frequency of relapses. Effect sizes are for age (mean), gender (categorical), frequency of relapses (relative risk).
- Subgroup analysis that will include:
Screened and eligible studies will be quantitatively analyzed using the CMA Software Version 3 (BioStat, USA). For each reported relapse or remission, standard error and variance for each specific eligible study will be calculated by the CMA software. Subgroup analysis will also be done. To test for heterogeneity Cochrane’s Q value and its p value, I², Ʈ² will be used. The effect size to be used is RR and 95% confidence Interval (CI, 95%). Publication bias will be assessed using a funnel plot. As a rule of thumb, I² values of less than 40% will be considered low heterogeneity while values > 40 but < 75 % will be considered moderate and values > 75% are high. Subgroups analysis will be done using treatment modalities as a categorical data and moderator.
- Children with frequent relapses (categorical)
- Children who are steroid dependent (categorical)
- Children resistant to steroid treatment (categorical)
Meta-regression will be done with dose, age and duration of illness. The pooled effect size (relative risk) and subgroups analysis will be reported in forest plots. Both random and fixed effect models will be assessed, and the appropriate model will be taken based on the forest plots. Publication bias in the selection of studies will be tested using funnel plot (trim and fill method) and test for funnel plot asymmetry.