A systematic review on the design and analysis of antileishmanial clinical efficacy studies

A systematic review on the design and analysis of antileishmanial clinical efficacy studies

Conducting a systematic review of the literature on study design, endpoint definitions and statistical methodologies used in clinical studies in Visceral Leishmaniasis (VL).

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Systematic review updates for the identification of included studies is now complete. Data extraction and analysis is ongoing with expected completion of the research activity mid-2019. Publication and dissemination of results will follow in late 2019.


Clinical trials in VL have been conducted for over 100 years and there has been a progressive understanding of the biological factors underpinning antileishmanial drug efficacy. Methodological approaches in trial design and analysis which inevitably affect the derived estimate of effect sizes (Verret 2009, Flandre 2011, Dahal 2017) has been hitherto overlooked or gathered little attention in the VL literature. A robust design is critical for scientific validity and reproducibility of the trial results and can have policy implications. At patient level, reliable estimates of the efficacy generated from such trials can lead to optimal case management.


The overarching aim of this review is to capture the current practices in design, conduct, analysis, and reporting of results in VL studies in clinical literature.

The specific objectives are:

  • Provide a description of methodological approaches in VL studies.
  • Identify study design questions which in the future could be targeted in the individual participant data (IPD) meta-analysis from the IDDO repository.
Inclusion criteria for studies

This review builds upon a recently published systematic review which identified clinical trials in VL from 1983 to 2015 (Bush 2017). An update of the review has been completed (up to September 2018) by retaining the same search terms, databases and inclusion and exclusion criteria (Table 1).

Table 1: Systematic Review inclusion and exclusion criteria

Study Inclusion Criterion

Studies reporting VL treatment outcomes

Study Exclusion Criteria

Studies focusing on: cutaneous leishmaniasis, post kala-azar dermal leishmaniasis (PKDL), canine VL, vector control, nets, prevalence estimation, diagnostic tests, vaccines or prophylaxis

Non-intervention studies, case reports, retrospective studies

Individual studies enrolling fewer than six patients


clinicaltrials.gov, WHO International

Clinical Trials Registry Platform (ICTRP), the Cochrane Library and PubMed.

Search Terms

((kala AND azar) OR (visceral AND leishmaniasis)) AND (pentamidine OR ambisome OR amphotericin OR paromomycin OR miltefosine OR pentavalent OR sodium)

Data extraction and statistical analysis

Data on the following aspects of the study design and analysis is currently being extracted from studies that met the eligibility criteria:

  1. Study design (randomisation, blinding, duration of follow-up)
  2. Power and sample size calculation, including statistical software used
  3. The primary and secondary endpoints adopted in VL studies and definition of these endpoints
  4. Statistical method for analysing each endpoint
  5. Definition of analysis populations and subgroups
  6. Study inclusion and exclusion criteria
  7. Laboratory methods used
  8. Ethical approval

This research activity is led by Dr Prabin Dahal. For further information, email Prabin Dahal (prabin.dahal@iddo.org)


Verret WJ, Dorsey G, Nosten F, Price RN: The effect of varying analytical methods on estimates of anti-malarial clinical efficacy. Malaria Journal. 2009 Apr 22; 8:77.

Flandre, P.  Statistical Methods in Recent HIV Noninferiority Trials: Reanalysis of 11 Trials. PLoS One. 2011; 6(9): e22871.

Dahal P, Simpson JADorsey GGuérin PJPrice RNStepniewska K. Statistical methods to derive efficacy estimates of anti-malarials for uncomplicated Plasmodium falciparum malaria: pitfalls and challenges. Malaria Journal. 2017 Oct 26;16(1):430.

Bush JT, Wasunna M, Alves F, Alvar J, Olliaro PL, Otieno M, et al. Systematic review of clinical trials assessing the therapeutic efficacy of visceral leishmaniasis treatments: A first step to assess the feasibility of establishing an individual patient data sharing platform. PLoS Neglected Tropical Diseases. 2017; 11:1–16.