Estimating the Proportion of Relapse Following Treatment of Visceral Leishmaniasis: Meta-Analysis Using Infectious Diseases Data Observatory (IDDO) Living Systematic Review

Chhajed, Rutuja; Dahal, Prabin; Singh-Phulgenda, Sauman; Brack, Matthew; Naylor, Caitlin; Sundar, Shyam; Alves, Fabiana; Stepniewska, Kasia; Guérin, Philippe J

doi:10.2139/ssrn.4464863

Cited by 2 publications

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“…In particular, the assessment of definitive cure requires a careful evaluation as this requires absence of relapse. Field observations have reported that a substantial proportion of patients develop relapse after 6-months 16,17 suggesting that a 6-months follow-up duration may be overestimating efficacy 18 . Asymptomatic relapse as observed in a trial from India 19 , can pose further challenges as the current algorithm for detection of relapse is conditional upon a patient showing clinical signs and symptoms.…”

Section: Discussionmentioning

confidence: 99%

Design, conduct, analysis, and reporting of therapeutic efficacy studies in Visceral Leishmaniasis: A systematic review of published reports, 2000-2021

Dahal,

Singh-Phulgenda,

Naylor

et al. 2023

Preprint

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A systematic review (SR) of published efficacy studies in visceral leishmaniasis (VL) was carried out to describe methodological aspect of design, analysis, conduct and reporting. Studies published during 2000-2021 and indexed in the Infectious Diseases Data Observatory (IDDO) VL library of clinical studies were eligible for inclusion (n=89 studies). The IDDO VL library is a living SR of prospective therapeutic studies (PROSPERO: CRD42021284622) and is updated bi-annually. A total of 40 (44.9%) studies were randomised, 33 (37.1%) were single-armed, 14 (15.7%) were non-randomised multi-armed studies, and randomisation was unclear in 2 (2.2%). After initial screening, patients were enrolled into the study upon confirmation of VL using parasitological method in 26 (29.2%), and serological and parasitological method in 63 (70.8%). Post-treatment follow-up duration was <6months in 3 (3.3%) studies, 6-months in 75 (84.3%), and >6months in 11 (12.4%) studies. Relapse was defined solely based on clinical suspicion in 4 (4.5%) studies, parasitological demonstration in 64 (71.9%), using molecular/serological/parasitological in 6 (6.7%), and was unclear in 15 (16.9%). Quality control of laboratory measures adopted was unclear in 66 (74.2%) studies, sample size calculation was reported in only 34 (38.2%) studies, and cured proportion was presented only as a point estimate in 39 (43.8%) studies. This review highlights substantial variations in definitions adopted for patient screening, disease diagnosis and therapeutic outcomes suggesting an urgent need for harmonisation of VL clinical trials protocol.

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Section: Discussionmentioning

confidence: 99%

Design, conduct, analysis, and reporting of therapeutic efficacy studies in Visceral Leishmaniasis: A systematic review of published reports, 2000-2021

Dahal,

Singh-Phulgenda,

Naylor

et al. 2023

Preprint

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“…A mixed effects logistic regression model will be used for identifying the risk factors for definitive cure in a one-stage IPD-MA. Given a relatively low number of expected events (for relapse) in each included study, 17 to avoid imprecise estimates from small events and continuity corrections, a one-stage IPD approach is preferred. 29 A random intercept regression model will be considered with study sites specified as random effects to account for within-site clustering of the patients (as some of the trials are multicentre studies).…”

Section: Statistical Analysis and Reportingmentioning

confidence: 99%

“… 11–16 Additionally, the heterogeneity introduced by variation in study design and conduct leads to challenges in reliably comparing the effect measures across the studies. A major challenge in reliably assessing risk factors of therapeutic outcomes is that at individual study level, the number of relapses is often small, 17 which limits the precision of the estimated effect. Individual participant data (IPD) meta-analysis (IPD-MA) of existing studies can overcome this limitation by increasing the effective sample size and allows for a greater power in detecting differential treatment effects across individuals in trials.…”

Section: Introductionmentioning

confidence: 99%

Host, parasite and drug determinants of clinical outcomes following treatment of visceral leishmaniasis: a protocol for individual participant data meta-analysis

Kumar,

Dahal,

Singh-Phulgenda

et al. 2023

BMJ Open

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IntroductionVisceral leishmaniasis (VL) is a parasitic disease with an estimated 30 000 new cases occurring annually. There is an observed variation in the efficacy of the current first-line therapies across different regions. Such heterogeneity could be a function of host, parasite and drug factors. An individual participant data meta-analysis (IPD-MA) is planned to explore the determinants of treatment outcomes.Methods and analysisThe Infectious Diseases Data Observatory (IDDO) VL living systematic review (IDDO VL LSR) library is an open-access resource of all published therapeutic studies in VL since 1980. For this current review, the search includes all clinical trials published between 1 January 1980 and 2 May 2021. Studies indexed in the IDDO VL LSR library were screened for eligibility for inclusion in this IPD-MA. Corresponding authors and principal investigators of the studies meeting the eligibility criteria for inclusion were invited to be part of the collaborative IPD-MA. Authors agreeing to participate in this collaborative research were requested to share the IPD using the IDDO VL data platform. The IDDO VL data platform currently holds data sets from clinical trials standardised to a common data format and provides a unique opportunity to identify host, parasite and drug determinants of treatment outcomes. Multivariable regression models will be constructed to identify determinants of therapeutic outcomes using generalised linear mixed-effects models accounting for within-study site clustering.Ethics and disseminationThis IPD-MA meets the criteria for waiver of ethical review as defined by the Oxford Tropical Research Ethics Committee (OxTREC) granted to IDDO, as the research consists of secondary analysis of existing anonymised data (Exempt granted on 29 March 2023, OxTREC REF: IDDO) Ethics approval was granted by the ICMR-Rajendra Memorial Research Institute of Medical Sciences ethics committee (Letter no: RMRI/EC/30/2022) on 04-07-2022. The results of this IPD-MA will be disseminated at conferences, IDDO website and any peer-reviewed publications. All publications will be open source. Findings of this research will be critically important for the control programmes at regional/global levels, policy makers and groups developing new VL treatments.PROSPERO registrationCRD42021284622.

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Estimating the Proportion of Relapse Following Treatment of Visceral Leishmaniasis: Meta-Analysis Using Infectious Diseases Data Observatory (IDDO) Living Systematic Review

Cited by 2 publications

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Design, conduct, analysis, and reporting of therapeutic efficacy studies in Visceral Leishmaniasis: A systematic review of published reports, 2000-2021

Design, conduct, analysis, and reporting of therapeutic efficacy studies in Visceral Leishmaniasis: A systematic review of published reports, 2000-2021

Host, parasite and drug determinants of clinical outcomes following treatment of visceral leishmaniasis: a protocol for individual participant data meta-analysis

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