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Case report form for uncomplicated visceral leishmaniasis

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CRF for uncomplicated VL

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Visceral leishmaniasis case report form

Working together IDDO, Drugs for Neglected Diseases initiative, clinicians and scientists from the visceral leishmaniasis (VL) research community, pharmaceutical industry, drug regulators, and key national and global health partners engaged in a collaborative project to develop the first freely-available poverty-related infectious disease case report forms (CRF) for VL to have been annotated using CDISC standards.

Health department worker looking at paperwork

Previously, there was no recognised standard approach to guide methods of recording, storing and reporting VL clinical trial data. This resulted in challenges when comparing data relating to the efficacy of treatments from different groups of researchers. In 2020 the collaborative project launched the first CRF for uncomplicated VL. However, during the development of the uncomplicated VL CRF, it was recognised that VL-HIV coinfected patients are a vulnerable population often under-studied. With progress in elimination, this population will become increasingly burdened with the bulk of infections, yet often do not fit in standard VL trial design and data collection. Based on the uncomplicated VL CRF, a VL-HIV CRF has been developed by a group of subject matter experts from across endemic regions, led by researchers from IDDO, DNDi, Rajendra Memorial Research Institute of Medical Sciences (RMRI), and Médecins Sans Frontières (MSF). Both CRFs and respective user guides can be freely downloaded.

Uncomplicated VL CRF

The CRF allows collection of clinical trials data for uncomplicated VL in a standard format according to global data standards, facilitating the sharing of individual patient data (IPD) to address knowledge gaps, advance research and support subsequent drug development.
The CRF does not prescribe what data to collect, but rather is a template that provides researchers with a standardised means of recording the data they choose to collect for a study.
Download the CRF for uncomplicated VL
Download the user guide for the CRF for uncomplicated VL

VL-HIV coinfection CRF

The CRF incorporates data fields important for assessing a VL-HIV coinfection, and the user guide reflects the guidance required to account for the different disease progression seen and treatment used in coinfections
Like the uncomplicated VL CRF, the VL-HIV coinfection CRF provides a resource for researchers to build a data collection tool based on the requirements of their trial design
Download the CRF for VL-HIV coinfection
Download the user guide for the CRF for VL-HIV coinfection

Read more about the VL global collaboration.

Find out more about the process behind the development of a CRF

Download CRF for uncomplicated VL

View user guide for CRF for uncomplicated VL

Download CRF for VL HIV coinfection

View the user guide for CRF for VL HIV coinfection

Gender imbalance in visceral leishmaniasis clinical trials

17 Mar 2021

Researchers have found that despite an ongoing trend for a decreasing proportion of males being enrolled in antileishmanial therapeutic efficacy trials over time, there are still 1.8 times as many males as females involved in clinical trials. A new systematic review and meta-analysis published today suggests that existing knowledge on drug efficacy is derived from a study population that is heavily skewed towards adult males. At the same time, substantially less is known about the optimal treatment response in female patients.

The study, Gender disparity in cases enrolled in clinical trials of visceral leishmaniasis: a systematic review and meta-analysis, identified 135 clinical treatment trials of visceral leishmaniasis (VL) published in the past 40 years (1980-2019) enrolling 32,177 patients of whom 21,193 (65.9%) were male and 10,984 (34.1%) female, overwhelmingly from high-burden countries of the Indian subcontinent and Eastern Africa.

While this kind of gender imbalance has been observed in this review and elsewhere for cutaneous leishmaniasis and in a post-kala-azar dermal leishmaniasis (PKDL) studies, it was not the same across the region and time. Researchers found a gradual increase in female enrolment over time which might be due to wider access to health facilities, diagnostic availability and improved literacy. Concurrently, researchers also observed a progressive reduction in mean duration of illness at clinical presentation over time – a metric that possibly indicates improved access to care or awareness or both.

A higher caseload of VL has been observed among males in several community-based surveys conducted in endemic settings. This systematic review highlights that such gender disparity is also observed in patients enrolled in clinical VL studies. This is thought to be due to the association of males with agriculture and construction, both sectors that involve frequent contact with the breeding sites of sandflies, a vector that transmits Leishmania parasites. It is also thought to be due to gender differences in treatment-seeking behaviour and differential access to healthcare.

Visceral leishmaniasis (VL) is a neglected tropical disease that currently has an annual estimated incidence of 50,000 to 90,000 cases in 2019 but the case burden used to be much higher. This drop is mostly the result of the ongoing elimination campaign that begun in the Indian subcontinent in 2005.

The Infectious Diseases Data Observatory (IDDO) is currently working towards collating and standardising VL datasets from several clinical studies included in this systematic review which could provide a valuable resource to understand if differences in treatment outcomes can be expected and what the underlying factors might be.

Dr Sauman Singh, Clinical Research Fellow at IDDO and one of the study co-leads remarked: “While we were able to quantify the degree of disparity in caseloads between males and females over different geographical settings and time-period, the elucidation of exact nature of such distribution requires access to screening logs of patients from clinical trials and access to individual participant data (IPD). Now, that is a huge challenge! The IPD database collated by IDDO, in collaboration by major VL research institutes around the world, is therefore a unique resource not only for exploring the distribution of caseload in a more granular way but also for delineation of the impact of gender on early and late therapeutic outcomes.”

To date, the IDDO VL clinical trials library has indexed 180 therapeutic efficacy studies since 1983. The library is a living systematic review, and the database is continually updated every six months in accordance with the Preferred Reporting Items for Systematic-Reviews and Meta-Analyses (PRISMA) guidelines.

Gender disparity in cases enrolled in clinical trials of visceral leishmaniasis: A systematic review and meta-analysis

PLOS Neglected Tropical Diseases

Published

16 Mar 2021

Authors

Prabin Dahal, Sauman Singh-Phulgenda, Piero L. Olliaro, Philippe J. Guerin

DOI

https://doi.org/10.1371/journal.pntd.0009204

Background

A higher caseload of visceral leishmaniasis (VL) has been observed among males in community-based surveys. We carried out this review to investigate how the observed disparity in gender distribution is reflected in clinical trials of antileishmanial therapies.

Methods

We identified relevant studies by searching a database of all published clinical trials in VL from 1980 through 2019 indexed in the Infectious Diseases Data Observatory (IDDO) VL clinical trials library. The proportion of male participants enrolled in studies eligible for inclusion in this review were extracted and combined using random effects meta-analysis of proportion. Results were expressed as percentages and presented with respective 95% confidence intervals (95% CIs). Heterogeneity was quantified using I2 statistics and sub-group meta-analyses were carried out to explore the sources of heterogeneity.

Results

We identified 135 published studies (1980–2019; 32,177 patients) with 68.0% [95% CI: 65.9%–70.0%; I2 = 92.6%] of the enrolled participants being males. The corresponding estimates were 67.6% [95% CI: 65.5%–69.7%; n = 91 trials; I2 = 90.5%; 24,218 patients] in studies conducted in the Indian sub-continent and 74.1% [95% CI: 68.4%–79.1%; n = 24 trials; I2 = 94.4%; 6,716 patients] in studies from Eastern Africa. The proportion of male participants was 57.9% [95% CI: 54.2%–61.5%] in studies enrolling children aged <15 years, 78.2% [95% CI: 66.0%–86.9%] in studies that enrolled adults (≥15 years), and 68.1% [95% CI: 65.9%–70.0%] in studies that enrolled patients of all ages. There was a trend for decreased proportions of males enrolled over time: 77.1% [95% CI: 70.2%–82.8%; 1356 patients] in studies published prior to the 1990s whereas 64.3% [95% CI: 60.3%–68.2%; 15,611 patients] in studies published on or after 2010. In studies that allowed the inclusion of patients with HIV co-infections, 76.5% [95% CI: 63.8%–85.9%; 5,123 patients] were males and the corresponding estimate was 64.0% [95% CI: 61.4%–66.5% 17,500 patients] in studies which excluded patients with HIV co-infections.

Conclusions

Two-thirds of the participants enrolled in clinical studies in VL conducted in the past 40 years were males, though the imbalance was less in children and in more recent trials. VL treatment guidelines are informed by the knowledge of treatment outcomes from a population that is heavily skewed towards adult males. Investigators planning future studies should consider this fact and ensure approaches for more gender-balanced inclusion.

Read the review

Applications for RSTMH 2021 grants open

26 Feb 2021

The small grants programme offers early career researchers and global health professionals based anywhere in the world the opportunity to apply for funding in a topic related to tropical medicine and global health. The programme funds projects across the research spectrum, including lab-based, clinical, implementation and policy-related research.

The aim of the programme is to develop the next generation of global health researchers by providing seed funding to enable them to generate preliminary data to secure follow-on grants and further their career. Applications focused on the thematic areas listed in RSTMH’s five-year strategy will be prioritised, namely:

Neglected tropical diseases, with a particular focus on their overlap with non-communicable diseases and the Sustainable Development Goals
Malaria, with a particular focus on drug resistance
One Health and wider planetary health
The consideration of human health alongside animal health and the environment, in the context of social, economic and political factors
Topical issues including, but not limited to, emerging diseases
Drug resistant infections

The deadline for applications is April 29. The maximum awarded is £5,000 (including VAT) and for up to one year in duration

RSTMH is also interested to see applications related to snakebite, mycetoma and other skin NTDs and other deep mycoses, co-morbidity and NCDs, coronavirus and emerging diseases. Find out more and how to apply here.

Anaemia among patients with visceral leishmaniasis and haematological dynamics post treatment

Rationale

In patients with visceral leishmaniasis (VL), anaemia is a classical haematological sign at presentation. The baseline haemoglobin levels are usually around 7–10 g/dL but can be as low as 4 g/dL [1]. Data from clinical trials indicate that the disease induced haematological loss is around 6–7 g/dL on average [2]. The anaemia in VL patients arises due to one or more of the following: haemolysis of the parasitised reticulo-endothelial cells in the spleen, bone marrow suppression and dyserythropoeisis, bleeding, or due to iron deficiency [1,3–7]. The severity of anaemia at diagnosis tends to increase with the duration of clinical illness and is exacerbated by iron deficiency and co-infection with helminths [8,9]. Initiation of treatment may lead to further haematological insult as indicated in a recent publication following single-dose liposomal amphotericin B [10]. However, the temporal dynamics of haematological parameters following treatment remains to be fully understood. This study group aims to characterise the haematological parameters at baseline and during the initial treatment and the ensuing follow-up period using individual participant data hosted at IDDO VL data platform.

Objectives

The specific objectives are:

To identify host (including age, sex, gender, clinical characteristics) and parasite (initial load) determinants associated with anaemia at presentation
To characterise the haematological dynamics during the treatment phase including assessment of any potential drug related (mg/kg drug dosage) haematological insult
To quantify VL attributable fall in haemoglobin concentration using the longitudinal haematological trajectory if available

Essential inclusion criteria

Prospective clinical efficacy studies in patients with parasitologically and/or serologically confirmed VL
Information on name, date and dose of treatment regimen
Baseline data on age and gender
Data on haemoglobin or haematocrit at baseline and at least two further time-points during treatment or at follow-up

Desirable criteria

Information of WBC, Platelets and differential cell counts
Methodology used for haematological quantification, e.g. name of devices
Blood transfusion status before, during or after treatment
Co-administration of iron supplement
Information on type of anaemia (e.g.: normocytic, aplastic)
Duration of illness at presentation and other clinical characteristics such as baseline parasite load
History of disease or treatment including information regarding if the infection is primary or relapsing/unresponsive/resistant cases
Information on concomitant illness such as HIV, TB or malaria
Information on severity of disease (mild, moderate or severe VL)
Anthropometric indicators e.g. weight, height

Data standardisation and analysis

Data uploaded to the IDDO VL data platform will be standardised according to the IDDO VL data standardisation protocol into a single database of quality-assured individual patient data using recently developed VL CDISC standards [11]. A detailed statistical analysis plan will be developed and published in an appropriate journal prior to the analyses and will be shared among data contributors beforehand.

Study group governance

The Study Group comprises participating investigators who contribute relevant data sets to the pooled analysis. Data sets will remain the property of the investigators. The Study Group collectively makes decisions with respect to including additional studies, data analysis and plans for publication, in line with the IDDO Publication Policy [12]. The Study Group will identify one or two people to coordinate activities including data analysis, and drafting of publications and reports for group review.

Dr Prabin Dahal and Dr Sauman Singh will be responsible for statistical analyses and co-leading the study group. For further information, please contact prabin.dahal@iddo.org; sauman.singh@iddo.org.

References

1. Boelaert M, Sundar S. Leishmaniasis. Manson’s Trop. Dis. Twenty-Third Ed. 2013;631–51.

2. Thakur CP, Kumar M, Pandey AK. Evaluation of efficacy of longer durations of therapy of fresh cases of kala-azar with sodium stibogluconate. Indian J Med Res. 1991;93:103–10.

3. Das A, Sen Gupta P. Relapse of kala azar after splenectomy. Lancet. 1950;1:681–3.

4. Woodruff AW, Topley E, Knight R, Downie CGB. The Anaemia of Kala Azar. Br. J. Haematol. 1972;22:319–29.

5. Woodruff AW. Recent work on anaemias in the tropics. Br. Med. Bull. 1972;28:92–5.

6. Woodruff AW. Mechanisms involved in anaemia associated with infection and splenomegaly in the tropics. Trans. R. Soc. Trop. Med. Hyg. 1973;67:313–25.

7. Rees PH, Kager PA, Wellde BT, Hockmeyer WT. The response of Kenyan kala-azar to treatment with sodium stibogluconate. Am. J. Trop. Med. Hyg. 1984;33:357–61.

8. Thakur CP. Epidemiological, clinical and therapeutic features of Bihar kala-azar (including post kala-azar dermal leishmaniasis). Trans. R. Soc. Trop. Med. Hyg. 1984;78:391–8.

9. Chulay JD, Bhatt SM, Muigai R, Ho M, Gachihi G, Were JBO, et al. A Comparison of 3 Dosage Regimens of Sodium Stibogluconate in the Treatment of Visceral Leishmaniasis in Kenya. J. Infect. Dis. 1983;148:148–55.

10. Mondal D, Alvar J, Hasnain MG, Hossain MS, Ghosh D, Huda MM, et al. Efficacy and safety of single-dose liposomal amphotericin B for visceral leishmaniasis in a rural public hospital in Bangladesh: A feasibility study. Lancet Glob. Heal. 2014;2:e51–7.

11. IDDO. New global collaboration developing standards for standardised data collection across the VL research community [Internet]. iddo.org. 2020 [cited 2020 Nov 15]. Available from: https://www.iddo.org/news/new-global-collaboration-developing-standards-standardised-data-collection-across-vl-research

12. WWARN Policy on Data Use and Publication. https://www.wwarn.org/tools-resources/publication-policy. Updated: 16^th April 2019.

Host, parasite, and drug determinants of therapeutic responses

mothers and babies in clinic waiting room

Rationale

There is a marked regional heterogeneity in therapeutic response against antileishmanial therapy in visceral leishmaniasis (VL)[1]. Single dose Liposomal Amphotericin B (L-AmB) remains the current first line therapy in the Indian subcontinent due to the emergence and evolution of drug resistant parasites against pentavalent antinomy (PA) [2]. However, PA has demonstrated a high efficacy in Africa and continues to be used as a first line therapy -mainly as a combination regimen with Paromomycin [1]. All other existing drug regimens have a poor efficacy for the treatment of patients infected in the east African region [1,3]. Such heterogeneity in therapeutic responses has been thought to arise due to regional differences in parasite sensitivity/susceptibility [3]. The importance of host and drug parameters as a determinant of observed differences in clinical response demand further investigations. For example, the host immune system plays an important role in post-treatment clearance of residual parasites [4]. The differences in patient population enrolled and the variations in baseline characteristics might indicate differences in immunity level that could have led the observed differences in clinical outcomes. In particular, the number of late failures (relapses) in any given trial are few and exploration of determinants of relapses necessitates an individual participant data meta-analysis from several clinical trials. The IDDO VL platform provides a unique opportunity to address this question and this study group proposes to identify host, parasite, and drug factors associated with initial cure, definitive cure, relapse, and mortality.

Objectives

The specific objectives are:

To identify host (age, immunity, nutritional status), parasite (parasite load, primary or relapsing cases), and drug (mg/kg drug dosage, monotherapy/combination) determinants of initial cure
To identify host (age, immunity, nutritional status), parasite (parasite load, primary or relapsing cases), and drug (mg/kg drug dosage, monotherapy/combination) determinants of definitive cure (or relapse)
To identify host (age, immunity, nutritional status), parasite (parasite load, primary or relapsing cases), and drug (mg/kg drug dosage, monotherapy/combination) determinants of mortality (if available)

Essential inclusion criteria

Prospective clinical efficacy studies in patients with parasitologically and/or serologically confirmed VL for any antileishmanial drugs from any endemic regions
Information on name, date and dose of treatment regimen
Baseline data on age and gender
At least one of the following clinical outcomes reported: initial cure (or non-response), definitive cure, or relapse

Desirable criteria

Duration of illness at presentation and other clinical characteristics such as baseline parasite load
History of disease or treatment including information regarding if the infection is primary or relapsing/unresponsive/resistant cases
Information on concomitant illness such as HIV, TB or malaria
Information on severity of disease (mild, moderate or severe VL)
Baseline haematological parameters
Nutritional status of the patient and anthropometric indicators e.g. derived from weight and height

Data standardisation and analysis

Data uploaded to the IDDO VL data platform will be standardised according to the IDDO VL data standardisation protocol into a single database of quality-assured individual patient data using recently developed VL CDISC standards [5]. A detailed statistical analysis plan will be developed and published in an appropriate journal prior to the analyses and will be shared among data contributors beforehand.

Study group governance

The Study Group comprises participating investigators who contribute relevant data sets to the pooled analysis. Data sets will remain the property of the investigators. The Study Group collectively makes decisions with respect to including additional studies, data analysis and plans for publication, in line with the IDDO Publication Policy [6]. The Study Group will identify one or two people to coordinate activities including data analysis, and drafting of publications and reports for group review.

Dr Prabin Dahal and Dr Sauman Singh will be responsible for statistical analyses and co-leading the study group. For further information, please contact prabin.dahal@iddo.org; sauman.singh@iddo.org.

References

1. Alves F, Bilbe G, Blesson S, Goyal V, Monnerat S, Mowbray C, et al. Recent Development of Visceral Leishmaniasis Treatments: Successes, Pitfalls, and Perspectives. Clin. Microbiol. Rev. 2018;31:1–30.

2. Singh OP, Singh B, Chakravarty J, Sundar S. Current challenges in treatment options for visceral leishmaniasis in India: A public health perspective. Infect. Dis. Poverty. 2016;5:1–15.

3. Khalil EAG, Weldegebreal T, Younis BM, Omollo R, Musa AM, Hailu W, et al. Safety and Efficacy of Single Dose versus Multiple Doses of AmBisome® for Treatment of Visceral Leishmaniasis in Eastern Africa: A Randomised Trial. PLoS Negl. Trop. Dis. 2014;8:e2613.

4. Seaman J, Pryce D, Sondorp HE, Moody A, Bryceson ADM, Davidson RN. Epidemic Visceral Leishmaniasis in Sudan: A Randomized Trial of Aminosidine plus Sodium Stibogluconate versus Sodium Stibogluconate Alone. J. Infect. Dis. 1993;168:715–20.

5. IDDO. New global collaboration developing standards for standardised data collection across the VL research community [Internet]. iddo.org. 2020 [cited 2020 Nov 15]. Available from: https://www.iddo.org/news/new-global-collaboration-developing-standards-standardised-data-collection-across-vl-research

6. WWARN Policy on Data Use and Publication. https://www.wwarn.org/tools-resources/publication-policy. Updated: 16th April 2019.

VL Study Groups

IDDO facilitates collaborative Study Groups to undertake individual patient data meta-analyses to answer specific research questions about visceral leishmaniasis (VL) treatments. Gathering and combining datasets from multiple studies allows for the study of differential treatment effects across sub-populations of interest and helps to explore sources of between-study heterogeneity in therapeutic responses.

Working together, and combining data from different regions and populations, is improving our understanding of the disease, and will advance research and subsequent drug development.

Geneva Health Forum panel on the elimination of NTDs and the new WHO Roadmap

04 Feb 2021

The WHO 2030 NTD Roadmap has just been launched and a recent Geneva Health Forum panel took that as its starting point to discuss the possibility of eliminating neglected tropical diseases (NTDs).

IDDO’s Director, Professor Philippe Guérin joined co-panellists Dr Amy Fall, the Global Health Medical for Africa Region Lead at Sanofi, Dr Mwele Malecela, Director of the Department of Control of Neglected Tropical Diseases at the WHO, and Dr Nathalie Strub-Wourgaft, Medical Director at Drugs for Neglected Diseases initiative (DNDi) back in November 2020.

The wide-ranging discussion highlighted:

The need for more R&D: Diseases, like leishmaniasis and Chagas, take time to develop so a key part of elimination is understanding who is most at risk, measuring effective treatments and then being able to deploy this at scale. All NTDs share one common denominator, a lack of data, which becomes crucial in the last phase of elimination where sustained research is needed to complete the job.
Sustainability: In the field, researchers work across different diseases in the same regions, transferring knowledge from one group to another. The wider research community needs to ensure that the expertise of these hyperspecialised technicians does not vanish and that these skills are passed onto the next generation of researchers. While surveillance is a key component of elimination, there can’t be a one-size-fits-all solution as it cannot assess the epidemiological specifics and treatments for certain diseases like Chagas, leishmaniasis, schistosomiasis and soil-transmitted helminthiases.
Good health creates good wealth: Eliminating schistosomiasis and soil-transmitted helminthiases has already boosted GDP in four countries so the long-term economic benefits speak for themselves.

The WHO identified 20 diseases as endemic in 150 countries and these have been officially listed as NTDs. A resolution to eliminate these diseases was set out in the WHO’s 2020 Roadmap, and the new 2030 Roadmap builds on that work to deliver individual programmes to reduce the burden of these NTDs. While major progress has been made in the last decade, panellists agreed that more work was needed in terms of diagnostics, tools and surveillance in the current political and economic climate.

Watch the discussion