Eligibility criteria and outcome measures adopted in clinical trials of treatments of cutaneous leishmaniasis: systematic literature review covering the period 1991-2015.

OBJECTIVE: To document the sources of heterogeneity in outcomes and shortcomings in trial designs reported by previous systematic reviews. METHODS: Systematic review of clinical trials of CL treatments published since 1991, to assess and compare eligibility criteria and outcome measures in trials (any type of treatment) of CL (any form) reported before and after the publication of the CONSORT statement. RESULTS: We identified 106 eligible trials published between 1991 and 2015, 74% after the 2001 CONSORT statement; 58% (n = 63) were on Old-World CL and 37% (n = 40) in New-World CL; overall, 11 531 patients enrolled in 243 treatment groups on 30 different treatments. Both requirements and definitions for eligibility and outcome criteria varied. Compliance with CONSORT requirements increased for studies published after the 2010 update. As for entry criteria, 94% of studies had a requirement for sex (74% of those enrolling also women excluded those who were pregnant or lactating), 69% for age (variable age ranges), 99% parasitological confirmation, 43% prior duration of illness (14% excluded cases with previous episodes), 46% defined the number, 28% the size and 13% the type of lesions (27% with restrictions as to their anatomical location). Follow-up ranged 1-24 months, with 14% and 91% of studies, respectively, having defined initial and final cure. CONCLUSIONS: This review documents changes in reporting before and after the publication of the CONSORT statement. Lack of standardisation, compounded with the small number of trials relative to the magnitude of the disease in its multiple forms, and with the range of treatments tested explains why evidence to inform treatment guidelines is generally weak for CL. Adopting standardised methodologies will improve the quality and consistency of clinical trials, and ultimately yield better treatments for CL.

Comprehensive economic evaluation of thermotherapy for the treatment of cutaneous leishmaniasis in Colombia.

BACKGROUND: Cutaneous leishmaniasis causes a high disease burden in Colombia, and available treatments present systemic toxicity, low patient compliance, contraindications, and high costs. The purpose of this study was to estimate the cost-effectiveness of thermotherapy versus Glucantime in patients with cutaneous leishmaniasis in Colombia. METHODS: Cost-effectiveness study from an institutional perspective in 8133 incident cases. Data on therapeutic efficacy and safety were included, calculating standard costs; the outcomes were disability adjusted life years (DALYs) and the number of patients cured. The information sources were the Colombian Public Health Surveillance System, disease burden studies, and one meta-analysis of controlled clinical trials. Incremental cost-effectiveness was determined, and uncertainty was evaluated with tornado diagrams and Monte Carlo simulations. RESULTS: Thermotherapy would generate costs of US$ 501,621; the handling of adverse effects, US$ 29,224; and therapeutic failures, US$ 300,053. For Glucantime, these costs would be US$ 2,731,276, US$ 58,254, and US$ 406,298, respectively. With thermotherapy, the cost would be US$ 2062 per DALY averted and US$ 69 per patient cured; with Glucantime, the cost would be US$ 4241 per DALY averted and US$ 85 per patient cured. In Monte Carlo simulations, thermotherapy was the dominant strategy for DALYs averted in 67.9% of cases and highly cost-effective for patients cured in 72%. CONCLUSION: In Colombia, thermotherapy can be included as a cost-effective strategy for the management of cutaneous leishmaniasis. Its incorporation into clinical practice guidelines could represent savings of approximately US$ 10,488 per DALY averted and costs of US$ 116 per additional patient cured, compared to the use of Glucantime. These findings show the relevance of the incorporation of this treatment in our country and others with similar parasitological, clinical, and epidemiological patterns.

Efficacy of cryotherapy for the treatment of cutaneous leishmaniasis: meta-analyses of clinical trials.

BACKGROUND: Cryotherapy is a local treatment for cutaneous leishmaniasis with variable efficacy and greater safety than conventional treatment. The objective of this study is to evaluate the efficacy and safety of cryotherapy for the treatment of cutaneous leishmaniasis and to compare it with pentavalent antimonials. METHODS: A meta-analysis based on a search of nine databases with eight strategies was conducted. Inclusion and exclusion criteria were applied, the methodological quality of each article was evaluated, and the reproducibility of the study selection and information extraction from each clinical trial was assured. The per lesion and per patient efficacy was calculated, and a meta-analysis of relative risks with the random effects model and the Dersimonian and Laird's, Begg, and Egger tests, along with a sensitivity analysis, were performed. A meta-regression based on the methodological quality of the trials included was also performed. RESULTS: Eight studies were included in which respective per lesion efficacies of 67.3 % and 67.7 % were reported for cryotherapy and pentavalent antimonials. In 271 patients treated with cryotherapy and in 199 with pentavalent antimonials, respective per protocol and intent to treat efficacies of 63.6 % and 54.2 % were found in the first group, and per protocol and intent to treat efficacies of 74.7 % and 68.3 % were found in the second group. The relative risk for the comparison of efficacy in the two groups was 0.73 (0.42-1.29). The results of the sensitivity analysis and the meta-regression analysis of relative risks were statistically equal to the overall results. CONCLUSION: This investigation provides evidence in favor of the use of cryotherapy given that its efficacy is similar to that of pentavalent antimonials.

Involving patients in drug development for Neglected Tropical Diseases (NTDs): A qualitative study exploring and incorporating preferences of patients with cutaneous leishmaniasis into Target Product Profile development.

BACKGROUND: Target Product Profiles (TPPs) are instrumental to help optimise the design and development of therapeutics, vaccines, and diagnostics - these products, in order to achieve the intended impact, should be aligned with users' preferences and needs. However, patients are rarely involved as key stakeholders in building a TPP. METHODOLOGY: Thirty-three cutaneous leishmaniasis (CL) patients from Brazil, Colombia, and Austria, infected with New-World Leishmania species, were recruited using a maximum variation approach along geographic, sociodemographic and clinical criteria. Semi-structured interviews were conducted in the respective patient's mother tongue. Transcripts, translated into English, were analysed using a framework approach. We matched disease experiences, preferences, and expectations of CL patients to a TPP developed by DNDi (Drug for Neglected Diseases initiative) for CL treatment. PRINCIPAL FINDINGS: Patients' preferences regarding treatments ranged from specific efficacy and safety endpoints to direct and significant indirect costs. Respondents expressed views about trade-offs between efficacy and experienced discomfort/adverse events caused by treatment. Reasons for non-compliance, such as adverse events or geographical and availability barriers, were discussed. Considerations related to accessibility and affordability were relevant from the patients' perspective. CONCLUSIONS/SIGNIFICANCE: NTDs affect disadvantaged populations, often with little access to health systems. Engaging patients in designing adapted therapies could significantly contribute to the suitability of an intervention to a specific context and to compliance, by tailoring the product to the end-users' needs. This exploratory study identified preferences in a broad international patient spectrum. It provides methodological guidance on how patients can be meaningfully involved as stakeholders in the construction of a TPP of therapeutics for NTDs. CL is used as an exemplar, but the approach can be adapted for other NTDs.

How has research on the effectiveness and safety of COVID-19 vaccination been evaluated: a scope review with emphasis on CoronaVac.

Introduction: The control of the COVID-19 epidemic has been focused on the development of vaccines against SARS-CoV-2. All developed vaccines have reported safety and efficacy results in preventing infection and its consequences, although the quality of evidence varies depending on the vaccine considered. Different methodological designs have been used for their evaluation, which can influence our understanding of the effects of these interventions. CoronaVac is an inactivated vaccine, and it has been assessed in various studies, including clinical trials and observational studies. Given these differences, our objective was to explore the published information to answer the question: how has the efficacy/effectiveness and safety of CoronaVac been evaluated in different studies? This is to identify potential gaps and challenges to be addressed in understanding its effect. Methods: A scoping review was carried out following the methodology proposed by the Joanna Briggs Institute, which included studies carried out in humans as of 2020, corresponding to systematic reviews, clinical trials, analytical or descriptive observational studies, in which the effectiveness and/or safety of vaccines for COVID19 were evaluated or described. There were no age restrictions for the study participants. Results: The efficacy/effectiveness and safety of this vaccine was assessed through 113 studies. Nineteen corresponded to experimental studies, 7 of Phase II, 5 of Phase IV, and 4 were clinical trials with random assignment. Although some clinical trials with random assignment have been carried out, these have limitations in terms of feasibility, follow-up times, and with this, the possibility of evaluating safety outcomes that occur with low frequencies. Not all studies have used homogeneous methods of analysis. Both the prevention of infection, and the prevention of outcomes such as hospitalization or death, have been valued through similar outcomes, but some through multivariate analysis of dependencies, and others through analysis that try to infer causally through different control methods of confounding. Conclusion: Published information on the evaluation of the efficacy/effectiveness and safety of the CoronaVac is abundant. However, there are differences in terms of vaccine application schedules, population definition, outcomes evaluated, follow-up times, and safety assessment, as well as non-standardization in the reporting of results, which may hinder the generalizability of the findings. It is important to generate meetings and consensus strategies for the methods and reporting of this type of studies, which will allow to reduce the heterogeneity in their presentation and a better understanding of the effect of these vaccines.

Real-world effectiveness of the CoronaVac vaccine in a retrospective population-based cohort in four Colombian cities (2021-2022).

OBJECTIVES: The National Vaccination Plan against SARS-CoV-2/COVID-19 was launched by the Ministry of Health and Social Protection on 14 February 2021. The main objective of this study was to evaluate the effectiveness of the CoronaVac in preventing the three clinical outcomes of infection, hospitalisation, or death, in a real-world scenario. DESIGN: This was a population-based retrospective dynamic cohort study using a multivariate Cox model to calculate hazard ratios to estimate vaccine effectiveness from 17 February 2021 to 30 June 2022. The data were collected from surveillance systems for 12 months for each individual. Four cities were selected on the basis of the reliability of their data bases. RESULTS: The rates of CoronaVac effectiveness were 32% (95% confidence interval [CI] 31-33) for preventing infection, 55% (95% CI 54-56) for hospitalisation, and 90% (95% CI 89-90) for death, at the end of follow-up. These findings were more consistent during the first 4 months. Compared with the unvaccinated group, homologous booster doses appeared to increase effectiveness in preventing hospitalisation, whereas heterologous booster doses increased protection for both hospitalisation and death. Booster doses did not improve effectiveness among those already vaccinated with CoronaVac, even when they received heterologous boosters. CONCLUSIONS: CoronaVac demonstrated effectiveness in preventing death and hospitalisation during the first year of follow-up, but its effectiveness in preventing infection was lower, decreasing rapidly after the first 4 months of follow-up. The effectiveness was higher among children aged between 3 and 12 years, and among adults aged ≥60 years. Booster doses did not improve effectiveness among those already vaccinated with CoronaVac.

Patients' preferences of cutaneous leishmaniasis treatment outcomes: Findings from an international qualitative study.

BACKGROUND: Cutaneous leishmaniasis (CL) is a disease that often affects exposed skin areas and may heal leaving lifelong scars. Patients' expectations from treatment are rarely considered in drug development for CL. An initiative aiming to address shortcomings in clinical trial design and conduct for CL treatments involving the researchers' community is on-going. This manuscript presents patient-preferred outcomes for CL and an assessment on how to consider these in the conduct of future trials. METHODOLOGY/PRINCIPAL FINDINGS: We report preferred treatment outcomes by 74 patients with confirmed CL in endemic regions of Brazil, Burkina Faso, Colombia, Iran, Morocco, Peru and Tunisia during individual in-depth interviews. Beyond outcomes customarily considered in trials (such as lesion appearance and adverse events), patients talked about a large number of outcomes related to quality of life, such as pain, scar formation, and others affecting their work and daily activities. They also reported fears around getting rid of the parasite, disease recurrence, and possible sequelae. CONCLUSIONS/SIGNIFICANCE: The study results provide a rich insight into important outcomes for CL treatments, as well as related topics, from the perspective of a diverse patient population. Among the outcomes identified, we argue that those related to quality of life as well as recurrence should be included to a greater extent for assessment in clinical trials, and discuss the suitability of measurement instruments such as the Dermatology Quality of Life Index (DLQI). Interviews also point out the potential need to address concerns related to parasitological cure or scar formation, such as social stigmatization and disability. In addition, patients should be given information in order to clarify reported misconceptions. This study therefore suggests a methodology for consulting CL patients on outcomes as elements of clinical trial design, and how to incorporate these outcomes in trials. It also discusses how reported outcomes could be addressed in clinical care.

An international qualitative study exploring patients' experiences of cutaneous leishmaniasis: study set-up and protocol.

INTRODUCTION: Lack of investments in drug development, lack of standardisation of clinical trials and the complexity of disease presentations contribute to the current lack of effective, safe and adapted treatments for cutaneous leishmaniasis (CL). One aspect concerns outcomes affecting patients' quality of life (QoL): these are hardly assessed in trials, despite potential functional and/or aesthetic impairment caused by CL, which typically affects disadvantaged and vulnerable people living in rural areas. Here, we describe the approach used to bring perspectives of patients with CL into designing and assessing treatments. METHODS AND ANALYSIS: This international qualitative study uses interviews with patients to explore their experiences with CL to (1) elicit outcomes and eligibility criteria for clinical trials important to them and (2) to better understand their needs and views about the disease and their requirements and expectations from treatment. Here, we describe the set-up of this collaborative study and the protocol. Data collection is ongoing.The protocol includes study design, preparation, conduct and analysis of individual interviews with approximately 80 patients in seven countries (Burkina Faso, Brazil, two sites in Colombia, Iran, Morocco, Peru and Tunisia) where CL is prevalent. Principal investigators and sites were selected through an open call, and two workshops were organised for protocol development and training in conduct and analysis of qualitative health research. Patient recruitment aims at covering a maximum variation of experiences. Transcripts will be analysed to identify outcomes and eligibility criteria as well as further topics that are expected to emerge from the interviews, such as direct and indirect costs related to CL, its psychological impact, preferred modes of drug administration and traditional treatments. ETHICS AND DISSEMINATION: The study received ethical approval by the responsible committees of each of the participating institutions. Findings will be disseminated through publication in peer-reviewed journals, scientific meetings and to participants and their communities.

Harmonized clinical trial methodologies for localized cutaneous leishmaniasis and potential for extensive network with capacities for clinical evaluation.

INTRODUCTION: Progress with the treatment of cutaneous leishmaniasis (CL) has been hampered by inconsistent methodologies used to assess treatment effects. A sizable number of trials conducted over the years has generated only weak evidence backing current treatment recommendations, as shown by systematic reviews on old-world and new-world CL (OWCL and NWCL). MATERIALS AND METHODS: Using a previously published guidance paper on CL treatment trial methodology as the reference, consensus was sought on key parameters including core eligibility and outcome measures, among OWCL (7 countries, 10 trial sites) and NWCL (7 countries, 11 trial sites) during two separate meetings. RESULTS: Findings and level of consensus within and between OWCL and NWCL sites are presented and discussed. In addition, CL trial site characteristics and capacities are summarized. CONCLUSIONS: The consensus reached allows standardization of future clinical research across OWCL and NWCL sites. We encourage CL researchers to adopt and adapt as required the proposed parameters and outcomes in their future trials and provide feedback on their experience. The expertise afforded between the two sets of clinical sites provides the basis for a powerful consortium with potential for extensive, standardized assessment of interventions for CL and faster approval of candidate treatments.

Cost-effectiveness analysis of thermotherapy versus pentavalent antimonials for the treatment of cutaneous leishmaniasis.

OBJECTIVE: The treatment of cutaneous leishmaniasis is toxic, has contraindications, and a high cost. The objective of this study was to estimate the cost-effectiveness of thermotherapy versus pentavalent antimonials for the treatment of cutaneous leishmaniasis. METHODS: Effectiveness was the proportion of healing and safety with the adverse effects; these parameters were estimated from a controlled clinical trial and a meta-analysis. A standard costing was conducted. Average and incremental cost-effectiveness ratios were estimated. The uncertainty regarding effectiveness, safety, and costs was determined through sensitivity analyses. RESULTS: The total costs were $66,807 with Glucantime and $14,079 with thermotherapy. The therapeutic effectiveness rates were 64.2% for thermotherapy and 85.1% for Glucantime. The average cost-effectiveness ratios ranged between $721 and $1275 for Glucantime and between $187 and $390 for thermotherapy. Based on the meta-analysis, thermotherapy may be a dominant strategy. CONCLUSION: The excellent cost-effectiveness ratio of thermotherapy shows the relevance of its inclusion in guidelines for the treatment.

Efficacy of thermotherapy to treat cutaneous leishmaniasis: a meta-analysis of controlled clinical trials.

INTRODUCTION: The efficacy of thermotherapy for the treatment of cutaneous leishmaniasis presents diverse results with low statistical power. OBJECTIVE: To evaluate the efficacy of thermotherapy to treat cutaneous leishmaniasis. METHODS: A meta-analysis of controlled clinical trials in 12 databases based on the implementation of a research protocol with inclusion and exclusion criteria and an assessment of methodological quality. The reproducibility and completeness were guaranteed in the information search and extraction. Heterogeneity, sensitivity and publication bias were assessed by graphical methods (Galbraith, L'Abblé, funnel plot, Egger plot, and influence plot) and analytical methods (DerSimonian-Laird, Begg and Egger). Random-effects forest plots were constructed, and a cumulative meta-analysis was performed. RESULTS: Eight studies were included with 622 patients who underwent thermotherapy, with an efficacy of 73.2% (95% confidence interval (CI) = 69.6-76.7%), and with 667 patients who underwent systemic treatment, with an efficacy of 70.6% (95% CI=67.1-74.1%). Heterogeneity between studies, good sensitivity for the combined measure, and no publication bias were observed. The relative risk for comparison of the efficacy of treatment was 1.02 (95%CI=0.91, 1.15), showing that the effectiveness of thermotherapy is equal to that of pentavalent antimonial drugs. CONCLUSION: Due to its efficacy, greater safety and lower cost, thermotherapy should be the first treatment option for cutaneous leishmaniasis in areas where the prevalence of the mucocutaneous form is low and in patients with contraindications to systemic treatment, such as kidney, liver and heart diseases, as well as in pregnant women, infants, and patients with human immunodeficiency virus infection/acquired immune deficiency syndrome.