Post-kala-azar dermal leishmaniasis (PKDL) drug efficacy study landscape: A systematic scoping review of clinical trials and observational studies to assess the feasibility of establishing an individual participant-level data (IPD) platform.

BACKGROUND: Post-kala-azar dermal leishmaniasis (PKDL) is a dermatosis which can occur after successful treatment of visceral leishmaniasis (VL) and is a public health problem in VL endemic areas. We conducted a systematic scoping review to assess the characteristics of published PKDL clinical studies, understand the scope of research and explore the feasibility and value of developing a PKDL individual patient data (IPD) platform. METHODS: A systematic review of published literature was conducted to identify PKDL clinical studies by searching the following databases: PubMed, Scopus, Ovid Embase, Web of Science Core Collection, WHO Global Index Medicus, PASCAL, Clinicaltrials.gov, Ovid Global Health, Cochrane Database and CENTRAL, and the WHO International Clinical Trials Registry Platform. Only prospective studies in humans with PKDL diagnosis, treatment, and follow-up measurements between January 1973 and March 2023 were included. Extracted data includes variables on patient characteristics, treatment regimens, diagnostic methods, geographical locations, efficacy endpoints, adverse events and statistical methodology. RESULTS: A total of 3,418 records were screened, of which 56 unique studies (n = 2,486 patients) were included in this review. Out of the 56 studies, 36 (64.3%) were from India (1983-2022), 12 (21.4%) from Sudan (1992-2021), 6 (10.7%) were from Bangladesh (1991-2019), and 2 (3.6%) from Nepal (2001-2007). Five (8.9%) studies were published between 1981-1990 (n = 193 patients), 10 (17.9%) between 1991-2000 (n = 230 patients), 10 (17.9%) between 2001-2010 (n = 198 patients), and 31 (55.4%) from 2011 onwards (n = 1,865 patients). Eight (14.3%) were randomised clinical trials, and 48 (85.7%) were non-randomised studies. The median post-treatment follow-up duration was 365 days (range: 90-540 days) in 8 RCTs and 360 days (range: 28-2,373 days) in 48 non-randomised studies. Disease diagnosis was based on clinical criterion in 3 (5.4%) studies, a mixture of clinical and parasitological methods in 47 (83.9%) and was unclear in 6 (10.7%) studies. Major drugs used for treatment were miltefosine (n = 636 patients), liposomal amphotericin B (L-AmB) (n = 508 patients), and antinomy regimens (n = 454 patients). Ten other drug regimens were tested in 270 patients with less than 60 patients per regimen. CONCLUSIONS: Our review identified studies with very limited sample size for the three major drugs (miltefosine, L-AmB, and pentavalent antimony), while the number of patients combined across studies suggest that the IPD platform would be valuable. With the support of relevant stakeholders, the global PKDL community and sufficient financing, a PKDL IPD platform can be realised. This will allow for exploration of different aspects of treatment safety and efficacy, which can potentially guide future healthcare decisions and clinical practices.

Protocol and statistical analysis plan for the mega randomised registry trial comparing conservative vs. liberal oxygenation targets in adults with sepsis in the intensive care unit (Mega-ROX Sepsis).

Background: The effect of conservative vs. liberal oxygen therapy on 90-day in-hospital mortality in adults with sepsis receiving unplanned invasive mechanical ventilation in the intensive care unit (ICU) is uncertain. Objective: The objective of this study was to summarise the protocol and statistical analysis plan for the Mega-ROX Sepsis trial. Design setting and participants: The Mega-ROX Sepsis trial is an international randomised clinical trial that will be conducted within an overarching 40,000-patient registry-embedded clinical trial comparing conservative and liberal ICU oxygen therapy regimens. We anticipate that between 10,000 and 13,000 patients with sepsis who are receiving unplanned invasive mechanical ventilation in the ICU will be enrolled in this trial. Main outcome measures: The primary outcome is in-hospital all-cause mortality up to 90 days from the date of randomisation. Secondary outcomes include duration of survival, duration of mechanical ventilation, ICU length of stay, hospital length of stay, and the proportion of patients discharged home. Results and conclusions: Mega-ROX Sepsis will compare the effect of conservative vs. liberal oxygen therapy on 90-day in-hospital mortality in adults with sepsis who are receiving unplanned invasive mechanical ventilation in the ICU. The protocol and a prespecified approach to analyses are reported here to mitigate analysis bias.

Protocol and statistical analysis plan for the mega randomised registry trial comparing conservative vs. liberal oxygenation targets in adults with nonhypoxic ischaemic acute brain injuries and conditions in the intensive care unit (Mega-ROX Brains).

Background: The effect of conservative vs. liberal oxygen therapy on 90-day in-hospital mortality in adults who have nonhypoxic ischaemic encephalopathy acute brain injuries and conditions and are receiving invasive mechanical ventilation in the intensive care unit (ICU) is uncertain. Objective: The objective of this study was to summarise the protocol and statistical analysis plan for the Mega-ROX Brains trial. Design setting and participants: Mega-ROX Brains is an international randomised clinical trial, which will be conducted within an overarching 40,000-participant, registry-embedded clinical trial comparing conservative and liberal ICU oxygen therapy regimens. We expect to enrol between 7500 and 9500 participants with nonhypoxic ischaemic encephalopathy acute brain injuries and conditions who are receiving unplanned invasive mechanical ventilation in the ICU. Main outcome measures: The primary outcome is in-hospital all-cause mortality up to 90 d from the date of randomisation. Secondary outcomes include duration of survival, duration of mechanical ventilation, ICU length of stay, hospital length of stay, and the proportion of participants discharged home. Results and conclusions: Mega-ROX Brains will compare the effect of conservative vs. liberal oxygen therapy regimens on 90-day in-hospital mortality in adults in the ICU with acute brain injuries and conditions. The protocol and planned analyses are reported here to mitigate analysis bias. Trial Registration: Australian and New Zealand Clinical Trials Registry (ACTRN 12620000391976).

Definitions matter: Heterogeneity of COVID-19 disease severity criteria and incomplete reporting compromise meta-analysis.

Therapeutic efficacy in COVID-19 is dependent upon disease severity (treatment effect heterogeneity). Unfortunately, definitions of severity vary widely. This compromises the meta-analysis of randomised controlled trials (RCTs) and the therapeutic guidelines derived from them. The World Health Organisation 'living' guidelines for the treatment of COVID-19 are based on a network meta-analysis (NMA) of published RCTs. We reviewed the 81 studies included in the WHO COVID-19 living NMA and compared their severity classifications with the severity classifications employed by the international COVID-NMA initiative. The two were concordant in only 35% (24/68) of trials. Of the RCTs evaluated, 69% (55/77) were considered by the WHO group to include patients with a range of severities (12 mild-moderate; 3 mild-severe; 18 mild-critical; 5 moderate-severe; 8 moderate-critical; 10 severe-critical), but the distribution of disease severities within these groups usually could not be determined, and data on the duration of illness and/or oxygen saturation values were often missing. Where severity classifications were clear there was substantial overlap in mortality across trials in different severity strata. This imprecision in severity assessment compromises the validity of some therapeutic recommendations; notably extrapolation of "lack of therapeutic benefit" shown in hospitalised severely ill patients on respiratory support to ambulant mildly ill patients is not warranted. Both harmonised unambiguous definitions of severity and individual patient data (IPD) meta-analyses are needed to guide and improve therapeutic recommendations in COVID-19. Achieving this goal will require improved coordination of the main stakeholders developing treatment guidelines and medicine regulatory agencies. Open science, including prompt data sharing, should become the standard to allow IPD meta-analyses.

A scoping review of registry captured indicators for evaluating quality of critical care in ICU.

BACKGROUND: Excess morbidity and mortality following critical illness is increasingly attributed to potentially avoidable complications occurring as a result of complex ICU management (Berenholtz et al., J Crit Care 17:1-2, 2002; De Vos et al., J Crit Care 22:267-74, 2007; Zimmerman J Crit Care 1:12-5, 2002). Routine measurement of quality indicators (QIs) through an Electronic Health Record (EHR) or registries are increasingly used to benchmark care and evaluate improvement interventions. However, existing indicators of quality for intensive care are derived almost exclusively from relatively narrow subsets of ICU patients from high-income healthcare systems. The aim of this scoping review is to systematically review the literature on QIs for evaluating critical care, identify QIs, map their definitions, evidence base, and describe the variances in measurement, and both the reported advantages and challenges of implementation. METHOD: We searched MEDLINE, EMBASE, CINAHL, and the Cochrane libraries from the earliest available date through to January 2019. To increase the sensitivity of the search, grey literature and reference lists were reviewed. Minimum inclusion criteria were a description of one or more QIs designed to evaluate care for patients in ICU captured through a registry platform or EHR adapted for quality of care surveillance. RESULTS: The search identified 4780 citations. Review of abstracts led to retrieval of 276 full-text articles, of which 123 articles were accepted. Fifty-one unique QIs in ICU were classified using the three components of health care quality proposed by the High Quality Health Systems (HQSS) framework. Adverse events including hospital acquired infections (13.7%), hospital processes (54.9%), and outcomes (31.4%) were the most common QIs identified. Patient reported outcome QIs accounted for less than 6%. Barriers to the implementation of QIs were described in 35.7% of articles and divided into operational barriers (51%) and acceptability barriers (49%). CONCLUSIONS: Despite the complexity and risk associated with ICU care, there are only a small number of operational indicators used. Future selection of QIs would benefit from a stakeholder-driven approach, whereby the values of patients and communities and the priorities for actionable improvement as perceived by healthcare providers are prioritized and include greater focus on measuring discriminable processes of care.

The Chagas disease study landscape: A systematic review of clinical and observational antiparasitic treatment studies to assess the potential for establishing an individual participant-level data platform.

BACKGROUND: Chagas disease (CD), caused by the parasite Trypanosoma cruzi, affects ~6-7 million people worldwide. Significant limitations still exist in our understanding of CD. Harnessing individual participant data (IPD) from studies could support more in-depth analyses to address the many outstanding research questions. This systematic review aims to describe the characteristics and treatment practices of clinical studies in CD and assess the breadth and availability of research data for the potential establishment of a data-sharing platform. METHODOLOGY/PRINCIPAL FINDINGS: This review includes prospective CD clinical studies published after 1997 with patients receiving a trypanocidal treatment. The following electronic databases and clinical trial registry platforms were searched: Cochrane Library, PubMed, Embase, LILACS, Scielo, Clintrials.gov, and WHO ICTRP. Of the 11,966 unique citations screened, 109 (0.9%) studies (31 observational and 78 interventional) representing 23,116 patients were included. Diagnosis for patient enrolment required 1 positive test result in 5 (4.6%) studies (2 used molecular method, 1 used molecular and serology, 2 used serology and parasitological methods), 2 in 60 (55.0%), 3 in 14 (12.8%) and 4 or more in 4 (3.7%) studies. A description of treatment regimen was available for 19,199 (83.1%) patients, of whom 14,605 (76.1%) received an active treatment and 4,594 (23.9%) were assigned to a placebo/no-treatment. Of the 14,605 patients who received an active treatment, benznidazole was administered in 12,467 (85.4%), nifurtimox in 825 (5.6%), itraconazole in 284 (1.9%), allopurinol in 251 (1.7%) and other drugs in 286 (1.9%). Assessment of efficacy varied largely and was based primarily on biological outcome; parasitological efficacy relied on serology in 67/85 (78.8%) studies, molecular methods in 52/85 (61.2%), parasitological in 34/85 (40.0%), microscopy in 3/85 (3.5%) and immunohistochemistry in 1/85 (1.2%). The median time at which parasitological assessment was carried out was 79 days [interquartile range (IQR): 30-180] for the first assessment, 180 days [IQR: 60-500] for second, and 270 days [IQR: 18-545] for the third assessment. CONCLUSIONS/SIGNIFICANCE: This review demonstrates the heterogeneity of clinical practice in CD treatment and in the conduct of clinical studies. The sheer volume of potential IPD identified demonstrates the potential for development of an IPD platform for CD and that such efforts would enable in-depth analyses to optimise the limited pharmacopoeia of CD and inform prospective data collection.

Serious adverse events following treatment of visceral leishmaniasis: A systematic review and meta-analysis.

BACKGROUND: Despite a historical association with poor tolerability, a comprehensive review on safety of antileishmanial chemotherapies is lacking. We carried out an update of a previous systematic review of all published clinical trials in visceral leishmaniasis (VL) from 1980 to 2019 to document any reported serious adverse events (SAEs). METHODS: For this updated systematic review, we searched the following databases from 1st Jan 2016 through 2nd of May 2019: PUBMED, Embase, Scopus, Web of Science, Cochrane, clinicaltrials.gov, WHO ICTRP, and the Global Index Medicus. We included randomised and non-randomised interventional studies aimed at assessing therapeutic efficacy and extracted the number of SAEs reported within the first 30 days of treatment initiation. The incidence rate of death (IRD) from individual treatment arms were combined in a meta-analysis using random effects Poisson regression. RESULTS: We identified 157 published studies enrolling 35,376 patients in 347 treatment arms. Pentavalent antimony was administered in 74 (21.3%), multiple-dose liposomal amphotericin B (L-AmB) in 52 (15.0%), amphotericin b deoxycholate in 51 (14.7%), miltefosine in 33 (9.5%), amphotericin b fat/lipid/colloid/cholesterol in 31 (8.9%), and single-dose L-AmB in 17 (4.9%) arms. There was a total of 804 SAEs reported of which 793 (including 428 deaths) were extracted at study arm level (11 SAEs were reported at study level only). During the first 30 days, there were 285 (66.6%) deaths with the overall IRD estimated at 0.068 [95% confidence interval (CI): 0.041-0.114; I2 = 81.4%; 95% prediction interval (PI): 0.001-2.779] per 1,000 person-days at risk; the rate was 0.628 [95% CI: 0.368-1.021; I2 = 82.5%] in Eastern Africa, and 0.041 [95% CI: 0.021-0.081; I2 = 68.1%] in the Indian Subcontinent. In 21 study arms which clearly indicated allowing the inclusion of patients with HIV co-infections the IRD was 0.575 [95% CI: 0.244-1.355; I2 = 91.9%] compared to 0.043 [95% CI: 0.020-0.090; I2 = 62.5%] in 160 arms which excluded HIV co-infections. CONCLUSION: Mortality within the first 30 days of VL treatment initiation was a rarely reported event in clinical trials with an overall estimated rate of 0.068 deaths per 1,000 person-days at risk, though it varied across regions and patient populations. These estimates may serve as a benchmark for future trials against which mortality data from prospective and pharmacovigilance studies can be compared. The methodological limitations exposed by our review support the need to assemble individual patient data (IPD) to conduct robust IPD meta-analyses and generate stronger evidence from existing trials to support treatment guidelines and guide future research.

Baseline results of a living systematic review for COVID-19 clinical trial registrations.

Background: Since the coronavirus disease 2019 (COVID-19) outbreak was first reported in December 2019, many independent trials have been planned that aim to answer similar questions. Tools allowing researchers to review studies already underway can facilitate collaboration, cooperation and harmonisation. The Infectious Diseases Data Observatory (IDDO) has undertaken a living systematic review (LSR) to provide an open, accessible and frequently updated resource summarising characteristics of COVID-19 study registrations. Methods: Review of all eligible trial records identified by systematic searches as of 3 April 2020 and initial synthesis of clinical study characteristics were conducted. In partnership with Exaptive, an open access, cloud-based knowledge graph has been created using the results.  Results: There were 728 study registrations which met eligibility criteria and were still active. Median (25 th, 75 th percentile) sample size was 130 (60, 400) for all studies and 134 (70, 300) for RCTs. Eight lower middle and low income countries were represented among the planned recruitment sites. Overall 109 pharmacological interventions or advanced therapy medicinal products covering 23 drug categories were studied. Majority (57%, 62/109) of them were planned only in one study arm, either alone or in combination with other interventions. There were 49 distinct combinations studied with 90% (44/49) of them administered in only one or two study arms. The data and interactive platform are available at https://iddo.cognitive.city/. Conclusions:  Baseline review highlighted that the majority of investigations in the first three months of the outbreak were small studies with unique treatment arms, likely to be unpowered to provide solid evidence.  The continued work of this LSR will allow a more dependable overview of interventions tested, predict the likely strength of evidence generated, allow fast and informative filtering of relevant trials for specific user groups and provide the rapid guidance needed by investigators and funders to avoid duplication of efforts.