Health-related quality of life trajectories in critical illness: Protocol for a Monte Carlo simulation study.

BACKGROUND: Health-related quality of life (HRQoL) is a patient-centred outcome increasingly used as a secondary outcome in critical care research. It may cover several important dimensions of clinical status in intensive care unit (ICU) patients that arguably elude other more easily quantified outcomes such as mortality. Poor associations with harder outcomes, conflicting data on HRQoL in critically ill compared to the background population, and paradoxical effects on HRQoL and mortality complicate the current operationalisation in critical care trials. This protocol outlines a simulation study that will gauge if the areas under the HRQoL trajectories could be a viable alternative. METHODS: We will gauge the behaviour of the proposed HRQoL operationalisation through Monte Carlo simulations, under clinical scenarios that reflect a broad critical care population eligible for inclusion in a large pragmatic trial. We will simulate 15,360 clinical scenarios based on a full factorial design with the following seven simulation parameters: number of patients per arm, relative mortality reduction in the interventional arm, acceleration of HRQoL improvement in the interventional arm, the relative improvement in final HRQoL in the interventional arm, dampening effect of mortality on HRQoL values at discharge from the ICU, proportion of so-called mortality benefiters in the interventional arm and mortality trajectory shape. For each clinical scenario, we will simulate 100,000 two-arm trials with 1:1 randomisation. HRQoL will be sampled fortnightly after ICU discharge. Outcomes will include HRQoL in survivors and all patients at the end of follow-up; mean areas under the HRQoL trajectories in both arms; and mean difference between areas under the HRQoL trajectories and single-sampled HRQoLs at the end of follow-up. DISCUSSION: In the outlined simulation study, we aim to assess whether the area under the HRQoL trajectory curve could be a candidate for reconciling the seemingly paradoxical effects on improved mortality and reduced HRQoL while remaining sensitive to early or accelerated improvement in patient outcomes. The resultant insights will inform subsequent methodological work on prudent collection and statistical analysis of such data from real critically ill patients.

Effects of duration of follow-up and lag in data collection on the performance of adaptive clinical trials.

Different combined outcome-data lags (follow-up durations plus data-collection lags) may affect the performance of adaptive clinical trial designs. We assessed the influence of different outcome-data lags (0-105 days) on the performance of various multi-stage, adaptive trial designs (2/4 arms, with/without a common control, fixed/response-adaptive randomisation) with undesirable binary outcomes according to different inclusion rates (3.33/6.67/10 patients/day) under scenarios with no, small, and large differences. Simulations were conducted under a Bayesian framework, with constant stopping thresholds for superiority/inferiority calibrated to keep type-1 error rates at approximately 5%. We assessed multiple performance metrics, including mean sample sizes, event counts/probabilities, probabilities of conclusiveness, root mean squared errors (RMSEs) of the estimated effect in the selected arms, and RMSEs between the analyses at the time of stopping and the final analyses including data from all randomised patients. Performance metrics generally deteriorated when the proportions of randomised patients with available data were smaller due to longer outcome-data lags or faster inclusion, that is, mean sample sizes, event counts/probabilities, and RMSEs were larger, while the probabilities of conclusiveness were lower. Performance metric impairments with outcome-data lags ≤45 days were relatively smaller compared to those occurring with ≥60 days of lag. For most metrics, the effects of different outcome-data lags and lower proportions of randomised patients with available data were larger than those of different design choices, for example, the use of fixed versus response-adaptive randomisation. Increased outcome-data lag substantially affected the performance of adaptive trial designs. Trialists should consider the effects of outcome-data lags when planning adaptive trials.

Intravenous MELAtonin for prevention of Postoperative Agitation and Emergence Delirium in children (MELA-PAED): A protocol and statistical analysis plan for a randomized clinical trial.

BACKGROUND: Emergence agitation and delirium in children remain a common clinical challenge in the post-anesthetic care unit. Preoperative oral melatonin has been suggested as an effective preventive drug with a favorable safety profile. The oral bioavailability of melatonin, however, is low. Therefore, the MELA-PAED trial aims to investigate the efficacy and safety of intraoperative intravenous melatonin for the prevention of emergence agitation in pediatric surgical patients. METHODS: MELA-PAED is a randomized, double-blind, parallel two-arm, multi-center, superiority trial comparing intravenous melatonin with placebo. Four hundred participants aged 1-6 years will be randomized 1:1 to either the intervention or placebo. The intervention consists of intravenous melatonin 0.15 mg/kg administered approximately 30 min before the end of surgery. Participants will be monitored in the post-anesthetic care unit (PACU), and the Post Hospitalization Behavior Questionnaire for Ambulatory Surgery (PHBQ-AS) will be performed on days 1, 7, and 14 after the intervention. Serious Adverse Events (SAE) will be assessed up to 30 days after the intervention. RESULTS: The primary outcome is the incidence of emergence agitation, assessed dichotomously as any Watcha score >2 during the participant's stay in the post-anesthetic care unit. Secondary outcomes are opioid consumption in the post-anesthetic care unit and adverse events. Exploratory outcomes include SAEs, postoperative pain, postoperative nausea and vomiting, and time to awakening, to first oral intake, and to discharge readiness. CONCLUSION: The MELA-PAED trial investigates the efficacy of intravenous intraoperative melatonin for the prevention of emergence agitation in pediatric surgical patients. Results may provide further knowledge concerning the use of melatonin in pediatric perioperative care.

Use of days alive without life support and similar count outcomes in randomised clinical trials - an overview and comparison of methodological choices and analysis methods.

BACKGROUND: Days alive without life support (DAWOLS) and similar outcomes that seek to summarise mortality and non-mortality experiences are increasingly used in critical care research. The use of these outcomes is challenged by different definitions and non-normal outcome distributions that complicate statistical analysis decisions. METHODS: We scrutinized the central methodological considerations when using DAWOLS and similar outcomes and provide a description and overview of the pros and cons of various statistical methods for analysis supplemented with a comparison of these methods using data from the COVID STEROID 2 randomised clinical trial. We focused on readily available regression models of increasing complexity (linear, hurdle-negative binomial, zero-one-inflated beta, and cumulative logistic regression models) that allow comparison of multiple treatment arms, adjustment for covariates and interaction terms to assess treatment effect heterogeneity. RESULTS: In general, the simpler models adequately estimated group means despite not fitting the data well enough to mimic the input data. The more complex models better fitted and thus better replicated the input data, although this came with increased complexity and uncertainty of estimates. While the more complex models can model separate components of the outcome distributions (i.e., the probability of having zero DAWOLS), this complexity means that the specification of interpretable priors in a Bayesian setting is difficult. Finally, we present multiple examples of how these outcomes may be visualised to aid assessment and interpretation. CONCLUSIONS: This summary of central methodological considerations when using, defining, and analysing DAWOLS and similar outcomes may help researchers choose the definition and analysis method that best fits their planned studies. TRIAL REGISTRATION: COVID STEROID 2 trial, ClinicalTrials.gov: NCT04509973, ctri.nic.in: CTRI/2020/10/028731.

Association between days alive without life support/out of hospital and health-related quality of life.

BACKGROUND: Trials in critically ill patients increasingly focus on days alive without life support (DAWOLS) or days alive out of hospital (DAOOH) and health-related quality of life (HRQoL). DAWOLS and DAOOH convey more information than mortality and are simpler and faster to collect than HRQoL. However, whether these outcomes are associated with HRQoL is uncertain. We thus aimed to assess the associations between DAWOLS and DAOOH and long-term HRQoL. METHODS: Secondary analysis of the COVID STEROID 2 trial including adults with COVID-19 and severe hypoxaemia and the Handling Oxygenation Targets in the Intensive Care Unit (HOT-ICU) trial including adult intensive care unit patients with acute hypoxaemic respiratory failure. Associations between DAWOLS and DAOOH at day 28 and 90 and long-term HRQoL (after 6 or 12 months) using the EuroQol 5-dimension 5-level survey (EQ VAS and EQ-5D-5L index values) were assessed using flexible models and evaluated using measures of fit and prediction adequacy in both datasets (comprising internal performance and external validation), non-parametric correlation coefficients and graphical presentations. RESULTS: We found no strong associations between DAWOLS or DAOOH and HRQoL in survivors at HRQoL-follow-up (615 and 1476 patients, respectively). There was substantial variability in outcomes, and predictions from the best fitted models were poor both internally and externally in the other trial dataset, which also showed inadequate calibration. Moderate associations were found when including non-survivors, although predictions remained uncertain and calibration inadequate. CONCLUSION: DAWOLS and DAOOH were poorly associated with HRQoL in adult survivors of severe or critical illness included in the COVID STEROID 2 and HOT-ICU trials.

An overview of methodological considerations regarding adaptive stopping, arm dropping, and randomization in clinical trials.

BACKGROUND AND OBJECTIVES: Adaptive features may increase flexibility and efficiency of clinical trials, and improve participants' chances of being allocated to better interventions. Our objective is to provide thorough guidance on key methodological considerations for adaptive clinical trials. METHODS: We provide an overview of key methodological considerations for clinical trials employing adaptive stopping, adaptive arm dropping, and response-adaptive randomization. We cover pros and cons of different decisions and provide guidance on using simulation to compare different adaptive trial designs. We focus on Bayesian multi-arm adaptive trials, although the same general considerations apply to frequentist adaptive trials. RESULTS: We provide guidance on 1) interventions and possible common control, 2) outcome selection, follow-up duration and model choice, 3) timing of adaptive analyses, 4) decision rules for adaptive stopping and arm dropping, 5) randomization strategies, 6) performance metrics, their prioritization, and arm selection strategies, and 7) simulations, assessment of performance under different scenarios, and reporting. Finally, we provide an example using a newly developed R simulation engine that may be used to evaluate and compare different adaptive trial designs. CONCLUSION: This overview may help trialists design better and more transparent adaptive clinical trials and to adequately compare them before initiation.

Can BCG vaccination at first health-facility contact reduce early infant mortality? Study protocol for a cluster-randomised trial (CS-BCG).

INTRODUCTION: Increasing evidence suggests that the BCG vaccine has non-specific effects, altering the susceptibility to non-tuberculous infections. Thus, early BCG vaccination may reduce mortality. BCG is recommended at birth but is often delayed. Vaccination opportunities are missed due to multidose vials not being opened for a few children. We will assess the effect of making BCG available at the first health-facility contact on early infant mortality and morbidity in a rural setting in Guinea-Bissau. METHODS AND ANALYSIS: In a cluster-randomised crossover trial, we randomise 23 health centres to two different treatment groups. In half of the health centres, BCG is provided as per current practice; in the remaining health centres, we make BCG available everyday to allow opening a vial of BCG if there is just one eligible child present. The randomisation of centres will be crossed over after 12 months and enrolment will continue for another 12 months.We will use logistic regression models with adjustment for village to assess the effect of making BCG available at the first health-facility contact. The main outcome is non-accidental mortality between day 1 and day 42 after birth. We will adjust for sex, health centre, period (before/after crossover) and level of surveillance (level 1 or level 2). Further analyses include assessment of the effect on hospital admission and a cost-effectiveness evaluation. ETHICS AND DISSEMINATION: If BCG vaccination reduces early infant mortality, missed opportunities and delays of vaccinations expose infants in several low-income countries to unnecessary excess mortality risk. The present trial will provide information on the effect of implementing a feasible intervention, where all children receive BCG at their first health-facility contact. Consent is obtained from all pregnant women registered as part of the trial. The results of the study will be published and communicated to the National Institute of Public Health in Guinea-Bissau. TRIAL REGISTRATION NUMBER: NCT04658680; Clinicaltrials.gov.

Interactions in the 2×2×2 factorial randomised clinical STEPCARE trial and the potential effects on conclusions: a protocol for a simulation study.

BACKGROUND: Randomised clinical trials with a factorial design may assess the effects of multiple interventions in the same population. Factorial trials are carried out under the assumption that the trial interventions have no interactions on outcomes. Here, we present a protocol for a simulation study investigating the consequences of different levels of interactions between the trial interventions on outcomes for the future 2×2×2 factorial designed randomised clinical Sedation, TEmperature, and Pressure after Cardiac Arrest and REsuscitation (STEPCARE) trial in comatose patients after out-of-hospital cardiac arrest. METHODS: By simulating a multisite trial with 50 sites and 3278 participants, and a presumed six-month all-cause mortality of 60% in the control population, we will investigate the validity of the trial results with different levels of interaction effects on the outcome. The primary simulation outcome of the study is the risks of type-1 and type-2 errors in the simulated scenarios, i.e. at what level of interaction is the desired alpha and beta level exceeded. When keeping the overall risk of type-1 errors ≤ 5% and the risk of type-2 errors ≤ 10%, we will quantify the maximum interaction effect we can accept if the planned sample size is increased by 5% to take into account possible interaction between the trial interventions. Secondly, we will assess how interaction effects influence the minimal detectable difference we may confirm or reject to take into account 5% (small interaction effect), 10% (moderate), or 15% (large) positive interactions in simulations with no 'true' intervention effect (type-1 errors) and small (5%), moderate (10%), or large negative interactions (15%) in simulations with 'true' intervention effects (type-2 errors). Moreover, we will investigate how much the sample size must be increased to account for a small, moderate, or large interaction effects. DISCUSSION: This protocol for a simulation study will inform the design of a 2×2×2 factorial randomised clinical trial of how potential interactions between the assessed interventions might affect conclusions. Protocolising this simulation study is important to ensure valid and unbiased results. TRIAL REGISTRATION: Not relevant.

Long-term mortality and health-related quality of life of lower versus higher oxygenation targets in ICU patients with severe hypoxaemia.

PURPOSE: We assessed outcomes after 1 year of lower versus higher oxygenation targets in intensive care unit (ICU) patients with severe hypoxaemia. METHODS: Pre-planned analyses evaluating 1-year mortality and health-related quality-of-life (HRQoL) outcomes in the previously published Handling Oxygenation Targets in the ICU trial which randomised 2928 adults with acute hypoxaemia to targets of arterial oxygen of 8 kPa or 12 kPa throughout the ICU stay up to 90 days. One-year all-cause mortality was assessed in the intention-to-treat population. HRQoL was assessed using EuroQol 5 dimensions 5 levels (EQ-5D-5L) questionnaire and EQ visual analogue scale score (EQ-VAS), and analyses were conducted in both survivors only and the intention-to-treat population with assignment of the worst scores to deceased patients. RESULTS: We obtained 1-year vital status for 2887/2928 (98.6%), and HRQoL for 2600/2928 (88.8%) of the trial population. One year after randomisation, 707/1442 patients (49%) in the lower oxygenation group vs. 704/1445 (48.7%) in the higher oxygenation group had died (adjusted risk ratio 1.00; 95% confidence interval 0.93-1.08, p = 0.92). In total, 1189/1476 (80.4%) 1-year survivors participated in HRQoL interviews: median EQ-VAS scores were 65 (interquartile range 50-80) in the lower oxygenation group versus 67 (50-80) in the higher oxygenation group (p = 0.98). None of the five EQ-5D-5L dimensions differed between groups. CONCLUSION: Among adult ICU patients with severe hypoxaemia, a lower oxygenation target (8 kPa) did not improve survival or HRQoL at 1 year as compared to a higher oxygenation target (12 kPa).

Adverse Events Associated With Coprescription of Phosphodiesterase Type 5 Inhibitors and Oral Organic Nitrates in Male Patients With Ischemic Heart Disease : A Case-Crossover Study.

BACKGROUND: Concomitant use of oral organic nitrates (nitrates) and phosphodiesterase type 5 (PDE5) inhibitors is contraindicated. OBJECTIVE: To measure temporal trends in the coprescription of nitrates and PDE5 inhibitors and to measure the association between cardiovascular outcomes and the coprescription of nitrates with PDE5 inhibitors. DESIGN: Case-crossover design. SETTING: Nationwide study of Danish patients from 2000 to 2018. PATIENTS: Male patients with International Classification of Diseases, 10th Revision (ICD-10) codes for ischemic heart disease (IHD), including those who had a continuing prescription for nitrates and a new, filled prescription for PDE5 inhibitors. MEASUREMENTS: Two composite outcomes were measured: 1) cardiac arrest, shock, myocardial infarction, ischemic stroke, or acute coronary arteriography and 2) syncope, angina pectoris, or drug-related adverse event. RESULTS: From 2000 to 2018, 249 541 male patients with IHD were identified. Of these, 42 073 patients had continuing prescriptions for nitrates. During this period, the prescription rate for PDE5 inhibitors in patients with IHD who were taking nitrates increased from an average of 0.9 prescriptions (95% CI, 0.5 to 1.2 prescriptions) per 100 persons per year in 2000 to 19.5 prescriptions (CI, 18.0 to 21.1 prescriptions) in 2018. No statistically significant association was found between the coprescription of nitrates with PDE5 inhibitors and the risk for either composite outcome (odds ratio [OR], 0.58 [CI, 0.28 to 1.13] for the first outcome and OR, 0.73 [CI, 0.40 to 1.32] for the second outcome). LIMITATION: An assumption was made that concurrently filled prescriptions for nitrates and PDE5 inhibitors equaled concomitant use. CONCLUSION: From 2000 to 2018, the use of PDE5 inhibitors increased 20-fold among Danish patients with IHD who were taking nitrates. A statistically significant association between concomitant use of these medications and cardiovascular adverse events could not be identified. PRIMARY FUNDING SOURCE: Ib Mogens Kristiansens Almene Fond and Helsefonden.

Health-related quality of life and days alive without life support or out of hospital: Protocol.

BACKGROUND: Mortality is often the primary outcome in randomised clinical trials (RCTs) conducted in critically ill patients. Due to increased awareness on survivors after critical illness and outcomes other than mortality, health-related quality of life (HRQoL) and days alive without life support (DAWOLS) or days alive and out of hospital (DAAOOH) are increasingly being used. DAWOLS and DAAOOH convey more information than mortality, are easier to collect than HRQoL, and are usually assessed at earlier time points, which may be preferable in some situations. However, the associations between DAWOLS-DAAOOH and HRQoL are uncertain. METHODS: We will assess associations between DAWOLS-DAAOOH at day 28 and 90 (independent variables/predictors) and HRQoL assessed using the EuroQol EQ-5D-5L questionnaire (EQ-VAS and EQ-5D-5L index values) at 6 or 12 months (dependent variables) in two RCTs: the COVID STEROID 2 RCT conducted in adult patients with COVID-19 and severe hypoxaemia and the Handling Oxygenation Targets in the Intensive Care Unit (HOT-ICU) RCT conducted in adult intensive care patients with acute hypoxaemic respiratory failure. We will describe associations using best-fitting fractional polynomial transformations separately in each dataset, with the resulting models presented and assessed in both datasets graphically and using measures of fit and prediction adequacy (i.e., internal performance and external validation). We will use multiple imputation if missingness exceeds 5%. DISCUSSION: The outlined study will provide important knowledge on the associations between DAWOLS-DAAOOH and HRQoL in adult critically ill patients, which may help researchers and clinical trialists prioritise and select outcomes in future RCTs conducted in this population.

Patient-important outcomes other than mortality in recent ICU trials: Protocol for a scoping review.

BACKGROUND: Randomised clinical trials (RCTs) conducted in intensive care units (ICUs) frequently focus on all-cause mortality, but other patient-important outcomes are increasingly used and recommended. Their use, however, is not straightforward: choices and definitions, operationalisation of death, handling of missing data, choice of effect measures, and statistical analyses for these outcomes vary greatly. METHODS: We will conduct a scoping review in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews. We will search 10 selected general and speciality journals for RCTs conducted in adult ICU patients from 2018 and onwards reporting at least 1 patient-important outcome other than mortality (including days alive without life support/days alive and out of hospital-type outcomes, health-related quality of life, functional/cognitive/neurological outcomes, and other general patient-important outcomes). We will summarise data on outcome measures and definitions, assessment time points, proportions and handling of death, proportions and handling of missing data, and effect measures and statistical methods used for analysis. DISCUSSION: The outlined scoping review will provide an overview of choices, definitions and handling of patient-important outcomes other than mortality in contemporary RCTs conducted in adult ICU patients. This may guide discussions with patients and relatives, the design of future RCTs, and research on optimal outcome choices and handling.

Out-of-Sequence Vaccinations With Measles Vaccine and Diphtheria-Tetanus-Pertussis Vaccine: A Reanalysis of Demographic Surveillance Data From Rural Bangladesh.

BACKGROUND: Due to delays in vaccinations, diphtheria-tetanus-whole-cell-pertussis (DTP) is often given with or after measles vaccine (MV)-out of sequence. We reanalyzed data from Matlab, Bangladesh, to examine how administration of MV and DTP out-of-sequence was associated with child survival. METHODS: In sum, 36 650 children born between 1986 and 1999 were followed with registration of vaccinations and survival. Controlling for background factors using Cox proportional hazards models, survival was analyzed between 9 and 24 months of age. We measured the mortality rate ratio (MRR) to compare vaccination groups. Oral polio vaccine (OPV) campaigns, which started in 1995, reduced the mortality rate and reduced the difference between vaccination groups. In the main analysis, we therefore censored for OPV campaigns; there were 151 nonaccident deaths before the OPV campaigns. RESULTS: Compared with MV administered alone (MV-only), DTP administered with or after MV had MRR 2.20 (1.31-3.70), and DTP-only had MRR 1.78 (1.01-3.11). Compared with MV-only, DTP administered with MV had a female-male MRR 0.56 (0.13-2.38), significantly different to DTP administered after MV, which had MRR 14.83 (1.88-117.1), test of interaction P = .011. Compared with having DTP (no MV) as most recent vaccination, MV-only had a nonaccident MRR of 0.56 (0.32-0.99). CONCLUSION: The negative effects of non-live DTP with or after live MV are not explained merely by selection bias. These observations support a live-vaccine-last policy where DTP should not be given with or after MV.

Timeliness of DTaP-IPV-Hib Vaccination and Development of Atopic Dermatitis Between 4 Months and 1 Year of Age-Register-Based Cohort Study.

BACKGROUND: An Australian study including 4433 children found that delayed Diphtheria-Tetanus-acellular Pertussis-containing vaccination was associated with reduced risk of developing atopic dermatitis (AD) before age 1 year. OBJECTIVE: We assessed whether delayed vaccination against diphtheria, tetanus, acellular pertussis, polio, and Haemophilus influenzae type b (Diphtheria, Tetanus, acellular Pertussis - Inactivated Polio vaccine - Haemophilus influenzae type b [DTaP]) was associated with a reduced risk of new cases of AD before age 1 year in Denmark. METHODS: We used nationwide registers to follow 883,160 children born in Denmark from 1997 to 2012. Binary regression models adjusting for potential confounding factors were applied to estimate relative risks (adjusted relative risks [aRRs]) of developing AD among children with delayed DTaP vaccination (defined as given 1 month or more after the recommended age) compared with timely vaccinated children. RESULTS: Among 143,429 children with a delayed first dose of DTaP, 4,847 (3.4%) developed AD between age 4 months and 1 year, compared with 27,628 (3.7%) among 739,731 children not having delayed DTaP (aRR 0.94; 95% CI, 0.91-0.97). The aRR was 0.94 (95% CI, 0.90-0.99) for children with a delayed second dose, and the aRR was 0.88 (95% CI, 0.82-0.93) when comparing children with delayed first and second doses with all timely vaccinated children. CONCLUSIONS: The results support the hypothesis that delayed vaccination with DTaP is associated with reduced risk of developing new cases of AD after age 4 months. The dose-dependent relationship strengthens the evidence of a causal relationship. Some countries are introducing maternal pertussis vaccination and delaying the first dose of DTaP, providing a possibility for further testing the hypothesis.

Penta is associated with an increased female-male mortality ratio: cohort study from Bangladesh.

Diphtheria-tetanus-pertussis (DTP) vaccine may be associated with excess female deaths. There are few studies of possible nonspecific effects of the DTP-containing vaccine Penta (DTP-hepatitis B-Haemophilus influenzae type b). We therefore investigated whether Penta vaccinations were associated with excess female deaths in rural Bangladesh. Between June 29, 2011 and April 20, 2016, we examined the mortality rates of 7644 children followed between 6 weeks and 9 months of age. We analyzed mortality using crude mortality rate ratio (MRR) and age-adjusted MRR (aMRR) from a Cox proportional hazards model. Mortality was analyzed according to sex, number of doses of Penta, and the order in which BCG and Penta were administered. During follow-up, 43 children died. For children who were only BCG vaccinated (BCG-only), the adjusted F/M MRR was 0.47 (0.09-2.48). However, among children who had Penta as their most recent vaccination, the adjusted F/M MRR was 9.91 (1.16-84.44). Hence, the adjusted F/M MRR differed significantly for BCG-only and for Penta as the most recent administered vaccination. Although the mortality rate was low in rural Bangladesh, there was a marked difference between adjusted F/M MRR's for children vaccinated with BCG-only compared with children where Penta was the most recent administered vaccination. Although usually ascribed to differential treatment and access to care, DTP-containing vaccines may be part of the explanation for the excessive female mortality reported in some regions.

Using BCG vaccine to enhance non-specific protection of health care workers during the COVID-19 pandemic: A structured summary of a study protocol for a randomised controlled trial in Denmark.

OBJECTIVES: The Bacille Calmette-Guérin (BCG) vaccine against tuberculosis is associated with non- specific protective effects against other infections, and significant reductions in all-cause morbidity and mortality have been reported. We aim to test whether BCG vaccination may reduce susceptibility to and/or the severity of COVID-19 and other infectious diseases in health care workers (HCW) and thus prevent work absenteeism.The primary objective is to reduce absenteeism due to illness among HCW during the COVID-19 pandemic. The secondary objectives are to reduce the number of HCW that are infected with SARS-CoV-2, and to reduce the number of hospital admissions among HCW during the COVID-19 pandemic. HYPOTHESIS: BCG vaccination of HCW will reduce absenteeism by 20% over a period of 6 months. TRIAL DESIGN: Placebo-controlled, single-blinded, randomised controlled trial, recruiting study participants at several geographic locations. The BCG vaccine is used in this study on a different indication than the one it has been approved for by the Danish Medicines Agency, therefore this is classified as a phase III study. PARTICIPANTS: The trial will recruit 1,500 HCW at Danish hospitals.To be eligible for participation, a subject must meet the following criteria: Adult (≥18 years); Hospital personnel working at a participating hospital for more than 22 hours per week.A potential subject who meets any of the following criteria will be excluded from participation in this study: Known allergy to components of the BCG vaccine or serious adverse events to prior BCG administration Known prior active or latent infection with Mycobacterium tuberculosis (M. tuberculosis) or other mycobacterial species Previous confirmed COVID-19 Fever (>38 C) within the past 24 hours Suspicion of active viral or bacterial infection Pregnancy Breastfeeding Vaccination with other live attenuated vaccine within the last 4 weeks Severely immunocompromised subjects. This exclusion category comprises: a) subjects with known infection by the human immunodeficiency virus (HIV-1) b) subjects with solid organ transplantation c) subjects with bone marrow transplantation d) subjects under chemotherapy e) subjects with primary immunodeficiency f) subjects under treatment with any anti-cytokine therapy within the last year g) subjects under treatment with oral or intravenous steroids defined as daily doses of 10 mg prednisone or equivalent for longer than 3 months h) Active solid or non-solid malignancy or lymphoma within the prior two years Direct involvement in the design or the execution of the BCG-DENMARK-COVID trial Intervention and comparator: Participants will be randomised to BCG vaccine (BCG-Denmark, AJ Vaccines, Copenhagen, Denmark) or placebo (saline). An adult dose of 0.1 ml of resuspended BCG vaccine (intervention) or 0.1 ml of sterile 0.9% NaCl solution (control) is administered intradermally in the upper deltoid area of the right arm. All participants will receive one injection at inclusion, and no further treatment of study participants will take place. MAIN OUTCOMES: Main study endpoint: Days of unplanned absenteeism due to illness within 180 days of randomisation.Secondary study endpoints: The cumulative incidence of documented COVID-19 and the cumulative incidence of hospital admission for any reason within 180 days of randomisation.Randomisation: Randomisation will be done centrally using the REDCap tool with stratification by hospital, sex and age groups (+/- 45 years of age) in random blocks of 4 and 6. The allocation ratio is 1:1.Blinding (masking): Participants will be blinded to treatment. The participant will be asked to leave the room while the allocated treatment is prepared. Once ready for injection, vaccine and placebo will look similar, and the participant will not be able to tell the difference.The physicians administering the treatment are not blinded.Numbers to be randomised (sample size): Sample size: N=1,500. The 1,500 participants will be randomised 1:1 to BCG or placebo with 750 participants in each group.Trial Status: Current protocol version 5.1, from July 6, 2020.Recruitment of study participants started on May 18, 2020 and we anticipate having finished recruiting by the end of December 2020. TRIAL REGISTRATION: The trial was registered with EudraCT on April 16, 2020, EudraCT number: 2020-001888-90, and with ClinicalTrials.gov on May 1, 2020, registration number NCT04373291.Full protocol: The full protocol is attached as an additional file, accessible from the Trialswebsite (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.

Reduction in Short-term Outpatient Consultations After a Campaign With Measles Vaccine in Children Aged 9-59 Months: Substudy Within a Cluster-Randomized Trial.

BACKGROUND: We assessed a measles vaccination campaign's potential short-term adverse events. METHODS: In a cluster-randomized trial assessing a measles vaccination campaign's effect on all-cause mortality and hospital admission among children aged 9-59 months in Guinea-Bissau, children received a measles vaccination (intervention) or a health check-up (control). One month to 2 months later, we visited a subgroup of children to ask mothers/guardians about outpatient consultations since enrollment. In log-binomial models, we estimated the relative risk (RR) of nonaccidental outpatient consultations. RESULTS: Among 8319 children (4437 intervention/3882 control), 652 nonaccidental outpatient consultations occurred (322 intervention/330 control). The measles vaccination campaign tended to reduce nonaccidental outpatient consultations by 16% (RR, 0.84 [95% confidence interval {CI}, .65-1.11]), especially if caused by respiratory symptoms (RR, 0.68 [95% CI, .42-1.11]). The reduction tended to be larger in children who prior to trial enrollment had a pentavalent vaccination (diphtheria, tetanus, pertussis, hepatitis B, and Haemophilus influenzae type b) as the most recent vaccination (RR, 0.61 [95% CI, .42-.89]) than in children who prior to trial enrollment had a routine measles vaccination as the most recent vaccination (RR, 0.93 [95% CI, .68-1.26]) (P = .04 for interaction). CONCLUSIONS: In the short term, a measles vaccination campaign seems not to increase nonaccidental outpatient consultations but may reduce them. CLINICAL TRIALS REGISTRATION: NCT03460002.

The effect of early measles vaccination on morbidity and growth: A randomised trial from Guinea-Bissau.

BACKGROUND: Measles vaccine (MV) has beneficial non-specific effects protecting against non-measles infections in some situations. Within a trial of the effect of MV on mortality, we assessed effects of early MV on the secondary outcomes consultations and growth, overall, and by sex and exposure to campaigns with oral polio vaccine (OPV). MATERIALS AND METHODS: Children were randomly assigned to MV at 4.5 + 9 months or MV at 9 months as recommended. At enrolment and 9 months children had their mid-upper-arm-circumference (MUAC) and weight measured. Consultations (out/inpatient) were registered at monthly home visits. Weight-for-age and MUAC-for-age Z-scores were obtained using the WHO growth reference and compared by group in linear regression models. Consultation rates between enrolment and 9 months were compared in Cox proportional hazards models, providing consultation Hazard Ratios (HRs) for early MV versus no early MV. We tested whether the effect of early MV was modified by OPV campaigns by splitting observation time at exposure to OPV campaigns. RESULTS: Among 3548 children enrolled between 2012 and 2015, early MV had no effect on MUAC-for-age (mean difference comparing early MV vs. no MV -0.01, 95% CI -0.06-0.04), weight-for-age (mean difference -0.03, 95% CI -0.07-0.02) or rates of consultations (HR = 1.03, 95% CI 0.92-1.16). The rate of consultations for children enrolled was lower after exposure to OPV campaigns (HR = 0.81, 95% CI 0.71-0.92). The effect of MV differed before exposure to OPV campaigns (HR = 1.12, 95% CI 0.98-1.29) and after OPV campaigns (HR = 0.83, 95% CI 0.67-1.03) (test for interaction: p = 0.03). Associations did not differ by sex. CONCLUSION: Early MV had no overall effect on consultation rates and growth between enrolment and 9 months of age. However, early MV tended to have beneficial effects for children subsequently exposed to OPV campaigns. As beneficial effects were observed in subgroups, the results should be interpreted with caution. CLINICAL TRIALS REGISTRATION: NCT01644721.

Maternal Priming: Bacillus Calmette-Guérin (BCG) Vaccine Scarring in Mothers Enhances the Survival of Their Child With a BCG Vaccine Scar.

BACKGROUND AND HYPOTHESIS: Maternal priming might enhance the beneficial nonspecific effects (NSEs) of live measles vaccination (MV). Children with a bacillus Calmette-Guérin (BCG) vaccine scar have a lower mortality rate than those without a scar that is not explained by protection against tuberculosis. We examined the hypothesis that BCG scarring would have a stronger effect on a child if the mother also had a BCG scar. METHODS: In a randomized controlled trial (RCT) of early MV in children aged 4.5 months, the BCG-scar status of the children and their mother were registered at enrollment at 4.5 months of age. The children were followed up until they were 36 months of age. Using a Cox proportional hazards model, we compared mortality rate ratios according to maternal and child BCG-scar status after adjusting for where the BCG vaccine was given (the national hospital or elsewhere). We censored for other interventions that have immunomodulating effects on child survival, including neonatal vitamin A supplementation and early MV. RESULTS: A total of 2213 children had not received neonatal vitamin A supplementation and early MV; 83% of these children and 44% of the mothers had a BCG scar. Children whose mother had a BCG scar were not more likely to have a BCG scar than those whose mother did not have a BCG scar (risk ratio, 1.01 [95% confidence interval (CI), 0.98-1.05]). Among the children, having a BCG scar was associated with a 41% (95% CI, 5%-64%) lower mortality between the ages of 4.5 and 36 months. The reduction in mortality was 66% (95% CI, 33%-83%) if the mother also had a BCG scar but only 8% (95% CI, -83% to 53%) if the mother had no BCG scar (test of interaction, P = .04). CONCLUSIONS: Maternal BCG priming might be important for the effect of BCG vaccination on child survival. Ensuring better BCG vaccine scarring among mothers and children could have a considerable effect on child mortality levels.

Correction: Effect of early measles vaccine on pneumococcal colonization: A randomized trial from Guinea-Bissau.

[This corrects the article DOI: 10.1371/journal.pone.0177547.].