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SUMMARY: Events occurring after randomization, such as use of rescue medication, treatment discontinuation, or death, are common in randomized trials. These events can change either the existence or interpretation of the outcome of interest. However, appropriate handling of these intercurrent events is often unclear. The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) E9(R1) addendum introduced the estimand framework, which aligns trial objectives with the design, conduct, statistical analysis, and interpretation of results. This article describes how the estimand framework can be used in anesthesia trials to precisely define the treatment effect to be estimated, key attributes of an estimand, common intercurrent events in anesthesia trials with strategies for handling them, and use of the estimand framework in a hypothetical anesthesia trial on postoperative delirium. When planning anesthesia trials, clearly defining the estimand is vital to ensure that what is being estimated is clearly understood, is clinically relevant, and helps answer the clinical questions of interest.
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Anestesia , Ensayos Clínicos Controlados Aleatorios como Asunto , Humanos , Anestesia/métodos , Ensayos Clínicos Controlados Aleatorios como Asunto/métodos , Proyectos de Investigación , Interpretación Estadística de Datos , Ensayos Clínicos como Asunto/métodosRESUMEN
BACKGROUND: Rheumatic Heart Disease (RHD) persists as a major cardiovascular driver of mortality and morbidity among young people in low-and middle-income countries. Secondary antibiotic prophylaxis (SAP) with penicillin remains the cornerstone of RHD control, however, suboptimal treatment adherence undermines most secondary prevention programs. Many of the barriers to optimal SAP adherence are specific to the intramuscular form of penicillin and may potentially be overcome by use of oral penicillin. This noninferiority trial is comparing the efficacy of intramuscular to oral penicillin SAP to prevent progression of mild RHD at 2 years. METHODS/DESIGN: The Intramuscular vs Enteral Penicillin Prophylaxis to Prevent Progression of Rheumatic Heart Disease (GOALIE) trial is randomizing Ugandan children aged 5 to 17 years identified by echocardiographic screening with mild RHD (Stage A or B as defined by 2023 World Heart Federation criteria) to Benzathine Benzyl Penicillin G (BPG arm, every-28-day intramuscular penicillin) or Phenoxymethyl Penicillin (Pen V arm, twice daily oral penicillin) for a period of 2 years. A blinded echocardiography adjudication panel of 3 RHD experts and 2 cardiologists is determining the echocardiographic stage of RHD at enrollment and will do the same at study completion by consensus review. Treatment adherence and study retention are supported through peer support groups and case management strategies. The primary outcome is the proportion of children in the Pen V arm who progress to more advanced RHD compared to those in the BPG arm. Secondary outcomes are patient-reported outcomes (treatment acceptance, satisfaction, and health related quality of life), costs, and cost-effectiveness of oral compared to intramuscular penicillin prophylaxis for RHD. A total sample size of 1,004 participants will provide 90% power to demonstrate noninferiority using a margin of 4% with allowance for 7% loss to follow-up. Participant enrollment commenced in October 2023 and final participant follow-up is expected in December 2026. The graphical abstract (Fig. 1) summarizes the flow of echocardiographic screening, participant enrollment and follow-up. DISCUSSION: The GOALIE trial is critical in global efforts to refine a pragmatic approach to secondary prevention for RHD control. GOALIE insists that the inferiority of oral penicillin be proven contemporarily and against the most important near-term clinical outcome of progression of RHD severity. This work also considers other factors that could influence the adoption of oral prophylaxis and change the calculus for acceptable efficacy including patient-reported outcomes and costs. TRIAL REGISTRATION: ClinicalTrials.gov: NCT05693545.
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Streptococcus pyogenes (S. pyogenes) is a Gram-positive bacteria which causes a spectrum of diseases ranging from asymptomatic infection to life-threatening sepsis. Studies report up to 2000 times greater risk of invasive S. pyogenes disease in close contacts of index cases within 30-days of symptom onset. Despite this, there is variability in the management of asymptomatic carriage of S. pyogenes and those at risk of secondary cases of invasive S. pyogenes infection. OBJECTIVE: Our systematic review assessed the efficacy of different antibiotic regimens used for eradication of S. pyogenes from the pharynx in asymptomatic individuals. METHODS: We searched Pubmed, EMBASE (1974-), OVID Medline (1948-) and the Cochrane CENTRAL registry. We included randomised controlled trials (RCTs) with asymptomatic participants with >50% with pharyngeal cultures positive with S. pyogenes at baseline. Only studies with microbiological methods including culture (+/- polymerase chain reaction, PCR) were included. We included studies published in English. Each included study was assessed by two independent reviewers for data extraction and risk of bias. RESULTS: Of 1166 unique records identified, three RCTs were included in the review. Two of the three included RCTs found oral clindamycin for 10-days was the most efficacious regimen, compared to intramuscular benzathine penicillin G followed by 4 days of oral rifampicin, or monotherapy using benzathine penicillin, phenoxymethylpenicillin or erythromycin. Two RCTs were assessed as being at high risk of bias, with the third study demonstrating low/some risk of bias. CONCLUSIONS: Current available evidence for the optimal antibiotic in eradicating pharyngeal S. pyogenes carriage is limited. Future RCTs should include penicillin, first-generation cephalosporins, rifampicin, macrolides (such as azithromycin) and clindamycin.
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Antibacterianos , Portador Sano , Faringe , Infecciones Estreptocócicas , Streptococcus pyogenes , Humanos , Streptococcus pyogenes/efectos de los fármacos , Streptococcus pyogenes/aislamiento & purificación , Antibacterianos/uso terapéutico , Portador Sano/tratamiento farmacológico , Portador Sano/microbiología , Infecciones Estreptocócicas/tratamiento farmacológico , Infecciones Estreptocócicas/microbiología , Faringe/microbiología , Niño , Adulto , Ensayos Clínicos Controlados Aleatorios como Asunto , Infecciones Asintomáticas , PreescolarRESUMEN
Background: Few studies have assessed the potential indirect effects of childhood pneumococcal conjugate vaccine (PCV) programs on the adult pneumonia burden in resource-limited settings. We evaluated the impact of childhood PCV13 immunisation on adult all-cause pneumonia following a phased program introduction from 2016. Methods: We conducted a time-series analysis to assess changes in pneumonia hospitalisation incidence at four district hospitals in Mongolia. Adults (≥18 years) that met the clinical case definition for all-cause pneumonia were enrolled. A negative binomial mixed-effects model was used to assess the impact of PCV13 introduction on monthly counts of pneumonia admissions from January 2015-February 2022. We also performed a restricted analysis excluding the COVID-19 pandemic period. All models were stratified by age and assessed separately. Additional analyses assessed the robustness of our findings. Findings: The average annual incidence of all-cause pneumonia hospitalisation was highest in adults 65+ years (62.81 per 10,000 population) and declined with decreasing age. After adjusting for the COVID-19 pandemic period, we found that rates of pneumonia hospitalisation remained largely unchanged over time. We did not observe a reduction in pneumonia hospitalisation in any age group. Results from restricted and sensitivity analyses were comparable to the primary results, finding limited evidence of a reduced pneumonia burden. Interpretation: We did not find evidence of indirect protection against all-cause pneumonia in adults following childhood PCV13 introduction. Direct pneumococcal vaccination and other interventions should be considered to reduce burden of pneumonia among older adults. Funding: Pfizer clinical research collaboration agreement (contract number: WI236621).
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Background: Sugar-sweetened beverage (SSB) and non-nutritive sweetened beverage (NNSB) consumption is associated with obesity and are targets for population-level dietary interventions. In children (<16 years), we evaluate whether SSB or NNSB consumption is associated with subsequent (2 years later) overweight and/or obesity, and the effect of consumption on subsequent overweight/obesity differs by BMI polygenic risk score (BMI-PRS). Methods: The nationally representative Longitudinal-Study-of-Australian-Children had biennial data collection from birth (n = 5107) until age 14/15 years (n = 3127). At age 11/12 years, a comprehensive biomedical assessment, including PRS assessment, was undertaken (n = 1422). Parent- or self-reported beverage consumption (SSBs: soft drinks, energy drinks, and/or juice; NNSBs: diet drinks) was measured as any/none over previous 24 hours. BMI-PRS was derived using published results (high PRS ≥75th percentile). At ages 4/5-14/15 children were classified as having obesity, overweight/obesity, or not having overweight/obesity using BMI z-score (CDC cut points). Results: SSB consumption had limited association with subsequent overweight/obesity. NNSB consumption was associated with â¼8% more children with subsequent overweight/obesity at most ages. In older children with high BMI-PRS, associations between NNSB consumption and subsequent overweight/obesity strengthened with age [at age 14-15 for high BMI-PRS, difference in proportion with overweight/obesity among NNSB consumers vs. nonconsumers = 0.38 (95% confidence interval: 0.22 to 0.55, p ≤ 0.001)]. There was limited association between SSB consumption and BMI-PRS. Conclusion: NNSB consumption was associated with increased risk of overweight/obesity for children with greater genetic risk at older ages (12-15 years). Focused intervention among children with high genetic risk could target NNSB consumption; however, reverse causality (children with genetic risk and/or high BMI consume more NNSBs) cannot be excluded.
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Detection of respiratory viruses requires testing of the upper respiratory tract to obtain specimens for analysis. However, nasal and throat swabs can cause discomfort and procedural anxiety in children. Respiratory sampling methods which are accurate and less invasive are needed. We aim to determine the positive and negative percentage agreement of a novel anterior nasal swab (ANS) compared with the combined throat and anterior nasal swab (CTN), the reference standard, for detection of respiratory viruses. Children 5 - 18 years of age presenting to a tertiary paediatric hospital with respiratory symptoms were tested with both swabs in randomised order. Respiratory samples were tested on a multiplex RT-PCR panel. Viral detections, RT-PCR cycle-threshold values and child/parent/clinician experience of the swab were recorded. There were 157 viral detections from 249 participant CTN swabs. In comparison with the CTN, the overall positive and negative percentage agreement of ANS for detection of respiratory viruses was 96.2% (95% CI, 91.8-98.3%) and 99.8% (95% CI, 99.6-99.9%), respectively. The ANS was "extremely comfortable", or only a "little uncomfortable" for 90% of children compared with 48% for CTN. 202 children (84%) rated the ANS as the preferred swab, and 208 (87%) indicated they would prefer ANS for future testing. The ANS required additional laboratory handling processes compared to the CTN. The ANS has high positive percentage agreement and is comparable to the current standard of care. The high acceptability from the less invasive ANS provides a more comfortable method for respiratory virus testing in children.Trial registrationClinicalTrials.gov ID NCT05043623.
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Virus , Niño , Humanos , Reacción en Cadena de la Polimerasa Multiplex/métodos , Faringe , Estudios Prospectivos , Sensibilidad y Especificidad , Manejo de Especímenes/métodosRESUMEN
BACKGROUND: Mass drug administration (MDA) based on two doses of ivermectin, one week apart, substantially reduces prevalence of both scabies and impetigo. The Regimens of Ivermectin for Scabies Elimination (RISE) trial assessed whether one-dose ivermectin-based MDA would be as effective. METHODS: RISE was a cluster-randomised trial in Solomon Islands. We assigned 20 villages in a 1:1 ratio to one- or two-dose ivermectin-based MDA. We planned to test whether the impact of one dose on scabies prevalence at 12 and 24 months was non-inferior to two, at a 5% non-inferiority margin. RESULTS: We deferred endpoint assessment to 21 months due to COVID-19. We enrolled 5239 participants in 20 villages at baseline and 3369 at 21 months from an estimated population of 5500. At baseline scabies prevalence was similar in the two arms (one-dose 17·2%; two-dose 13·2%). At 21 months, there was no reduction in scabies prevalence (one-dose 18·7%; two-dose 13·4%), and the confidence interval around the difference included values substantially greater than 5%. There was however a reduction in prevalence among those who had been present at the baseline assessment (one-dose 15·9%; two-dose 10·8%). Additionally, we found a reduction in both scabies severity and impetigo prevalence in both arms, to a similar degree. CONCLUSIONS: There was no indication of an overall decline in scabies prevalence in either arm. The reduction in scabies prevalence in those present at baseline suggests that the unexpectedly high influx of people into the trial villages, likely related to the COVID-19 pandemic, may have compromised the effectiveness of the MDA. Despite the lack of effect there are important lessons to be learnt from this trial about conducting MDA for scabies in high prevalence settings. TRIAL REGISTRATION: Registered with Australian New Zealand Clinical Trials Registry ACTRN12618001086257.
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COVID-19 , Impétigo , Escabiosis , Humanos , Ivermectina/uso terapéutico , Escabiosis/tratamiento farmacológico , Escabiosis/epidemiología , Escabiosis/prevención & control , Administración Masiva de Medicamentos , Impétigo/tratamiento farmacológico , Impétigo/epidemiología , Impétigo/prevención & control , Pandemias , Australia , COVID-19/epidemiologíaRESUMEN
BACKGROUND: Mental health problems, such as behavioural and emotional problems, are prevalent in children. These problems can have long lasting, detrimental effects on the child, their parents and society. Most children with a mental health problem do not receive professional help. Those that do get help can face long wait times. While waiting, parents want to learn how they can help their child. To address this need, we co-designed a new website to help parents find ways of helping their child's mental health problem while waiting to get specialist help. OBJECTIVES: To assess the acceptability and feasibility of a new co-designed website, FindWays, through a pilot randomised controlled trial. The protocol is registered with ISRCTN (ISRCTN64605513). METHODS: This study will recruit up to 60 parents of children aged two-twelve years old referred to a paediatrician for behavioural and/or emotional problems. Participants will be randomly allocated by computer generated number sequence to either the intervention or control group. Intervention group participants will receive access to the FindWays website to help them manage their child's mental health problem while they wait to see the paediatrician. Acceptability and feasibility will be assessed over the 4-month intervention through mixed methods including: recruitment, adherence, retention, net promoter score (quantitative measures) and semi-structured interviews to gain an in-depth understanding of parents' experience and potential adverse effects (qualitative measure). Secondary outcomes measured by parent survey at 4-months post randomisation include child mental health, parent mental health, impact of the child's mental health problem on their functioning and family, and health service use and associated costs. RESULTS: Recruitment commenced June 2022 with publication expected in October 2023. CONCLUSION: This study will provide novel data on the acceptability and feasibility of a new website co-designed with parents to help them find ways of managing their child's behaviour and emotions.
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Alfabetización en Salud , Salud Mental , Humanos , Niño , Preescolar , Proyectos Piloto , Padres/psicología , Encuestas y Cuestionarios , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
Importance: Obstructive sleep-disordered breathing (SDB) in children is characterized by snoring and difficulty breathing during sleep. SDB affects at least 12% of otherwise healthy children and is associated with significant morbidity. Evidence from small clinical trials suggests that intranasal corticosteroids improve SDB as measured by polysomnography; however, the effect on symptoms and quality of life is unclear. Objective: To determine whether intranasal mometasone furoate is more effective than intranasal saline for improving symptoms and quality of life in children with SDB. Design, Setting, and Participants: The MIST trial was a multicenter, randomized, double-blind, placebo-controlled trial, recruiting participants from June 8, 2018, to February 13, 2020. Children aged 3 to 12 years who were referred to a specialist for significant SDB symptoms were included; exclusions were previous adenotonsillectomy, body mass index greater than the 97th percentile, and severe SDB. Randomization was stratified by site, and data were analyzed on an intention-to-treat basis from October 28, 2020, to September 25, 2022. Interventions: Participants were randomly assigned to receive mometasone furoate, 50 µg, or sodium chloride (saline), 0.9%, 1 spray per nostril daily, dispensed in identical bottles. Main Outcomes and Measures: The primary outcome was resolution of significant SDB symptoms (ie, reduction to a level no longer requiring referral to a specialist as per the American Academy of Pediatrics guidelines) at 6 weeks, measured by parental report of symptoms using the SDB Score. Results: A total of 276 participants (mean [SD] age, 6.1 [2.3] years; 146 male individuals [53%]) were recruited, 138 in each treatment arm. Resolution of significant SDB symptoms occurred in 56 of 127 participants (44%) in the mometasone group and 50 of 123 participants (41%) in the saline group (risk difference, 4%; 95% CI, -8% to 16%; P = .51) with 26 participants lost to follow-up and missing values managed by multiple imputation. The main adverse effects were epistaxis, affecting 12 of 124 participants (9.7%) in the mometasone group and 18 of 120 participants (15%) in the saline group, and nasal itch/irritation, affecting 12 of 124 participants (9.7%) in the mometasone group and 22 of 120 participants (18%) in the saline group. Conclusions and Relevance: Results of this randomized clinical trial suggest that there was no difference in treatment effect between intranasal mometasone and saline for the management of SDB symptoms. The results suggest that almost one-half of children with SDB could be initially managed in the primary care setting and may not require referral to specialist services, as is currently recommended. Trial Registration: Australian New Zealand Clinical Trials Registry: ANZCTRN12618000448246.
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Calidad de Vida , Síndromes de la Apnea del Sueño , Masculino , Humanos , Niño , Furoato de Mometasona , Rociadores Nasales , Australia , Administración Intranasal , Prurito , Solución Salina , Resultado del TratamientoRESUMEN
AIM: Respiratory testing with rapid antigen tests (RATs) in children under 5 years of age may be uncomfortable and presents specific challenges to testing due to compliance and procedural distress. The aim of this study was to investigate sensitivity and feasibility of self-collected nasal and saliva RAT tests compared with a combined nose and throat (CTN) swab PCR in children under 5. METHODS: Children aged between 1 month and 5 years, with confirmed COVID-19 or who were a household contact within 7 days were included. A saliva RAT, nasal RAT and CTN swab were collected by the parent. SARS-CoV-2 cycle threshold (Ct) values for CTN tested by PCR were compared with saliva and nasal RAT results. Parent preference for method of sample was recorded. RESULTS: Forty-one children were recruited with median age of 1.5 (interquartile range 0.7-4.0) years. Only 22/41 (54%) of parents were able to successfully collect a saliva RAT from their child. Sensitivity of the nasal RAT and saliva RAT was 0.889 (95% confidence interval (CI) 0.739-0.969) and 0.158 (95% CI 0.034-0.396), respectively. Upper limit of nasal RAT detection by CTN Ct value was higher than saliva (36.05 vs. 27.29). While saliva RAT was rated most comfortable, nasal RAT was rated the preferred specimen by parents for future testing, due to saliva collection difficulties and time taken. CONCLUSIONS: Rapid antigen testing with nasal RAT is a more feasible and sensitive method for SARS-CoV-2 detection in young children compared with saliva RAT.
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COVID-19 , Humanos , COVID-19/diagnóstico , SARS-CoV-2 , Saliva , Reacción en Cadena de la Polimerasa , Manejo de Especímenes , NasofaringeRESUMEN
Background: Community-acquired pneumonia is a leading cause of morbidity and mortality among children and adults worldwide. Adult pneumonia surveillance remains limited in many low- and middle-income settings, resulting in the disease burden being largely unknown. Methods: A retrospective cohort study was conducted by reviewing medical charts for respiratory admissions at four district hospitals in Ulaanbaatar during January 2015-February 2019. Characteristics of community-acquired pneumonia cases were summarized by disease severity and age. To explore factors associated with severe pneumonia, we ran univariable and age-adjusted logistic regression models. Incidence rates were calculated using population denominators. Results: In total, 4290 respiratory admissions met the case definition for clinical pneumonia, including 430 admissions of severe pneumonia. The highest proportion of severe pneumonia admissions occurred in adults >65 years (37.4%). After adjusting for age, there were increased odds of severe pneumonia in males (adjusted odds ratio [aOR]: 1.63; 95% confidence interval [CI]: 1.33-2.00) and those with ≥1 underlying medical condition (aOR: 1.46; 95% CI: 1.14-1.87). The incidence of hospitalized pneumonia in adults ≥18 years increased from 13.49 (95% CI: 12.58-14.44) in 2015 to 17.65 (95% CI: 16.63-18.71) in 2018 per 10,000 population. The incidence of severe pneumonia was highest in adults >65 years, ranging from 9.29 (95% CI: 6.17-13.43) in 2015 to 12.69 (95% CI: 9.22-17.04) in 2018 per 10,000 population. Interpretations: Vaccination and other strategies to reduce the risk of pneumonia, particularly among older adults and those with underlying medical conditions, should be prioritized. Funding: Pfizer clinical research collaboration agreement (contract number: WI236621).
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BACKGROUND: Screening programmes using echocardiography offer opportunity for intervention through identification and treatment of early (latent) rheumatic heart disease (RHD). We aimed to compare two methods for classifying progression or regression of latent RHD: serial review method and blinded, side-by-side review. METHODS: A four-member expert panel reviewed 799 enrolment (in 2018) and completion (in 2020) echocardiograms from the GOAL Trial of latent RHD in Uganda to make consensus determination of normal, borderline RHD or definite RHD. Serial interpretations (enrolment and completion echocardiograms read at two different time points, 2 years apart, not beside one another) were compared with blinded side-by-side comparisons (enrolment and completion echocardiograms displayed beside one another in random order on same screen) to determine outcomes according to prespecified definitions of disease progression (worsening), regression (improving) or no change. We calculated inter-rater agreement using Cohen's kappa. RESULTS: There were 799 pairs of echocardiogram assessments included. A higher number, 54 vs 38 (6.8% vs 4.5%), were deemed as progression by serial interpretation compared with side-by-side comparison. There was good inter-rater agreement between the serial interpretation and side-by-side comparison methods (kappa 0.89). Disagreement was most often a result of the difference in classification between borderline RHD and mild definite RHD. Most discrepancies between interpretation methods (46 of 47, 98%) resulted from differences in valvular morphological evaluation, with valves judged to be morphologically similar between enrolment and final echocardiograms when compared side by side but classified differently on serial interpretation. CONCLUSIONS: There was good agreement between the methods of serial and side-by-side interpretation of echocardiograms for change over time, using the World Heart Federation criteria. Side-by-side interpretation has higher specificity for change, with fewer differences in the interpretation of valvular morphology, as compared with serial interpretation.
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Cardiopatía Reumática , Niño , Humanos , Cardiopatía Reumática/diagnóstico por imagen , Ecocardiografía , Corazón , ConsensoRESUMEN
INTRODUCTION: The Victorian COVID-19 Cancer Network (VCCN) Telehealth Expert Working Group aimed to evaluate the telehealth (TH) experience for cancer patients, carers and clinicians with the rapid uptake of TH in early 2020 during the COVID-19 pandemic. METHODS: We conducted a prospective multi-centre cross-sectional survey involving eight Victorian regional and metropolitan cancer services and three consumer advocacy groups. Patients or their carers and clinicians who had TH consultations between 1 July 2020 and 31 December 2020 were invited to participate in patient and clinician surveys, respectively. These surveys were opened from September to December 2020. RESULTS: The acceptability of TH via both video (82.9%) and phone (70.4%) were high though acceptability appeared to decrease in older phone TH users. Video was associated with higher satisfaction compared to phone (87.1% vs 79.7%) even though phone was more commonly used. Various themes from the qualitative surveys highlighted barriers and enablers to rapid TH implementation. DISCUSSION: The high TH acceptability supports this as a safe and effective strategy for continued care and should persist beyond the pandemic environment, where patient preferences are considered and clinically appropriate. Ongoing support to health services for infrastructure and resources, as well as expansion of reimbursement eligibility criteria for patients and health professionals, including allied health and nursing, are crucial for sustainability.
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Background: Oxycodone is a frequently used opioid in cancer. Opioid-induced constipation (OIC) is common. Oxycodone/Naloxone Prolonged Release (OXN PR) contains naloxone, which mitigates OIC. Trials have either focused on non-cancer pain, or conducted before significant experience of using OXN PR. This trial aims to: demonstrate (1) analgesic equivalence between OXN PR and Oxycodone Prolonged Release (Oxy PR), and (2) superiority of constipation outcomes in OXN PR compared to Oxy PR in cancer pain. Unlike other trials, it will only include patients with at least moderate pain scores (≥4/10), allow usual laxatives, and exclude potential liver dysfunction. Methods: This is a multi-centre, open-label, randomised, phase IV study of OXN PR vs Oxy PR in patients with cancer-related pain. The primary outcome is pain difference on Brief Pain Inventory-Short Form (BPI-SF) at 5 weeks. Secondary outcomes are comparison of other pain outcomes (BPI-SF) and neuropathic pain measures (Leeds Assessment of Neuropathic Symptoms & Signs (S-LANNS)), constipation (Bowel Function Index (BFI)), quality of life (EORTC-QLQ-C30), rescue analgesia use, total opioid dose, and total laxative dose over 5 weeks. Conclusion: The comparison of analgesic efficacy between both arms, and superiority of constipation in the OXN PR arm will add new knowledge on the comparisons of both agents, and oxycodone independently. This trial will extend knowledge of the effectiveness, safety, and adverse effect profiles of both drugs in terms of pain, constipation, quality of life outcomes for patients with cancer pain, and provide clinicians with high quality data to guide decision making. Trial registration: Name of the registry: ANZCTR. Trial registration number: ACTRN12619001282178. Date of registration: 17/09/2019. URL of trial registry record: https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=377673&isReview=trueProtocol version 2.1_28 August 2020.
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There are several methodological challenges when conducting randomised controlled trials in palliative care. These include worsening function and high mortality, leading to treatment discontinuation, some of which will be unrelated to the intervention being evaluated.Recently, a new framework for handling postrandomisation events, such as attrition, has been released. This framework aims to align trial objectives, design, conduct and analysis by clarifying what and how to estimate treatment effects in the presence of data affected by postrandomisation events.The purpose of this paper is to introduce palliative care researchers to this framework and how it can guide trial design, and efficacy and safety analysis in a palliative care context where individual withdrawal from the trial is common.In this paper, we describe the estimand framework and the background for it. We also consider postrandomisation events that are frequently encountered in palliative care trials and how these might affect objectives of interest. We then construct efficacy and safety estimands for a trial in palliative care. Better trial design and alignment of objectives with analysis can improve our understanding of what treatments do and do not work in palliative care.
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Enfermería de Cuidados Paliativos al Final de la Vida , Cuidados Paliativos , Humanos , Proyectos de InvestigaciónRESUMEN
BACKGROUND: Obesity is characterized by heightened inflammation, and both phenotypes are associated with hearing loss. We aimed to determine if inflammation mediates the associations between obesity and hearing ability in mid-childhood and mid-life. METHODS: Participants: 1165 11- to 12-year-old children and 1316 parents in the population-based cross-sectional Child Health CheckPoint within the Longitudinal Study of Australian Children. Adiposity measures: Body mass index (BMI) classified as normal, overweight and obesity; waist-to-height ratio (WHtR) classified as <0.5 and ≥0.5; fat mass index. Inflammatory biomarkers: Serum glycoprotein A (GlycA); high-sensitivity C-reactive protein (hsCRP). Audiometry: Composite high Fletcher Index (mean threshold of 1, 2, 4 kHz) in the better ear. ANALYSIS: Causal mediation analysis decomposed a 'total effect' (obesity on hearing status) into 'indirect' effect via a mediator (eg GlycA, hsCRP) and 'direct' effect via other pathways, adjusting for age, sex and socioeconomic position. RESULTS: Compared to adults with BMI within the normal range, those with obesity had hearing thresholds 1.9 dB HL (95% CI 1.0-2.8) higher on the high Fletcher Index; 40% of the total effect was mediated via GlycA (indirect effect: 0.8 dB HL, 95% CI 0.1-1.4). Children with obesity had hearing thresholds 1.3 dB HL (95% CI 0.2-2.5) higher than those with normal BMI, of which 67% (indirect effect: 0.9 dB HL, 95% CI 0.4-1.4) was mediated via GlycA. Similar mediation effects were noted using other adiposity measures. Similar but less marked mediation effects were observed when hsCRP was used as the inflammatory biomarker (6-23% in adults and 23-33% in children). CONCLUSIONS: Inflammation may play an important mediating role in the modest hearing reductions associated with obesity, particularly in children. These findings offer insights into possible mechanisms and early prevention strategies for hearing loss.
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Proteína C-Reactiva , Pérdida Auditiva , Australia/epidemiología , Biomarcadores , Índice de Masa Corporal , Proteína C-Reactiva/metabolismo , Niño , Estudios Transversales , Glicoproteínas , Audición , Pérdida Auditiva/epidemiología , Pérdida Auditiva/etiología , Humanos , Inflamación , Estudios Longitudinales , Obesidad/complicaciones , Obesidad/epidemiologíaRESUMEN
BACKGROUND: Approximately one in ten men experience mental health difficulties during the early years of fatherhood, and these can have negative impacts on children and families. However, few evidence-based interventions targeting fathers' mental health are available. The aim of the trial is to evaluate the effectiveness and cost-effectiveness of Working Out Dads (WOD) - a facilitated peer support group intervention for fathers of young children, in reducing psychological distress and other mental health symptoms. METHODS: This trial will employ a parallel-arm randomised controlled trial (RCT) to evaluate the effectiveness and cost effectiveness of WOD peer support group intervention compared to usual care (a 30-min mental health and service focused phone consultation with a health professional). A total of 280 fathers of young children (aged 0-4 years) who are experiencing mental health difficulties and/or are at risk of poor mental health will be recruited. Randomisation and analyses will be at the level of the individual participant. The primary outcome is psychological distress symptoms, measured by the Kessler Psychological Distress Scale (K10) from baseline to 24 weeks post randomisation. A range of secondary outcomes will be assessed including suicidal ideation; mental health disorders, specific symptoms of depression, anxiety, and stress; social support, quality of life, health service use, and health care costs. Data will be collected at baseline, 10- and 24 weeks post-randomisation. DISCUSSION: This trial will examine the effectiveness of a novel group-based peer support intervention in reducing the psychological distress and other mental health symptoms of fathers compared to usual care. The economic and process evaluation will guide policy decision making along with informing the future implementation of WOD on a larger scale if effectiveness is demonstrated. TRIAL REGISTRATION: The current trial has been registered with ClinicalTrials.gov (Registration ID - NCT04813042 ). Date of Registration: March 22nd, 2021.
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Trastornos Mentales , Distrés Psicológico , Niño , Preescolar , Análisis Costo-Beneficio , Consejo , Humanos , Masculino , Trastornos Mentales/psicología , Salud Mental , Calidad de Vida , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
Background: Peritoneal dialysis (PD) is a commonly used therapy after infant cardiac surgery. It is unclear whether early PD commenced soon after admission to an intensive care unit (ICU) after cardiac surgery results in better outcomes. Objective: To describe the study protocol and statistical analysis plan for the Early Peritoneal Dialysis in Infants after Cardiac Surgery (EPICS) trial. Design, setting, participants and intervention: The EPICS trial is an open, randomised, two-group, single-centre clinical study of infants ≤ 180 days of age who had cardiac surgery (in Risk-Adjusted Classification for Congenital Heart Surgery version 1 categories 3-6) with cardiopulmonary bypass. Participants will be randomly assigned 1:1 to early PD (treatment group) or no early PD (control group). Those assigned to the treatment group will begin receiving PD soon after ICU admission and continue receiving it for 24 hours. Those in the control group will not receive PD during the first 24 hours. Main outcome measures: The primary outcome is a composite measure consisting of one or more of death, cardiac arrest, emergency chest reopening, and requirement for extracorporeal membrane oxygenation (ECMO) within 90 days. The main secondary outcomes are duration of mechanical ventilation, ICU length of stay, hospital length of stay, vasoactive-inotropic score at 24 hours, and cumulative per cent fluid balance by end of Day 2. At Day 90, events such as mortality, requirement for ECMO, cardiac arrest, chest reopening, volume of packed red blood cell transfusion, postoperative infection, readmission to ICU, renal injury and brain injury will be assessed. Conclusions: The EPICS trial aims to evaluate the role of early PD after infant cardiac surgery in lowering the rate of a composite major outcome. In addition, it will test the effect of early PD on duration of mechanical ventilation, and on ICU and hospital length of stay. Trial registration: ACTRN12617001614381.
RESUMEN
CONTEXT: Missing data are common in hospice/palliative care randomized trials due to high drop-out because of the demographic of interest. It can introduce bias in the estimate of the treatment effect and its precision. OBJECTIVES: The International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) released updated guidance on statistical principles for clinical trials introducing the estimand framework to align trial objectives, trial conduct, statistical analysis and interpretation of results. Our objective is to present how the estimand framework can be used to guide the handling of missing data in palliative care trials. METHODS: We outline the estimand framework by highlighting the five elements of an estimand: treatment, population, variable, summary measure and intercurrent event handling. We list common intercurrent events in palliative care trials and present the five strategies for handling intercurrent events outlined in the ICH guidance. RESULTS: We describe common intercurrent events in palliative care trials and discuss and justify what analytic strategies could be followed with each. We provide an example using a palliative care trial comparing two opioids for pain relieve in participants with cancer pain. CONCLUSION: When planning a palliative care trial, the estimand should be explicitly stated, including how intercurrent events will be handled in the analysis. This should be informed by the scientific objectives of the trial. The estimand guides the handling of missing data during the conduct and analysis of the trial. Defining an estimand is not a statistical activity, but a multi-disciplinary process involving all stakeholders.