Primary Trial Outcome Research Articles

California Stress, Trauma, and Resilience Study (CalSTARS) protocol: A multiomics-based cross-sectional investigation and randomized controlled trial to elucidate the biology of ACEs and test a precision intervention for reducing stress and enhancing resilience

Adverse Childhood Experiences (ACEs) are very common and presently implicated in 9 out of 10 leading causes of death in the United States. Despite this fact, our mechanistic understanding of how ACEs impact health is limited. Moreover, interventions for reducing stress presently use a one-size-fits-all approach that involves no treatment tailoring or precision. To address these issues, we developed a combined cross-sectional study and randomized controlled trial, called the California Stress, Trauma, and Resilience Study (CalSTARS), to (a) characterize how ACEs influence multisystem biological functioning in adults with all levels of ACE burden and current perceived stress, using multiomics and other complementary approaches, and (b) test the efficacy of our new California Precision Intervention for Stress and Resilience (PRECISE) in adults with elevated perceived stress levels who have experienced the full range of ACEs. The primary trial outcome is perceived stress, and the secondary outcomes span a variety of psychological, emotional, biological, and behavioral variables, as assessed using self-report measures, wearable technologies, and extensive biospecimens (i.e. DNA, saliva, blood, urine, & stool) that will be subjected to genomic, transcriptomic, proteomic, metabolomic, lipidomic, immunomic, and metagenomic/microbiome analysis. In this protocol paper, we describe the scientific gaps motivating this study as well as the sample, study design, procedures, measures, and planned analyses. Ultimately, our goal is to leverage the power of cutting-edge tools from psychology, multiomics, precision medicine, and translational bioinformatics to identify social, molecular, and immunological processes that can be targeted to reduce stress-related disease risk and enhance biopsychosocial resilience in individuals and communities worldwide.

Why might fears and worries persist after a pain education-grounded multimodal intervention for chronic back pain? A qualitative study.

The effect of pain education (PE) on pain intensity and function diminishes after a few months in people with chronic low back pain (CLBP). One possible explanation is the return of underlying fears and worries related to the condition. To explore topics related to participants' beliefs and feelings that might explain why fears and worries persist after a PE-grounded intervention for CLBP. We conducted a qualitative study involving semistructured interviews with participants from the active arm of a randomised controlled trial who received an individualised PE-grounded intervention for adults with CLBP. We used reflexive thematic analysis with an inductive approach. Twenty participants were interviewed (9 women and 11 men, median age = 54 years, median pain duration = 4 years, 13 reporting at least 30% pain reduction on the trial primary outcome). Three themes were identified: 1) "Are you implying my pain is not real?": a few participants believed the validity of their pain was being questioned. 2) "You don't understand, my pain is different": most participants considered the influence of an altered nervous system but did not exclude the possibility of having structural and biomechanical influences for the persistence of their back pain. 3) "I am unsure how to fit it into my daily life": fear and worries persisted when participants could not figure out how to apply an alternative way of making sense of pain in their daily lives. Patients' perceptions about PE should be monitored and might be addressed with communication strategies, educational content that matches patients' characteristics, and reinforcements over time.

Abstract 4125939: Bayesian re-analysis of the STeroids to REduce Systemic inflammation after infant heart Surgery (STRESS) trial

Background: Prophylactic steroids are often used to reduce the systemic inflammatory response to cardiopulmonary bypass in infants undergoing heart surgery. The STRESS trial found that the likelihood of a worse outcome did not differ between infants randomized to methylprednisolone vs placebo in a risk-adjusted primary analysis (adjusted odds ratio [OR], 0.86; 95% CI, 0.71 to 1.05; P=0.14). However, secondary unadjusted analyses showed possible benefits with methylprednisolone. We re-analyzed the STRESS trial using Bayesian analytics to assess probability of benefit with methylprednisolone. Methods: We used a covariate-adjusted proportional odds model using the original STRESS trial model covariates and primary outcome (a ranked composite of death, transplant, major complications and post-op length of stay). We assessed effect thresholds from OR 0.6 to 1.25 (OR <1 conveys benefit, OR >1 conveys harm). We assumed a neutral probability of benefit vs harm with weak prior belief (SD of the normal prior distribution = 0.425). In sensitivity analyses, we evaluated pessimistic (5%-30% prior likelihood of benefit), neutral and optimistic (70%-95% prior likelihood of benefit) prior beliefs, and controlled strength of prior belief as weak (SD = 0.425), moderate (SD = 0.215) and strong (SD = 0.135). We compared posterior distribution of the OR under these priors with the reference results under the vague prior distribution. Analyses consisted of 10 Markov Chain Monte Carlo simulations each consisting of 2000 iterations with a 1000 iteration burn-in to ensure proper posterior convergence. Results: In primary analysis, the posterior probability of benefit from methylprednisolone was 92% and the probability of harm was 8%. The mean absolute benefit was 12%. In sensitivity analyses, the probability of benefit was ≥ 79% for all informative priors except the most pessimistic (Table/Figure). Conclusion: In Bayesian re-analysis of the STRESS trial, probability of benefit with prophylactic methylprednisolone is high and harm is unlikely. Assessing probability of benefit or harm may be more informative than frequentist analytics relying on a p-value threshold. Another advantage is the ability to consider a range of prior evidence.

Participants’ baseline characteristics and feedback of the nature-based social intervention “friends in nature” among lonely older adults in assisted living facilities in finland: a randomised controlled trial of the RECETAS EU-project

BackgroundLoneliness is common among older adults in institutional settings. It leads to adverse effects on health and wellbeing, for which nature contact with peers in turn may have positive impact. However, the effects of nature engagement among older adults have not been studied in randomised controlled trials (RCT). The “Friends in Nature” (FIN) group intervention RCT for lonely older adults in Helsinki assisted living facilities (ALFs) aims to explore the effects of peer-related nature experiences on loneliness and health-related quality of life (HRQoL). In this study we aim describe the participants’ baseline characteristics of the RCT, feasibility of FIN intervention and intervention participants’ feedback on the FIN.MethodsLonely participants were recruited from 22 ALFs in Helsinki area, Finland, and randomised into two groups: 1) nature-based social intervention once a week for nine weeks (n = 162) and 2) usual care (n = 157). Demographics, diagnoses and medication use were retrieved from medical records, and baseline cognition, functioning, HRQoL, loneliness and psychological wellbeing were assessed. Primary trial outcomes will be participants’ loneliness (De Jong Giervald Loneliness Scale) and HRQoL (15D).ResultsThe mean age of participants was 83 years, 73% were female and mean Minimental State Examination of 21 points. The participants were living with multiple co-morbidities and/or disabilities. The intervention and control groups were comparable at baseline. The adherence with intervention was moderate, with a mean attendance of 6.8 out of the nine sessions. Of the participants, 14% refused, fell ill or were deceased, and therefore, participated three sessions or less. General subjective alleviation of loneliness was achieved in 57% of the intervention participants. Of the respondents, 96% would have recommended a respective group intervention to other older adults. Intervention participants appreciated their nature excursions and experiences.ConclusionsWe have successfully randomised 319 lonely residents in assisted living facilities into a trial about the effects of nature experiences in a group-format. The feedback from participants was favourable. The trial will provide important information about possibilities of alleviating loneliness with peer-related nature-based experiences in frail residents.Trial registrationClinicalTrials.gov, ID: NCT05507684. Registration 19/08/2022.

Baseline financial distress and cost-related social risks among participants in the Cancer Financial Experience (CAFÉ) trial.

172 Background: Cancer Financial Experience (CAFÉ) is a multi-site, three-arm randomized controlled trial to test the impact of a novel financial navigation intervention on financial distress among cancer patients. We compared the baseline prevalence of financial distress among CAFÉ trial participants, using two instruments (InCharge and COST), and assessed cost-related social risks. Methods: Three hundred seventy one (n=371) participants were consented and randomized between August 2021-March 2023. Eligible participants (n=2033) included adults (18+ years of age), diagnosed with invasive cancer within 120 prior to a recent visit to a CAFÉ study clinic/site, members of Kaiser Permanente Northwest or Kaiser Permanente Washington, and spoke English or Spanish. Following consent, participants were randomized to one of three trial arms: enhanced usual care; brief intervention; enhanced intervention. The two primary trial outcomes were: financial distress, measured using the InCharge Financial Distress/Financial Well-Being scale, and cancer-specific health-related quality of life, measured by the FACT-G7 scale. Additionally, we collected the COST measure and cost-related social risks. All participant-reported outcomes, demographic, and socioeconomic data were collected via telephone survey at baseline and 12 months by trained interviewers. Survey data was stored in REDCap. Descriptive statistics were used to assess participant demographic, socioeconomic, and outcome data at baseline. Results: Among randomized participants (n=371), mean age was 61 years (standard deviation=14 years), 63% were female, 11% Hispanic, 9% Asian, 8% Black , 61% married or living with partner, 31% were employed full-time, 37% retired, 44% had annual income of $20000-$74999, 45% had Medicare, and 38% had breast cancer. At baseline, InCharge scores showed 31% (n=113) of participants had high, 19% had moderate, and 50% had low financial distress. Based on COST scores, 2.2% (n=16) of participants had high, 63% had moderate, and 39% had low financial distress. Forty percent (n=148) of participants reported any cost-related social risk, including heat and electricity (15%) and housing (15%). Conclusions: Baseline findings from the CAFÉ trial indicate that nearly one-third of patients with cancer may have high financial distress around the time of diagnosis, though this may vary by screening tool. The ideal screening tool for use at diagnosis is worthy of further study. Assessing and assisting patients with social risks, including financial distress, is essential to advancing cancer health equity. Clinical trial information: NCT05018000 .

Conservative management of brain arteriovenous malformations: results of the prospective observation registry of a pragmatic trial.

Many patients recruited in the Treatment of Brain Arteriovenous Malformations Study (TOBAS) are managed conservatively. The aim of this study was to monitor what happened to those patients. TOBAS comprises two randomized controlled trials and multiple prospective registries. All patients with brain arteriovenous malformations (AVMs) can participate. This report concerns patients selected for conservative management. The primary trial outcome measure is related death or dependency (modified Rankin Scale [mRS] score > 2) at 10 years. Secondary outcomes include intracranial hemorrhages, nonhemorrhagic neurological events, and serious adverse events (SAEs). For this report, outcome results are presented using patient-years, Kaplan-Meier survival curves, and Cox log-rank tests. There was no blinding. From June 2014 to May 2021, 1010 patients were recruited, of whom 498 (49%) were proposed the prospective observation registry. After exclusions, 434 (87%) patients remained for analysis. The majority of patients had unruptured AVMs (378/434 [87%]), of which 195 (52%) were low grade (Spetzler-Martin grade I or II). During a mean follow-up period of 3.2 years (total 1368 patient-years), the primary outcome occurred in 23 of 434 (5%) patients, corresponding to an incidence of 1.7 (95% CI 1.1-2.5) per 100 patient-years. For unruptured AVMs the incidence was 1.1 (95% CI 0.7-1.9) per 100 patient-years, and for low-grade unruptured AVMs it was 0.6 (95% CI 0.2-1.7) per 100 patient-years. Poor outcomes were more frequent in patients with a history of rupture (HR 5.6 [95% CI 2.4-13.0], p < 0.001), infratentorial AVMs (HR 2.9 [95% CI 1.1-7.3], p = 0.027), and age ≥ 55 years (HR 3.2 [95% CI 1.4-7.6], p = 0.007). Major intracranial hemorrhage occurred in 35 of 434 (8%) patients (incidence of 2.6 [95% CI 1.9-3.6] per 100 patient-years; 2.0 [95% CI 1.3-2.9] per 100 patient-years for unruptured AVMs and 1.3 [95% CI 0.6-2.6] per 100 patient-years for low-grade unruptured AVMs). Major AVM hemorrhages were more frequent in ruptured (HR 4.4 [95% CI 2.1-8.9], p < 0.001), large (HR 2.6 [95% CI 1.1-6.6], p = 0.039), and high-grade (HR 2.5 [95% CI 1.2-5.3], p = 0.013) AVMs and those with deep venous drainage (HR 2.1 [95% CI 1.1-4.2], p = 0.032). SAEs occurred in 48 of 434 (11%) patients (incidence of 3.6 [95% CI 2.7-4.8] per 100 patient-years). For unruptured AVMs the incidence was 2.8 (95% CI 2.0-4.0) per 100 patient-years, and for low-grade unruptured AVMs it was 1.8 (95% CI 1.0-3.2) per 100 patient-years. Nearly half of TOBAS participants were observed. Rates of untoward neurological events were within expected boundaries.

Cost-effectiveness of bioimpedance-guided fluid management in patients undergoing haemodialysis: the BISTRO RCT.

The BioImpedance Spectroscopy to maintain Renal Output randomised controlled trial investigated the effect of bioimpedance spectroscopy added to a standardised fluid management protocol on the risk of anuria and preservation of residual kidney function (primary trial outcomes) in incident haemodialysis patients. Despite the economic burden of kidney disease, the cost-effectiveness of using bioimpedance measurements to guide fluid management in haemodialysis is not known. To assess the cost-effectiveness of bioimpedance-guided fluid management against current fluid management without bioimpedance. Within-trial economic evaluation (cost-utility analysis) carried out alongside the open-label, multicentre BioImpedance Spectroscopy to maintain Renal Output randomised controlled trial. Thirty-four United Kingdom outpatient haemodialysis centres, both main and satellite units, and their associated inpatient hospitals. Four hundred and thirty-nine adult haemodialysis patients with > 500 ml urine/day or residual glomerular filtration rate > 3 ml/minute/1.73 m2. The study intervention was the incorporation of bioimpedance technology-derived information about body composition into the clinical assessment of fluid status in patients with residual kidney function undergoing haemodialysis. Bioimpedance measurements were used in conjunction with usual clinical judgement to set a target weight that would avoid excessive fluid depletion at the end of a dialysis session. The primary outcome measure of the BioImpedance Spectroscopy to maintain Renal Output economic evaluation was incremental cost per additional quality-adjusted life-year gained over 24 months following randomisation. In the main (base-case) analysis, this was calculated from the perspective of the National Health Service and Personal Social Services. Sensitivity analyses explored the impact of different scenarios, sources of resource use data and value sets. The bioimpedance-guided fluid management group was associated with £382 lower average cost per patient (95% CI -£3319 to £2556) and 0.043 more quality-adjusted life-years (95% CI -0.019 to 0.105) compared with the current fluid management group, with neither values being statistically significant. The probability of bioimpedance-guided fluid management being cost-effective was 76% and 83% at commonly cited willingness-to-pay threshold of £20,000 and £30,000 per quality-adjusted life-year gained, respectively. The results remained robust to a series of sensitivity analyses. The missing data level was high for some resource use categories collected through case report forms, due to COVID-19 disruptions and a significant dropout rate in the informing BioImpedance Spectroscopy to maintain Renal Output trial. Compared with current fluid management, bioimpedance-guided fluid management produced a marginal reduction in costs and a small improvement in quality-adjusted life-years. Results from both the base-case and sensitivity analyses suggested that use of bioimpedance is likely to be cost-effective. Future work exploring the association between primary outcomes and longer-term survival would be useful. Should an important link be established, and relevant evidence becomes available, it would be informative to determine whether and how this might affect longer-term costs and benefits associated with bioimpedance-guided fluid management. This article presents independent research funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme as award number HTA 14/216/01 (NIHR136142).

A parenting program delivered through existing community-based peer groups to improve early child development in Homabay and Busia Counties, Kenya: study protocol for a cluster-randomized controlled trial

BackgroundPoor early childhood development (ECD) is a major global health concern that is associated with various adverse outcomes over the lifecourse. Parenting interventions especially during the earliest years of life can benefit ECD. However, there is limited evidence from Kenya about the effectiveness of parenting interventions for improving ECD outcomes especially across rural disadvantaged communities. This paper describes the study protocol for an impact and implementation evaluation of a community-based group parenting program that aims to improve ECD in rural Kenya.MethodsWe will conduct a cluster-randomized controlled trial to determine the effectiveness of a parenting program for caregivers of young children in Homabay and Busia counties in Western Kenya. Sixty-four village clusters will be randomly assigned to either the parenting intervention arm or the waitlist control arm with stratification by county. In each village, 10 primary caregivers with a child aged 0–24 months will be enrolled. The parenting program will be delivered through existing peer groups within communities whereby caregivers will receive counseling and psychosocial support to enhance their parenting skills and wellbeing to in turn promote ECD. The intervention curriculum comprises 21 sessions targeting various nurturing care messages, including early learning, responsive caregiving, child nutrition, health, protection, and caregiver mental health. Group sessions are facilitated by a trained volunteer biweekly for a total of 11 months. The primary trial outcome is an overall measure of ECD using the Global Scales of Early Development long form version. Secondary outcomes include various caregiver outcomes (e.g., parenting practices, mental health) and other child outcomes (e.g., socioemotional development, dietary diversity). All outcomes will be assessed at baseline and endline. We will also conduct a qualitative implementation evaluation at endline and interview various stakeholders to assess program fidelity, quality, and sustainability.DiscussionThis trial will evaluate the effectiveness of a parenting intervention on ECD and caregiving outcomes and assess program implementation quality as delivered through existing community-based peer groups. This study will provide rigorous evidence that can be used to inform scale-up of this program model that leverages existing community social networks and resources for improving caregivers’ parenting skills and promoting ECD in rural Kenya and other similar settings across LMICs.Trial registrationClinicalTrials.gov #NCT06165315. Registered on December 11, 2023.

Randomised controlled pilot trial of the EndoSMS supportive text message intervention for individuals with endometriosis: Feasibility and acceptability results

ObjectiveDiminished quality of life, inadequate support and social isolation are commonly experienced by individuals living with the chronic pain condition, endometriosis. We aimed to determine the feasibility and acceptability of EndoSMS, a psychologically-focused text message intervention designed to support individuals living with endometriosis. MethodsAs part of a two-arm parallel pilot randomised controlled trial with waitlist control, the feasibility and acceptability of a brief (3-month) version of EndoSMS was assessed using a mixed methods approach. Feasibility data (uptake, attrition, text message delivery analytics) and user acceptability (via self-report survey items and written feedback) were assessed. Qualitative data were thematically analysed using the template approach. Primary trial outcomes are not reported in this paper. ResultsFeasibility was indicated by: high conversion rate (99.1 %), low attrition (14.2 %), few opt-outs (0.02 %) and a high message delivery rate (99.8 %). Most intervention participants indicated user acceptability (mean = 4.02/5) across self-report questions. Most rated the length of the program (65.5 %), and the number (80.9 %) and language (94.5 %) of the text messages to be ‘just right’. Thematic analysis created four themes: A shared “battle”: Feeling less isolated and alone; “Be kind to yourself”: A focus on self-care, self-compassion and active coping; Keeping endometriosis at the forefront: Helpful or stressful?; Mixed perceptions surrounding the provision of general endometriosis information; and, Tailoring of text messages. ConclusionEndoSMS supportive text message program was feasible and acceptable for individuals with endometriosis. Future developments of the program should consider greater tailoring of content to user needs.Trial Registration: Australian New Zealand Clinical Trials Registry (ACTRN12621001642875).

Sex and gender reporting in UK emergency medicine trials from 2010 to 2023: a systematic review

BackgroundFemale participants are underrepresented in randomised control trials conducted in urgent care settings. Although sex and gender are frequently reported within demographic data, it is less common for primary outcomes...

Monitoring Overall Survival in Pivotal Trials in Indolent Cancers

Indolent cancers are characterized by lengthy overall survival (OS) times. Therefore, powering a clinical trial to provide definitive assessment of the effects of an experimental intervention on OS in a reasonable timeframe is generally infeasible. Instead, the primary outcome in many pivotal trials is an intermediate clinical response such as progression-free survival. In several recently reported pivotal trials of interventions for indolent cancers that yielded promising results on an intermediate outcome, however, more mature data or post-approval trials showed concerning OS trends. These problematic results have prompted a keen interest in quantitative approaches for monitoring OS that can support regulatory decision-making related to the risk of an unacceptably large detrimental effect on OS. The US Food and Drug Administration, the American Association for Cancer Research, and the American Statistical Association recently organized a one-day multi-stakeholder workshop entitled “Overall Survival in Oncology Clinical Trials.” In this article, we propose OS monitoring guidelines tailored for the setting of indolent cancers. Our pragmatic approach is modeled, in part, on the monitoring guidelines the FDA has used in cardiovascular safety trials conducted in Type 2 Diabetes Mellitus. We illustrate proposals through application to several examples informed by actual case studies.

Community-engaged randomised controlled trial to disseminate COVID-19 vaccine-related information and increase uptake among Black individuals in two US cities with rheumatic conditions.

Inequities in COVID-19 infection and vaccine uptake among historically marginalised racial and ethnic groups in the USA persist. Individuals with rheumatic conditions, especially those who are immunocompromised, are especially vulnerable to severe infection, with significant racialised inequities in infection outcomes and in vaccine uptake. Structural racism, historical injustices and misinformation engender racial and ethnic inequities in vaccine uptake. The Popular Opinion Lleader (POL) model, a community-based intervention that trains trusted community leaders to disseminate health information to their social network members (eg, friends, family and neighbours), has been shown to reduce stigma and improve care-seeking behaviours. This is a community-based cluster randomised controlled trial led by a team of community and academic partners to compare the efficacy of training POLs with rheumatic or musculoskeletal conditions using a curriculum embedded with a racial justice vs a biomedical framework to increase COVID-19 vaccine uptake and reduce vaccine hesitancy. This trial began recruitment in February 2024 in Boston, Massachusetts and Chicago, Illinois, USA. Eligible POLs are English-speaking adults who identify as Black and/or of African descent, have a diagnosis of a rheumatic or musculoskeletal condition and have received >=1 COVID-19 vaccine after 31 August 2022. POLs will be randomised to a 6-module virtual educational training; the COVID-19 and vaccine-related content will be the same for both groups however the framing for arm 1 will be with a racial justice lens and for arm 2, a biomedical preventative care-focused lens. Following the training, POLs will disseminate the information they learned to 12-16 social network members who have not received the most recent COVID-19 vaccine, over 4 weeks. The trial's primary outcome is social network member COVID-19 vaccine uptake, which will be compared between intervention arms. This trial has ethical approval in the USA. This has been approved by the Mass General Brigham Institutional Review Board (IRB, 2023P000686), the Northwestern University IRB (STU00219053), the Boston University/Boston Medical Center IRB (H-43857) and the Boston Children's Hospital IRB (P00045404). Results will be published in a publicly accessible peer-reviewed journal. NCT05822219.

Ethnicity and Observed Oxygen Saturations, Fraction of Inspired Oxygen, and Clinical Outcomes: A Post-Hoc Analysis of the Oxy-PICU Trial of Conservative Oxygenation.

A conservative oxygenation strategy, targeting peripheral oxygen saturations (Sp o2 ) between 88% and 92% in mechanically ventilated children in PICU, was associated with a shorter duration of organ support and greater survival compared with Sp o2 greater than 94% in our recent Oxy-PICU trial. Sp o2 monitors may overestimate arterial oxygen saturation (Sa o2 ) in patients with higher levels of skin pigmentation compared with those with less skin pigmentation. We investigated if ethnicity was associated with changes in distributions of Sp o2 and F io2 and outcome. Post-hoc analysis of a pragmatic, open-label, multicenter randomized controlled trial. Fifteen PICUs across the United Kingdom and Scotland. Children aged 38 weeks corrected gestational age to 15 years accepted to a participating PICU as an unplanned admission and receiving invasive mechanical ventilation with supplemental oxygen for abnormal gas exchange. Hierarchical regression models for Sp o2 and F io2 , and ordinal models for the primary trial outcome of a composite of the duration of organ support at 30 days and death, were used to examine the effects of ethnicity, accounting for baseline Sp o2 , F io2 , and mean airway pressure and trial allocation. Ethnicity data were available for 1577 of 1986 eligible children, 1408 (89.3%) of which were White, Asian, or Black. Sp o2 and F io2 distributions did not vary according to Black or Asian ethnicity compared with White children. The trial primary outcome measure also did not vary significantly with ethnicity. The point estimate for the treatment effect of conservative oxygenation in Black children was 0.64 (95% CI, 0.33-1.25) compared with 0.84 (0.68-1.04) in the overall trial population. These data do not suggest that the association between improved outcomes and conservative oxygenation strategy in mechanically ventilated children in PICU is modified by ethnicity.

Chauhan Weighted Trajectory Analysis Reduces Sample Size Requirements and Expedites Time-to-Efficacy Signals in Advanced Cancer Clinical Trials

(1) Background: As Kaplan–Meier (KM) analysis is limited to single unidirectional endpoints, most advanced cancer randomized clinical trials (RCTs) are powered for either progression-free survival (PFS) or overall survival (OS). This discards efficacy information carried by partial responses, complete responses, and stable disease that frequently precede progressive disease and death. Chauhan Weighted Trajectory Analysis (CWTA) is a generalization of KM that simultaneously assesses multiple rank-ordered endpoints. We hypothesized that CWTA could use this efficacy information to reduce sample size requirements and expedite efficacy signals in advanced cancer trials. (2) Methods: We performed 100-fold and 1000-fold simulations of solid tumor systemic therapy RCTs with health statuses rank-ordered from complete response (Stage 0) to death (Stage 4). At increments of the sample size and hazard ratio, we compared KM PFS and OS with CWTA for (i) sample size requirements to achieve a power of 0.8 and (ii) the time to first significant efficacy signal. (3) Results: CWTA consistently demonstrated greater power, and it reduced the sample size requirements by 18% to 35% compared to KM PFS and 14% to 20% compared to KM OS. CWTA also expedited time-to-efficacy signals by 2- to 6-fold. (4) Conclusions: CWTA, by incorporating all efficacy signals in the cancer treatment trajectory, provides a clinically relevant reduction in the required sample size and meaningfully expedites the efficacy signals of cancer treatments compared to KM PFS and KM OS. Using CWTA rather than KM as the primary trial outcome has the potential to meaningfully reduce the numbers of patients, trial duration, and costs to evaluate therapies in advanced cancer.

Novel measures of cognition and function for the AD spectrum in the Novel Measures for Alzheimer's Disease Prevention Trials (NoMAD) project: Psychometric properties, convergent validation, and contrasts with established measures.

This study derived composite scores for two novel cognitive measures, the No Practice Effect (NPE) battery and the Miami Computerized Functional Skills Assessment and Training system for use in early-stage Alzheimer's disease (AD) clinical trials. Their psychometric properties and associations with AD risk markers were compared to those of well-established measures. For 291 older adults with healthy cognition or early mild cognitive impairment, Exploratory factor analyses were used to identify the factor structure of the NPE. Factor and total scores were examined for their psychometric properties and associations with AD risk biomarkers. Composite scores from the novel cognitive and functional measures demonstrated better psychometric properties (distribution and test-retest reliability) and stronger associations with AD-related demographic, genetic, and brain risk markers than well-established measures, DISCUSSION: These novel measures have potential for use as primary cognitive and functional outcomes in early-stage AD clinical trials. Well-established cognitive tests may not accurately detect subtle cognitive changes. No Practice Effect (NPE) and Computerized Functional Skills Assessment and Training are novel measures designed to have improved psychometric properties. NPE had Executive Function, Cognitive Control/Speed, and Episodic Memory domains. Novel measures had better psychometric properties compared to established measures. Significant associations with Alzheimer's disease biomarkers were found with novel measures.

Composite end points and competing risks analysis.

Composite end points are common primary outcomes in clinical trials. Their main benefit of utilizing a composite outcome is increasing the number of primary outcome events, meaning fewer participants are required to deliver an adequately powered trial. By combining multiple important end points in the primary outcome rather than having to select only 1, composite end points potentially make clinically meaningful benefits easier to detect and avoid ranking outcomes hierarchically. However, there are a number of important considerations when designing and interpreting clinical trials that utilize composite end points. In this Statistical Primer, issues with composite end points such as competing events, halo effect, risk of bias, time-to-event limitations and the win ratio are discussed in the context of real world clinical trials.

Impact of RA treatment strategies on lipids and vascular inflammation in rheumatoid arthritis: a secondary analysis of the TARGET randomized active comparator trial

BackgroundTreatments for rheumatoid arthritis (RA) are associated with complex changes in lipids and lipoproteins that may impact cardiovascular (CV) risk. The objective of this study was to examine lipid and lipoprotein changes associated with two common RA treatment strategies, triple therapy or tumor necrosis factor inhibitor (TNFi), and association with CV risk.MethodsIn this secondary data analysis of the TARGET trial, methotrexate (MTX) inadequate responders with RA were randomized to either add sulfasalazine and hydroxychloroquine (triple therapy), or TNFi for 24-weeks. The primary trial outcome was the change in arterial inflammation measured in the carotid arteries or aorta by FDG-PET/CT at baseline and 24-weeks; this change was described as the target-to-background ratio (TBR) in the most diseased segment (MDS). Routine lipids and advanced lipoproteins were measured at baseline and 24-weeks; subjects on statin therapy at baseline were excluded. Comparisons between baseline and follow-up lipid measurements were performed within and across treatment arms, as well as change in lipids and change in MDS-TBR.ResultsWe studied 122 participants, 61 in each treatment arm, with median age 57 years, 76% female, and 1.5 year median RA disease duration. When comparing treatment arms, triple therapy had on average a larger reduction in triglycerides (15.9 mg/dL, p = 0.01), total cholesterol to HDL-C ratio (0.29, p-value = 0.01), and LDL particle number (111.2, p = 0.02) compared to TNFi. TNFi had on average a larger increase in HDL particle number (1.6umol/L, p = 0.006). We observed no correlation between change in lipid measurements and change in MDS-TBR within and across treatment arms.ConclusionsBoth treatment strategies were associated with improved lipid profiles via changes in different lipids and lipoproteins. These effects had no correlation with change in CV risk as measured by vascular inflammation by FDG-PET/CT.Trial registrationClinicalTrials.gov ID NCT02374021.

Enhancing HIV pre-exposure prophylaxis outcomes among Kenyan adolescent girls and young women with a novel pharmacy-based PrEP delivery platform: protocol for a cluster-randomized controlled trial

BackgroundIn Kenya, 65% of sexually active unmarried women use modern contraceptives, a population at increased risk of HIV acquisition compared to other populations. Anchoring HIV prevention services, including pre-exposure prophylaxis (PrEP), to trusted contraceptive delivery settings offers opportunities to efficiently reach this important population. In Kenya, almost half (40%) of women accessing contraception services do so outside traditional healthcare facilities, such as retail pharmacies. Thus, integrating PrEP services into retail pharmacies may increase options for reaching adolescent girls and young women (AGYW) who could benefit from PrEP. Efforts are underway to define care pathways for pharmacy-delivered PrEP services in Kenya, including unsupported and supported models with nurse navigators.MethodsThe AGYW Pharmacy PrEP study is an unblinded 2-arm cluster-randomized controlled trial in Kisumu, Kenya. The objective is to determine the effect that unsupported versus supported pharmacy-delivered PrEP services has on PrEP initiation, persistence, and adherence among AGYW seeking contraception. Twenty retail pharmacies offering pharmacy provider-led PrEP delivery will be randomized 1:1 to either receive or not receive a nurse navigator to support PrEP delivery. Eligible AGYW (n = 1900 total, n = 950/arm) will be ≥ 15 years old, purchasing a method of contraception at the pharmacy. Trained pharmacy provider will offer eligible AGYW either daily oral PrEP or the monthly DPV vaginal ring. The primary trial outcomes are PrEP initiation (use of PrEP at 1 month), persistence (use of PrEP at 10 months), and adherence (quantified by levels of TFV or DPV in hair samples). Additionally, several secondary (STI incidence, PrEP method selection, predictors of PrEP adherence) and exploratory outcomes (HIV incidence, quality of care, contraceptive method mix) will be explored.DiscussionWe hypothesize pharmacy-delivered PrEP services supported with nurse navigator, versus delivered by pharmacy providers alone, will improve PrEP outcomes among AGYW seeking contraception. Our results will help policy makers better understand how to potentially implement this novel differentiated service model for PrEP and prime pharmacies for the delivery of new PrEP agents in the pipeline (e.g., long-acting injectables and multi-purpose technologies). The study was initiated on May 13, 2023, and is expected to be completed by February 2025.Trial RegistrationClinicalTrials.gov (NCT05467306), with registration on July 20, 2022.

Sevoflurane multiple Wash In/Wash Out at the end of anesthesia to reduce agitation: A multicenter double-blind randomized controlled trial

BackgroundPostoperative agitation is common after non-cardiac surgery. It is associated with postoperative delirium and cognitive dysfunction, leading to prolonged hospital stay and delayed social readjustment. Prevention and treatment strategies are lacking. We assessed the efficacy of a novel approach, the Wash In/Wash Out procedure, in reducing post-anesthetic agitation. MethodsThis multicenter, parallel-group, double-blind randomized controlled trial is enrolling 200 patients undergoing open abdominal surgery. Participants are randomly assigned to either a control group receiving standard recovery methods or an investigational group undergoing the Wash In/Wash Out procedure. In the Wash In/Wash Out procedure group, sevoflurane is stopped and then promptly restarted when the patient shows the first signs of awakening to achieve an end-tidal concentration of 1 minimum alveolar concentration (MAC) for 5 min. This stop-and-restart cycle is performed three times. The trial's primary outcome is the rate of postoperative agitation. Secondary outcomes include rate of postoperative delirium and cognitive dysfunction, postoperative nausea and vomiting, and length of intensive care and hospital stay. DiscussionThe OPERA trial investigates the effect of the Wash In/Wash Out procedure to reduce post-anesthetic agitation in non-cardiac surgery. This study could offer a significant contribution to improving patient outcomes and optimizing recovery protocols in surgical settings.

Clinical Disease Measures in Palmoplantar Pustulosis: A Scoping Review

Background Palmoplantar pustulosis (PPP) is a rare, relapsing, disease characterized by pustules, pain, and fissuring. PPP is often combined with psoriasis, most commonly palmar plantar psoriasis, in clinical trials which further complicates our understanding of treatment response. Objective The objective of this scoping review is to describe all outcome measures (clinician-reported &amp; patient-reported) used in previous PPP clinical trials. Methods A search was conducted in Medline, Embase, and the Cochrane Central Register of Controlled Trials (CENTRAL) for clinical trials and prospective cohort studies performed in adults with PPP, with an intervention and pre-determined outcomes collected at pre specified time points. Results The initial search identified 1839 records, of which 69 met our inclusion criteria. The studies were published between 1970–2023 and included a total of 3301 patients. The most common primary study outcome was the clinician-reported Palmoplantar Pustulosis Psoriasis Area Severity Index (ppPASI) ( n = 39, 56.5%) and an endpoint of 12 weeks ( n = 23, 33.3%). Other common clinician reported outcomes identified were pustule count ( n = 26, 37.7%) and the Physician Global Assessment ( n = 16, 23.2%) The majority of studies ( n = 43, 62.3%) did not include any patient reported outcome measures. Of those that did include patient reported outcome measures, the Dermatology Life Quality Index was most utilized ( n = 17, 24.6%), followed by symptoms-specific instruments measuring pain ( n = 11, 15.9%) and itch ( n = 6, 8.7%). Conclusions While the clinician-reported ppPASI has become the standard primary outcome in PPP clinical trials, there is still considerable heterogeneity and lack of specificity in the patient reported outcomes used.