Interaction analysis of subgroup effects in randomized trials: the essential methodological points.

Subgroup analysis aims to identify subgroups (usually defined by baseline/demographic characteristics), who would (or not) benefit from an intervention under specific conditions. Often performed post hoc (not pre-specified in the protocol), subgroup analyses are prone to elevated type I error due to multiple testing, inadequate power, and inappropriate statistical interpretation. Aside from the well-known Bonferroni correction, subgroup treatment interaction tests can provide useful information to support the hypothesis. Using data from a previously published randomized trial where a p value of 0.015 was found for the comparison between standard and Hemopatch® groups in (the subgroup of) 135 patients who had hand-sewn pancreatic stump closure we first sought to determine whether there was interaction between the number and proportion of the dependent event of interest (POPF) among the subgroup population (patients with hand-sewn stump closure and use of Hemopatch®), Next, we calculated the relative excess risk due to interaction (RERI) and the "attributable proportion" (AP). The p value of the interaction was p = 0.034, the RERI was - 0.77 (p = 0.0204) (the probability of POPF was 0.77 because of the interaction), the RERI was 13% (patients are 13% less likely to sustain POPF because of the interaction), and the AP was - 0.616 (61.6% of patients who did not develop POPF did so because of the interaction). Although no causality can be implied, Hemopatch® may potentially decrease the POPF after distal pancreatectomy when the stump is closed hand-sewn. The hypothesis generated by our subgroup analysis requires confirmation by a specific, randomized trial, including only patients undergoing hand-sewn closure of the pancreatic stump after distal pancreatectomy.Trial registration: INS-621000-0760.

Handling of outcome missing data dependent on measured or unmeasured background factors in micro-randomized trial: Simulation and application study.

Background: Micro-randomized trials (MRTs) enhance the effects of mHealth by determining the optimal components, timings, and frequency of interventions. Appropriate handling of missing values is crucial in clinical research; however, it remains insufficiently explored in the context of MRTs. Our study aimed to investigate appropriate methods for missing data in simple MRTs with uniform intervention randomization and no time-dependent covariates. We focused on outcome missing data depending on the participants' background factors. Methods: We evaluated the performance of the available data analysis (AD) and the multiple imputation in generalized estimating equations (GEE) and random effects model (RE) through simulations. The scenarios were examined based on the presence of unmeasured background factors and the presence of interaction effects. We conducted the regression and propensity score methods as multiple imputation. These missing data handling methods were also applied to actual MRT data. Results: Without the interaction effect, AD was biased for GEE, but there was almost no bias for RE. With the interaction effect, estimates were biased for both. For multiple imputation, regression methods estimated without bias when the imputation models were correct, but bias occurred when the models were incorrect. However, this bias was reduced by including the random effects in the imputation model. In the propensity score method, bias occurred even when the missing probability model was correct. Conclusions: Without the interaction effect, AD of RE was preferable. When employing GEE or anticipating interactions, we recommend the multiple imputation, especially with regression methods, including individual-level random effects.

Capivasertib in combination with enzalutamide for metastatic castration resistant prostate cancer after docetaxel and abiraterone: Results from the randomized phase II RE-AKT trial.

BACKGROUND: PTEN loss and aberrations in PI3K/AKT signaling kinases associate with poorer response to abiraterone acetate (AA) in metastatic castration-resistant prostate cancer (mCRPC). In this study, we assessed antitumor activity of the AKT inhibitor capivasertib combined with enzalutamide in mCRPC with prior progression on AA and docetaxel. METHODS: This double-blind, placebo-controlled, randomized phase 2 trial, recruited men ≥ 18 years with progressing mCRPC and performance status 0-2 from 15 UK centers. Randomized participants (1:1) received enzalutamide (160 mg orally, once daily) with capivasertib (400 mg)/ placebo orally, twice daily on an intermittent (4 days on, 3 days off) schedule. Primary endpoint was composite response rate (RR): RECIST 1.1 objective response, ≥ 50 % PSA decrease from baseline, or circulating tumor cell count conversion (from ≥ 5 at baseline to < 5 cells/7.5 mL). Subgroup analyses by PTENIHC status were pre-planned. RESULTS: Overall, 100 participants were randomized (50:50); 95 were evaluable for primary endpoint (47:48); median follow-up was 43 months. RR were 9/47 (19.1 %) enzalutamide/capivasertib and 9/48 (18.8 %) enzalutamide/placebo (absolute difference 0.4 % 90 %CI -12.8 to 13.6, p = 0.58), with similar results in the PTENIHC loss subgroup. Irrespective of treatment, OS was significantly worse for PTENIHC loss (10.1 months [95 %CI: 4.6-13.9] vs 14.8 months [95 %CI: 10.8-18]; p = 0.02). Most common treatment-emergent grade ≥ 3 adverse events for the combination were diarrhea (13 % vs 2 %) and fatigue (10 % vs 6 %). CONCLUSIONS: Combined capivasertib/enzalutamide was well tolerated but didn't significantly improve outcomes from abiraterone pre-treated mCRPC.

Effect of PCI on Health Status in Ischemic Left Ventricular Dysfunction: Insights From REVIVED-BCIS2.

BACKGROUND: In the REVIVED-BCIS2 (Revascularization for Ischemic Ventricular Dysfunction) trial, percutaneous coronary intervention (PCI) did not reduce the incidence of death or hospitalization for heart failure (HHF). OBJECTIVES: This prespecified secondary analysis investigated the effect of PCI on health status measured with the Kansas City Cardiomyopathy Questionnaire (KCCQ) combined with the primary outcome in a win ratio. METHODS: Participants with severe ischemic left ventricular dysfunction were randomized to either PCI in addition to optimal medical therapy (OMT) (PCI) or OMT alone (OMT). The primary outcome was a hierarchical composite of all-cause death, HHF, and KCCQ-Overall Summary Score (OSS) at 24 months analyzed using the unmatched win ratio. The key secondary endpoint was a KCCQ-OSS responder analysis. RESULTS: A total of 347 participants were randomized to PCI and 353 to OMT. Median age was 70.0 years (Q1-Q3: 63.3-76.1 years). Mean left ventricular ejection fraction was 27.0 ± 6.7%. PCI did not improve the primary endpoint (win ratio for PCI vs OMT: 1.05; 95% CI: 0.88-1.26; P = 0.58). PCI resulted in more KCCQ-OSS responders than OMT at 6 months (54.1% vs 40.7%; OR: 1.96; 95% CI: 1.41-2.71; P < 0.001) and fewer deteriorators (25.2% vs 31.4%; OR: 0.69; 95% CI: 0.47-1.00; P = 0.048). PCI did not impact KCCQ-OSS responders or deteriorators at 12 or 24 months. CONCLUSIONS: PCI did not improve the hierarchical composite of death, HHF, and health status at 2 years. PCI improved KCCQ-OSS at 6 months, but this benefit was not sustained to 1- or 2-year follow-up. (Revacularization for Ischemic Ventricular Dysfunction [REVIVED-BCIS2]; NCT01920048).

Targeting Aging and Longevity with Exogenous Nucleotides (TALENTs): Rationale, Design, and Baseline Characteristics from a Randomized Controlled Trial in Older Adults.

Nucleotides (NTs), important biomolecules involved in numerous cellular processes, have been proposed as potential candidates for anti-aging interventions. However, whether nucleotides can act as an anti-aging supplement in older adults remains unclear. TALENTs is a randomized, double-blinded, placebo-controlled trial that evaluates the efficacy and safety of NTs as an anti-aging supplement in older adults by exploring the effects of NTs on multiple dimensions of aging in a rigorous scientific setting. Eligible community-dwelling adults aged 60-70 years were randomly assigned equally to two groups: nucleotides intervention group and placebo control group. Comprehensive geriatric health assessments were performed at baseline, 2-months, and 4-months of the intervention. Biological specimens were collected and stored for age-related biomarker testing and multi-omics sequencing. The primary outcome was the change from baseline to 4 months on leukocyte telomere length and DNA methylation age. The secondary aims were the changes in possible mechanisms underlying aging processes (immunity, inflammatory profile, oxidative stress, gene stability, endocrine, metabolism, and cardiovascular function). Other outcomes were changes in physical function, body composition and geriatric health assessment (including sleep quality, cognitive function, fatigue, frailty, and psychology). In the RCT, 301 participants were assessed for eligibility and 122 were enrolled. Participants averaged 65.65 years of age, and were predominately female (67.21%). All baseline characteristics were well-balanced between groups, as expected due to randomization. The majority of participants were pre-frailty and had at least one chronic condition. The mean scores for physical activity, psychological, fatigue and quality of life were within the normal range. However, nearly half of the participants still had room for improvement in cognitive level and sleep quality. This TALENTs trial will represent one of the most comprehensive experimental clinical trials in which supplements are administered to elderly participants. The findings of this study will contribute to our understanding of the anti-aging effects of NTs and provide insights into their potential applications in geriatric healthcare.

A phase 1, randomized, double-blind, placebo-controlled trial investigating the pharmacokinetics, pharmacodynamics, safety and tolerability of oral semaglutide in healthy Chinese subjects.

AIM: The trial (NCT04016974) investigated the pharmacokinetics, pharmacodynamics, safety and tolerability of oral semaglutide, the first orally administered glucagon-like peptide-1 analogue for type 2 diabetes, in healthy Chinese subjects. MATERIALS AND METHODS: This single-centre, multiple-dose, placebo-controlled trial randomized 32 healthy Chinese adults to once-daily oral semaglutide (3 mg escalating to 14 mg) or placebo for 12 weeks. Blood samples were collected regularly during treatment and follow-up. The primary endpoint was the area under the semaglutide concentration-time curve over a dosing interval (0-24 h) at steady state (AUC0-24h,sema,SS). Secondary pharmacokinetic endpoints included the maximum observed semaglutide plasma concentration at steady state (Cmax,sema,SS). Supportive secondary pharmacodynamics endpoints included changes in body weight and fasting plasma glucose. RESULTS: Treatment with all oral semaglutide doses showed dose-dependent increases in semaglutide exposure in healthy Chinese subjects at steady state, determined by AUC0-24h,sema,SS (233, 552 and 1288 h·nmol/L for 3, 7 and 14 mg of oral semaglutide, respectively) and Cmax,sema,SS. Oral semaglutide treatment was associated with significant reductions in body weight (p = .0001) and fasting plasma glucose (p = .0011) versus placebo at the end of treatment. The safety and tolerability of oral semaglutide were consistent with the known profile of glucagon-like peptide-1 receptor agonists, with no severe or blood-glucose-confirmed symptomatic hypoglycaemic events, serious adverse events or deaths. The most frequent adverse events were gastrointestinal disorders. CONCLUSIONS: At steady state, oral semaglutide exposure was dose dependent and close to dose proportionality in healthy Chinese subjects. This is consistent with previous clinical pharmacology results for oral semaglutide.

Postoperative quality of life and pain after upper hemisternotomy and conventional median sternotomy for aortic valve replacement: results of a randomized clinical trial.

OBJECTIVES: Surgical aortic valve replacement through conventional sternotomy yields excellent results. Minimally invasive techniques are deemed equally safe and serve as a viable and less traumatic alternative. However, it is unclear how both surgical techniques affect patient-reported outcomes. The objective of this trial is to compare postoperative cardiac-related quality of life and postoperative pain after upper hemisternotomy and conventional surgical aortic valve replacement. METHODS: In this single-centre, open-label, investigator-initiated randomized clinical trial, patients were randomized to upper hemisternotomy or conventional full median sternotomy. Patients unable to undergo randomization were monitored prospectively (registry group). Primary outcome was cardiac-specific quality of life, measured with the Kansas City Cardiomyopathy Questionnaire up to 1 year postoperatively. RESULTS: Patients undergoing upper hemisternotomy had a significantly higher physical limitation domain score across all postoperative time points than patients undergoing conventional surgical aortic valve replacement (estimated mean difference 2.12 points; P = 0.014). Patients undergoing upper hemisternotomy were more likely to have a pain score <30 the first 2 days postoperatively than patients undergoing conventional surgical aortic valve replacement (odds ratio 2.63; P = 0.007). This was associated with reduced opioid analgesic intake. Postoperative surgical outcome did not differ between both groups. CONCLUSIONS: Surgical aortic valve replacement through both conventional sternotomy and upper hemisternotomy resulted in clinically similar and important improvements in quality of life, with a small advantage for upper hemisternotomy, while there was no compromise in safety.

Effectiveness of a nurse-led management intervention on systolic blood pressure among type 2 diabetes patients in Uganda: a cluster randomized trial.

BACKGROUND: Hypertension (HT) is an orchestrator of atherosclerotic cardiovascular disease (ASCVD) in people living with type 2 diabetes (T2D). Control of systolic blood pressure (SBP) and HT as a whole is suboptimal in diabetes, partly due to the scarcity of doctors. While nurse-led interventions are pragmatic and cost-effective in the control of HT in primary health care, their effectiveness on SBP control among patients with T2D in Uganda is scantly known. AIM: We evaluated the effectiveness of a nurse-led management intervention on SBP among T2D patients with a high ASCVD risk in Uganda. METHODS: A two-armed cluster randomized controlled trial compared the nurse-led management intervention with usual doctor-led care. The intervention involved training nurses to provide structured health education, protocol-based HT/CVD management, 24-h phone calls, and 2-monthly text messages for 6 months. The primary outcome was the mean difference in SBP change among patients with T2D with a high ASCVD risk in the intervention and control groups after 6 months. The secondary outcome was the absolute difference in the number of patients at target for SBP, total cholesterol (TC), fasting blood glucose (FBG), glycated hemoglobin (HbA1C), low-density lipoprotein (LDL), triglycerides (TG), and body mass index (BMI) after the intervention. The study was analyzed according to the intention-to-treat principle. Generalized estimating equations were used to assess intra-cluster effect modifiers. Statistical significance was set at 0.05 for all analyses. RESULTS: Eight clinics (n = 388 patients) were included (intervention 4 clinics; n = 192; control 4 clinics; n = 196). A nurse-led intervention reduced SBP by -11.21 ± 16.02 mmHg with a mean difference between the groups of -13.75 mmHg (95% CI -16.48 to -11.02, p < 0.001). An increase in SBP of 2.54 ± 10.95 mmHg was observed in the control group. Diastolic blood pressure was reduced by -6.80 ± 9.48 mmHg with a mean difference between groups of -7.20 mmHg (95% C1 -8.87 to -5.48, p < 0.001). The mean differences in the change in ASCVD score and glycated hemoglobin were -4.73% (95% CI -5.95 to -3.51, p = 0.006) and -0.82% (95% CI -1.30 to -0.35, p = 0.001), respectively. There were significant absolute differences in the number of patients at target in SBP (p = 0.001), DBP (p = 0.003), and TC (p = 0.008). CONCLUSION: A nurse-led management intervention reduces SBP and ASCVD risk among patients with T2D. Such an intervention may be pragmatic in the screening and management of HT/ASCVD in Uganda. TRIAL REGISTRATION: Pan African Clinical Trial Registry, PACTR202001916873358, registered on 6th October 2019.

Impact of cash transfer programs on healthcare utilization and catastrophic health expenditures in rural Zambia: a cluster randomized controlled trial.

Background: Nearly 100 million people are pushed into poverty every year due to catastrophic health expenditures (CHE). We evaluated the impact of cash support programs on healthcare utilization and CHE among households participating in a cluster-randomized controlled trial focusing on adolescent childbearing in rural Zambia. Methods and findings: The trial recruited adolescent girls from 157 rural schools in 12 districts enrolled in grade 7 in 2016 and consisted of control, economic support, and economic support plus community dialogue arms. Economic support included 3 USD/month for the girls, 35 USD/year for their guardians, and up to 150 USD/year for school fees. Interviews were conducted with 3,870 guardians representing 4,110 girls, 1.5-2 years after the intervention period started. Utilization was defined as visits to formal health facilities, and CHE was health payments exceeding 10% of total household expenditures. The degree of inequality was measured using the Concentration Index. In the control arm, 26.1% of the households utilized inpatient care in the previous year compared to 26.7% in the economic arm (RR = 1.0; 95% CI: 0.9-1.2, p = 0.815) and 27.7% in the combined arm (RR = 1.1; 95% CI: 0.9-1.3, p = 0.586). Utilization of outpatient care in the previous 4 weeks was 40.7% in the control arm, 41.3% in the economic support (RR = 1.0; 95% CI: 0.8-1.3, p = 0.805), and 42.9% in the combined arm (RR = 1.1; 95% CI: 0.8-1.3, p = 0.378). About 10.4% of the households in the control arm experienced CHE compared to 11.6% in the economic (RR = 1.1; 95% CI: 0.8-1.5, p = 0.468) and 12.1% in the combined arm (RR = 1.1; 95% CI: 0.8-1.5, p = 0.468). Utilization of outpatient care and the risk of CHE was relatively higher among the least poor than the poorest households, however, the degree of inequality was relatively smaller in the intervention arms than in the control arm. Conclusions: Economic support alone and in combination with community dialogue aiming to reduce early childbearing did not appear to have a substantial impact on healthcare utilization and CHE in rural Zambia. However, although cash transfer did not significantly improve healthcare utilization, it reduced the degree of inequality in outpatient healthcare utilization and CHE across wealth groups. Trial Registration: https://classic.clinicaltrials.gov/ct2/show/NCT02709967, ClinicalTrials.gov, identifier (NCT02709967).

Experiential suicide prevention training for substance use treatment intensive outpatient program counselors: Stepped wedge cluster-randomized training study.

INTRODUCTION: The goal of this study was to evaluate changes in knowledge, attitudes, and other key suicide prevention issues for substance use disorder (SUD) counselors trained to administer the Preventing Addiction Related Suicide (PARS) module as part of a large-scale clinical trial. The PARS is a 3-hour, PowerPoint based intervention designed with and for community SUD agencies for their Intensive Outpatient (IOP) group therapy programs. A previous randomized study of 906 patients from 15 community SUD sites showed positive changes in patients' suicide prevention knowledge, attitudes, and help seeking. METHODS: Counselor participants completed measures of knowledge and attitudes about suicide and their confidence treating suicidal patients at each step of a large, stepped wedge cluster randomized trial of PARS, including after the final step. Data analysis compared scores in steps prior to counselors' training in PARS with scores in the steps following counselors' PARS training. RESULTS: A total of 126 counselors participated in the study (89 % of those approached; 89-92 % retention across follow-up). Evaluation of both PARS efficacy and the PARS training by SUD counselors was highly rated. Counselor scores after receiving PARS training (vs. scores prior to PARS training) showed greater suicide knowledge, less maladaptive attitudes about suicide, and greater confidence in working with suicidal patients. CONCLUSIONS: Based on this rigorous test of PARS training for SUD counselors working in community SUD intensive outpatient programs, PARS training, as well as doing the PARS intervention, was rated as highly effective and acceptable. PARS offers an integrated, brief, engaging, and effective training method to improve suicide care for both SUD counselors and SUD clients.

Inclisiran in individuals with diabetes or obesity: Post hoc pooled analyses of the ORION-9, ORION-10 and ORION-11 Phase 3 randomized trials.

AIMS: To conduct a pooled analysis of Phase 3 trials investigating the efficacy and safety of inclisiran across glycaemic and body mass index (BMI) strata. MATERIALS AND METHODS: Participants were randomized 1:1 to receive 300 mg inclisiran sodium or placebo twice yearly, after initial and 3-month doses up to 18 months, with background oral lipid-lowering therapy. Analyses were stratified by glycaemic status (normoglycaemia, prediabetes, and diabetes) or BMI (<25, ≥25 to <30, ≥30 to <35, and ≥35 kg/m2). Co-primary endpoints were percentage and time-adjusted percentage change in low-density lipoprotein (LDL) cholesterol from baseline. Safety was also assessed. RESULTS: Baseline characteristics were balanced between treatment arms and across strata. Percent LDL cholesterol change (placebo-corrected) with inclisiran from baseline to Day 510 ranged from -47.6% to -51.9% and from -48.8% to -54.4% across glycaemic/BMI strata, respectively. Similarly, time-adjusted percentage changes after Day 90 and up to Day 540 ranged from -46.8% to -52.0% and from -48.6% to -53.3% across glycaemic/BMI strata, respectively. Inclisiran led to significant reductions in proprotein convertase subtilisin/kexin type 9 and other atherogenic lipids and lipoproteins versus placebo across the glycaemic/BMI strata. The proportions of individuals achieving LDL cholesterol thresholds of <1.8 mmol/L and <1.4 mmol/L with inclisiran increased with increasing glycaemic and BMI strata. Across the glycaemic/BMI strata, a higher proportion of individuals had mild/moderate treatment-emergent adverse events (TEAEs) at the injection site with inclisiran (2.8%-7.7%) versus placebo (0.2%-2.1%). CONCLUSION: Inclisiran provided substantial and sustained LDL cholesterol lowering across glycaemic/BMI strata, with a modest excess of transient mild-to-moderate TEAEs at the injection site.

Targeting strategies for balanced energy and protein (BEP) supplementation in pregnancy: study protocol for the TARGET-BEP cluster-randomized controlled trial in rural Bangladesh.

BACKGROUND: The World Health Organization (WHO) recommends balanced energy and protein (BEP) supplementation be provided to all pregnant women living in undernourished populations, usually defined as having a prevalence > 20% of underweight women, to reduce the risk of stillbirths and small-for-gestational-age neonates. Few geographies meet this threshold, however, and a large proportion of undernourished women and those with inadequate gestational weight gain could miss benefiting from BEP. This study compares the effectiveness of individual targeting approaches for supplementation with micronutrient-fortified BEP vs. multiple micronutrient supplements (MMS) alone as control in pregnancy in improving birth outcomes. METHODS: The TARGET-BEP study is a four-arm, cluster-randomized controlled trial conducted in rural northwestern Bangladesh. Eligible participants are married women aged 15-35 years old identified early in pregnancy using a community-wide, monthly, urine-test-based pregnancy detection system. Beginning at 12-14 weeks of gestation, women in the study area comprising 240 predefined sectors are randomly assigned to one of four intervention arms, with sector serving as the unit of randomization. The interventions involving daily supplementation through end of pregnancy are as follows: (1) MMS (control); (2) BEP; (3) targeted BEP for those with pre-pregnancy body mass index (BMI) < 18.5 kg/m2 and MMS for others; (4) targeted BEP for those with pre-pregnancy BMI < 18.5 kg/m2, MMS for others, and women with inadequate gestational weight gain switched from MMS to BEP until the end of pregnancy. Primary outcomes include birth weight, low birth weight (< 2500 g), and small for gestational age, defined using the 10th percentile of the INTERGROWTH-21st reference, for live-born infants measured within 72 h of birth. Project-hired local female staff visit pregnant women monthly to deliver the assigned supplements, monitor adherence biweekly, and assess weight regularly during pregnancy. Trained data collectors conduct pregnancy outcome assessment and measure newborn anthropometry in the facility or home depending on the place of birth. DISCUSSION: This study will assess the effectiveness of targeted balanced energy and protein supplementation to improve birth outcomes among pregnant women in rural Bangladesh and similar settings. TRIAL REGISTRATION: ClinicalTrials.gov NCT05576207. Registered on October 5th, 2022.

Effect of maternal vaccination on infant morbidity in Bangladesh.

BACKGROUND: Risk factors of infant mortality in Africa and south Asian countries have been broadly discussed. However, infant morbidity is largely underestimated. We analyzed the data from a randomized vaccine trial in Bangladesh to identify and assess the effect of risk factors on infant morbidity. METHODS: Pregnant women were randomly assigned to receive either inactivated influenza vaccine or pneumococcal polysaccharide vaccine and the infants were randomly assigned to receive 7-valent pneumococcal conjugate vaccine or Hib conjugate vaccine at week 6, 10 and 14. The data were collected from August 2004 through December 2005. Each pair of infant and mother were followed for 24 weeks after birth with weekly visits. Generalized estimating equations (GEE) for repeated measurements and Poisson regression models were used to identify the risk factors and evaluate their effect on the longitudinal incidence and total number of episodes of respiratory illness with fever (RIF), diarrhea disease, ear problem and pneumonia. RESULTS: A total of 340 pregnant women were randomized with mean age of 25 years. The baseline mother and infant characteristics were similar between two treatment groups. Exclusive breastfeeding and higher paternal education level were common factors associated with lower infant morbidity of RIF (adjusted OR = 0.40 and 0.94 with p < 0.01 and p = 0.02, respectively), diarrhea disease (adjusted OR = 0.39 and 0.95 with p < 0.01 and p = 0.04, respectively), and ear problem (adjusted OR = 0.20 and 0.76 with p < 0.01 and p < 0.01, respectively). Maternal influenza vaccine significantly reduced the incidence of RIF (adjusted OR = 0.54; p < 0.01) but not diarrhea disease or ear problem (p > 0.05). Female infants had lower incidence of diarrhea disease (adjusted OR = 0.67; p = 0.01) and ear problem (adjusted OR = 0.12; p = 0.01). CONCLUSIONS: Maternal influenza vaccination, exclusive breastfeeding, female children, and higher paternal education level significantly reduced the infant morbidity within the 24 weeks after birth in Bangladesh.

Making informed choices on incorporating chemoprevention into carE (MiCHOICE, SWOG 1904): Design and methods of a cluster randomized controlled trial.

INTRODUCTION: Women with atypical hyperplasia (AH) or lobular carcinoma in situ (LCIS) have a significantly increased risk of breast cancer, which can be substantially reduced with antiestrogen therapy for chemoprevention. However, antiestrogen therapy for breast cancer risk reduction remains underutilized. Improving knowledge about breast cancer risk and chemoprevention among high-risk patients and their healthcare providers may enhance informed decision-making about this critical breast cancer risk reduction strategy. METHODS/DESIGN: We are conducting a cluster randomized controlled trial to evaluate the effectiveness and implementation of patient and provider decision support tools to improve informed choice about chemoprevention among women with AH or LCIS. We have cluster randomized 26 sites across the U.S. through the SWOG Cancer Research Network. A total of 415 patients and 200 healthcare providers are being recruited. They are assigned to standard educational materials alone or combined with the web-based decision support tools. Patient-reported and clinical outcomes are assessed at baseline, after a follow-up visit at 6 months, and yearly for 5 years. The primary outcome is chemoprevention informed choice after the follow-up visit. Secondary endpoints include other patient-reported outcomes, such as chemoprevention knowledge, decision conflict and regret, and self-reported chemoprevention usage. Barriers and facilitators to implementing decision support into clinic workflow are assessed through patient and provider interviews at baseline and mid-implementation. RESULTS/DISCUSSION: With this hybrid effectiveness/implementation study, we seek to evaluate if a multi-level intervention effectively promotes informed decision-making about chemoprevention and provide valuable insights on how the intervention is implemented in U.S. TRIAL REGISTRATION: NCT04496739.

A Randomized Controlled Trial Comparing Efficacy and Safety of Antidepressant Monotherapy.

BACKGROUND AND OBJECTIVES: The majority of mainstream antidepressants lack the promise of complete amelioration of symptoms. Other pitfalls include the latency period and side effects. These issues prompted investigations concerning the various roles of serotonin (5-HT) neurotransmissions in the etiology of depression. In this study, each study participant received vilazodone, vortioxetine, and escitalopram monotherapy for major depressive disorder (MDD) for 16 weeks. After that, the subject's scores on the Hamilton Depression Rating Scale (HDRS)-17 item version and the Montgomery Åsberg Depression Rating Scale (MADRS) were evaluated. In the study population, we kept track of the incidence of adverse events. METHODS: Ninety-six patients with MDD participated in this open-label, randomized, three-arm study. Participants were allotted into three groups according to a 1:1:1 ratio and given vilazodone (20-40 mg/day), vortioxetine (5-20 mg/day), or escitalopram (10-20 mg/day) for 16 weeks. Vortioxetine and vilazodone are test medications, with escitalopram serving as the control. After the baseline visit, follow-up appointments were scheduled every four weeks. Per-protocol (PP) and intent-to-treat (ITT) populations served as means for efficacy and safety evaluations, respectively. We prospectively registered this research in the Clinical Trial Registry, India (CTRI) (2022/07/043808). RESULTS: Out of the 134 patients we screened, 109 (81.34%) were eligible. Ninety-six (88.07%) of them completed the 16-week trial. In the PP population (n = 96), we analyzed efficacy. They had a mean age of 46.3 ± 6.2 years. At baseline, each group's median HDRS score was 30.0 (p = 0.964). Following 16 weeks of antidepressant therapy, these scores dropped to 15.0, 14.0, and 13.0 (p = 0.002). Baseline MADRS scores for all groups were 36.0 (p = 0.741). They had corresponding values of 20.0, 18.0, and 17.0 at 16 weeks (p < 0.001). Regarding both efficacy endpoints, the post-hoc analysis with the Bonferroni correction demonstrated statistically significant differences (p < 0.001). We performed the safety assessments within our ITT population (n = 109). Ninety-six adverse events were recorded. Nonetheless, none of them seemed serious. Still, five participants opted out because of their side effects. Vomiting and nausea were the most frequent side effects. CONCLUSION: Compared to escitalopram and vilazodone, vortioxetine demonstrated a statistically significant reduction in HDRS and MADRS scores. It also had fewer and milder side effects. We recommend conducting studies involving a broader population to investigate the antidepressant effects of these medications further.

Optimal designs using generalized estimating equations in cluster randomized crossover and stepped wedge trials.

Cluster randomized crossover and stepped wedge cluster randomized trials are two types of longitudinal cluster randomized trials that leverage both the within- and between-cluster comparisons to estimate the treatment effect and are increasingly used in healthcare delivery and implementation science research. While the variance expressions of estimated treatment effect have been previously developed from the method of generalized estimating equations for analyzing cluster randomized crossover trials and stepped wedge cluster randomized trials, little guidance has been provided for optimal designs to ensure maximum efficiency. Here, an optimal design refers to the combination of optimal cluster-period size and optimal number of clusters that provide the smallest variance of the treatment effect estimator or maximum efficiency under a fixed total budget. In this work, we develop optimal designs for multiple-period cluster randomized crossover trials and stepped wedge cluster randomized trials with continuous outcomes, including both closed-cohort and repeated cross-sectional sampling schemes. Local optimal design algorithms are proposed when the correlation parameters in the working correlation structure are known. MaxiMin optimal design algorithms are proposed when the exact values are unavailable, but investigators may specify a range of correlation values. The closed-form formulae of local optimal design and MaxiMin optimal design are derived for multiple-period cluster randomized crossover trials, where the cluster-period size and number of clusters are decimal. The decimal estimates from closed-form formulae can then be used to investigate the performances of integer estimates from local optimal design and MaxiMin optimal design algorithms. One unique contribution from this work, compared to the previous optimal design research, is that we adopt constrained optimization techniques to obtain integer estimates under the MaxiMin optimal design. To assist practical implementation, we also develop four SAS macros to find local optimal designs and MaxiMin optimal designs.

Rationale and Design of a Phase 2, Double-blind, Placebo-Controlled, Randomized Trial Evaluating AMP Kinase-Activation by Metformin in Focal Segmental Glomerulosclerosis.

Introduction: Focal segmental glomerulosclerosis (FSGS), the most common primary glomerular disease leading to end-stage kidney disease (ESKD), is characterized by podocyte injury and depletion, whereas minimal change disease (MCD) has better outcomes despite podocyte injury. Identifying mechanisms capable of preventing podocytopenia during injury could transform FSGS to an "MCD-like" state. Preclinical data have reported conversion of an MCD-like injury to one with podocytopenia and FSGS by inhibition of AMP-kinase (AMPK) in podocytes. Conversely, in FSGS, AMPK-activation using metformin (MF) mitigated podocytopenia and azotemia. Observational studies also support beneficial effects of MF on proteinuria and chronic kidney disease (CKD) outcomes in diabetes. A randomized controlled trial (RCT) to test MF in podocyte injury with FSGS has not yet been conducted. Methods: We report the rationale and design of phase 2, double-blind, placebo-controlled RCT evaluating the efficacy and safety of MF as adjunctive therapy in FSGS. By randomizing 30 patients with biopsy-confirmed FSGS to MF or placebo (along with standard immunosuppression), we will study mechanistic biomarkers that correlate with podocyte injury or depletion and evaluate outcomes after 6 months. We specifically integrate novel urine, blood, and tissue markers as surrogates for FSGS progression along with unbiased profiling strategies. Results and Conclusion: Our phase 2 trial will provide insight into the potential efficacy and safety of MF as adjunctive therapy in FSGS-a crucial step to developing a larger phase 3 study. The mechanistic assays here will guide the design of other FSGS trials and contribute to understanding AMPK activation as a potential therapeutic target in FSGS. By repurposing an inexpensive agent, our results will have implications for FSGS treatment in resource-poor settings.

The LIVER CARE trial - screening for liver disease in individuals attending treatment for alcohol use disorder: a randomized controlled feasibility trial.

BACKGROUND: Alcohol-related liver disease is a preventable disease with high mortality. If individuals with alcohol-related liver disease were to be diagnosed earlier by screening and they reduced their alcohol consumption, lives lost to alcohol-related liver disease might be saved. A liver stiffness measurement (FibroScan©) is a key tool to screen for alcohol-related liver disease in asymptomatic individuals. No randomized controlled trials have been conducted to test if screening for liver disease reduces alcohol consumption in individuals with alcohol use disorders, in addition to what can be obtained by motivational interventions. We aimed to assess the feasibility of a randomized controlled trial of a screening for liver disease on the prevalence of alcohol abstinence or light consumption after 6 months in individuals attending outpatient treatment for alcohol use disorder. METHODS: We used an interdisciplinary approach to develop the format of the randomized controlled trial. Individuals were recruited from one outpatient treatment facility for alcohol use disorders. Study participants were randomized 1:1 to receive a) a liver stiffness measurement in addition to usual care (intervention) or b) usual care (control). Follow-up on alcohol consumption was assessed by telephone interview after 6 months and corroborated by data from records from public hospitals and the alcohol treatment facility. Feasibility was assessed by probabilities of recruitment, retention, and completion and estimated by the exact binominal test, with success defined as > 50% participation for each endpoint. The study design was evaluated at interdisciplinary meetings with staff and researchers from the outpatient alcohol treatment facility and the hospital clinic. RESULTS: Forty of 57 invited individuals agreed to participate in the study (recruitment = 70% (95% CI: 57-82)); 19 of 20 participants randomized to the intervention showed up for the screening (retention = 95% (95% CI: 75-100)). Follow-up telephone interviews succeeded for 33 of 39 reachable participants (completion = 85% (95% CI: 69-94)). Treatment records indicated that the 6 participants who were lost to follow-up for the telephone interview had not achieved alcohol abstinence or light consumption. There was no evidence that the intervention increased abstinence or light alcohol consumption at follow-up: 45% (95% CI: 23-68) in the intervention group and 65% (95% CI: 41-85) in the control group had a alcohol consumption below 10 standard drinks/week at 6 months. The main obstacle regarding study feasibility was to avoid disappointment in individuals randomized as controls. CONCLUSIONS: This feasibility study developed a study design to test the influence of screening for liver disease on abstinence or light alcohol consumption in individuals attending treatment for alcohol use disorder. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT05244720; registered on February 17, 2022.

Optimizing the physical activity intervention for older adults with mild cognitive impairment: a factorial randomized trial.

Background: Physical activity (PA) intervention is one of the most effective interventions to promote cognitive function of older adults with mild cognitive impairment (MCI). However, the level of PA remains low. Based on the two core interventions (X-CircuiT and health education), this study aimed to examine the effect of three implementation strategies (viz., role modeling, goal-setting, and reminding) on the PA level among older adults with MCI using the multiphase optimization strategy (MOST). Methods: Participants were randomized into one of eight conditions in a factorial design involving three factors with two levels: (i) role modeling (on vs. off); (ii) goal-setting (on vs. off); and (iii) reminding (on vs. off). The primary outcome was PA level at 12 weeks. The secondary outcomes were cognitive function, self-efficacy, and cost-effectiveness at 12 weeks. The intention-to-treat (ITT) analysis was performed as the main analysis and the per-protocol (PP) analysis as the sensitivity analysis. Results: A total of 107 participants were included and randomly assigned into three groups, each receiving different implementation strategies. The results of the multivariate regression analysis showed that the three implementation strategies, namely, reminding (B = 0.31, p < 0.01), role modeling (B = 0.21, p < 0.01), and goal-setting (B = 0.19, p < 0.01), could significantly improve PA level. Specifically, it was found that role modeling (B = 0.68, p = 0.03) could significantly improve cognitive function. There were no significant interactions among the three implementation strategies. Role modeling was the most cost-effective strategy, costing 93.41 RMB for one unit of PA. Conclusions: Role modeling was likely to be the best implementation strategy. The value-based and cost-effective PA intervention package could include the core intervention (X-CircuiT and health education) and implementation strategy (role modeling). Clinical Trial Registration: https://www.chictr.org.cn, The study was retrospectively registered on 30 June 2022 (ChiCTR2200061693).

HPV Multilevel Intervention Strategies Targeting Immunization in Community Settings (HPV MISTICS): Study protocol for a hybrid 1 stepped-wedge cluster randomized trial.

BACKGROUND: This protocol paper describes the overall design for HPV MISTICS, a multilevel intervention to increase human papillomavirus (HPV) vaccination initiation and completion rates among adolescents aged 11-17. METHODS: We will conduct a hybrid type 1 implementation-effectiveness trial using a stepped-wedge cluster randomized trial in eight federally qualified health centers (FQHCs) in Florida. Intervention components target three levels: system, providers, and parents. Outcomes will be assessed using quantitative (e.g., vaccination data, survey data) and qualitative methods (e.g., staff and parent interviews). We expect to quantify changes in HPV vaccine series initiation and completion rates for adolescents ages 11-17 in the eight FQHCs. We have hypothesized a 20-percentage point increase in HPV vaccine series initiation and a 10-percentage point increase in series completion. We also anticipate being able to explore factors at the system, provider, and patient levels as potential covariates. Implementation outcomes, barriers, and facilitators identified in the study will help characterize the implementation process and inform potential future intervention scale-up. RESULTS: The project is ongoing; effectiveness and implementation outcomes will be determined following project completion. CONCLUSIONS: Findings will provide evidence of an equity-informed research design and implementation procedures that could help improve HPV vaccination rates in similar health systems. CLINICAL TRIALS IDENTIFIER: NCT05677360 (date registered: 2022-12-22); https://clinicaltrials.gov/study/NCT05677360?lead=Moffitt%20Cancer%20Center%20&aggFilters=status:rec&page=2&rank=17.