Randomized Intervention Groups Research Articles

Sample size calculation for randomized trials via inverse probability of response weighting when outcome data are missing at random.

Randomized trials are an established method to evaluate the causal effects of interventions. Despite concerted efforts to retain all trial participants, some missing outcome data are often inevitable. It is unclear how best to account for missing outcome data in sample size calculations. A standard approach is to inflate the sample size by the inverse of one minus the anticipated dropout probability. However, the performance of this approach in the presence of informative outcome missingness has not been well-studied. We investigate sample size calculation when outcome data are missing at random given the randomized intervention group and fully observed baseline covariates under an inverse probability of response weighted (IPRW) estimating equations approach. Using M-estimation theory, we derive sample size formulas for both individually randomized and cluster randomized trials (CRTs). We illustrate the proposed method by calculating a sample size for a CRT designed to detect a difference in HIV testing strategies under an IPRW approach. We additionally develop an R shiny app to facilitate implementation of the sample size formulas.

Analysis of Maternal Prenatal Weight and Offspring Cognition and Behavior: Results From the Promotion of Breastfeeding Intervention Trial (PROBIT) Cohort

Prenatal experiences can influence fetal brain development. To examine associations of maternal prenatal body mass index (BMI) with cognition and behavior of offspring born full-term. This cohort study examined follow-up data from a breastfeeding promotion intervention at 31 hospitals and affiliated polyclinics in the Republic of Belarus. Participants included 11 276 children who were evaluated from birth (1996-1997) to adolescence (2017-2019), with maternal BMI information available in prenatal medical records. Maternal BMI, calculated as weight in kilograms divided by height in meters squared, after 35 weeks gestation; secondary analyses examined maternal BMI at other time points and paternal BMI. Trained pediatricians assessed child cognition with the Wechsler Abbreviated Scales of Intelligence (WASI) at 6.5 years and the computerized self-administered NeuroTrax battery at 16 years, both with an approximate mean (SD) of 100 (15). Parents and teachers rated behaviors at 6.5 years using the Strengths and Difficulties Questionnaire (SDQ, range 0-40). Mixed-effects linear regression analyses corrected for clustering, adjusted for the randomized intervention group and baseline parental sociodemographic characteristics, and were considered mediation by child BMI. Among 11 276 participants, 9355 women (83%) were aged 20 to 34 years, 10 128 (89.8%) were married, and 11 050 (98.0%) did not smoke during pregnancy. Each 5-unit increase in of maternal late-pregnancy BMI (mean [SD], 27.2 [3.8]) was associated with lower offspring WASI performance intelligence quotient (IQ) (-0.52 points; 95% CI, -0.87 to -0.17 points) at 6.5 years and lower scores on 5 of 7 NeuroTrax subscales and the global cognitive score at 16 years (-0.67 points; 95% CI, -1.06 to -0.29 points). Results were similar after adjustment for sociodemographic characteristics, pregnancy complications, and paternal BMI and were not mediated by child weight. Higher late pregnancy maternal BMI was also associated with more behavioral problems reported on the SDQ by teachers but not associated with parent-reported behaviors (externalizing behaviors: 0.13 points; 95% CI, 0.02 to 0.24 points; and total difficulties: 0.14 points, 95% CI, -0.02 to 0.30 points). Results were similar for maternal BMI measured in the first trimester or postpartum. In contrast, higher 6.5-year paternal BMI was associated with slightly better child cognition (WASI verbal IQ: 0.42 points; 95% CI, 0.02 to 0.82 points; NeuroTrax executive function score: 0.68 points; 95% CI, 0.24 to 1.12 points) and fewer teacher-reported behavioral problems (total difficulties: -0.29 points; 95% CI, -0.46 to -0.11 points). This cohort study supports findings from animal experiments and human observational studies in settings with higher maternal BMI and obesity rates. Higher maternal prenatal BMI may be associated with poorer offspring brain development, although residual confounding cannot be excluded.

Mortality Outcomes With Intensive Blood Pressure Targets in Chronic Kidney Disease Patients.

Hypertension is highly prevalent and morbid in the chronic kidney disease population, and blood pressure (BP) targets for this population are unclear. We aimed to compare all-cause mortality outcomes with intensively targeting systolic BP to <130 mm Hg versus a standard of <140 mm Hg. Individual patient data from 4983 chronic kidney disease patients with hypertension were pooled from 4 multicenter randomized control trials-AASK (African American Study of Kidney Disease and Hypertension), ACCORD (Action to Control Cardiovascular Risk in Diabetes), MDRD (Modification of Diet in Renal Disease), and the SPRINT (Systolic Blood Pressure Intervention Trial). Patients were assigned their trial-assigned randomized intervention group-standard (n=2474) versus intensive (n=2509) BP targets. Additional analyses included excluding patients with a glomerular filtration rate ≥60 mL/min per 1.73 m2 along with those undergoing intensive glycemic control. The primary outcome was all-cause mortality. Average achieved BP was 125.0 mm Hg in the intensive group and 136.9 mm Hg in the standard group. In the primary analysis, the all-cause mortality rate trended towards improved outcomes with intensive treatment but was not statistically significant (hazard ratio: 0.87 [0.69-1.08]; P=0.21). One hundred seventy-three of 2474 patients (1.95% per year) in the standard group and 153 of 2509 patients (1.71% per year) in the intensive group died. After excluding patients with higher glomerular filtration rate values and those undergoing intensive glycemic control, there was a statistically significant decrease in all-cause mortality rate (hazard ratio: 0.79 [0.63-1.00]; P=0.048). An intensive BP target of <130 mm Hg decreases all-cause mortality when compared with a standard target of <140 mm Hg in patients with chronic kidney disease stage 3 or greater who are not undergoing intensive glycemic therapy.

Influence of a periodized circuit training protocol on intermuscular adipose tissue of patients with knee osteoarthritis: protocol for a randomized controlled trial

BackgroundThe objective of this study is to analyze the influence of a 14-week periodized circuit training protocol on patients with knee osteoarthritis (OA), in randomized intervention groups, on thigh intermuscular adipose tissue (interMAT), body composition, systemic inflammation, cartilage degradation, and its repercussion on pain, functional performance and quality of life.MethodsThis study presents a protocol for a randomized controlled trial. Sixty selected participants diagnosed with knee OA grades II and III, 40–65 years old and BMI < 30 kg/m2, will be randomly divided into three groups:periodized circuit training, strength training, and educational protocol. The circuit training and strength training protocols consist of 14-week training protocols conducted 3 times a week. The circuit training group will perform selected exercises previously stratified as light, moderate, and intense, arranged progressively in a circuit model, the strength group will perform regular strength exercises, and the educational protocol group will participate in a 14-week protocol with lectures twice a month about healthy lifestyles. Baseline and follow-up evaluations will be conducted for thigh interMAT (computed tomography), body composition (DXA), inflammation (IL-1β, IL-6, IL-10, TNF-α, leptin, and adiponectin), and joint degradation biomarkers (uCTX-II and sCOMP), performance-based tests (30s Chair Stand Test, 40 m Fast-paced Walk Test and Stair Climb Test), quadriceps and hamstring maximal isometric voluntary contraction (MIVC), and questionnaires (WOMAC and pain catastrophizing scale). Repeated measures ANOVA will be used to compare differences between groups (circuit training X strength training X educational protocol) at the different times of assessment (baseline x follow-up or baseline x during protocol x follow-up) for each of the dependent variables. When significant main effects were found, the pots hoc Bonferroni test will be used to identify statistical differences. A significance level of 5% (p < 0.05) will be adopted.DiscussionThis will be the first randomized controlled trial to assess the effects of a circuit training protocol on patients with knee OA on thigh intermuscular adipose tissue (interMAT). Given the prevalence and impact of OA and the widespread availability of this intervention, assessing the efficacy of a low-cost, non-pharmacological, and non-invasive treatment for knee OA patients has the potential for immediate and high clinical impact.Trial registrationClinicalTrials.gov, NCT02761590, registered in May 4, 2016.

A4214 The Rationale, Design, and Baseline Characteristics of BP-CONNECT

Objectives: Only 13.8% of 27 million hypertension patients controlled their BP in China. Although mhealth technology have been used in many health improvement context, rigorous evidence is still rarely seen. Practical and well-designed study is needed to evaluate the efficacy in patients with uncontrolled hypertension with modern mhealth technology. To determine whether an intervention that combines usual routine care, mHealth based home BP telemonitoring, patient case management with community health workers and virtual social media support improves BP control comparing with usual care plus normal BP telemonitoring at 6,12 and 18 months in patients with uncontrolled hypertension in primary care settings. Methods: The BP-CONNET study was designed as a community-based multi-center open-labeled randomized controlled comparative effectiveness trial conducted in Beijing China. Results: Between January 2017 and June 2017, BP-CONNET enrolled 601 hypertensive patients with uncontrolled BP from 19 community health centers. Three hundred and seven patients were randomized intervention group which provide mobile internet base home BP monitoring plus case management with community health worker and WeChat based virtual social media support. Two hundred and ninety-four were randomized to control group which provide usual care and normal BP telemonitoring. For the intervention group, physicians and community health workers collaborated through mobile internet based on the home BP data to provide BP case management services. The length of the intervention is 12 months, with follow-up to 18 months to determine the durability of the intervention. Conclusion: The results will provide important new evidence regarding effects of this intervention model in real world community clinic settings and primary care hypertensive population.

Abstract P121: The Effect of Intensive Blood Pressure Targets on Mortality in Chronic Kidney Disease Patients: An Individual Patient Data Meta-Analysis of Randomized Controlled Trials

Introduction: Current evidence is conflicting on whether intensive blood pressure (BP) management, specifically with targets of &lt;130/90 mmHg, produces a mortality benefit in non-diabetic chronic kidney disease (CKD) patients. MDRD, AASK, and SPRINT are the largest randomized controlled trials available investigating intensive targets in CKD patients. The MDRD and AASK recruited exclusively CKD patients, while SPRINT had a large CKD subpopulation within its cohort. MDRD assigned patients to a standard mean arterial pressure (MAP) target of 107 mmHg vs. an intensive target of 92 mmHg (achieved BPs of 134/81 mmHg vs 126/77 mmHg, respectively). AASK assigned African American patients to a MAP of 102-107 mmHg vs. &lt;92 mmHg (achieved BPs of 141/85 mmHg vs. 128/78 mmHg, respectively). SPRINT compared a systolic target of 140 mmHg vs. 120 mmHg (achieved BPs of 137/74 vs. 123/67 in the CKD subpopulation). Our study pools individual patient data (IPD) from these three trials. Methods: IPD for all patients in MDRD, AASK, and SPRINT were obtained and screened for non-diabetic CKD patients. The resulting 4537 patients were assigned to their original randomized intervention group – 2258 patients to the standard group and 2279 to the intensive group. The primary outcome was mortality. Statistical analysis for primary outcome was performed with Cox proportional hazards models stratified by clinical site/center. Interactions between outcome and trial enrollment were also assessed. Results: There was no statistically significant difference in mortality rate between intensive and standard BP control (HR: 0.84; 95% CI: 0.66, 1.07; p = 0.148). 126 patients (5.5%) in the intensive group and 149 patients (6.6%) in the standard group expired. No interaction was present between treatment and trial enrollment (MDRD, AASK, SPRINT) (p-value of interaction: 0.080). Conclusion: Intensive BP targets do not improve mortality for non-diabetic patients with CKD. Further investigation needs to be performed to determine if this lack of benefit is consistent across subpopulations.

Work-Related Medical Rehabilitation in Cancer Rehabilitation - Short-Term Results from a Cluster-Randomized Multicenter-Trial

Rehabilitation programs that support return to work become increasingly relevant for cancer survivors. In Germany, such programs were established as work-related medical rehabilitation (WMR). The study investigated whether WMR leads to better results compared to medical rehabilitation (MR). We report effects on secondary outcomes when the rehabilitation program was completed. Clusters of participants were randomly assigned to WMR or MR. Patients of working age and an elevated risk of not returning to work were included. The grade of implementation was assessed by dose delivered and dose received. Study outcomes were assessed using scales measuring functioning and symptoms, coping with illness as well as self-reported work ability. Treatment effects were estimated using mixed linear models. From 232 planned randomized intervention groups, 165 (71%) were realized. In total, 476 patients were included. Mean age of participants was 50.7 years (SD=7.3). Most frequent primary diagnoses were malignant neoplasms of the breast. Participants in the WMR program reported significantly better outcomes regarding quality of life (SMD=0.17-0.25), fatigue (SMD=0.18-0.27), coping with illness (SMD=0.17-0.22), and self-reported work-ability (SMD=0.16) compared to participants in MR program (all p<0.05). The results indicate a positive effect in favor of WMR for cancer patients with an elevated risk of not returning to work at the end of their treatment.

Social Cognitive Constructs Did Not Mediate the BEAT Cancer Intervention Effects on Objective Physical Activity Behavior Based on Multivariable Path Analysis.

Most breast cancer survivors do not meet physical activity recommendations. Understanding mediators of physical activity behavior change can improve interventions designed to increase physical activity in this at-risk population. Study aims were to determine the 3-month Better Exercise Adherence after Treatment for Cancer (BEAT Cancer) behavior change intervention effects on social cognitive theory constructs and the mediating role of any changes on the increase in accelerometer-measured physical activity previously reported. Post-treatment breast cancer survivors (N=222) were randomized to BEAT Cancer or usual care. Assessments occurred at baseline, 3months (M3), and 6months (M6). Adjusted linear mixed model analysis of variance determined intervention effects on walking self-efficacy, outcome expectations, goal setting, and perceived barrier interference at M3. Path analysis determined mediation of intervention effects on physical activity at M6 by changes in social cognitive constructs during the intervention (i.e., baseline to M3). BEAT Cancer significantly improved self-efficacy, goals, negative outcome expectations, and barriers. Total path analysis model explained 24% of the variance in M6 physical activity. There were significant paths from randomized intervention group to self-efficacy (β=0.15, p<.05) and barriers (β=-0.22, p<.01). Barriers demonstrated a borderline significant association with M6 physical activity (β=-0.24, p=.05). No statistically significant indirect effects were found. Although BEAT Cancer significantly improved social cognitive constructs, no significant indirect effects on physical activity improvements 3months post-intervention were observed (NCT00929617).

Predictors of Participation in the Family Check-Up Program: a Randomized Trial of Yearly Services from Age 2 to 10 Years.

A key challenge of community-based prevention programs is engaging families in the context of services settings involving children and families. The Family Check-Up (FCU) program is designed to engage families in parenting support appropriate to their level of need by use of assessment-enhanced motivational interviewing. This study involved families screened for risk who were seeking services at women, infant, and children's offices in three geographical regions (N = 731). Families in the randomized intervention group (N = 367) were offered the FCU yearly, from age 2 through 10. The results of multivariate modeling indicated that caregivers reporting high levels of perceived caregiving stress (i.e., depression, low parenting satisfaction, daily hassles) participated at a higher rate in two critical components (feedback and follow-up support interventions) of the FCU program over the 8-year trial period than caregivers reporting lesser degrees of stress. The implications of these findings are discussed in the context of family-centered programs for the prevention of child behavior problems and directions for future research.

Emergency Department Management of Sepsis Patients: A Randomized, Goal-Oriented, Noninvasive Sepsis Trial

The noninvasive cardiac output monitor and passive leg-raising maneuver has been shown to be reasonably accurate in predicting fluid responsiveness in critically ill patients. We examine whether using a noninvasive protocol would result in more rapid lactate clearance after 3 hours in patients with severe sepsis and septic shock in the emergency department. In this open-label randomized controlled trial, 122 adult patients with sepsis and serum lactate concentration of greater than or equal to 3.0 mmol/L were randomized to receive usual care or intravenous fluid bolus administration guided by measurements of change of stroke volume index, using the noninvasive cardiac output monitor after passiveleg-raising maneuver. The primary outcome was lactate clearance of more than 20% at 3 hours. Secondary outcomes included mortality, length of hospital and ICU stay, and total hospital cost. Analysis was intention to treat. Similar proportions of patients in the randomized intervention group (70.5%; N=61) versus control group (73.8%; N=61) achieved the primary outcome, with a relative risk of 0.96 (95% confidence interval [CI] 0.77 to 1.19). Secondary outcomes were similar in both groups (P>.05 for all comparisons). Hospital mortality occurred in 6 patients (9.8%) each in the intervention and control groups on or before 28 days (relative risk=1.00; 95% CI 0.34 to 2.93). Among a subgroup of patients with underlying fluid overload states, those in the intervention group tended to receive clinically significantly more intravenous fluids at 3 hours (difference=975 mL; 95% CI -450 to 1,725 mL) and attained better lactate clearance (difference=19.7%; 95% CI -34.6% to 60.2%) compared with the control group, with shorter hospital lengths of stay (difference=-4.5 days; 95% CI -9.5 to 2.5 days). Protocol-based fluid resuscitation of patients with severe sepsis and septic shock with the noninvasive cardiac output monitor and passive leg-raising maneuver did not result in better outcomes compared with usual care. Future studies to demonstrate the use of the noninvasive protocol-based care in patients with preexisting fluid overload states may be warranted.

Higher Prehospital Priority Level of Stroke Improves Thrombolysis Frequency and Time to Stroke Unit

Early initiated treatment of stroke increases the chances of a good recovery. This randomized controlled study evaluates how an increased priority level for patients with stroke, from level 2 to 1, from the Emergency Medical Communication Center influences thrombolysis frequency, time to stroke unit, and whether other medical emergencies reported negative consequences. Patients aged 18 to 85 years in Stockholm, Sweden, with symptoms of stroke within 6 hours were randomized from the Emergency Medical Communication Center or emergency medical services to an intervention group, priority level 1, immediate call of an ambulance, or to a control group with standard priority level, that is, priority level 2 (within 30 minutes). Before study start, an educational program on identification of stroke and importance of early initiated treatment was directed to all medical dispatchers and ambulance and emergency department personnel. During 2008, 942 patients were randomized of which 53% (n=496) had a final stroke/transient ischemic attack diagnosis. Patients in the Emergency Medical Communication Center randomized intervention group reached the stroke unit 26 minutes earlier than the control group (P<0.001) after the emergency call. Thrombolysis was given to 24% of the patients in the intervention group compared with 10% of the control subjects (P<0.001). The higher priority level showed no negative effect on other critical ill patients requiring priority level 1 prehospital attention. This randomized study shows negligible harm to other medical emergencies, a significant increase in thrombolysis frequency, and a shorter time to the stroke unit for patients with stroke upgraded to priority level 1 from the Emergency Medical Communication Center and through the acute chain of stroke care.

Experiencing flow in different types of physical activity intervention programs: three randomized studies

This study explores whether inactive individuals can experience flow, a rewarding, psychological state, during an exercise intervention and if there are differences according to the type of intervention they perform. Furthermore, the study investigates if experiencing flow is connected to physiological improvements attained during the exercise intervention. The 12- to 16-week interventions included six randomized intervention groups, two female and four male groups performing continuous running, football, interval running and strength training. The results indicate that all six randomized exercise intervention groups experience rather high levels of flow regardless of whether the intervention is a team or individual sport. Differences in experiencing flow, worry and exertion as well as physiological improvements could be found for the different types of sports and the two genders, with the male football group having the highest score for physiological improvement and the lowest score for worry. A connection between experiencing flow and physiological improvement could not be found. Future research should investigate the influence that the participant's gender and also the type of sport have on experiencing flow, worry and perceived exertion. Furthermore, it should be investigated whether experiencing flow is linked to the long-term compliance of regular physical activity.