Two-arm Superiority Research Articles

Improvement in cardiac function but not structure in adults born preterm following a prescribed moderate to high intensity exercise intervention: a randomized clinical trial

Abstract Background People born preterm (<37 weeks’ gestation) have a potentially adverse cardiac phenotype that progresses with blood pressure elevation and may explain their increased risk of early heart failure and cardiovascular-related mortality. It remains unknown whether lifestyle or pharmacological interventions lead to beneficial left ventricle (LV) and right ventricle (RV) structural and/or functional changes in preterm-born adults. Purpose To determine whether preterm-born adults with elevated and stage 1 hypertension exhibit similar cardiac remodelling following a 16-week aerobic exercise intervention as their term-born peers with comparable blood pressures. Methods We conducted an open, parallel, two-arm superiority randomised controlled (1:1) trial in n=203 adults aged 18-35 years old with elevated or stage 1 hypertension. Participants were randomised to a 16-week aerobic exercise intervention targeting three, 60-minute supervised sessions per week at 60-80% peak heart rate (exercise intervention) or sign-posted to educational materials (controls). In a pre-specified cardiovascular magnetic resonance imaging (CMR) sub-study in n=100 individuals, CMR was performed before and after the 16-week intervention. Group differences in outcome variables after the intervention were examined using ANCOVA adjusting for baseline outcome variables, sex, and age. Interactions between birth category and intervention effect were investigated by including an interaction term in the intervention ANCOVA analyses. Results One hundred participants completed CMR scans at baseline and after the 16-week intervention, with n=47 in the exercise intervention group (n=26 term-born; n=21 preterm-born) and n=53 controls (n=32 term-born; n=21 preterm-born). Cardiac structural measures in preterm-born adults did not change following the intervention. However, term-born adults in the exercise intervention group decreased LV mass to end-diastolic volume ratio (adjusted mean difference: -0.03, 95% CI: -0.06,-0.01, interaction term p=0.027) and increased RV stroke volume (adjusted mean difference: 5.53mL/m2, 95% CI: 2.60,8.47, interaction term p=0.076) versus controls. Preterm-born adults in the exercise intervention group increased LV basal- and mid-ventricular circumferential strain versus controls (adjusted mean difference: -1.33%, 95% CI: -2.07,-0.60, interaction term p=0.057 and adjusted mean difference: -1.54%, 95% CI: -2.46,-0.63, interaction term p=0.046, respectively), which was not observed in term-born adults. Similarly, preterm-born adults improved RV longitudinal strain versus controls (adjusted mean difference: -0.51%, 95% CI: -1.49,0.46, interaction term p=0.053), which was also not observed in term-born adults. Conclusions Aerobic exercise training improves myocardial function but not cardiac structure in preterm-born adults. Modified exercise protocols or combination with pharmacological intervention may lead to additional cardiac remodelling benefits.

Breaking the cycle of reoccurring low back pain with integrated motivational interviewing and cognitive behavioural therapy to facilitate education and exercise advice: a superiority randomised controlled trial study protocol

BackgroundNon-specific low back pain is a common and costly global issue. Many people with low back pain live for years with ongoing symptom recurrence and disability, making it crucial to find effective prevention strategies. Motivational interviewing (MI) is an evidence-based patient-centred counselling style that helps motivate individuals to change their behaviours. In combination, MI and cognitive-behavioural therapy (MI-CBT) has the potential to yield long term improvements in pain and disability and reduce incidence of recurrence.MethodThis is a two-arm superiority randomised controlled trial comparing MI-CBT and Education (n = 83) with Education only (n = 83). Participants that have recovered from a recent episode of non-specific low back pain (7th consecutive day with pain ≤ 2 on a 0–10 numeric pain rating scale) will be eligible for inclusion into the study. Both groups will receive five 30-min sessions over a 10-week period as well as the Navigating Pain booklet, homework book and a standardised exercise programme. In the intervention group, MI-CBT techniques will be used to provide individualised support, identify beliefs, and increase engagement with the resources provided. Outcomes measures include pain (current and in the last 7 days) as rated on the numeric pain rating scale. This will be used to determine recurrence (number of participants who report back pain ≥ 3 out of 10 on the numeric pain rating scale). Furthermore, self-reported (1) pain intensity; (2) pain catastrophizing; (3) fear-avoidance beliefs; (4) pain self-efficacy; (5) depression and anxiety; (6) disability will be measured. All outcomes will be measured at baseline, and again at 3-, 6-, and 12-months post allocation.DiscussionThe effective delivery of self-management strategies to prevent recurrence of low back pain is an important aspect that requires urgent attention. This study will provide new information on the effectiveness of using an MI-CBT approach to facilitate self-management through education and exercise to improve low back pain outcomes. Evidence emerging from this trial has the potential to inform clinical practice and healthcare management of non-specific low back pain.Trial registrationProspectively registered with Australian New Zealand Clinical Trials Registry: ACTRN12623000746639 (10/07/2023).

Hybrid classical-Bayesian approach to sample size determination for two-arm superiority clinical trials

Abstract Traditional methods for Sample Size Determination (SSD) based on power analysis exploit relevant fixed values or preliminary estimates for the unknown parameters. A hybrid classical-Bayesian approach can be used to formally incorporate information or model uncertainty on unknown quantities by using prior distributions according to the Bayesian approach, while still analysing the data in a frequentist framework. In this paper, we propose a hybrid procedure for SSD in two-arm superiority trials, that takes into account the different role played by the unknown parameters involved in the statistical power. Thus, different prior distributions are used to formalize design expectations and to model information or uncertainty on preliminary estimates involved at the analysis stage. To illustrate the method, we consider binary data and derive the proposed hybrid criteria using three possible parameters of interest, i.e. the difference between proportions of successes, the logarithm of the relative risk and the logarithm of the odds ratio. Numerical examples taken from the literature are presented to show how to implement the proposed procedure.

Effectiveness of degradable polymer film in the management of severe or moderate intrauterine adhesions (PREG-2): a randomized, double-blind, multicenter, stratified, superiority trial

To study the effectiveness of a new intrauterine degradable polymer film (Womed Leaf®) in the management of moderate to severe IUA. PREG2 study was a multi-centre, double-blind, randomised, controlled, stratified, two-arm superiority clinical trial conducted in 16 centres in 7 countries. Patients ≥18 years scheduled for hysteroscopic adhesiolysis because of symptomatic severe or moderate adhesions (according to American fertility society (AFS) IUA score) were considered eligible for the study. Following adhesiolysis, patients were randomised at a 1:1 ratio to either have a Womed Leaf film inserted (intervention group) or not (control group). The primary effectiveness endpoint of the study was the change in AFS IUA score on second-look hysteroscopy (SLH), assessed by an independent evaluator, compared to baseline. Information on rate of no IUA and responder rate were collected as secondary effectiveness outcomes, and reported adverse events and patient reported outcomes as safety and tolerability measures. Between October 26, 2021, and September 28, 2023, a total of 160 women were randomised (Womed Leaf: n=75 and controls: n=85). The reduction in IUA AFS score on SLH was significantly higher in the intervention compared to the control group (mean 5.2 ± 2.8 vs. 4.2 ± 3.2; p=0.0153). Similarly, the absence of adhesions on SLH was significantly higher in the intervention group (41% vs 24% OR 2.44 [CI 1.161 - 5.116]; p=0.0189). None of the reported adverse events were serious or considered related to the device. Womed Leaf is effective and safe in the management of symptomatic severe or moderate intrauterine adhesions.

Squatting biomechanics following physiotherapist-led care or hip arthroscopy for femoroacetabular impingement syndrome: a secondary analysis from a randomised controlled trial.

Femoroacetabular impingement syndrome (FAIS) can cause hip pain and chondrolabral damage that may be managed non-operatively or surgically. Squatting motions require large degrees of hip flexion and underpin many daily and sporting tasks but may cause hip impingement and provoke pain. Differential effects of physiotherapist-led care and arthroscopy on biomechanics during squatting have not been examined previously. This study explored differences in 12-month changes in kinematics and moments during squatting between patients with FAIS treated with a physiotherapist-led intervention (Personalised Hip Therapy, PHT) and arthroscopy. A subsample (n = 36) of participants with FAIS enrolled in a multi-centre, pragmatic, two-arm superiority randomised controlled trial underwent three-dimensional motion analysis during squatting at baseline and 12-months following random allocation to PHT (n = 17) or arthroscopy (n = 19). Changes in time-series and peak trunk, pelvis, and hip biomechanics, and squat velocity and maximum depth were explored between treatment groups. No significant differences in 12-month changes were detected between PHT and arthroscopy groups. Compared to baseline, the arthroscopy group squatted slower at follow-up (descent: mean difference -0.04 m∙s-1 (95%CI [-0.09 to 0.01]); ascent: -0.05 m∙s-1 [-0.11 to 0.01]%). No differences in squat depth were detected between or within groups. After adjusting for speed, trunk flexion was greater in both treatment groups at follow-up compared to baseline (descent: PHT 7.50° [-14.02 to -0.98]%; ascent: PHT 7.29° [-14.69 to 0.12]%, arthroscopy 16.32° [-32.95 to 0.30]%). Compared to baseline, both treatment groups exhibited reduced anterior pelvic tilt (descent: PHT 8.30° [0.21-16.39]%, arthroscopy -10.95° [-5.54 to 16.34]%; ascent: PHT -7.98° [-0.38 to 16.35]%, arthroscopy -10.82° [3.82-17.81]%), hip flexion (descent: PHT -11.86° [1.67-22.05]%, arthroscopy -16.78° [8.55-22.01]%; ascent: PHT -12.86° [1.30-24.42]%, arthroscopy -16.53° [6.72-26.35]%), and knee flexion (descent: PHT -6.62° [0.56- 12.67]%; ascent: PHT -8.24° [2.38-14.10]%, arthroscopy -8.00° [-0.02 to 16.03]%). Compared to baseline, the PHT group exhibited more plantarflexion during squat ascent at follow-up (-3.58° [-0.12 to 7.29]%). Compared to baseline, both groups exhibited lower external hip flexion moments at follow-up (descent: PHT -0.55 N∙m/BW∙HT[%] [0.05-1.05]%, arthroscopy -0.84 N∙m/BW∙HT[%] [0.06-1.61]%; ascent: PHT -0.464 N∙m/BW∙HT[%] [-0.002 to 0.93]%, arthroscopy -0.90 N∙m/BW∙HT[%] [0.13-1.67]%). Exploratory data suggest at 12-months follow-up, neither PHT or hip arthroscopy are superior at eliciting changes in trunk, pelvis, or lower-limb biomechanics. Both treatments may induce changes in kinematics and moments, however the implications of these changes are unknown. Australia New Zealand Clinical Trials Registry reference: ACTRN12615001177549. Trial registered 2/11/2015.

Optimal sample size allocation for two-arm superiority and non-inferiority trials with binary endpoints.

The sample size of a clinical trial has to be large enough to ensure sufficient power for achieving the aim the study. On the other side, for ethical and economical reasons it should not be larger than necessary. The sample size allocation is one of the parameters that influences the required total sample size. For two-arm superiority and non-inferiority trials with binary endpoints, we performed extensive computations over a wide range of scenarios to determine the optimal allocation ratio that minimizes the total sample size if all other parameters are fixed. The results demonstrate, that for both superiority and non-inferiority trials the optimal allocation may deviate considerably from the case of equal sample size in both groups. However, the saving in sample size when allocating the total sample size optimally as compared to balanced allocation is typically small.

Development and testing the feasibility of a sports-based mental health promotion intervention in Nepal: a protocol for a pilot cluster-randomised controlled trial

BackgroundMental wellbeing encompasses life satisfaction, social connectedness, agency and resilience. In adolescence, mental wellbeing reduces sexual health risk behaviours, substance use and violence; improves educational outcomes; and protects mental health in adulthood. Mental health promotion seeks to improve mental wellbeing and can include activities to engage participants in sport. However, few high-quality trials of mental health promotion interventions have been conducted with adolescents, especially in low- and middle-income countries. We sought to address this gap by testing SMART (Sports-based Mental heAlth pRomotion for adolescenTs) in a pilot cluster-randomised controlled trial (cRCT) in Bardiya, Nepal.MethodsThe objectives of the trial are to assess the acceptability and feasibility of SMART, test trial procedures, explore outcome distributions in intervention and control clusters and calculate the total annual cost of the intervention and unit cost per adolescent. The trial design is a parallel-group, two-arm superiority pilot cRCT with a 1:1 allocation ratio and two cross-sectional census surveys with adolescents aged 12–19, one pre-intervention (baseline) and one post-intervention (endline). The study area is four communities of approximately 1000 population (166 adolescents per community). Each community represents one cluster. SMART comprises twice weekly football, martial arts and dance coaching, open to all adolescents in the community, led by local sports coaches who have received psychosocial training. Sports melas (festivals) and theatre performances will raise community awareness about SMART, mental health and the benefits of sport. Adolescents in control clusters will participate in sport as usual. In baseline and endline surveys, we will measure mental wellbeing, self-esteem, self-efficacy, emotion regulation, social support, depression, anxiety and functional impairment. Using observation checklists, unstructured observation and attendance registers from coaching sessions, and minutes of meetings between coaches and supervisors, we will assess intervention fidelity, exposure and reach. In focus group discussions and interviews with coaches, teachers, caregivers and adolescents, we will explore intervention acceptability and mechanisms of change. Intervention costs will be captured from monthly project accounts, timesheets and discussions with staff members.DiscussionFindings will identify elements of the intervention and trial procedures requiring revision prior to a full cRCT to evaluate the effectiveness of SMART.Trial registrationISRCTN, ISRCTN15973986, registered on 6 September 2022; ClinicalTrials.gov, NCT05394311, registered 27 May 2022.

Bayesian design and analysis of two-arm cluster randomized trials using assurance.

We consider the design of a two-arm superiority cluster randomized controlled trial (RCT) with a continuous outcome. We detail Bayesian inference for the analysis of the trial using a linear mixed-effects model. The treatment is compared to control using the posterior distribution for the treatment effect. We develop the form of the assurance to choose the sample size based on this analysis, and its evaluation using a two loop Monte Carlo sampling scheme. We assess the proposed approach, considering the effect of different forms of prior distribution, and the number of Monte Carlo samples needed in both loops for accurate determination of the assurance and sample size. Based on this assessment, we provide general advice on each of these choices. We apply the approach to the choice of sample size for a cluster RCT into poststroke incontinence, and compare the resulting sample size to that from assurance based on a Wald test for the treatment effect. The Bayesian approach to design and analysis developed in this article can offer advantages in terms of an increase in the robustness of the chosen sample size to parameter mis-specification and reduced sample sizes if prior information indicates the treatment effect is likely to be larger than the minimal clinically important difference.

Sample size estimation in clinical trials using ventilator-free days as the primary outcome: a systematic review

BackgroundVentilator-free days (VFDs) are a composite endpoint increasingly used as the primary outcome in critical care trials. However, because of the skewed distribution and competitive risk between components, sample size estimation remains challenging. This systematic review was conducted to systematically assess whether the sample size was congruent, as calculated to evaluate VFDs in trials, with VFDs’ distribution and the impact of alternative methods on sample size estimation.MethodsA systematic literature search was conducted within the PubMed and Embase databases for randomized clinical trials in adults with VFDs as the primary outcome until December 2021. We focused on peer-reviewed journals with 2021 impact factors greater than five. After reviewing definitions of VFDs, we extracted the sample size and methods used for its estimation. The data were collected by two independent investigators and recorded in a standardized, pilot-tested forms tool. Sample sizes were calculated using alternative statistical approaches, and risks of bias were assessed with the Cochrane risk-of-bias tool.ResultsOf the 26 clinical trials included, 19 (73%) raised “some concerns” when assessing risks of bias. Twenty-four (92%) trials were two-arm superiority trials, and 23 (89%) were conducted at multiple sites. Almost all the trials (96%) were unable to consider the unique distribution of VFDs and death as a competitive risk. Moreover, significant heterogeneity was found in the definitions of VFDs, especially regarding varying start time and type of respiratory support. Methods for sample size estimation were also heterogeneous, and simple models, such as the Mann–Whitney–Wilcoxon rank-sum test, were used in 14 (54%) trials. Finally, the sample sizes calculated varied by a factor of 1.6 to 17.4.ConclusionsA standardized definition and methodology for VFDs, including the use of a core outcome set, seems to be required. Indeed, this could facilitate the interpretation of findings in clinical trials, as well as their construction, especially the sample size estimation which is a trade-off between cost, ethics, and statistical power.Systematic review registration PROSPERO ID: CRD42021282304. Registered 15 December 2021 (https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021282304).

On Top of Everything: a study protocol for a cluster-randomised controlled trial testing a teacher training programme to teach mindfulness among students in Danish upper secondary schools and schools of health and social care

BackgroundMental health is decreasing among young people in Denmark. Our primary aim is to evaluate the effectiveness of a teacher training programme to teach mindfulness as part of regular classroom teaching in Danish upper secondary schools and schools of health and social care on students’ self-reported mental well-being 6 months from baseline. Secondary aims are (1) to evaluate the effectiveness in a vulnerable subgroup as well as in the total population of students 3 and 6 months from baseline using other outcome measures on mental health and (2) to investigate the facilitators and barriers among teachers to implement mindfulness in schools.MethodsThis pragmatic cluster-randomised two-arm superiority trial includes 30 upper secondary schools, 13 schools of health and social care, 76 teachers, and approximately 1100 students aged 16 to 24 years. Our intervention is multi-level and consists of (a) a teacher training programme and (b) a mindfulness programme delivered to students. Students in control schools receive education as usual. Our primary study population is the total population of students. The primary outcome is changes in the short version of the Warwick-Edinburgh Mental Well-Being Scale (SWEMWBS). We also evaluate the effectiveness in a vulnerable subgroup (the 15% with the lowest SWEMWBS score), as well as in the total population of students 3 and 6 months from baseline using other outcome measures on mental health. Data will be analysed using repeated measurement models taking clusters into account. Facilitators and barriers among teachers to implement mindfulness in schools will be investigated through qualitative focus group interviews.DiscussionThe trial will estimate the effectiveness of a population-based strategy on mental health in Danish young people enrolled in education.Trial registrationClinicalTrials.gov NCT04610333. Registered on October 10 2020.

Aerobic exercise increases brain vessel lumen size and blood flow in young adults with elevated blood pressure. Secondary analysis of the TEPHRA randomized clinical trial

ImportanceCerebrovascular changes are already evident in young adults with hypertension and exercise is recommended to reduce cardiovascular risk. To what extent exercise benefits the cerebrovasculature at an early stage of the disease remains unclear. ObjectiveTo investigate whether structured aerobic exercise increases brain vessel lumen diameter or cerebral blood flow (CBF) and whether lumen diameter is associated with CBF. DesignOpen, parallel, two-arm superiority randomized controlled (1:1) trial in the TEPHRA study on an intention-to-treat basis. The MRI sub-study was an optional part of the protocol. The outcome assessors remained blinded until the data lock. SettingSingle-centre trial in Oxford, UK. ParticipantsParticipants were physically inactive (<150 min/week moderate to vigorous physical activity), 18 to 35 years old, 24-hour ambulatory blood pressure 115/75 mmHg-159/99 mmHg, body mass index below 35 kg/m2 and never been on prescribed hypertension medications. Out of 203 randomized participants, 135 participated in the MRI sub-study. Randomisation was stratified for sex, age (<24, 24–29, 30–35 years) and gestational age at birth (<32, 32–37, >37 weeks). InterventionStudy participants were randomised to a 16 week aerobic exercise intervention targeting 3×60 min sessions per week at 60 to 80 % peak heart rate. Main outcomes and Measurescerebral blood flow (CBF) maps from ASL MRI scans, internal carotid artery (ICA), middle cerebral artery (MCA) M1 and M2 segments, anterior cerebral artery (ACA), basilar artery (BA), and posterior cerebral artery (PCA) diameters extracted from TOF MRI scans. ResultsOf the 135 randomized participants (median age 28 years, 58 % women) who had high quality baseline MRI data available, 93 participants also had high quality follow-up data available. The exercise group showed an increase in ICA (0.1 cm, 95 % CI 0.01 to 0.18, p =.03) and MCA M1 (0.05 cm, 95 % CI 0.01 to 0.10, p =.03) vessel diameter compared to the control group. Differences in the MCA M2 (0.03 cm, 95 % CI 0.0 to 0.06, p =.08), ACA (0.04 cm, 95 % CI 0.0 to 0.08, p =.06), BA (0.02 cm, 95 % CI −0.04 to 0.09, p =.48), and PCA (0.03 cm, 95 % CI −0.01 to 0.06, p =.17) diameters or CBF were not statistically significant. The increase in ICA vessel diameter in the exercise group was associated with local increases in CBF. Conclusions and RelevanceAerobic exercise induces positive cerebrovascular remodelling in young people with early hypertension, independent of blood pressure. The long-term benefit of these changes requires further study. Trial RegistrationClinicaltrials.gov NCT02723552, 30 March 2016

Online Parent Training for The Initial Management of ADHD referrals (OPTIMA): the protocol for a randomised controlled trial of a digital parenting intervention implemented to support parents and children on a treatment waitlist

BackgroundChildren referred for attention-deficit/hyperactivity disorder (ADHD) often present with a broader pattern of conduct problems including oppositionality and defiance. This combination can be extremely stressful to parents, lower parents’ self-esteem and negatively impact family life. The National Institute for Health and Care Excellence (NICE) recommends that families receive support as soon as possible after their referral. However, as clinical services are overstretched, and traditional in-person parenting intervention programmes are expensive, families often must wait times a long time prior to receiving this vital input. To address this, we have created a digital parenting programme called STEPS. It is delivered as a mobile phone app providing a set of tools and resources that can be easily accessed at parents’ convenience. This study aims to evaluate the clinical and cost-effectiveness of STEPS in supporting parents of children with high levels of hyperactivity/impulsivity, inattention and conduct problems, who are waiting to be assessed by specialist children’s clinical services.MethodsOnline Parent Training for The Initial Management of ADHD referrals (OPTIMA) is a two-arm superiority parallel randomised controlled trial with an internal pilot study. We aim to recruit 352 parents and their children, who have been accepted onto a waitlist in Child and Adolescent Mental Health Services or similar child health services. Parents who consent will be randomised 1:1 to either the STEPS or wait-as-usual (WAU) group. The trial will be conducted remotely (online and telephone) with measures taken at baseline and 3, 6, 9 and 12 months post-randomisation. The primary objective is to evaluate whether STEPS reduces the severity of children’s oppositional and defiant behaviour, as rated by parents, measured at 3 months post-randomisation compared to WAU.DiscussionDigital solutions, such as mobile phone apps, have potential for delivering psychological support for parents of children with clinical-level needs in a timely and inexpensive manner. This trial will provide data on the clinical and cost-effectiveness of the STEPS app, which could support the implementation of this scalable parenting intervention programme into standard clinical care and, ultimately, improve the outcomes for families of children referred to specialist child and adolescent health services.Trial registrationISRCTN 16523503. Prospectively registered on 18 November 2021. https://www.isrctn.com/ISRCTN16523503

Effectiveness of adjunct telephone-based postnatal care on maternal and infant illness in the Greater Accra Region, Ghana: a randomized controlled trial

IntroductionGlobally, postnatal care (PNC) is fraught with challenges. Despite high PNC coverages in Ghana’s Greater Accra Region (GAR), maternal and newborn health outcomes are of great concern. In 2017, neonatal and post-neonatal mortality rates in GAR were 19 and 13 per 1000 live births respectively despite PNC coverages of 93% for at least one PNC and 87.5% for PNC within 48 hours post-delivery. Telephone follow-up has been used to improve health outcomes in some settings, however, its usefulness in improving maternal and infant health during the postnatal period is not well known in Ghana. We assessed effectiveness of telephone-based PNC on infant and maternal illness in selected hospitals in GAR.MethodsAn open-label, assessor-blinded, parallel-group, two-arm superiority randomized controlled trial with 1:1 allocation ratio was conducted from September 2020 to March 2021. Mother-baby pairs in intervention arm, in addition to usual PNC, received midwife-led telephone counselling within 48 hours post-discharge plus telephone access to midwife during postnatal period. In control arm, only usual PNC was provided. Descriptive and inferential data analyses were conducted to generate frequencies, relative frequencies, risk ratios and 95% confidence intervals. Primary analysis was by intention-to-treat (ITT), complemented by per-protocol (PP) analysis.ResultsOf 608 mother-baby pairs assessed for eligibility, 400 (65.8%) were enrolled. During 3 months follow-up, proportion of infants who fell ill was 62.5% in intervention arm and 77.5% in control arm (p = 0.001). Maternal illness occurred in 27.5% of intervention and 38.5% of control participants (p = 0.02). Risk of infant illness was 20% less in intervention than control arm in both ITT analysis [RR = 0.8 (95%CI = 0.71–0.92] and PP analysis [RR = 0.8 (95%CI = 0.67–0.89)]. Compared to controls, risk of maternal illness in intervention arm was 30% lower in both ITT [RR = 0.7 (95%CI = 0.54–95.00)] and PP analysis [RR = 0.7 (95%CI = 0.51–0.94)].ConclusionTelephone-based PNC significantly reduced risk of maternal and infant illness within first 3 months after delivery. This intervention merits consideration as a tool for adoption and scale up to improve infant and maternal health.Trial registrationThis trial was retrospectively registered with the International Standard Randomized Controlled Trial Number (ISRCTN) Registry with number ISRCTN46905855 on 09/04/2021.

Comparing the usability of the World Health Organization's conventional tuberculosis guidelines to the eTB recommendations map: A two-arm superiority randomised controlled trial.

Best practices for the dissemination of global health guidelines has not undergone rigorous research. We used a new approach to digitizing World Health Organization (WHO) global tuberculosis guideline recommendations (eTB RecMap) and compared its usability to the conventional method of accessing TB recommendations using the WHO website. We conducted a two-arm superiority randomised controlled trial using a survey among global stakeholders who were past or planned future users of TB guidelines, recommendations, or policy advice. We assigned participants randomly (1:1) to complete an activity using the WHO eTB RecMap or the conventional website. The primary outcome was the accessibility of information and secondary outcomes understanding, satisfaction, and preference for one of the two formats. Between February 26 and August 29, 2021, we received 478 responses from stakeholders, of whom 244 (122 per group) were eligible and provided analysable results. Participants rated the eTB RecMap as more accessible, on average, when compared to the conventional website (on a seven-point scale, the mean difference {MD} was 0.9; 95% confidence interval {CI}: 0.6, 1.2; p < 0.001) and were more likely to correctly answer understanding questions. This is the first trial comparing digitized dissemination formats of health guideline recommendations. Stakeholders rated the WHO eTB RecMap as more accessible than the conventional WHO website for the tested recommendations. They also understood presented information better. The findings support better usability of TB information through the eTB RecMap and contribute to the effort to end the TB epidemic. Trial registration: This trial was registered with ClinicalTrials.gov (NCT04745897) on February 9, 2021.

Comparison of Walking Biomechanics After Physical Therapist–Led Care or Hip Arthroscopy for Femoroacetabular Impingement Syndrome: A Secondary Analysis From a Randomized Controlled Trial

Background: Femoroacetabular impingement syndrome is characterized by chondrolabral damage and hip pain. The specific biomechanics used by people with femoroacetabular impingement syndrome during daily activities may exacerbate their symptoms. Femoroacetabular impingement syndrome can be treated nonoperatively or surgically; however, differential treatment effects on walking biomechanics have not been examined. Purpose: To compare the 12-month effects of physical therapist–led care or arthroscopy on trunk, pelvis, and hip kinematics as well as hip moments during walking. Study Design: Secondary analysis of multi-centre, pragmatic, two-arm superiority randomized controlled trial subsample; Level of evidence, 1. Methods: A subsample of 43 participants from the Australian Full randomised controlled trial of Arthroscopic Surgery for Hip Impingement versus best cONventional (FASHIoN trial) underwent gait analysis and completed the International Hip Outcome Tool (iHOT-33) at both baseline and 12 months after random allocation to physical therapist–led care (personalized hip therapy; n = 22; mean age 35; 41% female) or arthroscopy (n = 21; mean age 36; 48% female). Changes in trunk, pelvis, and hip biomechanics were compared between treatment groups across the gait cycle using statistical parametric mapping. Associations between changes in iHOT-33 and changes in hip kinematics across 3 planes of motion were examined. Results: As compared with the arthroscopy group, the personalized hip therapy group increased its peak hip adduction moments (mean difference = 0.35 N·m/body weight·height [%] [95% CI, 0.05-0.65]; effect size = 0.72; P = .02). Hip adduction moments in the arthroscopy group were unchanged in response to treatment. No other between-group differences were detected. Improvements in iHOT-33 were not associated with changes in hip kinematics. Conclusion: Peak hip adduction moments were increased in the personalized hip therapy group and unchanged in the arthroscopy group. No biomechanical changes favoring arthroscopy were detected, suggesting that personalized hip therapy elicits greater changes in hip moments during walking at 12-month follow-up. Twelve-month changes in hip-related quality of life were not associated with changes in hip kinematics.

Bayesian Design of Superiority Trials: Methods and Applications

In this article, we lay out the basic elements of Bayesian sample size determination (SSD) for the Bayesian design of a two-arm superiority clinical trial. We develop a flowchart of the Bayesian SSD that highlights the critical components of a Bayesian design and provides a practically useful roadmap for designing a Bayesian clinical trial in real world applications. We empirically examine the amount of borrowing, the choice of noninformative priors, and the impact of model misspecification on the Bayesian Type I error and power. A formal and statistically rigorous formulation of conditional borrowing within the decision rule framework is developed. Moreover, by extending the partial borrowing power priors, a new borrowing-by-parts power prior for incorporating historical data is proposed. Computational algorithms are also developed to calculate the Bayesian Type I error and power. Extensive simulation studies are carried out to explore the operating characteristics of the proposed Bayesian design of a superiority trial.

Factors associated with altmetric attention scores for randomized phase III cancer clinical trials.

11014 Background: The rise of the internet and social media has created new opportunities for the rapid sharing of scientific findings among professional and public communities. Altmetric Attention Scores (Altmetrics) are real-time measures of scientific impact and attention through various public outlets, including news, blogs, and social media. Distributions and patterns of Almetrics for high-impact clinical cancer research remain under-reported. Our goal was to describe the relationship between Altmetrics and other characteristics of published trials. Methods: We identified all two-arm superiority phase III cancer randomized controlled trials (RCTs) with a publication date between 2015-2020 from HemOnc.org. For included trials, we tabulated the followed the data: Altmetric score as of February 11, 2022; positive study (yes/no); FDA registration trial (yes/no); primary endpoint (categorized as overall survival (OS), progression-free survival (PFS), event-free/disease-free survival (EFS/DFS), or other); journal tier (defined as tier 1: NEJM, Lancet, JAMA; tier 2: JCO, Blood, Lancet Oncology, JAMA Oncology, Annals of Oncology or Tier 3: other). Univariable testing was performed with Pearson correlation, Wilcoxon rank sum, and Kruskal-Wallis testing to identify associations between predictor variables and Altmetrics. For factors with significant univariable associations, we generated a multiple linear regression model to identify clinical trial factors predictive of Altmetric attention scores, with alpha = 0.05 defining statistical significance. Results: Of 673 publications identified per inclusion/exclusion criteria, Altmetric scores were found for 638 (95%). The median score was 38.9 (IQR 12.4-126.7) – well above the 95th percentile for all Altmetric scores. On univariable testing, positive studies (P &lt; 0.001), registration trials (P &lt; 0.001), those published in tier 1 journals (P &lt; 0.001), and trials with primary endpoint of OS (P = 0.002) were associated with increased Altmetric scores. On multivariable testing, positive studies (P = 0.006), registration trials (P &lt; 0.001), studies published tier 1 journals (P &lt; 0.001), and those reporting on OS (P = 0.03) persisted as significantly associated with increased engagement as measured by Altmetric scores. Conclusions: Social media and other online platforms represent an increasingly important avenue for the sharing of scientific and medical research. In this cross-sectional observational study, we found that certain characteristics of cancer clinical trials and publications are predictive of impact as measured by Altmetric scores. Specifically, positive registration trials published in traditionally defined high-impact journals and those reporting on OS as a primary endpoint tend to have the greatest Altmetric attention scores. The significance and consequences of these relationships warrant further investigation.

Multi-centre randomised controlled trial comparing arthroscopic hip surgery to physiotherapist-led care for femoroacetabular impingement (FAI) syndrome on hip cartilage metabolism: the Australian FASHIoN trial

BackgroundArthroscopic surgery for femoroacetabular impingement syndrome (FAI) is known to lead to self-reported symptom improvement. In the context of surgical interventions with known contextual effects and no true sham comparator trials, it is important to ascertain outcomes that are less susceptible to placebo effects. The primary aim of this trial was to determine if study participants with FAI who have hip arthroscopy demonstrate greater improvements in delayed gadolinium-enhanced magnetic resonance imaging (MRI) of cartilage (dGEMRIC) index between baseline and 12 months, compared to participants who undergo physiotherapist-led management.MethodsMulti-centre, pragmatic, two-arm superiority randomised controlled trial comparing physiotherapist-led management to hip arthroscopy for FAI. FAI participants were recruited from participating orthopaedic surgeons clinics, and randomly allocated to receive either physiotherapist-led conservative care or surgery. The surgical intervention was arthroscopic FAI surgery. The physiotherapist-led conservative management was an individualised physiotherapy program, named Personalised Hip Therapy (PHT). The primary outcome measure was change in dGEMRIC score between baseline and 12 months. Secondary outcomes included a range of patient-reported outcomes and structural measures relevant to FAI pathoanatomy and hip osteoarthritis development. Interventions were compared by intention-to-treat analysis.ResultsNinety-nine participants were recruited, of mean age 33 years and 58% male. Primary outcome data were available for 53 participants (27 in surgical group, 26 in PHT). The adjusted group difference in change at 12 months in dGEMRIC was -59 ms (95%CI − 137.9 to - 19.6) (p = 0.14) favouring PHT. Hip-related quality of life (iHOT-33) showed improvements in both groups with the adjusted between-group difference at 12 months showing a statistically and clinically important improvement in arthroscopy of 14 units (95% CI 5.6 to 23.9) (p = 0.003).ConclusionThe primary outcome of dGEMRIC showed no statistically significant difference between PHT and arthroscopic hip surgery at 12 months of follow-up. Patients treated with surgery reported greater benefits in symptoms at 12 months compared to PHT, but these benefits are not explained by better hip cartilage metabolism.Trial registration detailsAustralia New Zealand Clinical Trials Registry reference: ACTRN12615001177549. Trial registered 2/11/2015.

Mental health specialist video consultations versus treatment as usual in patients with depression or anxiety disorders in primary care: study protocol for an individually randomised superiority trial (the PROVIDE-C trial)

BackgroundMost people with mental disorders, including those with severe and chronic disorders, are treated solely by their general practitioner (GP). Nevertheless, specialised mental health care may be required for specific patients. Notably, the accessibility of mental health specialist care is mainly complicated by (a) long waiting times for an appointment with specialists, (b) long travel distances to specialists, particularly in rural and remote areas, and (c) patients’ reservations about mental health specialist care (including fear of being stigmatised by seeking such care). To mitigate those barriers, technology-based integrated care models have been proposed. The purpose of this study is to examine the effectiveness and cost-effectiveness of a mental health specialist video consultations model versus treatment as usual in patients with depression or anxiety disorders in primary care.MethodsIn an individually randomised, prospective, two-arm superiority trial with parallel group design, N = 320 patients with anxiety and/or depressive disorder will be recruited in general practices in Germany. The intervention includes a newly developed treatment model based on video consultations with focus on diagnostics, treatment planning, and short-term intervention by mental health specialists. We will systematically compare the effectiveness, cost-effectiveness, and adverse effects of this new model with usual care by the GP: the primary outcome is the absolute change in the mean depressive and anxiety symptom severity measured on the Patient Health Questionnaire Anxiety and Depression Scale (PHQ-ADS) from baseline to 6 months after baseline assessment. Follow-up in both groups will be conducted by blinded outcome assessors at 6 months and 12 months after baseline. The main analysis will be based on the intention-to-treat principle. We will optimise the likelihood of treatment effectiveness by strict inclusion criteria for patients, enhanced intervention integrity, and conducting a process evaluation.DiscussionTo the best of our knowledge, this is the first confirmatory study on a video-based, integrated care model for the treatment of anxiety and depressive disorders in GP patients in Germany.Trial registrationClinicalTrials.gov, United States National Institutes of Health NCT04316572. Prospectively registered on 20 March 2020.

Evaluation of FindMyApps: protocol for a randomized controlled trial of the effectiveness and cost-effectiveness of a tablet-based intervention to improve self-management and social participation of community-dwelling people with mild dementia, compared to usual tablet use

BackgroundFor the rising number of people living with dementia, cost-effective community-based interventions to support psychosocial care are needed. The FindMyApps intervention has been developed with and for people with dementia and their caregivers, to help them use tablets to facilitate self-management and engagement in meaningful social activities. A feasibility study and exploratory pilot trial evaluating FindMyApps have been carried out. This definitive trial further evaluates the effectiveness of the intervention and, for the first time, the cost-effectiveness.MethodsA randomized controlled non-blinded single-center two-arm superiority trial will be conducted. Community-dwelling people with Mild Cognitive Impairment (MCI), or dementia with a Mini Mental-State Examination (MMSE) of > 17 and < 26, or Global Deterioration Scale 3 or 4, with an informal caregiver and access to a wireless internet connection will be included. In total, 150 patient-caregiver dyads will be randomly allocated to receive either usual care (control arm – tablet computer; n = 75 dyads) or usual care and the FindMyApps intervention (experimental arm – tablet computer and FindMyApps; n = 75 dyads). The primary outcomes are: for people with dementia, self-management and social participation; for caregivers, sense of competence. In addition to a main effect analysis, a cost-effectiveness analysis will be performed. In line with MRC guidance for evaluation of complex interventions a process evaluation will also be undertaken.DiscussionResults of the trial are expected to be available in 2023 and will be submitted for publication in international peer-reviewed scientific journals, in addition to conference presentations and reporting via the EU Marie Sklodowska-Curie DISTINCT ITN network. By providing evidence for or against the effectiveness and cost-effectiveness of the FindMyApps intervention, the results of the trial will influence national implementation of FindMyApps. We hope that the results of the trial will further stimulate research and development at the intersection of technology and psycho-social care in dementia. We hope to further demonstrate that the randomized controlled trial is a valuable and feasible means of evaluating new digital technologies, to stimulate further high-quality research in this growing field.Trial registration numberNetherlands Trial Register: NL8157; registered 15th November 2019.