Complier Average Causal Effect Analysis Research Articles

Comparison of diclofenac with tramadol, tizanidine or placebo in the treatment of acute low back pain and sciatica: multi-center randomized controlled trial.

Low back pain (LBP) is a leading cause of disability worldwide and has posed numerous health and socioeconomic challenges. This study compared whether nonsteroidal anti-inflammatory drugs (NSAIDs) in combination with tramadol, tizanidine or placebo would be the best treatment regime to improve the Roland Morris Disability Questionnaire (RMDQ) scores at 1 week. This was a multi-center, double-blind, randomized, and placebo-controlled trial including adult patients with acute LBP and sciatica in three emergency departments in Hong Kong. Patients were randomized to the receive tramadol 50mg, tizanidine 2mg, or placebo every 6hours for 2weeks in a 1:1:1 ratio. The RMDQ and other secondary outcomes were measured at baseline, Day 2, 7, 14, 21, and 28. Data were analyzed on an intention to treat basis. Crude and adjusted mean differences in the changes of RMDQ and NRS scores from baseline to Day 7 between tizanidine/tramadol and placebo were determined with 95% confidence intervals. Two hundred and ninety-one patients were analyzed with the mean age of 47.4years and 57.7% were male. The primary outcome of mean difference in RMDQs on Day 7 (compared with baseline) was non-significant for tizanidine compared with placebo (adjusted mean difference - 0.56, 95% CI -2.48 to 1.37) and tramadol compared with placebo (adjusted mean difference - 0.85, 95% CI -2.80 to 1.10). Only 23.7% were fully compliant to the treatment allocated. Complier Average Causal Effect analysis also showed no difference in the primary outcome for the tizanidine and tramadol versus placebo. Among patients with acute LBP and sciatica presenting to the ED, adding tramadol or tizanidine to diclofenac did not improve functional recovery.

Power Analyses for Estimation of Complier Average Causal Effects Under Random Encouragement Designs in Education Research: Theory and Guidance

Random encouragement designs evaluate treatments that aim to increase participation in a program or activity. These randomized controlled trials (RCTs) can also assess the mediated effects of participation itself on longer term outcomes using a complier average causal effect (CACE) estimation framework. This article considers power analysis methods for such CACE analyses for a range of RCT designs, including nonclustered, clustered, and random block designs. The focus is on behavioral encouragements to promote action, such as text messaging, that are increasingly being tested in education trials. We derive asymptotic distributions of the CACE estimators using generalized estimating equations theory, which underlie the power formulas. We incorporate noncompliance from both the actual receipt of the encouragement and participation itself. An illustrative power analysis provides sample size guidance using an available Shiny R dashboard.

Effect of parental touch on relieving acute procedural pain in neonates and parental anxiety (Petal): a multicentre, randomised controlled trial in the UK

Touch interventions such as massage and skin-to-skin contact relieve neonatal pain. The Parental touch trial (Petal) aimed to assess whether parental stroking of their baby before a clinically required heel lance, at a speed of approximately 3 cm/s to optimally activate C-tactile nerve fibres, provides effective pain relief. Petal is a multicentre, randomised, parallel-group interventional superiority trial conducted in the John Radcliffe Hospital (Oxford University Hospitals NHS Foundation Trust, Oxford, UK) and the Royal Devon and Exeter Hospital (Royal Devon University Healthcare NHS Foundation Trust, Exeter, UK). Neonates without neurological abnormalities who were born at 35 weeks gestational age or more and required a blood test via a heel lance in the first week of life were randomly assigned (1:1) to receive parental touch for 10 s either before (intervention group) or after (control group) the clinically required heel lance. Randomisation was managed at the Oxford site using a web-based minimisation algorithm with allocation concealment. The primary outcome measure was the magnitude of noxious-evoked brain activity in response to the heel lance measured with electroencephalography (EEG). Secondary outcome measures were Premature Infant Pain Profile-Revised (PIPP-R) score, development of tachycardia, and parental anxiety score. For all outcomes, the per-protocol effect was estimated via complier average causal effect analysis on the full analysis set. The trial is registered on ISRCTN (ISRCTN14135962) and ClinicalTrials.gov (NCT04901611). Between Sept 1, 2021, and Feb 7, 2023, 159 parents were approached to participate in the study, and 112 neonates were included. 56 neonates were randomly assigned to the intervention group of parental stroking before the heel lance and 56 to the control group of parental stroking after the heel lance. The mean of the magnitude of the heel lance-evoked brain activity was 0·85 arbitrary units (a.u.; SD 0·70; n=39; a scaled magnitude of 1 a.u. represents the expected mean response to a heel lance in term-aged neonates) in the intervention group and 0·91 a.u. (SD 0·76; n=43) in the control group. Therefore, the primary outcome did not differ significantly between groups, with a mean difference of -0·11 a.u. (lower in intervention group; SD 0·77; 95% CI -0·42 to 0·20; p=0·38; n=82). No significant difference was observed across secondary outcomes. The PIPP-R difference in means was 1·10 (higher in intervention group, 95% CI -0·42 to 2·61; p=0·15; n=100); the odds ratio of becoming tachycardic was 2·08 (95% CI 0·46 to 9·46; p=0·34, n=105) in the intervention group with reference to the control group; and the difference in parental State-Trait Anxiety Inventory-State score was -0·44 (higher in control group; SD 6·85; 95% CI -2·91 to 2·02; p=0·72; n=106). One serious adverse event (desaturation) occurred in a neonate randomly assigned to the control group, which was not considered to be related to the study. Parental stroking delivered at an optimal speed to activate C-tactile fibres for a duration of 10 s before the painful procedure did not significantly change neonates' magnitude of pain-related brain activity, PIPP-R score, or development of tachycardia. The trial highlighted the challenge of translating an experimental researcher-led tactile intervention into a parent-led approach, and the value of involving parents in their baby's pain management. Wellcome Trust and Bliss.

Impact of a post-partum family planning intervention on contraception and fertility in Tanzania: two-year follow-up of a cluster-randomised controlled trial

Purpose We evaluate contraceptive use and pregnancy two years following an intervention in Tanzania, which provided antenatal post-partum family planning counselling and post-partum intrauterine device (PPIUD) services following delivery. Methods We analyse data from five hospitals in Tanzania using a difference-in-difference cluster randomised design, with randomisation at the hospital level. We use women-level data collected at the index birth and a follow-up survey two years later among 6,410 women. Outcomes (overall modern contraceptive use, contraceptive type, pregnancy) are modelled with an intent-to-treat (ITT) approach using linear regression. We compare with the complier average causal effect (CACE) of the intervention among those counselled. Results The intervention increased long-term PPIUD use by 5.8 percentage points (95% CI: 0.7–11.2%) through substitution away from other modern methods. There was no impact on overall modern contraceptive prevalence or pregnancy. Only 29% of women reported receiving PPIUD counselling. When accounting for this in the CACE analysis we saw a larger impact with 25.7% percentage point increase in PPIUD use (95% CI: 22.7–28.6%). Conclusion The intervention provided women an additional contraceptive choice, resulting in higher use of PPIUD over two years. Increase in PPIUD use was brought about by shifting methods, not creating new modern contraceptive users.

Effects of Compliance to a Training Intervention for High School Students with ADHD

ABSTRACT Objective We evaluated the effects of treatment compliance with the Challenging Horizons Program (CHP) for high school aged adolescents with attention-deficit hyperactivity disorder (ADHD). Method Participants were 185 high school aged adolescents (65% non-Hispanic White; 79% male) with a diagnosis of ADHD who were randomly assigned to either CHP or community control. Outcomes included parent-rated academic functioning, parent- and self-rated social-emotional functioning, and GPA. The complier average causal effect (CACE) was estimated using propensity-weighted models for youth engaging in ≥ 30 CHP individual sessions (15–20 min) across the academic year. Results Most (78%) CHP participants engaged in≥30 CHP sessions. CACE analyses using latent growth curve modeling revealed significant treatment effects among treatment compliers across ratings of academic and social outcomes relative to similar control participants. For most outcomes, CACE estimates were larger than those found in intent-to-treat analyses, especially at 6-months follow-up. Conclusions Compliance with 30 or more individual CHP sessions appeared to be an attainable threshold associated with incremental gains across several academic and social outcomes. Effects of compliance were amplified at 6-months follow-up, supporting the hypothesized theory of change of training interventions. Future work should focus on facilitators of treatment engagement and feasibility of the CHP as delivered by high school personnel.

A preoperative supervised exercise program potentially improves long-term survival after elective abdominal aortic aneurysm repair

ObjectiveA preoperative supervised exercise program (SEP) improves cardiorespiratory fitness and perioperative outcomes for patients undergoing elective abdominal aortic aneurysm (AAA) repair. The aim of this study was to assess the effect of a preoperative SEP on long-term survival of these patients. A secondary aim was to consider long-term changes in cardiorespiratory fitness and quality of life. MethodsPatients scheduled for open or endovascular AAA repair were previously randomized to either a 6-week preoperative SEP or standard management, and a significant improvement in a composite outcome of cardiac, pulmonary, and renal complications was seen following SEP. For the current analysis, patients were followed up to 5 years post-surgery. The primary outcome for this analysis was all-cause mortality. Data were analyzed on an intention to treat (ITT) and per protocol (PP) basis, with the latter meaning that patients randomized to SEP who did not attend any sessions were excluded. The PP analysis was further interrogated using a complier average causal effect (CACE) analysis on an all or nothing scale, which adjusts for compliance. Additionally, patients who agreed to follow-up attended the research center for cardiopulmonary exercise testing and/or provided quality of life measures. ResultsITT analysis demonstrated that the primary endpoint occurred in 24 of the 124 participants at 5 years, with eight in the SEP group and 16 in the control group (P = .08). The PP analysis demonstrated a significant survival benefit associated with SEP attendance (4 vs 16 deaths; P = .01). CACE analysis confirmed a significant intervention effect (hazard ratio, 0.36; 95% confidence interval, 0.16-0.90; P = .02). There was no difference between groups for cardiorespiratory fitness measures and most quality of life measures. ConclusionsThese novel findings suggest a long-term mortality benefit for patients attending a SEP prior to elective AAA repair. The underlying mechanism remains unknown, and this merits further investigation.

The Effectiveness of a Parents as Teachers Home Visitation Program on School Readiness: An Application of Complier Average Causal Effect Analysis

ABSTRACT Purpose The purpose of this study is to evaluate an encouragement trial of a Parents as Teachers (PAT) home visitation intervention on the school readiness of preschool children using an innovative analysis to address issues of selective enrollment. Method Families were given the opportunity to enroll in a PAT program through a randomized lottery. The PAT program is assessed using standardized measures of school readiness before and after the two-year program. A comparison of three different analyses is used to evaluate the program – Average Treatment Effect (ATE) analysis, Intent-to-Treat (ITT) analysis, and Complier Average Causal Effect (CACE) analysis. CACE is an innovative analysis developed specifically to diagnose bias arising from selective enrollment in the context of an encouragement trial. Result All three analyses (ATE, ITT, and CACE) provide statistically significant evidence of an effective PAT program. However, the effect sizes for the CACE analysis are over twice as large as the other two analyses. The Cohen’s D for CACE is .934 compared to .424 for ATE and .381 for ITT. Conclusion This study provides evidence of an effective PAT program. The comparison of ATE, ITT, and CACE analyses reveals the potential for meaningful under-reporting of the program’s impact if selective enrollment is ignored. CACE analysis demonstrates how selective enrollment can bias evaluations of home visitation interventions in general.

Transfer of thawed frozen embryo versus fresh embryo to improve the healthy baby rate in women undergoing IVF: the E-Freeze RCT.

Freezing all embryos, followed by thawing and transferring them into the uterine cavity at a later stage (freeze-all), instead of fresh-embryo transfer may lead to improved pregnancy rates and fewer complications during in vitro fertilisation and pregnancies resulting from it. We aimed to evaluate if a policy of freeze-all results in a higher healthy baby rate than the current policy of transferring fresh embryos. This was a pragmatic, multicentre, two-arm, parallel-group, non-blinded, randomised controlled trial. Eighteen in vitro fertilisation clinics across the UK participated from February 2016 to April 2019. Couples undergoing their first, second or third cycle of in vitro fertilisation treatment in which the female partner was aged < 42 years. If at least three good-quality embryos were present on day 3 of embryo development, couples were randomly allocated to either freeze-all (intervention) or fresh-embryo transfer (control). The primary outcome was a healthy baby, defined as a live, singleton baby born at term, with an appropriate weight for their gestation. Secondary outcomes included ovarian hyperstimulation, live birth and clinical pregnancy rates, complications of pregnancy and childbirth, health economic outcome, and State-Trait Anxiety Inventory scores. A total of 1578 couples were consented and 619 couples were randomised. Most non-randomisations were because of the non-availability of at least three good-quality embryos (n = 476). Of the couples randomised, 117 (19%) did not adhere to the allocated intervention. The rate of non-adherence was higher in the freeze-all arm, with the leading reason being patient choice. The intention-to-treat analysis showed a healthy baby rate of 20.3% in the freeze-all arm and 24.4% in the fresh-embryo transfer arm (risk ratio 0.84, 95% confidence interval 0.62 to 1.15). Similar results were obtained using complier-average causal effect analysis (risk ratio 0.77, 95% confidence interval 0.44 to 1.10), per-protocol analysis (risk ratio 0.87, 95% confidence interval 0.59 to 1.26) and as-treated analysis (risk ratio 0.91, 95% confidence interval 0.64 to 1.29). The risk of ovarian hyperstimulation was 3.6% in the freeze-all arm and 8.1% in the fresh-embryo transfer arm (risk ratio 0.44, 99% confidence interval 0.15 to 1.30). There were no statistically significant differences between the freeze-all and the fresh-embryo transfer arms in the live birth rates (28.3% vs. 34.3%; risk ratio 0.83, 99% confidence interval 0.65 to 1.06) and clinical pregnancy rates (33.9% vs. 40.1%; risk ratio 0.85, 99% confidence interval 0.65 to 1.11). There was no statistically significant difference in anxiety scores for male participants (mean difference 0.1, 99% confidence interval -2.4 to 2.6) and female participants (mean difference 0.0, 99% confidence interval -2.2 to 2.2) between the arms. The economic analysis showed that freeze-all had a low probability of being cost-effective in terms of the incremental cost per healthy baby and incremental cost per live birth. We were unable to reach the original planned sample size of 1086 and the rate of non-adherence to the allocated intervention was much higher than expected. When efficacy, safety and costs are considered, freeze-all is not better than fresh-embryo transfer. This trial is registered as ISRCTN61225414. This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 26, No. 25. See the NIHR Journals Library website for further project information.

Treatment guided by fractional exhaled nitric oxide in addition to standard care in 6- to 15-year-olds with asthma: the RAACENO RCT

BackgroundThe role of fractional exhaled nitric oxide in guiding asthma treatment in children is uncertain.ObjectiveTo compare treatment guided by both fractional exhaled nitric oxide and symptoms (intervention) with treatment guided by symptoms alone (standard care) in children with asthma who are at risk of an asthma exacerbation, in terms of the number of asthma exacerbations over 12 months.DesignThis was a pragmatic, multicentre, randomised controlled trial with embedded cost-effectiveness and qualitative process evaluations. Randomisation (1 : 1) was carried out using a remote web-based system and was minimised on recruitment centre, age, sex and British Thoracic Society treatment step. Clinical teams and participants were not blind to treatment allocation.SettingThe trial took place in 35 hospitals and seven primary care practices in the UK.ParticipantsChildren aged 6–15 years with a diagnosis of asthma who were currently prescribed inhaled corticosteroids and who had one or more parent-/patient-reported asthma exacerbation treated with oral corticosteroids in the 12 months prior to recruitment.InterventionsAsthma treatment guided by symptoms alone (standard care) and asthma treatment guided by symptoms plus fractional exhaled nitric oxide (intervention). Treatment recommendations in both groups were protocolised within a web-based algorithm, incorporating inhaled corticosteroid adherence (objectively measured using an electronic logging device) and current treatment.Main outcome measuresThe primary outcome measure was asthma exacerbations treated with oral corticosteroids in the year post randomisation. Secondary outcomes included time to first exacerbation, number of exacerbations, lung function, fractional exhaled nitric oxide, daily dose of inhaled corticosteroid, asthma control and quality of life.ResultsIn total, 509 eligible participants were recruited and the primary outcome was available for 506 participants. The primary outcome occurred in 123 out of 255 (48.2%) participants in the intervention group and 129 out of 251 (51.4%) participants in the standard-care group (adjusted odds ratio 0.88, 95% confidence interval 0.61 to 1.27). There was algorithm non-compliance on 21% of assessments. Per-protocol and complier-average causal effect analysis did not change the interpretation. This non-statistically significant estimate was consistent across predefined subgroups. There were no differences between the groups in secondary outcomes. There were no serious adverse events or deaths. No meaningful differences in health service costs, direct patient costs or indirect costs to society were identified between the groups. The economic evaluation does not provide evidence to support the cost-effectiveness of the intervention. In the qualitative process evaluation, 15 trial staff and six families were interviewed. Overall, their experiences were positive. The intervention was broadly acceptable, with caveats around clinicians using the algorithm recommendation as a guide and wariness around extreme step ups/downs in treatment in the light of contextual factors not being taken into account by the algorithm.LimitationsPotential limitations included the choice of cut-off point to define uncontrolled asthma and the change in fractional exhaled nitric oxide to trigger a change in treatment. Furthermore, the treatment decisions in the two groups may not have been sufficiently different to create a difference in outcomes.ConclusionsThe RAACENO (Reducing Asthma Attacks in Children using Exhaled Nitric Oxide) trial findings do not support the routine use of fractional exhaled nitric oxide measurements as part of asthma management in a secondary care setting. The potential for other objective markers to guide asthma management in children needs to be evaluated.Trial registrationThis trial was registered as ISRCTN67875351.FundingThis project was funded by the Efficacy and Mechanism Evaluation (EME) programme, a MRC and National Institute for Health and Care Research (NIHR) partnership. This will be published in full inEfficacy and Mechanism Evaluation; Vol. 9, No. 4. See the NIHR Journals Library website for further project information.

Effect of digital psychoeducation and peer support on the mental health of family carers supporting individuals with psychosis in England (COPe-support): a randomised clinical trial

SummaryBackgroundPsychoeducation delivered face-to-face is effective in alleviating mental health morbidities in family carers of individuals with psychosis. However, research in such interventions delivered online is scarce. We evaluated the effectiveness of a digital multicomponent intervention—COPe-support—in improving carers' mental wellbeing and caregiving-related outcomes.MethodsIn this two-arm, individually randomised, superiority trial, people aged 18 years or older who provided at least weekly support in any format for a relative or close friend affected by psychosis across England were randomly assigned (1:1) to either COPe-support or a passive online information resource using an independent online system. Participants were recruited through 30 mental health UK National Health Service trusts. The study team were masked to allocation and assessment of outcomes as all data collection took place online. Participants had access to either condition for 40 weeks and were advised to spend at least half an hour per week over the initial 20 weeks to go through materials at their own pace and to allow time to integrate knowledge and skills learned into practice. It was not feasible to mask participants or the online facilitator to intervention allocation. COPe-support provided psychoeducation on psychosis-related caregiving strategies and forums with professionals and other carers, and the control intervention comprised a passive online information resource. The primary outcome at 20 weeks was mental wellbeing measured by the Warwick-Edinburgh Mental Wellbeing Scale (WEMWBS; minimally clinically important difference [MCID] 3). This trial is registered with ISRCTN, 89563420.FindingsBetween March 1, 2018, and Feb 14, 2020, 407 participants were randomly assigned, with 204 allocated to COPe-support and 203 allocated to control. The participants (mean age 53·1 years, SD 13·2) were mostly female (330 [81%] of 407 participants) and White (359 [88%] of 407 participants). 346 (85%) of 407 participants provided primary endpoint data, 174 (85%) of 204 participants in the COPe-support group and 172 (85%) of 203 participants in the control group. The mean WEMWBS score at 20 weeks was 44·5 (SD 8·31) for the COPe-support group and 43·3 (9·19) for the control group. We found no evidence of a difference in wellbeing between the two groups (adjusted mean difference 0·37, 95% CI –1·14 to 1·88; p=0·63). In the COPe-support group, 106 (52%) of 204 participants met the complier definition of a minimum of two logins in separate weeks. The complier average causal effect analysis increased the difference in WEMWBS scores (adjusted difference 0·83, 95% CI –1·45 to 3·11; p=0·47), but this was lower than the MCID. There were no adverse events.InterpretationOur findings did not support the use of COPe-support over a passive online information resource. However, further research to optimise digital interventions adjunctive to face-to-face support for carers remains important.FundingNational Institute for Health Research.

Promoting parenting in home visiting: A CACE analysis of Family Foundations.

This randomized trial tested the impact of an established prevention program for first-time parents, Family Foundations, adapted for low-income mothers and fathers as a series of sessions provided to couples in their homes. To assess program impact, we recruited and randomly assigned a sample of 150 low-income adult mother-father dyads (not necessarily still romantically involved, cohabiting, or married) during pregnancy or shortly after birth. The randomly assigned intervention families participated in Family Foundations Home Visiting (FFHV), consisting of 11 in-home sessions focusing on parental cooperation, collaboration, and conflict management to support children's development. Complier average causal effect (CACE) analysis was used to examine program impact on parental adjustment and parenting for families completing nine or more program sessions. Results indicated significant positive complier effects for mothers' and fathers' reports of depression, Posttraumatic Stress Disorder (PTSD) symptoms, coping with stress, and psychological aggression by fathers toward mothers at post-intervention, controlling for pre-intervention scores. Intervention parents also demonstrated higher levels of affection, engagement, and sensitivity with the infant based on observer coding of videotaped parent-child interactions. These findings indicate that the focus of Family Foundations on enhancing coparenting offers similar benefits for low-income parents and children who are compliers as has the group-format Family Foundations (FF) version in trials with universal samples of cohabiting or married parents. Results are discussed in terms of implications for home visiting, engaging fathers, and optimizing child outcomes. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

The interleukin 1 receptor antagonist anakinra to reduce disease severity of palmoplantar pustulosis in adults: APRICOT RCT and PLUM mechanistic study

Background Palmoplantar pustulosis is a rare, debilitating, chronic skin disease involving the hands and feet, and there are limited treatment options. Mechanistic findings suggest that interleukin 1 may be a pathogenic driver. Objective To determine whether or not anakinra [Sobi (Swedish Orphan Biovitrum AB), Stockholm, Sweden], an interleukin 1 receptor antagonist, delivers therapeutic benefit in palmoplantar pustulosis. Design A Phase IV, randomised, double-blind, placebo-controlled study with two stages and an adaptive element (24 participants in stage 1, 64 participants in total) with an open-label extension. Setting Sixteen hospitals across England, Scotland and Wales. Participants Adults (aged ≥ 18 years) with a diagnosis of palmoplantar pustulosis and a disease duration of &gt; 6 months and of sufficient impact and severity to require systemic therapy. Interventions Participants were randomised (1 : 1) to daily self-administered subcutaneous injection of either anakinra or a placebo for 8 weeks. Main outcome measures The primary outcome was the Palmoplantar Pustulosis Area and Severity Index score measured at 0, 1, 4, 8 and 12 weeks, with the primary end point at 8 weeks adjusted for baseline. Secondary outcomes included other investigator-assessed efficacy measures of disease severity, safety measures and participant-reported measures of efficacy and impact. Results A total of 64 participants (mean baseline Palmoplantar Pustulosis Area and Severity Index score of 17.8, standard deviation 10.5) received anakinra (n = 31) or the placebo (n = 33). In the primary intention-to-treat analysis, which estimated the effect of the treatment policy, the mean treatment group difference at 8 weeks after adjustment for baseline Palmoplantar Pustulosis Area and Severity Index score was –1.65 (95% confidence interval –4.77 to 1.47; p = 0.300), in favour of anakinra relative to placebo, but was not statistically significant. Similarly, secondary investigator-assessed outcomes did not show statistical superiority of anakinra: the baseline-adjusted mean difference in fresh pustule count (palms and soles) between the anakinra group and the placebo group was 2.94 (95% confidence interval –26.44 to 32.33), in favour of placebo, and the mean difference in total pustule count was –30.08 (95% confidence interval –83.20 to 23.05), in favour of anakinra. Participant-assessed outcomes were consistent with these objective findings: the baseline-adjusted mean difference in Dermatology Life Quality Index between the anakinra group and the placebo group was 0.52 (95% confidence interval –2.04 to 3.07), in favour of placebo, and the mean difference in Palmoplantar Quality-of-Life Index was 1.27 (95% confidence interval –3.04 to 5.57), in favour of placebo. However, the proportion of participants who strongly agreed that treatment was worthwhile was greater in the anakinra group (12/29, 41%) than in the placebo group (4/28, 14%), a difference in proportion of 27% (95% confidence interval 5% to 49%). In the complier-average causal effect analysis, the baseline-adjusted mean treatment group difference in the week 8 Palmoplantar Pustulosis Area and Severity Index score in individuals who received ≥ 50% of injections was –2.30 (95% confidence interval –6.54 to 1.93; p = 0.287) and in those who received ≥ 90% of injections was –3.80 (95% confidence interval –10.76 to 3.16; p = 0.285), in favour of anakinra. No serious infections, significant neutropenia or other serious adverse events occurred. Injection site reactions were more frequent for those receiving anakinra (19/31, 61%) than for those receiving placebo (1/33, 3%). Conclusions There was no evidence that anakinra was superior to placebo. For the treatment of palmoplantar pustulosis, interleukin 1 blockade is not a useful intervention. Limitations The sample size was calculated to detect a large effect size. Treatment adherence was lower than expected. It cannot be ruled out that there was some selection bias towards less severe or unstable participants entering the trial given that the trial was placebo controlled with a required washout period. Future work Palmoplantar pustulosis remains an area of high unmet need and further research is recommended to (1) identify new drug targets, (2) determine the contributory role of drug exposure (including pharmacokinetics and adherence) and (3) validate outcome measures in palmoplantar pustulosis. Trial registration This trial is registered as ISCRTN13127147 and EudraCT 2015-003600-23. Funding This project was funded by the Efficacy and Mechanism Evaluation (EME) programme, a MRC and National Institute for Health Research (NIHR) partnership. This will be published in full in Efficacy and Mechanism Evaluation; Vol. 9, No. 2. See the NIHR Journals Library for further project information.

Exercise to prevent shoulder problems after breast cancer surgery: the PROSPER RCT.

Upper limb problems are common after breast cancer treatment. To investigate the clinical effectiveness and cost-effectiveness of a structured exercise programme compared with usual care on upper limb function, health-related outcomes and costs in women undergoing breast cancer surgery. This was a two-arm, pragmatic, randomised controlled trial with embedded qualitative research, process evaluation and parallel economic analysis; the unit of randomisation was the individual (allocated ratio 1 : 1). Breast cancer centres, secondary care. Women aged ≥ 18 years who had been diagnosed with breast cancer and were at higher risk of developing shoulder problems. Women were screened to identify their risk status. All participants received usual-care information leaflets. Those randomised to exercise were referred to physiotherapy for an early, structured exercise programme (three to six face-to-face appointments that included strengthening, physical activity and behavioural change strategies). The primary outcome was upper limb function at 12 months as assessed using the Disabilities of Arm, Hand and Shoulder questionnaire. Secondary outcomes were function (Disabilities of Arm, Hand and Shoulder questionnaire subscales), pain, complications (e.g. wound-related complications, lymphoedema), health-related quality of life (e.g. EuroQol-5 Dimensions, five-level version; Short Form questionnaire-12 items), physical activity and health service resource use. The economic evaluation was expressed in terms of incremental cost per quality-adjusted life-year and incremental net monetary benefit gained from an NHS and Personal Social Services perspective. Participants and physiotherapists were not blinded to group assignment, but data collectors were blinded. Between 2016 and 2017, we randomised 392 participants from 17 breast cancer centres across England: 196 (50%) to the usual-care group and 196 (50%) to the exercise group. Ten participants (10/392; 3%) were withdrawn at randomisation and 32 (8%) did not provide complete baseline data. A total of 175 participants (89%) from each treatment group provided baseline data. Participants' mean age was 58.1 years (standard deviation 12.1 years; range 28-88 years). Most participants had undergone axillary node clearance surgery (327/392; 83%) and 317 (81%) had received radiotherapy. Uptake of the exercise treatment was high, with 181 out of 196 (92%) participants attending at least one physiotherapy appointment. Compliance with exercise was good: 143 out of 196 (73%) participants completed three or more physiotherapy sessions. At 12 months, 274 out of 392 (70%) participants returned questionnaires. Improvement in arm function was greater in the exercise group [mean Disabilities of Arm, Hand and Shoulder questionnaire score of 16.3 (standard deviation 17.6)] than in the usual-care group [mean Disabilities of Arm, Hand and Shoulder questionnaire score of 23.7 (standard deviation 22.9)] at 12 months for intention-to-treat (adjusted mean difference Disabilities of Arm, Hand and Shoulder questionnaire score of -7.81, 95% confidence interval -12.44 to -3.17; p = 0.001) and complier-average causal effect analyses (adjusted mean difference -8.74, 95% confidence interval -13.71 to -3.77; p ≤ 0.001). At 12 months, pain scores were lower and physical health-related quality of life was higher in the exercise group than in the usual-care group (Short Form questionnaire-12 items, mean difference 4.39, 95% confidence interval 1.74 to 7.04; p = 0.001). We found no differences in the rate of adverse events or lymphoedema over 12 months. The qualitative findings suggested that women found the exercise programme beneficial and enjoyable. Exercise accrued lower costs (-£387, 95% CI -£2491 to £1718) and generated more quality-adjusted life years (0.029, 95% CI 0.001 to 0.056) than usual care over 12 months. The cost-effectiveness analysis indicated that exercise was more cost-effective and that the results were robust to sensitivity analyses. Exercise was relatively cheap to implement (£129 per participant) and associated with lower health-care costs than usual care and improved health-related quality of life. Benefits may accrue beyond the end of the trial. Postal follow-up was lower than estimated; however, the study was adequately powered. No serious adverse events directly related to the intervention were reported. This trial provided robust evidence that referral for early, supported exercise after breast cancer surgery improved shoulder function in those at risk of shoulder problems and was associated with lower health-care costs than usual care and improved health-related quality of life. Future work should focus on the implementation of exercise programmes in clinical practice for those at highest risk of shoulder problems. This trial is registered as ISRCTN35358984. This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 26, No. 15. See the NIHR Journals Library website for further project information.

Compliance with telephone-based lifestyle weight loss programs improves low back pain but not knee pain outcomes: complier average causal effects analyses of 2 randomised trials.

We conducted a complier average causal effect (CACE) analyses for 2 pragmatic randomised controlled trials. We aimed to assess the effectiveness of telephone-based lifestyle weight loss interventions compared with usual care among compliers. Participants from 2 trials with low back pain (n = 160) and knee osteoarthritis (n = 120) with a body mass index ≥27 kg/m2 were included. We defined adherence to the telephone-based lifestyle weight loss program as completing 60% (6 from 10) of telephone health coaching calls. The primary outcomes for CACE analyses were pain intensity (0-10 Numerical Rating Scale) and disability (Roland Morris Disability Questionnaire for low back pain and Western Ontario and McMaster Universities Osteoarthritis Index for knee osteoarthritis). Secondary outcomes were weight, physical activity, and diet. We used an instrumental variable approach to estimate CACE in compliers. From the intervention groups of the trials, 29% of those with low back pain (n = 23/80) and 34% of those with knee osteoarthritis (n = 20/60) complied. Complier average causal effect estimates showed potentially clinically meaningful effects, but with low certainty because of wide confidence intervals, for pain intensity (-1.4; 95% confidence interval, -3.1, 0.4) and small but also uncertain effects for disability (-2.1; 95% confidence interval, -8.6, 4.5) among compliers in the low back pain trial intervention compared with control but not in the knee osteoarthritis trial. Our findings showed that compliers of a telephone-based weight loss intervention in the low back pain trial generally had improved outcomes; however, there were inconsistent effects in compliers from the knee osteoarthritis trial. Complier average causal effect estimates were larger than intention-to-treat results but must be considered with caution.

Reducing Asthma Attacks in Children Using Exhaled Nitric Oxide as a Biomarker to Inform Treatment Strategy – A Randomised Trial

Background: The benefit of Fractional Exhaled Nitric Oxide (FeNO) in guiding asthma treatment is uncertain. Our hypothesis was that FeNO plus symptom-guided treatment reduces exacerbations in children with asthma compared to symptom-guided treatment alone. Methods: A multicentre randomised controlled trial recruited 6-15 year olds with asthma treated with inhaled corticosteroids (ICS) with an exacerbation in the previous year. Randomisation was to asthma treatment guided by FeNO plus symptoms (intervention) or by symptoms only (standard care). A web-based algorithm using symptom control, ICS adherence, current treatment and (within the intervention group) FeNO gave treatment recommendations. Participants attended assessments 3, 6, 9 and 12-months post-randomisation. The primary outcome was exacerbation requiring oral corticosteroid over the 12 months post-randomisation. Findings: There were 509 children recruited. At randomisation, the mean (SD) age was 10∙1y (2.6), median (IQR) FeNO 21 ppb (10, 48), mean (SD) %FEV 1 90% (18), 56% received ≤400 microg budesonide equivalent ICS and 50% had controlled symptoms. The primary outcome occurred in 123/255 (48%) of the intervention group and 129/251 (51%) of the standard care group. The adjusted difference in percentage of participants who received the intervention where the primary outcome occurred exacerbation compared to those receiving standard care was -3∙13% (95% CI: -11∙9% to 5∙6%). In adjusted intention-to-treat analysis, the odds ratio (OR) for primary outcome was 0 ∙88 [95%CI 0∙61 to 1∙27]. In 377 of 1771 assessments, the algorithm recommendation was not followed. In complier average causal effect analysis, adjusting for algorithm adherence, the OR for those fully adherent was 0∙82 [95% CI 0∙48 to 1∙41]. There were no differences in secondary outcomes between groups. Interpretation: In this exacerbation-prone population, adding FeNO to symptom-guided treatment did not reduce exacerbations. Trial Registration: ISRCTN number #67875351. Funding: This study was funded by the Efficacy and Mechanisms Evaluation programme of the National Institute for Health Research (reference 15-18-14). Declaration of Interest: David Price has board membership with AstraZeneca, Boehringer Ingelheim, Chiesi, Mylan, Novartis, Regeneron Pharmaceuticals, Sanofi Genzyme, Thermofisher; consultancy agreements with Airway Vista Secretariat, AstraZeneca, Boehringer Ingelheim, Chiesi, EPG Communication Holdings Ltd, FIECON Ltd, Fieldwork International, GlaxoSmithKline, Mylan, Mundipharma, Novartis, OM Pharma SA, PeerVoice, Phadia AB, Spirosure Inc, Strategic North Limited, Synapse Research Management Partners S.L., Talos Health Solutions, Theravance and WebMD Global LLC; grants and unrestricted funding for investigator-initiated studies (conducted through Observational and Pragmatic Research Institute Pte Ltd) from AstraZeneca, Boehringer Ingelheim, Chiesi, Mylan, Novartis, Regeneron Pharmaceuticals, Respiratory Effectiveness Group, Sanofi Genzyme, Theravance and UK National Health Service; payment for lectures/speaking engagements from AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, GlaxoSmithKline, Kyorin, Mylan, Mundipharma, Novartis, Regeneron Pharmaceuticals and Sanofi Genzyme; payment for travel/accommodation/meeting expenses from AstraZeneca, Boehringer Ingelheim, Mundipharma, Mylan, Novartis, Thermofisher; stock/stock options from AKL Research and Development Ltd which produces phytopharmaceuticals; owns 74% of the social enterprise Optimum Patient Care Ltd (Australia and UK) and 92.61% of Observational and Pragmatic Research Institute Pte Ltd (Singapore); 5% shareholding in Timestamp which develops adherence monitoring technology; is peer reviewer for grant committees of the UK Efficacy and Mechanism Evaluation programme, and Health Technology Assessment; and was an expert witness for GlaxoSmithKline. Ethical Approval: The study was approved by the North of Scotland Research Ethics Committee (16/NS/0106).

The effect of a one-year vigorous physical activity intervention on fitness, cognitive performance and mental health in young adolescents: the Fit to Study cluster randomised controlled trial

BackgroundPhysical activity (PA) may positively stimulate the brain, cognition and mental health during adolescence, a period of dynamic neurobiological development. High-intensity interval training (HIIT) or vigorous PA interventions are time-efficient, scalable and can be easily implemented in existing school curricula, yet their effects on cognitive, academic and mental health outcomes are unclear. The primary aim of the Fit to Study trial was to investigate whether a pragmatic and scalable HIIT-style VPA intervention delivered during school physical education (PE) could improve attainment in maths. The primary outcome has previously been reported and was null. Here, we report the effect of the intervention on prespecified secondary outcomes, including cardiorespiratory fitness, cognitive performance, and mental health in young adolescents.MethodsThe Fit to Study cluster randomised controlled trial included Year 8 pupils (n = 18,261, aged 12–13) from 104 secondary state schools in South/Mid-England. Schools were randomised into an intervention condition (n = 52), in which PE teachers delivered an additional 10 min of VPA per PE lesson for one academic year (2017–2018), or into a “PE as usual” control condition. Secondary outcomes included assessments of cardiorespiratory fitness (20-m shuttle run), cognitive performance (executive functions, relational memory and processing speed) and mental health (Strength and Difficulties Questionnaire and self-esteem measures). The primary intention-to-treat (ITT) analysis used linear models and structural equation models with cluster-robust standard errors to test for intervention effects. A complier-average causal effect (CACE) was estimated using a two-stage least squares procedure.ResultsThe HIIT-style VPA intervention did not significantly improve cardiorespiratory fitness, cognitive performance (executive functions, relational memory or processed speed), or mental health (all p > 0.05). Subgroup analyses showed no significant moderation of intervention effects by sex, socioeconomic status or baseline fitness levels. Changes in cardiorespiratory fitness were not significantly related to changes in cognitive or mental health outcomes. The trial was marked by high drop-out and low intervention compliance. Findings from the CACE analysis were in line with those from the ITT analysis.ConclusionThe one-academic year HIIT-style VPA intervention delivered during regular school PE did not significantly improve fitness, cognitive performance or mental health, but these findings should be interpreted with caution given low implementation fidelity and high drop-out. Well-controlled, large-scale, school-based trials that examine the effectiveness of HIIT-style interventions to enhance cognitive and mental health outcomes are warranted.Trial registrationISRCTN registry, 15,730,512. Trial protocol and analysis plan for primary outcome prospectively registered on 30th March 2017.ClinicalTrials.gov, NCT03286725. Secondary measures (focus of current manuscript) retrospectively registered on 18 September 2017.

Clinical efficacy of a Decision Support Tool (Link-me) to guide intensity of mental health care in primary practice: a pragmatic stratified randomised controlled trial

The volume and heterogeneity of mental health problems that primary care patients present with is a substantial challenge for health systems, and both undertreatment and overtreatment are common. We developed Link-me, a patient-completed Decision Support Tool, to predict severity of depression or anxiety, identify priorities, and recommend interventions. In this study, we aimed to examine if Link-me reduces psychological distress among individuals predicted to have minimal/mild or severe symptoms of anxiety or depression. In this pragmatic stratified randomised controlled trial, adults aged 18-75 years reporting depressive or anxiety symptoms or use of mental health medication were recruited from 23 general practices in Australia. Participants completed the Decision Support Tool and were classified into three prognostic groups (minimal/mild, moderate, severe), and those in the minimal/mild and severe groups were eligible for inclusion. Participants were individually and randomly assigned (1:1) by a computer-generated allocation sequence to receive either prognosis-matched care (intervention group) or usual care plus attention control (control group). Participants were not blinded but intervention providers were only notified of those allocated to the intervention group. Outcome assessment was blinded. The primary outcome was the difference in the change in scores between the intervention and control group, and within prognostic groups, on the 10-item Kessler Psychological Distress Scale at 6 months post randomisation. The trial was registered on the Australian and New Zealand Clinical Trials Registry, ACTRN12617001333303. Between Nov 21, 2017, and Oct 31, 2018, 24 616 patients were invited to complete the eligibility screening survey. 1671 of these patients were included and randomly assigned to either the intervention group (n=834) or the control group (n=837). Prognosis-matched care was associated with greater reductions in psychological distress than usual care plus attention control at 6 months (p=0·03), with a standardised mean difference (SMD) of -0·09 (95% CI -0·17 to -0·01). This reduction was also seen in the severe prognostic group (p=0·003), with a SMD of -0·26 (-0·43 to -0·09), but not in the minimal/mild group (p=0·73), with a SMD of 0·04 (-0·17 to 0·24). In the complier average causal effect analysis in the severe prognostic group, differences were larger among those who received some or all aspects of the intervention (SMD range -0·58 to -1·15). No serious adverse effects were recorded. Prognosis-based matching of interventions reduces psychological distress in patients with anxiety or depressive symptoms, particularly in those with severe symptoms, and is associated with better outcomes when patients access the recommended treatment. Optimisation of the Link-me approach and implementation into routine practice could help reduce the burden of disease associated with common mental health conditions such as anxiety and depression. Australian Government Department of Health.

Collaborative care for depression in older adults: How much is enough?

Collaborative care in primary care has been shown to be effective for subthreshold depression in older adults in the ‘CASPER’ trial. However, to understand the impact of adherence, and to explore the minimum effective dose of collaborative care, we reanalysed the trial data using a complier average causal effect (CACE) analysis. Data were available for 705 participants, 519 with 12-month PHQ-9 scores. ‘Compliance’ could be observed for participants in the intervention group. Latent complier status in the control group was estimated. Completion of five or more sessions of care was defined as ‘compliance’. Sensitivity analyses, using alternative cut-offs of two to eight sessions, assessed the impact of changing the definition of ‘compliance’. Compliers in the intervention group had lower PHQ-9 scores at 12-month follow up than assumed compliers in the control group (1.75 lower, 95% confidence interval 0.29 to 3.21, p = 0.02), a greater effect than originally reported. Sensitivity analyses confirmed statistically significant differences between the intervention and control groups in those attending five or more sessions. We conclude that collaborative care is causally effective in reducing subthreshold depressive symptoms in older people who adhere to treatment. Our findings suggest the minimum effective dose is five sessions.

Bounce Back: randomised trial of a brief, school-based group intervention for children with emergent mental health difficulties.

We report the findings of the first randomised trial of Bounce Back, a brief, school-based group intervention for children with emergent mental health difficulties, whose aim is to improve their understanding of resilience and well-being, support them to build their confidence and friendships, and provide practical skills to make positive behaviour changes. 24 primary schools (N = 326 children) were randomly allocated to deliver the intervention or continue practice as usual in a waitlist design. Children in the intervention arm of the trial worked in groups of up to 15, supported by a trained youth practitioner, over ten weekly sessions that were delivered during the school day for up to an hour. Measures of emotional symptoms, behavioural difficulties, problem-solving, and self-esteem were recorded at baseline and post-intervention follow-up. Routinely collected session attendance data were used as a proxy for intervention compliance. Intent to treat analyses revealed that Bounce Back produced significant reductions in emotional symptoms (d = -0.21). Furthermore, complier average causal effect analyses established that intervention compliance modified this treatment effect, such that children who attended more sessions accrued greater reductions in symptoms (moderate compliance d = -0.54; high compliance d = -0.61). There were no intervention effects for any of the other outcomes. Collectively, these findings provide robust preliminary evidence of the efficacy of Bounce Back.Trial registration: ISRCTN11162672.

The Effectiveness of a Community-Based Mentoring Program for Children Aged 5\u201311\xa0Years: Results from a Randomized Controlled Trial

The study, a two-arm, randomized controlled, parallel group, superiority trial, aimed to evaluate the implementation and effectiveness of a 12-month one-to-one volunteer mentoring program designed to improve behavioral and emotional outcomes in children aged 5 to 11 years who have teacher- and parent/carer-reported behavioral difficulties. Participants were 246 children (123 intervention, 123 control; mean age 8.4 years; 87% boys) in five sites in London, UK, scoring in the “abnormal” range on the teacher-rated Strengths and Difficulties Questionnaire (SDQ) Total Difficulties measure and in the “borderline” or abnormal range on the parent-rated SDQ Total Difficulties measure. Randomization on a 1:1 ratio took place using a computer-generated sequence and stratifying by site. Data collectors and statisticians were blind to participant allocation status. Outcome measures focused on parent- and teacher-rated child behavior and emotions, and child-rated self-perception and hope. Intention-to-treat analysis on all 246 randomized participants (using imputed data where necessary) showed that at post-intervention (16 months after randomization), there were no statistically significant effects on the primary outcome—parent-rated SDQ Total Difficulties (adjusted standardized mean difference = − 0.12; 95% CI: −0.38 to 0.13; p = 0.33)—or any secondary outcomes. Results from complier average causal effect (CACE) analysis using the primary outcome indicated the intervention was not effective for children who received the recommended duration of mentoring. Exploratory analyses found no sub-group effects on the primary outcome. The article concludes that the mentoring program had no effect on children’s behavior or emotional well-being, and that program content needs revising to satisfactorily address key risk and protective factors.