Subsequent Randomized Controlled Trials Research Articles

Perspectives of people experiencing homelessness with recent non-fatal street drug overdose on the Pharmacist and Homeless Outreach Engagement and Non-medical Independent prescribing Rx (PHOENIx) intervention.

In Scotland, a third of all deaths of people experiencing homelessness (PExH) are street-drug-related, and less than half of their multiple physical- and mental health conditions are treated. New, holistic interventions are required to address these health inequalities. PHOENIx (Pharmacist Homeless Outreach Engagement and Non-medical Independent prescribing Rx) is delivered on outreach by National Health Service (NHS) pharmacist independent prescribers in partnership with third sector homelessness charity workers. We describe participant's perspectives of PHOENIx. This study aims to understand experiences of the PHOENIx intervention by participants recruited into the active arm of a pilot randomised controlled trial (RCT). Semi-structured in-person interviews explored participants' evaluation of the intervention. In this study, the four components (coherence, cognitive participation, collective action, reflexive monitoring) of the Normalisation Process Theory (NPT) framework underpinned data collection and analyses. We identified four themes that were interpreted within the NPT framework that describe participant evaluation of the PHOENIx intervention: differentiating the intervention from usual care (coherence), embedding connection and consistency in practice (cognitive participation), implementation of practical and emotional operational work (collective action), and lack of power and a commitment to long-term support (reflexive monitoring). Participants successfully engaged with the intervention. Facilitators for participant motivation included the relationship-based work created by the PHOENIx team. This included operational work to fulfil both the practical and emotional needs of participants. Barriers included concern regarding power imbalances within the sector, a lack of long-term support and the impact of the intervention concluding. Findings identify and describe participants' evaluations of the PHOENIx intervention. NPT is a theoretical framework facilitating understanding of experiences, highlighting both facilitators and barriers to sustained engagement and investment. Our findings inform future developments regarding a subsequent definitive RCT of PHOENIx, despite challenges brought about by challenging micro and macro-economic and political landscapes.

Precision computerised cognitive behavioural therapy (cCBT) for adolescents with depression: a pilot and feasibility randomised controlled trial protocol for SPARX-UK

BackgroundA serious game called SPARX (Smart, Positive, Active, Realistic, X-factor thoughts), originally developed in New Zealand and incorporating cognitive behavioural therapy (CBT) principles, has been shown to help reduce symptoms of depression and anxiety in adolescents with mild to moderate depression in studies undertaken in Australasia. However, SPARX has never been trialled in the United Kingdom (UK), and there have been issues relating to low engagement when it has been used in a real-world context.AimsTo conduct the first pilot and feasibility randomised controlled trial (RCT) in England to explore the use of SPARX in different settings. The trial will explore whether SPARX supported by an e-coach (assistant psychologists) improves adherence and engagement compared with self-directed (i.e. self-help) use. The trial results will be used to inform the optimal mode of delivery (SPARX supported vs. SPARX self-directed), to calculate an appropriate sample size for a full RCT, and to decide which setting is most suitable.MethodsFollowing consultation with young people to ensure study suitability/appropriateness, a total of 120 adolescents (11–19 years) will be recruited for this three-arm study. Adolescents recruited for the study across England will be randomised to receive either SPARX with human support (from an e-coach), self-directed SPARX, or a waitlist control group. Assessments will be conducted online at baseline, week 4, and 8–10-week post-randomisation. The assessments will include measures which capture demographic, depression (Patient Health Questionnaire modified for adolescents [PHQ-A]) and anxiety (Revised Child Anxiety and Depression Scale [RCADS]) symptomatology, and health-related quality-of-life data (EQ-5D-Y and proxy version). Analyses will be primarily descriptive. Qualitative interviews will be undertaken with a proportion of the participants and clinical staff as part of a process evaluation, and the qualitative data gathered will be thematically analysed. Finally, feasibility data will be collected on recruitment details, overall study uptake and engagement with SPARX, participant retention, and youth-reported acceptability of the intervention.DiscussionThe findings will inform the design of a future definitive RCT of SPARX in the UK. If the subsequent definitive RCT demonstrates that SPARX is effective, then an online serious game utilising CBT principles ultimately has the potential to improve the provision of care within the UK’s health services if delivered en masse.Trial registrationISRCTN: ISRCTN15124804. Registered on 16 January 2023, https://www.isrctn.com/ISRCTN15124804.

A cautionary tale: an evaluation of the performance of treatment switching adjustment methods in a real world case study

BackgroundTreatment switching in randomised controlled trials (RCTs) is a problem for health technology assessment when substantial proportions of patients switch onto effective treatments that would not be available in standard clinical practice. Often statistical methods are used to adjust for switching: these can be applied in different ways, and performance has been assessed in simulation studies, but not in real-world case studies. We assessed the performance of adjustment methods described in National Institute for Health and Care Excellence Decision Support Unit Technical Support Document 16, applying them to an RCT comparing panitumumab to best supportive care (BSC) in colorectal cancer, in which 76% of patients randomised to BSC switched onto panitumumab. The RCT resulted in intention-to-treat hazard ratios (HR) for overall survival (OS) of 1.00 (95% confidence interval [CI] 0.82–1.22) for all patients, and 0.99 (95% CI 0.75–1.29) for patients with wild-type KRAS (Kirsten rat sarcoma virus).MethodsWe tested several applications of inverse probability of censoring weights (IPCW), rank preserving structural failure time models (RPSFTM) and simple and complex two-stage estimation (TSE) to estimate treatment effects that would have been observed if BSC patients had not switched onto panitumumab. To assess the performance of these analyses we ascertained the true effectiveness of panitumumab based on: (i) subsequent RCTs of panitumumab that disallowed treatment switching; (ii) studies of cetuximab that disallowed treatment switching, (iii) analyses demonstrating that only patients with wild-type KRAS benefit from panitumumab. These sources suggest the true OS HR for panitumumab is 0.76–0.77 (95% CI 0.60–0.98) for all patients, and 0.55–0.73 (95% CI 0.41–0.93) for patients with wild-type KRAS.ResultsSome applications of IPCW and TSE provided treatment effect estimates that closely matched the point-estimates and CIs of the expected truths. However, other applications produced estimates towards the boundaries of the expected truths, with some TSE applications producing estimates that lay outside the expected true confidence intervals. The RPSFTM performed relatively poorly, with all applications providing treatment effect estimates close to 1, often with extremely wide confidence intervals.ConclusionsAdjustment analyses may provide unreliable results. How each method is applied must be scrutinised to assess reliability.

Evaluation of a codesigned group cognitive–behavioural therapy intervention for trans young people (TAG TEAM): protocol for a feasibility trial and a subsequent pilot RCT

IntroductionTrans young people are at a higher risk of mental health difficulties such as depression, anxiety and suicidality than their cisgender peers, due in part to their experiences of minority...

The Early Benefits and Psychological Effects of Screening for Monoclonal Gammopathy of Undetermined Significance: Results of the Istopmm Study

Introduction: Multiple myeloma (MM) develops over years from the asymptomatic precursors, monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM). Recent evidence shows that initiating treatment at an asymptomatic stage improves outcomes in MM. However, a vast majority of MM patients are diagnosed at the point of symptomatic malignancy and never have the opportunity to receive early treatment. We aimed to evaluate systematic screening for MGUS as a way to significantly expand the availability of early treatment and improve overall outcomes. Despite the widespread use of cancer screening, the literature on the potential harms of screening, particularly psychological harms, is limited. Studies on the psychological effects of screening are therefore, urgently needed. The Iceland Screens, Treats, or Prevents Multiple Myeloma study (iStopMM) is a population-based screening study and randomized controlled trial (RCT) of follow-up strategies aimed at evaluating the potential benefits and harms of MGUS screening. Methods: All residents of Iceland born in 1975 or earlier were invited to participate of whom 80,759 individuals (54% of the eligible population) provided written informed consent for screening. Serum samples collected between 2016-2020 were screened by serum protein electrophoresis (SPEP) and free light-chain (FLC) assay. Those who had MGUS entered a RCT of follow-up strategies. Arm 1 was not notified; Arm 2 was followed according to guidelines; Arm 3 was followed according to a more intensive strategy. Participants who progressed were offered early treatment. Participants were followed to a diagnosis of MM, SMM, Waldenström's macroglobulinemia (WM), smoldering WM, chronic lymphocytic leukemia (CLL), and non-Hodgkin's lymphoma (NHL) with censoring at death. Progression rates were compared using the log-rank test. At registration, all participants were asked to answer the Patient Health Questionnaire 9 (PHQ-9), General Anxiety Disorder 7 (GAD-7), and the Satisfaction with Life Scale (SWLS), validated questionnaires that assess depression, anxiety, and satisfaction with life. These questionnaires were sent annually to all participants and two weeks after MGUS diagnosis to Arms 2 and 3. Scores for Arm 1 and Arms 2 and 3 combined were compared using a generalized estimating equations linear model to account for multiple and differential numbers of observations before and after MGUS diagnosis. Results: A total of 75,422 participants provided a serum sample for screening and 3,487 had previously unknown MGUS and entered the RCT. Over a median follow-up of 4-4.5 years (depending on the outcome of interest) a total of 33, 136, and 185 were diagnosed with MM, SMM, WM, SWM, CLL, or NHL in Arms 1, 2, and 3 (p<0.001), respectively (Figure). In total, 775 (65%) and 1,838 (72%) participants in Arm 1 and Arms 2 and 3 answered a total of 2,673 and 8,540 questionnaires respectively. PHQ-9 and GAD-7 scores were not higher and SWLS scores were not lower in those who were made aware of their MGUS status (Arms 2 and 3) either at MGUS diagnosis, one year after diagnosis, or at the end of follow-up. Thus, no negative psychological impact was observed. In fact, a small positive psychological impact of MGUS diagnosis was observed as demonstrated by lower scores on PHQ-9 and GAD-7. However, the effect sizes were small (Cohens' d range: 0.02-0.2) indicating no meaningful difference in psychological wellbeing between the groups (Table). Discussion: In this first, large population-based screening study for MGUS and subsequent RCT, we found that screening is feasible and leads to early diagnosis and treatment of MM and related disorders. Importantly, MGUS screening was not associated with any demonstrable psychological harm. This shows, for first time, that providing detailed and balanced information at diagnosis, and plans for follow-up can prevent psychological harm from the diagnosis of this precancerous condition, a finding which is of significance to the field of cancer screening in general. These findings are a major milestone towards establishing the role of MGUS screening. If they translate into the prevention of symptomatic malignancies and improvements in overall survival, screening for MGUS can produce a paradigm shift in the field of plasma cell disorders towards a future of early detection, early treatment, and prevention, and perhaps even a cure.

Allopurinol for Secondary Prevention in Patients with Cardiovascular Disease: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

The effects of allopurinol in patients with cardiovascular disease are not well defined; therefore, the latest evidence is summarized in this study. PubMed, Embase, Cochrane Library, and ClinicalTrials.gov databases were searched for randomized controlled trials (RCTs) of allopurinol in patients with cardiovascular disease published up to 11 February 2023. The primary outcome was cardiovascular death. We combined the results of 21 RCTs that included 22,806 patients. Compared to placebo/usual care, allopurinol treatment was not associated with a significant reduction in cardiovascular death (RR 0.60; 95% CI 0.33-1.11) or all-cause death (RR 0.90; 95% CI 0.72-1.12). However, evidence from earlier trials and studies with small sample sizes indicated that allopurinol might confer a protective effect in decreasing cardiovascular death (RR 0.34; 95% CI 0.15-0.76) across patients undergoing coronary artery bypass grafting (CABG) or having acute coronary syndrome (ACS). In comparisons between allopurinol and febuxostat, we observed no difference in cardiovascular death (RR 0.92; 95% CI 0.69-1.24) or all-cause death (RR 1.02; 95% CI 0.75-1.38). Allopurinol could not reduce cardiovascular (CV) death or major adverse CV outcomes significantly in patients with existing cardiovascular diseases. Given the limitations of the original studies, the potential advantages of allopurinol observed in patients undergoing CABG or presenting with ACS necessitate further confirmation through subsequent RCTs. In the comparisons between allopurinol and febuxostat, our analysis failed to uncover any marked superiority of allopurinol in reducing the risk of adverse cardiovascular incidents.

Feasibility of the Poverty-Targeted Pediatric Cancer Resource Equity (PediCARE) intervention.

10009 Background: Children with cancer living in poverty are more likely to relapse and die, even when treated uniformly on clinical trials. No evidence-based interventions targeting poverty as a risk factor for disparate outcomes exist in pediatric oncology. We previously developed and refined the Pediatric Cancer Resource Equity (PediCARE) intervention—a centrally-delivered, household material hardship (HMH)-targeted intervention that provides transportation and groceries to low-income pediatric oncology families. We report feasibility of administering PediCARE as a randomized intervention across 2-centers. Methods: We conducted a pilot randomized controlled trial (RCT) of PediCARE versus usual care at Dana-Farber Cancer Institute (DFCI) and University of Alabama Birmingham (UAB) between May 2019 and August 2021 (NCT03638453). Eligible participants included children age < 18 years with de novo cancer diagnosed in the prior 2-months, who were planned to receive at least 4-cycles of chemotherapy and lived in a household that screened positive for HMH (food, housing, utility or transportation insecurity). Participants were randomized 1:1 by site to receive PediCARE or usual care for 6-months. Parent/guardians completed a household survey at baseline and at completion of the 6-month intervention. The primary outcome was feasibility defined a priori as a recruitment and consent to randomization rate of > = 75% and < 20% attrition per arm—endpoints intended to justify the feasibility of a subsequent efficacy RCT. Secondary outcomes included proportion of recipients who successfully received the intervention and intervention acceptability. Results: A total of N = 40/40 eligible families (n = 12 UAB; n = 28 DFCI) were approached and offered an opportunity to participate (100% consent rate). Among participants, there was 0% attrition in either arm following randomization and the 6-month intervention period; 100% of parent/guardians completed both baseline and 6-month surveys. Among those randomized to PediCARE, 100% (n = 20) successfully received grocery and transportation resources; 100% reported that it was "easier to buy food for my family," 85% reported it was easier to get to and from the hospital, and 95% reported they would be “very likely to recommend the intervention to other families”. Conclusions: Stark disparities exist in pediatric oncology. Advancement in health equity science must include establishment of a robust, evidence-based portfolio of scalable health equity interventions for evaluation in the Children’s Oncology Group (COG) drug trial setting. Findings from this pilot RCT support feasibility and utility of a poverty-targeted intervention from the clinical oncology setting—as evidenced by 100% of parent/guardians consenting to randomization with 0% attrition across 2-centers. Immediate next steps include randomized efficacy evaluation in a COG trial-embedded study. Clinical trial information: NCT03638453 .

Surviving Sepsis Campaign.

Surviving Sepsis Campaign.

Network Meta-analysis of single Hirudo prescriptions in treatment of ischemic cerebrovascular disease

This study intended to evaluate the efficacy and safety of single Hirudo prescriptions in the treatment of ischemic cerebrovascular disease(ICVD) by frequency network Meta-analysis and traditional Meta-analysis. CNKI, Wanfang, VIP, SinoMed, PubMed, EMbase, and Cochrane Library databases were searched to collect the randomized controlled trial(RCT) of single Hirudo prescriptions for ICVD from the inception of the databases to May 2022. The quality of the included literature was evaluated by Cochrane risk of bias tool. Finally, 54 RCTs and 3 single Hirudo prescriptions were included. Statistical analysis was conducted by RevMan 5.3 and Stata SE 15. Network Meta-analysis showed that in terms of the clinical effective rate, the surface under the cumulative ranking curve(SUCRA) of intervention measures was as follows: Huoxue Tongmai Capsules+conventional treatment>Maixuekang Capsules+conventional treatment>Naoxuekang Capsules+conventional treatment>conventional treatment. Traditional Meta-analysis revealed that in terms of the safety of ICVD treatment, Maixuekang Capsules+conventional treatment had higher safety than conventional treatment alone. According to the network Meta-analysis and traditional Meta-analysis, it was found that conventional treatment combined with single Hirudo prescriptions improved the clinical efficacy of ICVD patients, and compared with that of conventional treatment alone, the incidence of adverse reactions of combined treatment was low and the safety was high. However, the methodological quality of the articles included in this study was generally low and there were large differences in the number of articles on the three combined medication. Therefore, the conclusion of this study needed to be confirmed by subsequent RCT.

Personalised exercise therapy and self-management support for people with multimorbidity: feasibility of the MOBILIZE intervention

BackgroundExercise therapy is safe and effective in people with single conditions, but the feasibility in people with two or more conditions is unclear. Therefore, the aim was to evaluate the feasibility of exercise therapy and self-management in people with multimorbidity prior to a randomised, controlled trial (RCT).MethodsThis was a mixed-methods feasibility study performed in two general hospitals and one psychiatric hospital. 20 adult patients (8 females; mean age (SD) 67 (6.9)) with at least two long-term conditions and a score of ≥ 3 on Disease Burden Impact Scale for at least one condition (at least moderate limitations of daily activities) and of ≥ 2 for at least one other condition. Patients with unstable health conditions, at risk of serious adverse events (SAE) or with terminal conditions were excluded. Participants received 12 weeks of exercise (18 60-min group-based and 6 home-based sessions) and self-management support (6 90-min group-based sessions) supervised by physiotherapists. Pre-defined progression to RCT criteria were the primary outcomes and included recruitment rate (acceptable 20 participants in 3 months), retention through follow-up (75% retention), compliance (75% complete > 9 of exercise and > 3 self-management sessions), outcome burden (80% do not find outcomes too burdensome), improvement in quality of life (EQ-5D-5L) and function (6-min walk test; ≥ 50% experience clinically relevant improvements) and intervention-related SAEs (No SAEs). Furthermore, a purposeful sample including eleven participants and two facilitators were interviewed about their experiences of participating/facilitating. Qualitative data was analysed using thematic analysis.ResultsRecruitment rate (20 in 49 days), retention (85%), outcome burden (95%), and SAEs (0 related to intervention) were acceptable, while compliance (70%) and improvements (35% in quality of life, 46% in function) were not (amendment needed before proceeding to RCT). The intervention was found acceptable by both participants and physiotherapists with some barriers among participants relating to managing multiple chronic conditions while caring for others or maintaining a job. Physiotherapists expressed a need for additional training.ConclusionsExercise therapy and self-management are feasible in people with multimorbidity. The subsequent RCT, amending the intervention according to progression criteria and feedback, will determine whether the intervention is superior to usual care alone.Trial registrationClinicalTrials.gov registration: NCT04645732Open Science Framework https://osf.io/qk6yg/

Internet-administered, low-intensity cognitive behavioral therapy for parents of children treated for cancer: A feasibility trial (ENGAGE).

Parents of children treated for cancer may experience mental health difficulties, such as depression and anxiety. There is a lack of evidence-based psychological interventions for parents, with psychological support needs unmet. An internet-administered, guided, low-intensity cognitive behavioral therapy-based (LICBT) self-help intervention may provide a solution. The feasibility and acceptability of such an intervention was examined using a single-arm feasibility trial (ENGAGE). Primary objectives examined: (1) estimates of recruitment and retention rates; (2) feasibility and acceptability of data collection instruments and procedures; and (3) intervention feasibility and acceptability. Clinical outcomes were collected at baseline, post-treatment (12 weeks), and follow-up (6months). The following progression criteria were met: sample size was exceeded within 5months, with 11.0% enrolled of total population invited, study dropout rate was 24.0%, intervention dropout was 23.6%, missing data remained at ≤10% per measure, and no substantial negative consequences related to participation were reported. Intervention adherence was slightly lower than progression criteria (47.9%). Findings suggest an internet-administered, guided, LICBT self-help intervention may represent a feasible and acceptable solution for parents of children treated for cancer. With minor study protocol and intervention modifications, progression to a pilot randomized controlled trial (RCT) and subsequent superiority RCT is warranted.

Integrative systemic and family therapy for social anxiety disorder: Manual and practice in a pilot randomized controlled trial (SOPHO-CBT/ST).

Social anxiety disorders (SAD) are among the most prevalent mental disorders (lifetime prevalence: 7-12%), with high impact on the life of an affected social system and its individual social system members. We developed a manualized disorder-specific integrative systemic and family therapy (ISFT) for SAD, and evaluated its feasibility in a pilot randomized controlled trial (RCT). The ISFT is inspired by Helm Stierlin's concept of related individuation developed during the early 1980s, which has since continued to be refined. It integrates solution-focused language, social network diagnostics, and genogram work, as well as resource- and problem orientation for both case conceptualization and therapy planning. Post-Milan symptom prescription to fluidize the presented symptoms is one of the core interventions in the ISFT. Theoretically, the IFST is grounded in radical constructivism and "Cybern-Ethics," multi-directional partiality, and a both/and attitude toward a disorder-specific vs. non-disorder-specific therapy approach. SAD is understood from the viewpoint of social systems theory, especially in adaptation to a socio-psycho-biological explanatory model of social anxiety. In a prospective multicenter, assessor-blind pilot RCT, we included 38 clients with SAD (ICD F40.1; Liebowitz Social Anxiety Scale, LSAS-SR > 30): 18 patients participated in the ISFT, and 20 patients in Cognitive Behavioral Therapy (CBT; age: M = 36 years, SD = 14). Within-group, simple-effect intention-to-treat analyses showed significant reduction in social anxiety (LSAS-SR; ISFT: d = 1.67; CBT: d = 1.04), while intention-to-treat mixed-design ANOVA demonstrated the advantage of ISFT (d = 0.81). Per-protocol analyses supported these results. The remission rate based on blind diagnosticians' ratings was good to satisfactory (Structured Clinical Interview, SCID; 78% in ST, 45% in CBT, p = 0.083); this has yet to be verified in a subsequent confirmatory RCT. The article will present the ISFT rationale and manual, including a special focus on multi-person settings, and the central findings from our pilot RCT.

Examining the empirical evidence for IDEAL 2b studies: the effects of preceding prospective collaborative cohort studies on the quality and impact of subsequent randomized controlled trials of surgical innovations – protocol for a systematic review and case–control analysis

Randomized controlled trials (RCTs) in surgery face methodological challenges, which often result in low quality or failed trials. The Idea, Development, Exploration, Assessment and Long-term (IDEAL) framework proposes preliminary prospective...

Do Early Phase Oncology Trials Predict Clinical Efficacy in Subsequent Biomarker-Enriched Phase III Randomized Trials?

Promising early phase trial results of biomarker-targeted therapies have occasionally led to regulatory approval. We examined if early phase trials were predictive of efficacy in randomized controlled trials (RCTs) with matching treatment settings. Cancer drug RCTs conducted between January 2006 and March 2021 were identified through Clinicaltrials.gov. Biomarker-enriched RCTs and associated matching early phase trials were included. Trial pairs were compared using objective response rate (ORR) and progression-free survival (PFS). We examined whether early phase trials results were associated with RCT results using logistic regression. The search yielded 2157 unique RCTs and 27 RCTs pairing with early phase trials were included. Based on average difference of trial pairs, ORR was similar (1.6%; 95% confidence interval (CI) - 2.5 to 5.6, p = 0.50) and median PFS was higher in early phase trials (2.0months; 95% CI 0.9-3.0, p < 0.05). On an individual pair basis, there was large variability in difference for ORR (range - 23.9 to 20.2%) and median PFS (range - 0.8 to 7.4months). The probability of the RCT meeting its primary endpoint is 95% (95% prediction interval (PI) 72.8-99.3%) when the early phase trial ORR is 77.7%. Overall, in early phase trials, ORR has minimal bias and median PFS appears to be slightly overestimated. Substantial variability between trials suggests early phase trial results may be inconsistent with subsequent RCT. Early phase trial results may be associated with RCTs meeting their primary endpoint when ORR is very high; however, caution must be exercised when using early phase trials as representative of RCTs.

A comic-based body image intervention for adolescents in semi-rural Indian schools: Study protocol for a randomized controlled trial

Adolescents in India experience body dissatisfaction, however, empirically supported interventions are lacking. This paper describes the protocol for the development, acceptability testing, and cluster randomized controlled trial (RCT) of a six-session comic-based intervention, which aims to improve body image and related outcomes among adolescents in semi-rural Indian schools. If found to be acceptable and effective, UNICEF will disseminate the intervention across schools in eight states of India. The acceptability study will be conducted with 24 students in Classes 6–8 (age 11–14) and nine teachers from Hindi-medium government schools using interviews and focus groups. The subsequent RCT will be conducted with 2400 students, with schools randomized to either the comic-based intervention or lessons-as-usual (control) groups. The primary outcome is body esteem, and secondary outcomes are disordered eating, appearance ideal internalization, body-image-related life disengagement, self-esteem, negative affect, and positive affect. Additional exploratory outcome measures are skin colour dissatisfaction, body hair dissatisfaction, appearance-based teasing, and endorsement of traditional gender roles. These outcomes will be examined at three timepoints: baseline (T1), 1 week-post-intervention (T2), and 12-weeks follow-up (T3). Analyses will compare outcomes in the intervention with the control group. This will be the first study to evaluate a body image intervention for adolescents in semi-rural Indian schools.

Do early phase trials predict clinical efficacy in subsequent phase III biomarker-enriched randomized trials?

3152 Background: Efficacy endpoints of randomized controlled trials (RCT) are commonly used as the basis of regulatory drug approvals. Recently, promising results in early phase trials have resulted in approval of biomarker-targeted therapies. We examined if early phase trial results were associated with efficacy in subsequent biomarker-enriched RCTs. Methods: All cancer drug RCTs conducted between January 2006 and March 2021 were identified through Clinicaltrials.gov. Trials were eligible if a biomarker was used to select a patient population for treatment with a targeted agent. Associated early phase trials were included if they matched the RCT in treatment setting and patient population. Trials pairs were compared using objective response rate (ORR) and progression-free survival (PFS). We assessed difference in endpoints using summary measures (e.g., average, range). We examined whether early phase trials results were associated with RCT results using logistic regression. Results: The search yielded 2,157 unique phase III RCTs and 27 RCTs met eligibility criteria pairing with associated early phase trials, where 17 RCTs met their primary endpoint. The most common biomarkers were EGFR+ (n = 8), HER2+ (n = 5) and PD-L1 (n = 5). Based on average difference of trial pairs, ORR was similar between trials (1.59%, 95% CI = -2.5-5.6, p = 0.50) and median PFS was slightly higher in early phase trials (1.95 months, 95% CI = 0.91-2.99, p &lt; 0.05). On an individual pair basis, there was large range of variability in the difference between early phase trials and RCTs for ORR (range = -23.9-20.2%) and median PFS (range = -0.8-7.4 months). The probability of the RCT meeting its primary endpoint is 50% or 95%, when the early phase trial ORR is 41.2% (95% CI = 35.2-47.1%) or 77.7% (95% CI = 71.7-83.6%), respectively. Conclusions: Through comparison of early phase trials and subsequent phase III RCT, we found that, overall, ORR has minimal bias in early phase trials, and median PFS appears to be slightly overestimated. Substantial variability in results for trial pairs suggests that, on an individual basis, results in early phase trial can be inconsistent with results in subsequent RCT. Early phase trial results may be associated with RCTs meeting their primary endpoint when ORR is very high; however, caution must be exercised when using early phase trials as representative of RCTs for decision-making as the predictive ability of early phase trials is limited.

An integrated mindfulness meditation and acceptance and commitment therapy intervention for chronic pain: Rationale, design, and methodology of a pilot randomized controlled trial of Acting with Mindfulness for Pain (AMP)

Acceptance and commitment therapy (ACT) is an evidence-based psychosocial intervention for chronic pain; however, in its present form ACT produces modest improvements in function and is no more effective than cognitive behavioral therapy (CBT), the current gold standard. This protocol paper describes the Acting with Mindfulness for Pain (AMP) protocol, which emphasizes and integrates formal mindfulness meditation practice within an ACT-based approach. This paper presents the rationale, design and methodology of an ongoing pilot randomized controlled trial (RCT) comparing AMP to CBT among Veterans with chronic pain (N = 86). Specifically, we argue that formal meditation practice is a necessary treatment component that directly targets key ACT processes which will help facilitate large treatment effects on function (e.g., general activity, social relationships, life enjoyment) among individuals with chronic pain. This study will be the first to consider formal mindfulness meditation practice as a principal treatment ingredient in the context of ACT for chronic pain. The purpose of this trial is to evaluate the feasibility of recruitment and collection of measures, and to examine preliminary treatment effects to determine the appropriateness of a subsequent full-scale RCT. This study will also explore within and between group change on primary and secondary outcomes including pain interference, pain acceptance, trait mindfulness, pain catastrophizing, values-based living, quality of life, practice adherence, and objective measures of physical activity. This study will help delineate the role of formal mindfulness practice within an ACT-based approach for chronic pain and provide preliminary data for a future fully powered RCT.

Identification and inference for subgroups with differential treatment efficacy from randomized controlled trials with survival outcomes through multiple testing.

With the uptake of targeted therapies, instead of the "one-fits-all" approach, modern randomized controlled trials (RCTs) often aim to develop treatments that target a subgroup of patients. Motivated by analyzing the Age-Related Eye Disease Study (AREDS) data, a large RCT to study the efficacy of nutritional supplements in delaying the progression of an eye disease, age-related macular degeneration (AMD), we develop a simultaneous inference procedure to identify and infer subgroups with differential treatment efficacy in RCTs with time-to-event outcomes. Specifically, we formulate the multiple testing problem through contrasts and construct their simultaneous confidence intervals, which appropriately control both within- and across-marker multiplicity. Realistic simulations are conducted using real genotype data to evaluate the method performance under various scenarios. The method is then applied to AREDS to assess the efficacy of antioxidants and zinc combination in delaying AMD progression. Multiple gene regions including ESRRB-VASH1 on chromosome 14 have been identified with subgroups showing differential efficacy. We further validate our findings in an independent subsequent RCT, AREDS2, by discovering consistent differential treatment responses in the targeted and non-targeted subgroups identified from AREDS. This multiple-testing-based simultaneous inference approach provides a step forward to confidently identify and infer subgroups in modern drug development.

Findings from the patch augmented rotator cuff surgery (PARCS) feasibility study

BackgroundA rotator cuff tear is a common disabling shoulder problem. Symptoms include pain, weakness, lack of mobility and sleep disturbance. Many patients require surgery to repair the tear; however, there is a high failure rate. There is a pressing need to improve the outcome of rotator cuff surgery. The use of patch augmentation to provide support to the healing process and improve patient outcomes holds new promise. Different materials (e.g. human/animal skin or intestine tissue, and completely synthetic materials) and processes (e.g. woven or a mesh) have been used to produce patches. However, clinical evidence on their use is limited. The patch augmented rotator cuff surgery (PARCS) feasibility study aimed to determine the design of a definitive randomised controlled trial (RCT) assessing the effectiveness and cost-effectiveness of a patch to augment surgical repair of the rotator cuff that is both acceptable to stakeholders and feasible.MethodsA mixed methods feasibility study of conducing a subsequent RCT. The project involved six stages: a systematic review of clinical evidence; a survey of the British Elbow and Shoulder Society’s (BESS) surgical membership; a survey of surgeon trialists; focus groups and interviews with stakeholders; a two-round Delphi study administered via online questionnaires and a 2-day consensus meeting.ResultsThe BESS surgeons’ survey identified a variety of patches in use (105 (21%) responses received). Twenty-four surgeons (77%) completed the trialist survey relating to trial design. Four focus groups were conducted involving 24 stakeholders. Twenty-nine (67% of invited) individuals took part in the Delphi. Differing views were held on a number of aspects including the appropriate patient population for trial participation. Agreement on the key research questions and the outline of two potential RCTs were achieved through the Delphi study and the consensus meeting.ConclusionsRandomised comparisons of on-lay patch use for completed rotator cuff repairs, and bridging patch use for partial rotator cuff repairs were identified as areas for further research. The value of an observational study to assess safety concerns of patch use was also highlighted. The main limitation was that the findings were influenced by the participants, who might not necessarily reflect all stakeholders.

Recurrence rate with inferior conjunctival autograft transplantation compared with superior conjunctival autograft transplantation in pterygium surgery: a meta-analysis

BackgroundConjunctival autograft transplantation from superior conjunctiva is often chosen to lower the postoperative recurrence rate for pterygium treatment. However, inferior conjunctival autograft (ICA) might be taken as an alternative surgery method, especially under certain conditions. Consequently, we designed this research to estimate and contrast the result of inferior conjunctival autograft and superior conjunctival autograft (SCA) on the postoperative recurrence rate.MethodsWe searched through network database (PubMed, Embase and Cochrane Central Register of Controlled Trials) to choose suitable randomized controlled trials (RCTs). Based on Cochrane review methods, we evaluated eligibility and risk of bias of included studies. The primary measures included postoperative recurrence rate. Pooled risk ratios (RRs) and 95% confidence intervals (CIs) were assessed. RevMan 5.3 software was utilized to conduct statistical analysis.ResultsFour RCTs composed of a total of 438 eyes were included in this meta-analysis, with 234 eyes in the inferior conjunctival autograft group and 204 eyes in the superior conjunctival autograft group. Statistical meta-analysis revealed that the postoperative recurrence rate was similar between the two groups (RR = 0.77, 95% CI: 0.36 to 1.62, P = 0.49). Only two RCTs applied the postoperative pain scale and one of them did not provided adequate numbers.ConclusionsOur meta-analysis indicated that inferior autograft transplantation and superior autograft transplantation had a similar effect on postoperative recurrence rate. The inferior autograft group might have a less postoperative pain. Subsequent RCTs which have more patients participated and more outcomes are needed to confirm our conclusions in years to come.