Adherence to adjuvant endocrine therapy in women with breast cancer is low. We conducted a 24-1 fractional factorial pilot optimization trial to test four intervention components supporting medication adherence [text messages, information leaflet, acceptance and commitment therapy (ACT), self-management website], in the preparation phase of the multiphase optimization strategy. Guided by the National Institute of Health Behavior Change Consortium fidelity framework, we investigated fidelity of design, training, delivery, receipt, and enactment of four intervention components. Women prescribed adjuvant endocrine therapy (n = 52) were randomized to one of eight experimental conditions comprised of combinations of the four intervention components (ISRCTN: 10487576). We assessed fidelity using self-report data (4 months post-randomization), trial data, ACT session observations, behavior change technique (BCT) coding, and interviews with participants (n = 20) and therapists (n = 6). Design: Each intervention component targeted unique behavior change techniques with some overlap. Training: All 10 therapists passed the competency assessment. Delivery: All leaflets (27/27) and website (26/26) details were sent, and ACT procedural fidelity was high (85.1%-94.3%). A median of 32.5/41 (range 11-41) text messages were delivered, but a system error prevented some messages being sent to 22 of 28 participants. Receipt: Most participants [63.0% (ACT, leaflet) to 71.4% (text messages)] read all or at least some of the intervention components they were randomized to receive. Enactment was reported most positively for ACT. All intervention components demonstrated adequate fidelity. We have provided an exemplar for assessing fidelity using the National Institute of Health Behavior Change Consortium framework in the preparation phase of multiphase optimization strategy.

BACKGROUND:Adherence to adjuvant endocrine therapy (AET) in women with breast cancer is poor. Multicomponent intervention packages are needed to address adherence barriers. Optimizing these packages prior to definitive evaluation can increase their effectiveness, affordability, scalability, and efficiency. PURPOSE:To pilot procedures for an optimization-randomized controlled trial (O-RCT) of the 'Refining and Optimizing Strategies to support Endocrine Therapy Adherence' (ROSETA) intervention. METHODS:This was a multisite individually randomized external pilot trial using a 24-1 fractional factorial design (ISRCTN10487576). Breast cancer survivors prescribed AET were recruited from 5 hospitals and randomized to one of 8 conditions, each comprising a combination of 4 intervention components set to "on" or "off" (SMS messages, information leaflet, guided self-help, and self-management website). We set criteria to inform the decision to progress to an O-RCT for consent rate, component adherence, and availability of outcome measures, with predefined cutoffs for "green" (proceed), "amber" (minor changes), and "red" (major changes). RESULTS:Among 141 eligible patients, 54 (38.3%) consented (green range). At least 50.0% of participants adhered to the minimum threshold set for each intervention component (green range). Data for one of the 3 medication adherence measures were available (amber range). Most (86.8%) participants were satisfied with their trial experience. Exploratory analysis indicated some evidence of a negative main effect of the information leaflet on medication adherence (adjusted mean difference = 0.088, 95% CI, 0.018, 0.158). CONCLUSIONS:Progression to a fully powered O-RCT of the ROSETA intervention package is feasible, but review of medication adherence measures is required.

Background: Adjuvant endocrine therapy (AET) reduces mortality risk in early-stage breast cancer, but adherence is low. We developed a multicomponent intervention to support AET adherence comprising: text messages; information leaflet; acceptance and commitment therapy (ACT); side-effect management website. Guided by the multiphase optimization strategy, the intervention components were tested in the ROSETA pilot optimization trial. Our mixed-methods process evaluation investigated component acceptability.Methods: The pilot optimization trial used a 24-1 fractional factorial design. Fifty-two women with breast cancer prescribed AET were randomized to one of eight experimental conditions, each containing a unique combination of components. An acceptability questionnaire was administered four months post-randomization, and semi-structured interviews with 20 participants further explored acceptability. Assessments were guided by four domains of the theoretical framework of acceptability; affective attitude, burden, perceived effectiveness, and coherence. Quantitative and qualitative findings were triangulated to identify agreements/disagreements.Results: There were high overall acceptability scores across components (median=14-15/20, range=11-20). Overall there was agreement between the qualitative and quantitative findings when triangulated. Most participants ‘liked’ or ‘strongly liked’ all components, and reported they generally required low effort to engage in. Perceived effectiveness was mixed, with 35.0% (text messages) to 55.6% (ACT) of participants ‘agreeing’ or ‘strongly agreeing’ that each component would improve their adherence. Interview data provided suggestions to improve acceptability. Conclusion: The four components were acceptable to women with breast cancer, and will be refined prior to a full optimization trial. Mixed-methods and triangulation were useful methodological approaches and could be applied in other optimization trial process evaluations.

Abstract Background Sexually transmitted infections (STIs) during pregnancy are associated with adverse birth outcomes, including preterm birth, low birth weight, perinatal death, and congenital infections such as increased mother-to-child HIV transmission. Prevalence of STIs among pregnant women in South Africa remains high, with most women being asymptomatic for their infection(s). Unfortunately, most STIs remain undetected and untreated due to standard practice syndromic management in accordance with World Health Organization (WHO) guidelines. Although lab-based and point-of-care molecular tests are available, optimal screening strategies during pregnancy, their health impact, and cost-effectiveness are unknown. Methods We will implement a 3-arm (1:1:1) type-1 hybrid effectiveness-implementation randomized-controlled trial (RCT). We will enroll 2500 pregnant women attending their first antenatal care (ANC) visit for their current pregnancy at participating health facilities in Buffalo City Metro District, Eastern Cape Province, South Africa. Participants allocated to arms 1 and 2 (intervention) will receive GeneXpert® point-of-care diagnostic testing for Neisseria gonorrhoeae, Chlamydia trachomatis, and Trichomonas vaginalis, with same-day treatment for detected infection(s). Arm 1 will additionally receive a test-of-cure 3 weeks post-treatment, while Arm 2 will receive a repeat test at 30–34 weeks’ gestation. Those allocated to Arm 3 will receive syndromic management (standard-of-care). The RE-AIM framework will be used to guide collection of implementation indicators to inform potential future scale up. Primary outcome measures include (1) frequency of adverse birth outcomes among study arms, defined by a composite measure of low birth weight and pre-term delivery, and (2) change in STI prevalence between baseline and birth outcome among intervention arms and compared to standard-of-care. Estimates and comparative costs of the different screening strategies relative to standard-of-care and the costs of managing adverse birth outcomes will be calculated. Cost-effectiveness will be assessed per STI and disability-adjusted life year averted. Discussion This trial is the first RCT designed to identify optimal, cost-effective screening strategies that decrease the burden of STIs during pregnancy and reduce adverse birth outcomes. Demonstrating the impact of diagnostic screening and treatment, compared to syndromic management, on birth outcomes will provide critical evidence to inform changes to WHO guidelines for syndromic management of STIs during pregnancy. Trial registration ClinicalTrials.gov NCT04446611 . Registered on 25 June 2020.

Abstract Background Irritable bowel syndrome (IBS) is a common functional bowel disorder that has a considerable impact on patient quality of life and substantial societal and health care resource costs. Current treatments are often ineffective. Tricyclic antidepressants have shown promise in secondary care populations but their effectiveness in a primary care setting remains unclear. Methods ATLANTIS is a randomised, multi-centre, parallel-group, two-arm, double-blind, placebo-controlled trial of low-dose amitriptyline as a second-line treatment for IBS in primary care. Participants will be invited by letter, or recruited opportunistically, from general practices in three regions of England (West Yorkshire, Wessex, and West of England) and screened for eligibility. A total of 518 adult patients with IBS, who are symptomatic despite first-line therapies, will be randomised 1:1 to amitriptyline or identical placebo for 6 months. Treatment will commence at a dose of 10 mg (or one placebo tablet) daily at night, with dose titration up to a maximum of 30 mg at night, depending on side effects and response to treatment. Participant-reported assessments will be conducted at baseline and 3, 6, and 12 months post-randomisation. The primary objective is to determine the effectiveness of amitriptyline, compared with placebo, in improving participant-reported global symptoms of IBS at 6 months (using the IBS Severity Scoring System). Secondary outcomes include relief of IBS symptoms, effect on IBS-associated somatic symptoms (Patient Health Questionnaire-12), anxiety and depression (Hospital Anxiety and Depression Scale), ability to work and participate in other activities (Work and Social Adjustment Scale), acceptability and tolerability of treatment, self-reported health care use, health-related quality of life (EQ-5D-3L), and cost-effectiveness. A nested, qualitative study will explore patient and general practitioner experiences of treatments and trial participation, including acceptability, adherence, unanticipated effects, and implications for wider use of amitriptyline for IBS in primary care. Discussion Determining the clinical and cost-effectiveness of low-dose amitriptyline as a second-line treatment for IBS in primary care will provide robust evidence to inform management decisions. Trial registration ISRCTN ISRCTN48075063 . Registered on 7th June 2019.

BACKGROUND:Eligibility criteria are a fundamental element of clinical trial design, defining who can and who should not participate in a trial. Problems with the design or application of criteria are known to occur and pose risks to participants' safety and trial integrity, sometimes also negatively impacting on trial recruitment and generalisability. We conducted a short, exploratory survey to gather evidence on UK recruiters' experiences interpreting and applying eligibility criteria and their views on how criteria are communicated and developed. METHODS:Our survey included topics informed by a wider programme of work at the Clinical Trials Research Unit, University of Leeds, on assuring eligibility criteria quality. Respondents were asked to answer based on all their trial experience, not only on experiences with our trials. The survey was disseminated to recruiters collaborating on trials run at our trials unit, and via other mailing lists and social media. The quantitative responses were descriptively analysed, with inductive analysis of free-text responses to identify themes. RESULTS:A total of 823 eligible respondents participated. In total, 79% of respondents reported finding problems with eligibility criteria in some trials, and 9% in most trials. The main themes in the types of problems experienced were criteria clarity (67% of comments), feasibility (34%), and suitability (14%). In total, 27% of those reporting some level of problem said these problems had led to patients being incorrectly included in trials; 40% said they had led to incorrect exclusions. Most respondents (56%) reported accessing eligibility criteria mainly in the trial protocol. Most respondents (74%) supported the idea of recruiter review of eligibility criteria earlier in the protocol development process. CONCLUSIONS:Our survey corroborates other evidence about the existence of suboptimal trial eligibility criteria. Problems with clarity were the most often reported, but the number of comments on feasibility and suitability suggest some recruiters feel eligibility criteria and associated assessments can hinder recruitment to trials. Our proposal for more recruiter involvement in protocol development has strong support and some potential benefits, but questions remain about how best to implement this. We invite other trialists to consider our other suggestions for how to assure quality in trial eligibility criteria.