Helen Mossop

Background: Adaptive designs (ADs) are increasingly used, whereby outcome data accumulated during the trial may inform a trial’s course in accordance with pre-specified rules at interim analyses. The benefits however will only be realised if the approaches to conducting interim analyses are optimised. This study aims to identify existing literature highlighting best practice (and existing evidence gaps) with regard to conducting high-quality, timely interim analyses. Methods: Medline and Embase databases were searched for studies published between 2005 and July 2025 to identify best practice models and lessons learned for interim analyses in the delivery of adaptive trials. Specifically, we considered papers that discussed adaptive trial methodological approaches (Phases II–IV) in any clinical population and condition. A narrative synthesis focused on the following outcomes was conducted: design considerations, project/trial management, data management, statistical processes, trial committee processes, the implementation of interim decisions and patient and public involvement and engagement (PPIE). Results: We screened 6720 articles from databases and citation chaining and assessed 329 articles at full text. One hundred and one articles representing 92 unique studies were deemed eligible for inclusion. Key issues included the following: (a) Detailed planning of interim analyses set out in the protocol, and all patient information sheets for possible changes prepared in advance; (b) Effective communication and collaborative decision-making processes across stakeholders, effective staff training, and prompt site query resolutions; (c) Use of electronic data capture with automated data flow processes with integrated query processes to improve data quality; and (d) Use of secure databases with data transfer procedures to maintain data integrity. Conclusion: The currently available data suggest that although there is a considerable volume of evidence with regards to the conduct of adaptive trials and good trial management, the existing literature base offers limited specific guidance for interim analyses. There are significant gaps in the literature regarding best practice guidance related to PPIE and statistical considerations in adaptive trials. While there are examples of innovative methods speeding up the collation and analysis of data used for interim analyses, we advocate more robust research exploring the operational opportunities and challenges with regards to undertaking adaptive trials.

Background: Orthostatic hypotension is a significant drop in blood pressure upon standing upright. It is very common and can result in symptoms such as postural dizziness, fainting and falls. Within the United Kingdom National Health Service, there are three principal treatments: non-drug therapies, and two medications – fludrocortisone or midodrine. Despite this we do not know which treatments are the most effective, nor whether they are cost-effective. Objective: Evaluate the feasibility of a randomised trial to evaluate the clinical and cost-effectiveness of fludrocortisone and midodrine in comparison to non-drug therapies for the treatment of orthostatic hypotension. Design: A 10-month pilot of a pragmatic, open-label, randomised, prospective, superiority, multiarm, multistage clinical trial. The pilot evaluated recruitment, attrition, crossover and quality of outcomes. Setting: Falls and Syncope, Movement Disorder, Geriatrics, and Cardiology clinics in United Kingdom National Health Service secondary care. Participants: Adults with symptomatic orthostatic hypotension. Interventions: Control: Non-drug therapies (conservative management). Interventions: Conservative management plus fludrocortisone (50–400 mcg daily) or conservative management plus midodrine (5–30 mg daily). Main outcome measures: Recruitment: Target was 40–64 participants from 14 sites. Attrition target: ≤ 15% participants withdraw before the primary end point. Crossover: To determine the rates of crossover between intervention arms. Outcome data: Assess the quality and completeness of outcomes. Other important outcomes included feedback via questionnaire and interview from sites and participants. Results: Two hundred and eighty-two patients were screened for eligibility during the pilot; of these, 13 were recruited from 4 of 9 open sites. Current or recent use of one of the study medications accounted for 120 (52%) exclusions due to ineligibility. At the primary end point of 6 months, 10 of the 13 participants (77%) remained in the study. Of those, completion rates for primary and secondary outcomes were 100%, except for the falls diaries, which was 60%. Feedback from sites revealed that redeployment of clinical and research staff due to COVID-19 negatively impacted on site opening and screening for eligible participants. Adapting the protocol to make it more flexible for remote clinics and more pragmatic for clinical use did not improve recruitment. Limitations: The sample size is too small to provide a reliable estimate of attrition and crossover rates for future studies. Conclusions: This study was not feasible in its current design. COVID-19 had an impact on staffing and site opening, while the exclusion criteria limited recruitment. Future work: To answer the research question, novel trial designs are needed. Funding: This synopsis presents independent research funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme as award number NIHR127385.

Background: Adaptive designs are increasingly being used in clinical trials within diverse clinical areas. They can offer advantages over traditional non-adaptive approaches, including improved efficiency and patient benefit. The level of improvement observed in practice depends to a large degree on conducting interim analyses (at which adaptations can be made to the trial based on collected data) rapidly and to a high standard. Methods: The ROBust INterims for adaptive designs (ROBIN) project aimed to identify best practice for conducting high-quality and rapid interim analyses. This was done through evidence synthesis of published work, qualitative research with trial stakeholders working at public sector clinical trials units, engagement with patients and the public, and a meeting of trial stakeholders to discuss findings and agree recommendations. Results: This paper provides recommendations for teams that conduct adaptive trials about how to ensure interim analyses are done rapidly and to a high standard. We break down recommendations by stage of the trial. We also identify a lack of methodology on how best to involve patients in adaptive trials and related decision-making. A limitation of our recommendations is that the research was mostly focused on UK academic settings, although we believe much of the recommendations are relevant in other countries and to industry-sponsored trials. Conclusions: When following the recommendations outlined in this paper, the process of planning and executing interim analyses will be smoother; in turn, this will lead to more benefits from using adaptive designs.

Background: Daily, low-dose antibiotic prophylaxis is the current standard care for women with recurrent urinary tract infection. Emerging antimicrobial resistance is a global health concern, prompting research interest in non-antibiotic agents such as methenamine hippurate, but comparative data on their efficacy and safety are lacking.Objective: To assess the clinical effectiveness and cost-effectiveness of methenamine hippurate (Hiprex^®; Mylan NV, Canonsburg, PA, USA) compared with current standard care (antibiotic prophylaxis) for recurrent urinary tract infection prevention in adult women.Design: Multicentre, pragmatic, open-label, randomised, non-inferiority trial of 12 months’ treatment with the allocated intervention, including an early, embedded qualitative study and a 6-month post-treatment observation phase. The predefined non-inferiority margin was one urinary tract infection per person-year.Setting: Eight UK NHS secondary care sites.Participants: A total of 240 adult women with recurrent urinary tract infection requiring preventative treatment participated in the trial.Interventions: A central randomisation system allocated participants 1 : 1 to the experimental (methenamine hippurate: 1 g twice daily) or control (once-daily low-dose antibiotics: 50/100 mg of nitrofurantoin, 100 mg of trimethoprim or 250 mg of cefalexin) arm. Crossover between treatment arms was permitted.Main outcome measures: The primary clinical outcome was incidence of symptomatic antibiotic-treated urinary tract infection during the 12-month treatment period. Cost-effectiveness was assessed by incremental cost per quality-adjusted life-year gained, extrapolated over the patient’s expected lifetime using a Markov cohort model. Secondary outcomes included post-treatment urinary tract infections, total antibiotic use, microbiologically proven urinary tract infections, antimicrobial resistance, bacteriuria, hospitalisations and treatment satisfaction.Results: Primary modified intention-to-treat analysis comprised 205 (85%) randomised participants [102/120 (85%) participants in the antibiotics arm and 103/120 (86%) participants in the methenamine hippurate arm] with at least 6 months’ data available. During treatment, the incidence rate of symptomatic, antibiotic-treated urinary tract infections decreased substantially in both arms to 1.38 episodes per person-year (95% confidence interval 1.05 to 1.72 episodes per person-year) for methenamine hippurate and 0.89 episodes per person year (95% confidence interval 0.65 to 1.12 episodes per person-year) for antibiotics (absolute difference 0.49; 90% confidence interval 0.15 to 0.84). This absolute difference did not exceed the predefined, strict, non-inferiority limit of one urinary tract infection per person-year. On average, methenamine hippurate was less costly and more effective than antibiotics in terms of quality-adjusted life-years gained; however, this finding was not consistent over the longer term. The urinary tract infection incidence rate 6 months after treatment completion was 1.72 episodes per year in the methenamine hippurate arm and 1.19 in the antibiotics arm. During treatment, 52% of urine samples taken during symptomatic urinary tract infections were microbiologically confirmed and higher proportions of participants taking daily antibiotics (46/64; 72%) demonstrated antibiotic resistance inEscherichia colicultured from perineal swabs than participants in the methenamine hippurate arm (39/70; 56%) (p-value = 0.05). Urine cultures revealed that during treatment higher proportions of participants and samples from the antibiotic arm grewE. coliresistant to trimethoprim/co-trimoxazole and cephalosporins, respectively. Conversely, post treatment, higher proportions of participants in the methenamine hippurate arm (9/45; 20%) demonstrated multidrug resistance inE. coliisolated from perineal swabs than participants in the antibiotic arm (2/39; 5%) (p = 0.06). All other secondary outcomes and adverse events were similar in both arms.Limitations: This trial could not define whether or not one particular antibiotic was more beneficial, and progressive data loss hampered economic evaluation.Conclusions: This large, randomised, pragmatic trial in a routine NHS setting has clearly shown that methenamine hippurate is not inferior to current standard care (daily low-dose antibiotics) in preventing recurrent urinary tract infections in women. The results suggest that antimicrobial resistance is proportionally higher in women taking prophylactic antibiotics.Recommendations for research: Future research should include evaluation of other non-antibiotic preventative treatments in well-defined homogeneous patient groups, preferably with the comparator of daily antibiotics.Trial registration: This trial is registered as ISRCTN70219762 and EudraCT 2015-003487-36.Funding: This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full inHealth Technology Assessment; Vol. 26, No. 23. See the NIHR Journals Library website for further project information.

Health Technology Assessment Volume: 25, Issue: 63, Published in November 2021

During independent re-analysis of the cost data for a PhD thesis, a coding error was identified in one of the sensitivity analyses of the cost-utility evaluation of the trial looking at the effect of excluding from the intervention and control costs the cost of missed school days.

Background: Adverse effects from young people’s alcohol consumption manifest in a range of physical and psychosocial factors, including neurological issues, cognitive impairment and risk-taking behaviours. The SIPS JR-HIGH pilot trial showed alcohol screening and brief intervention (ASBI) to be acceptable to young people and schools in the north-east of England.Objectives: To conduct a two-arm, individually randomised controlled trial to evaluate the effectiveness and cost-effectiveness of ASBI for risky drinking in young people aged 14–15 years in the school setting, to monitor the fidelity of ASBI and to explore the barriers to, and facilitators of, implementation with staff, young people and parents.Design: A baseline survey with a 12-month follow-up. Interviews with 30 school staff, 21 learning mentors and nine teachers, and 33 young people and two parents.Setting: Thirty state schools in four areas of England: north-east, north-west, Kent and London.Participants: Year 10 school pupils who consented to the study (aged 14–15 years, recruited between November 2015 and June 2016), school-based staff and parents of the young people who took part in the study.Interventions: Young people who screened positively on a single alcohol screening question and consented were randomised to the intervention or control arm (blinded). The intervention was a 30-minute one-to-one structured brief intervention with a trained learning mentor and an alcohol leaflet. The control group received a healthy lifestyle leaflet (no alcohol information).Main outcome measures: The primary outcome measure was total alcohol consumed in the last 28 days. Secondary outcomes related to risky drinking, general psychological health, sexual risk-taking, energy drink consumption, age of first smoking, quality of life, quality-adjusted life-years, service utilisation and demographic information.Results: A total of 4523 young people completed the baseline survey, with 1064 screening positively (24%) and 443 being eligible to take part in the trial. Of those 443, 233 (53%) were randomised to the control arm and 210 were randomised to the intervention arm. Of the 443, 374 (84%) were successfully followed up at 12 months (intervention,n = 178; control,n = 196). The results were that the intervention showed no evidence of benefit for any alcohol-related measure when compared with the control arm. At 12 months we found a reduction from 61.9% to 43.3% using the Alcohol Use Disorders Identification Test cut-off point of 8 and cut-off point of 4 (69.0% to 60.7%). These results were not significant. A cost-effectiveness analysis showed that the average net cost saving of the brief intervention was £2865 (95% confidence interval –£11,272 to £2707) per year compared with usual practice, with the intervention showing a 76% probability of being cost saving compared with usual practice. The interview findings showed that school was an acceptable setting to carry out ASBI among staff and young people.Limitations: Recruitment of parents to take part in interviews was poor. Only 18 ASBI sessions were recorded, making it difficult to assess internal validity.Conclusions: Although the intervention was ineffective in reducing risky drinking in young people aged 14–15 years, it was well received by the young people and school staff who participated.Future work: Uniform reporting of the outcomes used for ASBI would generate more robust conclusions on the effectiveness of ASBI in the future. Pilot feasibility studies should include more than one geographical area. Future work on involving parents is needed.Trial registration: Current Controlled Trials ISRCTN45691494.Funding: This project was funded by the National Institute for Health Research (NIHR) Public Health Research programme and will be published in full inPublic Health Research; Vol. 7, No. 9. See the NIHR Journals Library website for further project information.

Background Cough is a common, disabling symptom of idiopathic pulmonary fibrosis (IPF), which may be exacerbated by acid reflux. Inhibiting gastric acid secretion could potentially reduce cough. This study aimed to determine the feasibility of a larger, multicentre trial of omeprazole for cough in IPF, to assess safety and to quantify cough. Methods Single-centre, double-blind, randomised, placebo-controlled pilot trial of the proton pump inhibitor (PPI) omeprazole (20 mg twice daily for 3 months) in patients with IPF. Primary objectives were to assess feasibility and acceptability of trial procedures. The primary clinical outcome was cough frequency. Results Forty-five participants were randomised (23 to omeprazole, 22 to placebo), with 40 (20 in each group) having cough monitoring before and after treatment. 280 patients were screened to yield these numbers, with barriers to discontinuing antacids the single biggest reason for non-recruitment. Recruitment averaged 1.5 participants per month. Geometric mean cough frequency at the end of treatment, adjusted for baseline, was 39.1% lower (95% CI 66.0% lower to 9.3% higher) in the omeprazole group compared with placebo. Omeprazole was well tolerated and adverse event profiles were similar in both groups, although there was a small excess of lower respiratory tract infection and a small fall in forced expiratory volume and forced vital capacity associated with omeprazole. Conclusions A large randomised controlled trial of PPIs for cough in IPF appears feasible and justified but should address barriers to randomisation and incorporate safety assessments in relation to respiratory infection and changes in lung function.

At least half of all adult women will experience infective cystitis (urinary tract infection: UTI) at least once in their life and many suffer from repeated episodes. Recurrent urinary tract infection (rUTI) in adult women is usually treated with long-term, low-dose antibiotics and current national and international guidelines recommend this as the ‘gold standard’ preventative treatment. Although they are reasonably effective, long-term antibiotics can result in bacteria becoming resistant not only to the prescribed antibiotic but to other antimicrobial agents. The problem of antimicrobial resistance is recognised as a global threat and the recent drive for antibiotic stewardship has emphasised the need for careful consideration prior to prescribing antibiotics. This has led clinicians and patients alike to explore potential non-antibiotic options for recurrent UTI prevention. This is a multicentre, pragmatic, patient-randomised, non-inferiority trial comparing a non-antibiotic preventative treatment for rUTI in women, methenamine hippurate, against the current standard of daily low-dose antibiotics. Women who require preventative treatment for rUTI are the target population. This group is comprised of those with a diagnosis of rUTI, defined as three episodes in 1 year or two episodes in 6 months, and those with a single severe infection requiring hospitalisation. Participants will be recruited from secondary care urology / urogynaecology departments in the UK following referral with rUTI. Participants will be followed up during a 12-month period of treatment and in the subsequent 6 months following completion of the prophylactic medication. Outcomes will be assessed from patient recorded symptoms, quality of life questionnaires and microbiological examination of urine and perineal swabs. The primary outcome is the incidence of symptomatic antibiotic-treated UTI self-reported by participants during the 12-month period of preventative treatment. Health economic outcomes will also be assessed to define the cost-effectiveness of both treatments. A qualitative study will be conducted in the first 8 months of the trial to explore with participants/non-participants’ and recruiting clinicians’ views on trial processes and identify potential barriers to recruitment, reasons for participating and non-participation and for dropping out of the study. The study was commissioned and funded by the National Institute for Health Research (NIHR) and approved under the Medicines and Healthcare products Regulatory Agency (MHRA) notification scheme as a ‘Type A’ study. International Standard Randomised Controlled Trial Number (ISRCTN), registry number: ISRCTN70219762 . Registered on 31 May 2016.