The performance of a Bayesian value-based sequential clinical trial design in the presence of an equivocal cost-effectiveness signal: evidence from the HERO trial.

BACKGROUND: There is increasing interest in the capacity of adaptive designs to improve the efficiency of clinical trials. However, relatively little work has investigated how economic considerations - including the costs of the trial - might inform the design and conduct of adaptive clinical trials. METHODS: We apply a recently published Bayesian model of a value-based sequential clinical trial to data from the 'Hydroxychloroquine Effectiveness in Reducing symptoms of hand Osteoarthritis' (HERO) trial. Using parameters estimated from the trial data, including the cost of running the trial, and using multiple imputation to estimate the accumulating cost-effectiveness signal in the presence of missing data, we assess when the trial would have stopped had the value-based model been used. We used re-sampling methods to compare the design's operating characteristics with those of a conventional fixed length design. RESULTS: In contrast to the findings of the only other published retrospective application of this model, the equivocal nature of the cost-effectiveness signal from the HERO trial means that the design would have stopped the trial close to, or at, its maximum planned sample size, with limited additional value delivered via savings in research expenditure. CONCLUSION: Evidence from the two retrospective applications of this design suggests that, when the cost-effectiveness signal in a clinical trial is unambiguous, the Bayesian value-adaptive design can stop the trial before it reaches its maximum sample size, potentially saving research costs when compared with the alternative fixed sample size design. However, when the cost-effectiveness signal is equivocal, the design is expected to run to, or close to, the maximum sample size and deliver limited savings in research costs.

A 2x2 randomised factorial SWAT of the use of a pen and small, financial incentive to improve recruitment in a randomised controlled trial of yoga for older adults with multimorbidity.

Background: Monetary and other incentives may increase recruitment to randomised controlled trials. Methods: This was a 2x2 factorial 'study within a trial' of including a pen and/or £5 with a postal recruitment pack to improve randomisation rate (primary outcome) into the host Gentle Years Yoga trial in older adults with multimorbidity. Secondary outcomes: return, and time to return, of screening form, and the cost per additional participant recruited. Binary data were analysed using logistic regression and time to return data using Cox proportional hazards regression.  Results: 818 potential host trial participants included. Between those sent a pen (n=409) and not sent a pen (n=409), there was no evidence of a difference in the likelihood of being randomised (15 (3.7%) versus 11 (2.7%); OR 1.38, 95% CI 0.63-3.04), in returning a screening form (66 (16.1%) versus 61 (14.9%); OR 1.10, 95% CI 0.75-1.61) nor in time to return the screening form (HR 1.09, 95% CI 0.77-1.55). There was evidence of improved screening return rates (77 (18.8%) versus 50 (12.2%); OR 1.67, 95% CI 1.13-2.45) and time to return screening form (HR 1.56, 95% CI 1.09-2.22) but not randomisation (14 (3.4%) versus 12 (2.9%); OR 1.18, 95% CI 0.54-2.57) in those sent £5 (n=409) compared with those not sent £5 (n=409). No significant interaction effects between the interventions were observed. The cost per additional participant recruited was £32 for the pen and £1000 for the £5 incentive. Conclusion: Including a small, monetary incentive encouraged increased and faster response to the recruitment invitation but did not result in more participants being randomised into the host trial. Since it is relatively costly, we do not recommend this intervention for use to increase recruitment in this population. Pens are cheaper but did not provide evidence of benefit. Further studies may be required.

The REFORM study protocol: a cohort randomised controlled trial of a multifaceted podiatry intervention for the prevention of falls in older people.

INTRODUCTION: Falls and fall-related injuries are a serious cause of morbidity and cost to society. Foot problems and inappropriate footwear may increase the risk of falls; therefore podiatric interventions may play a role in reducing falls. Two Cochrane systematic reviews identified only one study of a podiatry intervention aimed to reduce falls, which was undertaken in Australia. The REFORM trial aims to evaluate the clinical and cost-effectiveness of a multifaceted podiatry intervention in reducing falls in people aged 65 years and over in a UK and Irish setting. METHODS AND ANALYSIS: This multicentre, cohort randomised controlled trial will recruit 2600 participants from routine podiatry clinics in the UK and Ireland to the REFORM cohort. In order to detect a 10% point reduction in falls from 50% to 40%, with 80% power 890 participants will be randomised to receive routine podiatry care and a falls prevention leaflet or routine podiatry care, a falls prevention leaflet and a multifaceted podiatry intervention. The primary outcome is rate of falls (falls/person/time) over 12 months assessed by patient self-report falls diary. Secondary self-report outcome measures include: the proportion of single and multiple fallers and time to first fall over a 12-month period; Short Falls Efficacy Scale-International; fear of falling in the past 4 weeks; Frenchay Activities Index; fracture rate; Geriatric Depression Scale; EuroQoL-five dimensional scale 3-L; health service utilisation at 6 and 12 months. A qualitative study will examine the acceptability of the package of care to participants and podiatrists. ETHICS AND DISSEMINATION: The trial has received a favourable opinion from the East of England-Cambridge East Research Ethics Committee and Galway Research Ethics Committee. The trial results will be published in peer-reviewed journals and at conference presentations. TRIAL REGISTRATION NUMBER: Current Controlled Trials ISRCTN68240461 assigned 01/07/2011.

An intervention to reassure patients about test results in rapid access chest pain clinic: a pilot randomised controlled trial.

BACKGROUND: Most people referred to rapid access chest pain clinics have non-cardiac chest pain, and in those diagnosed with stable coronary heart disease, guidance recommends that first-line treatment is usually medication rather than revascularisation. Consequently, many patients are not reassured they have the correct diagnosis or treatment. A previous trial reported that, in people with non-cardiac chest pain, a brief discussion with a health psychologist before the tests about the meaning of potential results led to people being significantly more reassured. The aim of this pilot was to test study procedures and inform sample size for a future multi-centre trial and to gain initial estimates of effectiveness of the discussion intervention. METHODS: This was a two-arm pilot randomised controlled trial in outpatient rapid access chest pain clinic in 120 people undergoing investigation for new onset, non-urgent chest pain. Eligible participants were randomised to receive either: a discussion about the meaning and implication of test results, delivered by a nurse before tests in clinic, plus a pre-test pamphlet covering the same information (Discussion arm) or the pre-test pamphlet alone (Pamphlet arm). Main outcome measures were recruitment rate and feasibility for a future multi-centre trial, with an estimate of reassurance in the groups at month 1 and 6 using a 5-item patient-reported scale. RESULTS: Two hundred and seventy people attended rapid access chest pain clinic during recruitment and 120/270 participants (44%) were randomised, 60 to each arm. There was no evidence of a difference between the Discussion and Pamphlet arms in the mean reassurance score at month 1 (34.2 vs 33.7) or at month 6 (35.3 vs 35.9). Patient-reported chest pain and use of heart medications were also similar between the two arms. CONCLUSIONS: A larger trial of the discussion intervention in the UK would not be warranted. Patients reported high levels of reassurance which were similar in patients receiving the discussion with a nurse and in those receiving a pamphlet alone. TRIAL REGISTRATION: Current Controlled Trials ISRCTN60618114 (assigned 27.05.2011).