Biomarker-guided trials: Challenges in practice.

Biomarker-guided trials have drawn considerable attention as they promise to lead to improvements in the benefit-risk ratio of treatments and enhanced opportunities for drug development. A variety of such designs have been proposed in the literature, many of which have been adopted in practice. Implementing such trial designs in practice can be challenging, and identifying those challenges was the main objective of a workshop organised by the MRC Hubs for Trials Methodology Research Network's Stratified Medicine Working Group in March 2017. Participants reflected on completed and ongoing biomarker-guided trials to identify the practical challenges encountered. Here, the key challenges identified during the workshop including those related to funding, ethical and regulatory issues, recruitment, monitoring of samples and laboratories, biomarker assessment, and data sharing and resources, are discussed. Despite the complexities often associated with biomarker-guided trials, the workshop concluded that they can play an important role in advancing the field of personalised medicine. Therefore, it is important that the practical challenges surrounding their implementation are acknowledged and addressed.

Laparoscopy-assisted gastrectomy in the elderly: experience from a UK centre.

BACKGROUND Gastric cancer has a high incidence in the elderly in the UK, with a significant number of patients aged 75 years or more. While surgery forms the mainstay of treatment, evidence pertaining to the management of gastric cancer in the Western population in this age group is scarce. METHODS We retrospectively reviewed the outcomes of laparoscopy-assisted total and distal gastrectomies at our centre from 2005 to 2015. Patients aged 70 years or above were included in the elderly group. RESULTS A total of 60 patients underwent laparoscopy-assisted gastrectomy over a 10-year period, with a predominance of male patients. There was no significant difference in the rate of overall surgical and non-surgical complications, in-hospital mortality, operation time and length of hospital stay, between the elderly and non-elderly groups. Univariate analysis, performed for risk factors relating to anastomotic leak and surgical complications, showed that age over 70 years and higher American Association of Anesthesiologists grades are associated with a higher, though not statistically significant, number of anastomotic leaks (P = 1.000 and P = 0.442, respectively) and surgical complications (P = 0.469 and P = 0.162, respectively). The recurrence rate within the first 3 years of surgery was significantly higher in the non-elderly group compared with the elderly group (Log Rank test, P = 0.002). There was no significant difference in survival between the two groups (Log Rank test, P = 0.619). CONCLUSIONS Laparoscopy-assisted gastrectomy is safe and feasible in an elderly population. There is a need for well-designed, prospective, randomised studies with quality of life data to inform our practice in future.

MAGNEsium Trial In Children (MAGNETIC): a randomised, placebo-controlled trial and economic evaluation of nebulised magnesium sulphate in acute severe asthma in children.

BACKGROUND: There are few data on the role of nebulised magnesium sulphate (MgSO4) in the management of acute asthma in children. Those studies that have been published are underpowered, and use different methods, interventions and comparisons. Thus, no firm conclusions can be drawn. OBJECTIVES: Does the use of nebulised MgSO4, when given as an adjunct to standard therapy in acute severe asthma in children, result in a clinical improvement when compared with standard treatment alone? DESIGN: Patients were randomised to receive three doses of MgSO4 or placebo, each combined with salbutamol and ipratropium bromide, for 1 hour. The Yung Asthma Severity Score (ASS) was measured at baseline, randomisation, and at 20, 40, 60 (T60), 120, 180 and 240 minutes after randomisation. SETTING: Emergency departments and children's assessment units at 30 hospitals in the UK. PARTICIPANTS: Children aged 2-15 years with acute severe asthma. INTERVENTIONS: Patients were randomised to receive nebulised salbutamol 2.5 mg (ages 2-5 years) or 5 mg (ages ≥ 6 years) and ipratropium bromide 0.25 mg mixed with either 2.5 ml of isotonic MgSO4 (250 mmol/l, tonicity 289 mOsm; 151 mg per dose) or 2.5 ml of isotonic saline on three occasions at approximately 20-minute intervals. MAIN OUTCOME MEASURES: The primary outcome measure was the ASS after 1 hour of treatment. Secondary measures included 'stepping down' of treatment at 1 hour, number and frequency of additional salbutamol administrations, length of stay in hospital, requirement for intravenous bronchodilator treatment, and intubation and/or admission to a paediatric intensive care unit. Data on paediatric quality of life, time off school/nursery, health-care resource usage and time off work were collected 1 month after randomisation. RESULTS: A total of 508 children were recruited into the study; 252 received MgSO4 and 256 received placebo along with the standard treatment. There were no differences in baseline characteristics. There was a small, but statistically significant difference in ASS at T60 in those children who received nebulised MgSO4 {0.25 [95% confidence interval (CI) 0.02 to 0.48]; p = 0.034} and this difference was sustained for up to 240 minutes [0.20 (95% CI 0.01 to 0.40), p = 0.042]. The clinical significance of this gain is uncertain. Assessing treatment-covariate interactions, there is evidence of a larger effect in those children with more severe asthma exacerbations ( p = 0.034) and those with a shorter duration of symptoms ( p = 0.049). There were no significant differences in the secondary outcomes measured. Adverse events (AEs) were reported in 19% of children in the magnesium group and 20% in the placebo group. There were no clinically significant serious AEs in either group. The results of the base-case economic analyses are accompanied by considerable uncertainty, but suggest that, from an NHS and Personal Social Services perspective, the addition of magnesium to standard treatment may be cost-effective compared with standard treatment only. The results of economic evaluation show that the probability of magnesium being cost-effective is over 60% at cost-effectiveness thresholds of £1000 per unit decrement in ASS and £20,000 per quality-adjusted life-year (QALY) gained, respectively; it is noted that for some parameter variations this probability is much lower, reflecting the labile nature of the cost-effectiveness ratio in light of the small differences in benefits and costs shown in the trial and the relation between the main outcome measure (ASS) and preference based measures of quality of life used in cost-utility analysis (European Quality of Life-5 Dimensions; EQ-5D). CONCLUSIONS: This study supports the use of nebulised isotonic MgSO4 at the dose of 151 mg given three times in the first hour of treatment as an adjuvant to standard treatment when a child presents with an acute episode of severe asthma. No harm is done by adding magnesium to salbutamol and ipratropium bromide, and in some individuals it may be clinically helpful. The response is likely to be more marked in those children with more severe attacks and with a shorter duration of exacerbation. Although the study was not powered to demonstrate this fully, the data certainly support the hypotheses that nebulised magnesium has a greater clinical effect in children who have more severe exacerbation with shorter duration of symptoms. TRIAL REGISTRATION: Current Controlled Trials ISRCTN81456894. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Depressive and manic symptoms are not opposite poles in bipolar disorder.

OBJECTIVE: This study of 236 individuals with bipolar disorders employed longitudinal analyses to determine whether the symptoms of mania and depression can be understood as one dimension (with depression and mania as opposites) or two relatively independent dimensions. METHOD: Weekly severity ratings of manic and depression were assessed using the Longitudinal Interval Follow-up Evaluation-II for 72 weeks. The within-subjects correlation of manic and depressive severity was examined using random effects regression. RESULTS: Contrary to the one-dimension model, mania and depression symptoms were not negatively related. Indeed, the correlations of mania with depressive symptoms were quite small. CONCLUSION: The data suggest that depressive and manic symptoms are not opposite poles. Rather depressive and manic symptoms appear to fluctuate relatively independently within bipolar disorder.

Prasugrel for the treatment of acute coronary artery syndromes with percutaneous coronary intervention.

This paper presents a summary of the evidence review group (ERG) report into the clinical effectiveness and cost-effectiveness of prasugrel for the treatment of coronary artery syndromes with percutaneous coronary intervention, based upon the evidence submission from Eli Lilly to the National Institute for Health and Clinical Excellence (NICE) as part of the single technology appraisal process. The submitted clinical evidence was based on a phase III double-blind, double-dummy randomised controlled trial which compared the use of prasugrel with clopidogrel. The primary clinical outcome measure was a composite end point of death from cardiovascular causes, non-fatal myocardial infarction (MI) or non-fatal stroke at 15 months. Secondary outcomes included the primary end point at 30 days and 90 days; a composite end point of death from cardiovascular causes, non-fatal MI or urgent target vessel revascularisation; a composite end point of death from cardiovascular causes, non-fatal MI, non-fatal stroke or rehospitalisation due to a cardiac ischaemic event; and stent thrombosis. For the overall trial cohort during the 15 month follow-up period, the results of the trial demonstrated a statistically significant benefit of prasugrel compared with clopidogrel on the primary outcome. The efficacy difference between treatment groups was, in the main, due to a statistically significant lower incidence of non-fatal MIs in the prasugrel group than in the clopidogrel group. No statistically significant differences were found for death from cardiovascular causes or non-fatal stroke. For the fully licensed and target populations, there was a statistically significant lower incidence of non-fatal MIs in the prasugrel group than in the clopidogrel group; there was no statistically significant difference in bleeding rates. The ERG recalculated the base-case cost-effectiveness results taking changes in parameters and assumptions into account: for example, revised drug costs, mid-cycle correction, amended relative risk mortality. Subgroup and threshold analyses were also explored by the ERG. For the fully licensed population (i.e. excluding patients with prior stroke or TIA), the manufacturer reported an incremental cost-effectiveness ratio (ICER) of 159,358 pounds per quality-adjusted life-year (QALY) gained at 12 months and an ICER of 3,220 pounds per QALY gained at 40 years. Considering the 15-month clinical trial data available for the fully licensed and target populations and current practice in England and Wales, the evidence was considered insufficient to support the conclusion that prasugrel is clinically more effective than clopidogrel or vice versa. Assuming that there is no evidence to distinguish between prasugrel and clopidogrel in terms of clinical effectiveness in the short term for this population, equipoise between prasugrel and clopidogrel at year 1 is achieved by a 20% reduction in the acquisition cost of prasugrel (approximately 120 pounds per patient). At the time of writing, the guidance/has not yet been published by NICE.

Enhanced relapse prevention for bipolar disorder by community mental health teams: cluster feasibility randomised trial.

BACKGROUND: Relapse prevention for bipolar disorder increases time to relapse but is not available in routine practice. AIMS: To determine the feasibility and effectiveness of training community mental health teams (CMHTs) to deliver enhanced relapse prevention. METHOD: In a cluster randomised controlled trial, CMHT workers were allocated to receive 12 h training in enhanced relapse prevention to offer to people with bipolar disorder or to continue giving treatment as usual. The primary outcome was time to relapse and the secondary outcome was functioning. RESULTS: Twenty-three CMHTs and 96 service users took part. Compared with treatment as usual, enhanced relapse prevention increased median time to the next bipolar episode by 8.5 weeks (hazard ratio 0.79, 95% CI 0.45-1.38). Social and occupational functioning improved with the intervention (regression coefficient 0.68, 95% CI 0.05-1.32). The clustering effect was negligible but imprecise (intracluster correlation coefficient 0.0001, 95% CI 0.0000-0.5142). CONCLUSIONS: Training care coordinators to offer enhanced relapse prevention for bipolar disorder may be a feasible effective treatment. Large-scale cluster trials are needed.

Joint modelling of longitudinal and competing risks data.

Available methods for joint modelling of longitudinal and survival data typically have only one failure type for the time to event outcome. We extend the methodology to allow for competing risks data. We fit a cause-specific hazards sub-model to allow for competing risks, with a separate latent association between longitudinal measurements and each cause of failure.The method is applied to data from the SANAD trial of anti-epileptic drugs (AEDs), as a means of investigating the effect of drug titration on the relative effects of lamotrigine (LTG) and carbamazepine (CBZ) on treatment failure. Concern had been expressed that differential titration rates may have been to the disadvantage of CBZ. The beneficial effect of LTG on unacceptable adverse events leading to drug withdrawal did not lessen and indeed increased slightly when a calibrated dose was accounted for in the joint model. Adjustment for the titration rate of LTG relative to CBZ resulted in an unchanged effect of the former on drug withdrawals due to inadequate seizure control. LTG remains the AED of choice from this analysis.

The influence of competing-risks setting on the choice of hypothesis test for treatment effect.

There is considerable debate regarding the choice of test for treatment difference in a randomized clinical trial in the presence of competing risks. This question arose in the study of standard and new antiepileptic drugs (SANAD) trial comparing new and standard antiepileptic drugs. This paper provides simulation results for the log-rank test comparing cause-specific hazard rates and Gray's test comparing cause-specific cumulative incidence curves. To inform the analysis of the SANAD trial, competing-risks settings were considered where both events are of interest, events may be negatively correlated, and the degree of correlation may differ in the 2 treatment groups. In settings where there are effects in opposite directions for the 2 event types, a likely situation for the SANAD trial, Gray's test has greater power to detect treatment differences than log-rank analysis. For the epilepsy application, conclusions were qualitatively similar for both log-rank and Gray's tests.