A multi-arm multi-stage clinical trial design for binary outcomes with application to tuberculosis

Randomised controlled trials are becoming increasingly costly and time-consuming. In 2011, Royston and colleagues proposed a particular class of multi-arm multi-stage (MAMS) designs intended to speed up the evaluation of new treatments in phase II and III clinical trials. Their design, which controls the type I error rate and power for each pairwise comparison, discontinues randomisation to poorly performing arms at interim analyses if they fail to show a pre-specified level of benefit over the control arm. Arms in which randomisation is continued to the final stage of the trial are compared against the control on a definitive time-to-event outcome measure. To increase efficiency, interim comparisons can be made on an intermediate time-to-event outcome which is on the causal pathway to the definitive outcome

Design issues and extensions of multi-arm multi-stage clinical trials

The increasing cost of randomised controlled trials is hindering the rate at which new, effective therapies reach patients. To accelerate drug development, more efficient clinical trial designs are needed. One such design which has had success in speeding up the evaluation of therapies in cancer is the multi-arm multi-stage (MAMS) design. This particular design compares multiple new treatments against a control in a single trial, obviating the need for multiple two-arm studies, and ceases recruitment to poorly performing arms during the study. To further increase efficiency, interim assessments can be based on an intermediate outcome which is on the causal pathway to the primary outcome of the trial, thus allowing phases 2 and 3 of evaluation to be incorporated into a single, seamless design. The MAMS design was initially developed for trials in cancer where time to event outcomes are commonly used. To make it more widely applicable to other disease areas, we first extend the design to other types of outcome measure such as binary. The new designs are then applied to trials in tuberculosis --- a disease area with many new treatments currently in the clinical pipeline and which may therefore benefit from using more efficient trial designs. We then consider more general design issues such as familywise error rate and expected sample size and present calculations of both measures using simulation. Methods are developed for finding designs which have the desired overall operating characteristics and which are the most efficient under particular optimality criteria, known as admissible designs. Guidance is provided for choosing the number of stages and allocation ratio for a particular number of arms and we apply the methods developed in the thesis to existing and hypothetical MAMS trials. Throughout, Stata programs are created and updated to accommodate the use of the methods in practice

Type I error rates of multi-arm multi-stage clinical trials: strong control and impact of intermediate outcomes

BACKGROUND: The multi-arm multi-stage (MAMS) design described by Royston et al. [Stat Med. 2003;22(14):2239-56 and Trials. 2011;12:81] can accelerate treatment evaluation by comparing multiple treatments with a control in a single trial and stopping recruitment to arms not showing sufficient promise during the course of the study. To increase efficiency further, interim assessments can be based on an intermediate outcome (I) that is observed earlier than the definitive outcome (D) of the study. Two measures of type I error rate are often of interest in a MAMS trial. Pairwise type I error rate (PWER) is the probability of recommending an ineffective treatment at the end of the study regardless of other experimental arms in the trial. Familywise type I error rate (FWER) is the probability of recommending at least one ineffective treatment and is often of greater interest in a study with more than one experimental arm. METHODS: We demonstrate how to calculate the PWER and FWER when the I and D outcomes in a MAMS design differ. We explore how each measure varies with respect to the underlying treatment effect on I and show how to control the type I error rate under any scenario. We conclude by applying the methods to estimate the maximum type I error rate of an ongoing MAMS study and show how the design might have looked had it controlled the FWER under any scenario. RESULTS: The PWER and FWER converge to their maximum values as the effectiveness of the experimental arms on I increases. We show that both measures can be controlled under any scenario by setting the pairwise significance level in the final stage of the study to the target level. In an example, controlling the FWER is shown to increase considerably the size of the trial although it remains substantially more efficient than evaluating each new treatment in separate trials. CONCLUSIONS: The proposed methods allow the PWER and FWER to be controlled in various MAMS designs, potentially increasing the uptake of the MAMS design in practice. The methods are also applicable in cases where the I and D outcomes are identical

Adding new experimental arms to randomised clinical trials: Impact on error rates

Background: Experimental treatments pass through various stages of development. If a treatment passes through early-phase experiments, the investigators may want to assess it in a late-phase randomised controlled trial. An efficient way to do this is adding it as a new research arm to an ongoing trial while the existing research arms continue, a so-called multi-arm platform trial. The familywise type I error rate is often a key quantity of interest in any multi-arm platform trial. We set out to clarify how it should be calculated when new arms are added to a trial some time after it has started. / Methods: We show how the familywise type I error rate, any-pair and all-pairs powers can be calculated when a new arm is added to a platform trial. We extend the Dunnett probability and derive analytical formulae for the correlation between the test statistics of the existing pairwise comparison and that of the newly added arm. We also verify our analytical derivation via simulations. / Results: Our results indicate that the familywise type I error rate depends on the shared control arm information (i.e. individuals in continuous and binary outcomes and primary outcome events in time-to-event outcomes) from the common control arm patients and the allocation ratio. The familywise type I error rate is driven more by the number of pairwise comparisons and the corresponding (pairwise) type I error rates than by the timing of the addition of the new arms. The familywise type I error rate can be estimated using Šidák’s correction if the correlation between the test statistics of pairwise comparisons is less than 0.30. / Conclusions: The findings we present in this article can be used to design trials with pre-planned deferred arms or to add new pairwise comparisons within an ongoing platform trial where control of the pairwise error rate or familywise type I error rate (for a subset of pairwise comparisons) is required

Systemic therapy for vulval Erosive Lichen Planus (the 'hELP' trial): study protocol for a randomised controlled trial

BACKGROUND: Erosive lichen planus affecting the vulva (ELPV) is a relatively rare, chronic condition causing painful raw areas in the vulvovaginal region. Symptoms are pain and burning, which impact upon daily living. There is paucity of evidence regarding therapy. A 2012 Cochrane systematic review found no randomised controlled trials (RCTs) in this field. Topically administered corticosteroids are the accepted first-line therapy: however, there is uncertainty as to which second-line treatments to use. Several systemic agents have been clinically noted to show promise for ELPV refractory to topically administered corticosteroids but there is no RCT evidence to support these. The 'hELP' study is a RCT with an internal pilot phase designed to provide high-quality evidence. METHODS/DESIGN: The objective is to test whether systemic therapy in addition to standard topical therapy is a beneficial second-line treatment for ELPV. Adjunctive systemic therapies used are hydroxychloroquine, methotrexate, mycophenolate mofetil and prednisolone. Topical therapy plus a short course of prednisolone given orally is considered the comparator intervention. The trial is a four-armed, open-label, pragmatic RCT which uses a blinded independent clinical assessor. To provide 80 % power for each comparison, 96 participants are required in total. The pilot phase aims to recruit 40 participants. The primary clinical outcome is the proportion of patients achieving treatment success at 6 months. 'Success' is defined by a composite measure of Patient Global Assessment score of 0 or 1 on a 4-point scale plus improvement from baseline on clinical photographs scored by a clinician blinded to treatment allocation. Secondary clinical outcomes include 6-month assessment of: (1) Reduction in pain/soreness; (2) Global assessment of disease; (3) Response at other affected mucosal sites; (4) Hospital Anxiety and Depression Scale scores; (5) Sexual function; (6) Health-related quality of life using 'Short Form 36' and 'Skindex-29' questionnaires; (7) Days of topical steroid use; (8) Treatment satisfaction; (9) Discontinuation of medications due to treatment failure; (10) Per participant cost of intervention in each treatment group. Adverse events will also be reported. DISCUSSION: 'hELP' is the first RCT to address second-line treatment of ELPV. The trial has encountered unique methodological challenges and has required collaborative efforts of the UK Dermatology Clinical Trials Network alongside expert clinicians. TRIAL REGISTRATION: CURRENT CONTROLLED TRIALS: ISRCTN 81883379 . Date of registration 12 June 2014

The value of the pragmatic-explanatory continuum indicator summary wheel in an ongoing study: the bullous pemphigoid steroids and tetracyclines study

BACKGROUND: The Pragmatic-Explanatory Continuum Indicator Summary (PRECIS) tool is intended to be used in the design phase of trials to help investigative teams design trials in-line with their purpose. Our team applied this tool to an ongoing trial (BLISTER) to determine whether the initial suggestion among some team members that the trial could be described as largely pragmatic was the consensus. METHODS: Each of the six members of the BLISTER trial team was sent a blank PRECIS wheel to independently complete. The results obtained were averaged and plotted on a single PRECIS wheel to illustrate the degree of pragmatism of the trial. RESULTS: The trial team found that the design of the trial was closest to the pragmatic end of the pragmatic-explanatory continuum. The strongest consensus was found on the 'flexibility of the comparison intervention' and 'practitioner adherence' domains (SD = 13). The trial team appeared to disagree most on the 'eligibility criteria' (SD = 35) and 'participant compliance' (SD = 31) domains, although the large standard deviations were a result of a single outlier in the two domains. CONCLUSION: The PRECIS tool can be used to retrospectively determine the pragmatism of a trial provided enough expertise and information on the trial is available. Illustrating the design of a trial on the PRECIS wheel can help research users more easily identify studies of interest. We hope our recommendations for applying this useful tool will encourage others to consider using it when designing, conducting and reporting studies. TRIAL REGISTRATION: Current Controlled Trials http://www.controlled-trials.com/ISRCTN13704604

Type I error rates of multi-arm multi-stage clinical trials: strong control and impact of intermediate outcomes

BACKGROUND: The multi-arm multi-stage (MAMS) design described by Royston et al. [Stat Med. 2003;22(14):2239-56 and Trials. 2011;12:81] can accelerate treatment evaluation by comparing multiple treatments with a control in a single trial and stopping recruitment to arms not showing sufficient promise during the course of the study. To increase efficiency further, interim assessments can be based on an intermediate outcome (I) that is observed earlier than the definitive outcome (D) of the study. Two measures of type I error rate are often of interest in a MAMS trial. Pairwise type I error rate (PWER) is the probability of recommending an ineffective treatment at the end of the study regardless of other experimental arms in the trial. Familywise type I error rate (FWER) is the probability of recommending at least one ineffective treatment and is often of greater interest in a study with more than one experimental arm. METHODS: We demonstrate how to calculate the PWER and FWER when the I and D outcomes in a MAMS design differ. We explore how each measure varies with respect to the underlying treatment effect on I and show how to control the type I error rate under any scenario. We conclude by applying the methods to estimate the maximum type I error rate of an ongoing MAMS study and show how the design might have looked had it controlled the FWER under any scenario. RESULTS: The PWER and FWER converge to their maximum values as the effectiveness of the experimental arms on I increases. We show that both measures can be controlled under any scenario by setting the pairwise significance level in the final stage of the study to the target level. In an example, controlling the FWER is shown to increase considerably the size of the trial although it remains substantially more efficient than evaluating each new treatment in separate trials. CONCLUSIONS: The proposed methods allow the PWER and FWER to be controlled in various MAMS designs, potentially increasing the uptake of the MAMS design in practice. The methods are also applicable in cases where the I and D outcomes are identical

Premenopausal endogenous oestrogen levels and breast cancer risk: a meta-analysis.

BACKGROUND: Many of the established risk factors for breast cancer implicate circulating hormone levels in the aetiology of the disease. Increased levels of postmenopausal endogenous oestradiol (E2) have been found to increase the risk of breast cancer, but no such association has been confirmed in premenopausal women. We carried out a meta-analysis to summarise the available evidence in women before the menopause. METHODS: We identified seven prospective studies of premenopausal endogenous E2 and breast cancer risk, including 693 breast cancer cases. From each study we extracted odds ratios of breast cancer between quantiles of endogenous E2, or for unit or s.d. increases in (log transformed) E2, or (where odds ratios were unavailable) summary statistics for the distributions of E2 in breast cancer cases and unaffected controls. Estimates for a doubling of endogenous E2 were obtained from these extracted estimates, and random-effect meta-analysis was used to obtain a pooled estimate across the studies. RESULTS: Overall, we found weak evidence of a positive association between circulating E2 levels and the risk of breast cancer, with a doubling of E2 associated with an odds ratio of 1.10 (95% CI: 0.96, 1.27). CONCLUSION: Our findings are consistent with the hypothesis of a positive association between premenopausal endogenous E2 and breast cancer risk

Prolonged Antibiotic Treatment does not Prevent Intra-Abdominal Abscesses in Perforated Appendicitis

Contains fulltext : 89619.pdf (publisher's version ) (Open Access)BACKGROUND: Children with perforated appendicitis have a relatively high risk of intra-abdominal abscesses. There is no evidence that prolonged antibiotic treatment after surgery reduces intra-abdominal abscess formation. We compared two patient groups with perforated appendicitis with different postoperative antibiotic treatment protocols. METHODS: We retrospectively reviewed patients younger than age 18 years who underwent appendectomy for perforated appendicitis at two academic hospitals between January 1992 and December 2006. Perforation was diagnosed during surgery and confirmed during histopathological evaluation. Patients in hospital A received 5 days of antibiotics postoperatively, unless decided otherwise on clinical grounds. Patients in hospital B received antibiotics for 5 days, continued until serum C-reactive protein (CRP) was <20 mg/l. Univariate logistic regression analysis was performed on intention-to-treat basis. p < 0.05 was considered significant. RESULTS: A total of 149 children underwent appendectomy for perforated appendicitis: 68 in hospital A, and 81 in hospital B. As expected, the median (range) use of antibiotics was significantly different: 5 (range, 1-16) and 7 (range, 2-32) days, respectively (p < 0.0001). However, the incidence of postoperative intra-abdominal abscesses was similar (p = 0.95). Regression analysis demonstrated that sex (female) was a risk factor for abscess formation, whereas surgical technique and young age were not. CONCLUSIONS: Prolonged use of antibiotics after surgery for perforated appendicitis in children based on serum CRP does not reduce postoperative abscess formation.1 december 201