Munyaradzi Dimairo

Sample size requirements to estimate key design parameters from external pilot randomised controlled trials: a simulation study

BackgroundExternal pilot or feasibility studies can be used to estimate key unknown parameters to inform the design of the definitive randomised controlled trial (RCT). However, there is little consensus on how large pilot studies need to be, and some suggest inflating estimates to adjust for the lack of precision when planning the definitive RCT.MethodsWe use a simulation approach to illustrate the sampling distribution of the standard deviation for continuous outcomes and the event rate for binary outcomes. We present the impact of increasing the pilot sample size on the precision and bias of these estimates, and predicted power under three realistic scenarios. We also illustrate the consequences of using a confidence interval argument to inflate estimates so the required power is achieved with a pre-specified level of confidence. We limit our attention to external pilot and feasibility studies prior to a two-parallel-balanced-group superiority RCT.ResultsFor normally distributed outcomes, the relative gain in precision of the pooled standard deviation (SDp) is less than 10% (for each five subjects added per group) once the total sample size is 70. For true proportions between 0.1 and 0.5, we find the gain in precision for each five subjects added to the pilot sample is less than 5% once the sample size is 60. Adjusting the required sample sizes for the imprecision in the pilot study estimates can result in excessively large definitive RCTs and also requires a pilot sample size of 60 to 90 for the true effect sizes considered here.ConclusionsWe recommend that an external pilot study has at least 70 measured subjects (35 per group) when estimating the SDp for a continuous outcome. If the event rate in an intervention group needs to be estimated by the pilot then a total of 60 to 100 subjects is required. Hence if the primary outcome is binary a total of at least 120 subjects (60 in each group) may be required in the pilot trial. It is very much more efficient to use a larger pilot study, than to guard against the lack of precision by using inflated estimates.

Computer Therapy Compared With Usual Care for People With Long-Standing Aphasia Poststroke A Pilot Randomized Controlled Trial

Background and Purpose— The purpose of this study was to test the feasibility of conducting a randomized controlled trial to study the effectiveness of self-managed computer treatment for people with long-standing aphasia after stroke. Method— In this pilot single-blinded, parallel-group, randomized controlled trial participants with aphasia were allocated to self-managed computer treatment with volunteer support or usual care (everyday language activity). The 5-month intervention period was followed by 3 months without intervention to investigate treatment maintenance. Results— Thirty-four participants were recruited. Seventeen participants were allocated to each group. Thirteen participants from the usual care group and 15 from the computer treatment group were followed up at 5 months. An average of 4 hours 43 minutes speech and language therapy time and 4 hours volunteer support time enabled an average of 25 hours of independent practice. The difference in percentage change in naming ability from baseline at 5 months between groups was 19.8% (95% CI, 4.4–35.2; P=0.014) in favor of the treatment group. Participants with more severe aphasia showed little benefit. Results demonstrate early indications of cost-effectiveness of self-managed computer therapy. Conclusion— This pilot trial indicates that self-managed computer therapy for aphasia is feasible and that it will be practical to recruit sufficient participants to conduct an appropriately powered clinical trial to investigate the effectiveness of self-managed computer therapy for people with long-standing aphasia. Clinical Trial Registration— www.controlled-trials.com. Unique identifier: ISRCTN91534629.

Risk factors for mortality in smear-negative tuberculosis suspects: a cohort study in Harare, Zimbabwe

OBJECTIVE To investigate mortality rates and risk factors for death among smear-negative tuberculosis (TB) suspects. DESIGN Cohort study nested within a cluster-randomised trial of community-based active case finding. Smear-negative TB suspects were followed for 12 months, with home tracing where necessary. We calculated mortality rates and used regression analysis to investigate the relationship between clinical characteristics and death. RESULTS Between February 2006 and June 2007, 1195 smear-negative TB suspects were followed for 1136.8 person-years. Human immunodeficiency virus (HIV) prevalence was 63.3%. During follow-up, 139 participants died (11.6%) and mortality rates remained high throughout; 119 (16.5%) HIV-positive individuals and 13 (3.1%) HIV-negative individuals died (HR = 5.8, 95%CI 3.3-10.4, P < 0.001). Advanced immunosuppression was the main risk factor for death among HIV-positive participants, with CD4 count < 50 cells/μ l associated with a 13-fold increased risk of death. Antiretroviral treatment (ART) was initiated by only 106 (14.7%), with long delays in accessing care. CONCLUSION HIV-positive smear-negative TB suspects are at high and sustained risk of death. Current guidelines for the management of HIV-infected TB suspects are limited, and this study adds to evidence that specific policies are required to promote earlier HIV and TB diagnosis and reduce delays in ART initiation.

Computerised cognitive behavioural therapy for the treatment of depression in people with multiple sclerosis: external pilot trial

BackgroundPeople with multiple sclerosis (MS) are at high risk of depression. We undertook a pilot trial of computerised cognitive behavioural therapy (CCBT) for the treatment of depression in people with MS to test the feasibility of undertaking a full trial.MethodsParticipants with a diagnosis of MS and clinical levels of depression were recruited through out-patient clinics and postal screening questionnaires at two UK centres and randomised to CCBT or usual care. Clinical outcomes included the Beck Depression Inventory (BDI-II) and Multiple Sclerosis Impact Scale (MSIS-29) at baseline, 8 and 21 weeks. Feasibility outcomes included: recruitment rate; reasons for refusal, withdrawal and dropout; feasibility and acceptability of the proposed outcome measures; sample size estimation and variation in and preferences for service delivery.ResultsTwenty-four participants were recruited. The recruitment rate, calculated as the proportion of those invited to fill in a screening questionnaire who were consented into the trial, was 4.1%. Recruitment through out-patient clinics was somewhat slower than through screening questionnaire mail-out but the overall recruitment yield was similar. Of the 12 patients in the CCBT arm, 9 (75%) completed at least four, and 6 completed all 8 CCBT sessions. For completers, the median time (IQR) to complete all eight CCBT sessions was 15 (13 to 20) weeks. Participants expressed concern about the face validity of the Beck Depression Inventory II for the measurement of self-reported depression in people with MS. The MSIS-29 was the patient-reported outcome measure which participants felt best reflected their concerns. The estimated sample size for a full trial is between 180 and 390 participants. NHS partners were not delivering CCBT in community facilities and participants preferred to access CCBT at home, with no one expressing a preference for use of CCBT in an alternative location.ConclusionsA definitive trial, with a recruitment window of one year, would require the participation of around 13 MS centres. This number of centres could be reduced by expanding the eligibility criteria to include either other neurological conditions or people with more severe depression. The MSIS-29 should be used as a patient-important outcome measurement.Trial registrationISRCTN: ISRCTN81846800

The Risk and Timing of Tuberculosis Diagnosed in Smear-Negative TB Suspects: A 12 Month Cohort Study in Harare, Zimbabwe

Background Cases of smear-negative TB have increased dramatically in high prevalence HIV settings and pose considerable diagnostic and management challenges. Methods and Findings Between February 2006 and July 2007, a cohort study nested within a cluster-randomised trial of community-based case finding strategies for TB in Harare, Zimbabwe was undertaken. Participants who had negative sputum smears and remained symptomatic of TB were follow-up for one year with standardised investigations including HIV testing, repeat sputum smears, TB culture and chest radiography. Defaulters were actively traced to the community. The objectives were to investigate the incidence and risk factors for TB. TB was diagnosed in 218 (18.2%) participants, of which 39.4% was bacteriologically confirmed. Most cases (84.2%) were diagnosed within 3 months, but TB incidence remained high thereafter (111.3 per 1000 person-years, 95% CI: 86.6 to 146.3). HIV prevalence was 63.3%, and HIV-infected individuals had a 3.5-fold higher risk of tuberculosis than HIV-negative individuals. Conclusion We found that diagnosis of TB was insensitive and slow, even with early radiography and culture. Until more sensitive and rapid diagnostic tests become widely available, a much more proactive and integrated approach towards prompt initiation of ART, ideally from within TB clinics and without waiting for TB to be excluded, is needed to minimise the risk and consequences of diagnostic delay.

Skin Disease Among Human Immunodeficiency Virus-Infected Adolescents in Zimbabwe: A Strong Indicator of Underlying HIV Infection

Background: Southern Africa is witnessing the emergence of an epidemic of long-term survivors of vertically acquired human immunodeficiency virus (HIV) infection presenting with untreated HIV as adolescents. Dermatologic conditions, common in both HIV-infected adults and children, have not been described in this age-group. We investigated the prevalence and spectrum of skin conditions in adolescents admitted to hospitals in Zimbabwe. Methods: A total of 301 consecutive adolescents admitted to 2 central Harare hospitals, underwent a dermatologic examination. Clinical history, HIV serology, and CD4 lymphocyte counts were obtained. Herpes simplex virus-2 serology was used as a surrogate marker for sexual activity. Results: A total of 139 (46%) patients were HIV-1 antibody positive, of whom only 2 (1.4%) were herpes simplex virus-2 antibody positive. The prevalence of any skin complaint among HIV-infected and uninfected participants was 88% and 14%, respectively (odds ratio: 37.7, 95% confidence interval: 19.4–72). The most common HIV-related conditions were pruritic papular eruptions (42%) and plane warts >5% of body area (24%). Having 3 or more skin conditions, a history of recurrent skin rashes and angular cheilitis were each associated with CD4 counts <200 cells/&mgr;L (P < 0.03, P < 0.01, and P < 0.05, respectively). Conclusions: Skin disease was a common and striking feature of underlying HIV-infection in hospitalized HIV-infected adolescents in Zimbabwe. In resource-poor settings with maturing epidemics, the presence of skin disease should be regarded as a strong indication for HIV testing and especially as it may reflect advanced immunosuppression. The high frequency of multiple plane warts has not previously been described, and may be a feature that distinguishes vertically-infected from horizontally-infected adolescents.

Adaptive designs undertaken in clinical research: a review of registered clinical trials

Adaptive designs have the potential to improve efficiency in the evaluation of new medical treatments in comparison to traditional fixed sample size designs. However, they are still not widely used in practice in clinical research. Little research has been conducted to investigate what adaptive designs are being undertaken. This review highlights the current state of registered adaptive designs and their characteristics. The review looked at phase II, II/III and III trials registered on ClinicalTrials.gov from 29 February 2000 to 1 June 2014, supplemented with trials from the National Institute for Health Research register and known adaptive trials. A range of adaptive design search terms were applied to the trials extracted from each database. Characteristics of the adaptive designs were then recorded including funder, therapeutic area and type of adaptation. The results in the paper suggest that the use of adaptive designs has increased. They seem to be most often used in phase II trials and in oncology. In phase III trials, the most popular form of adaptation is the group sequential design. The review failed to capture all trials with adaptive designs, which suggests that the reporting of adaptive designs, such as in clinical trials registers, needs much improving. We recommend that clinical trial registers should contain sections dedicated to the type and scope of the adaptation and that the term ‘adaptive design’ should be included in the trial title or at least in the brief summary or design sections.

Missing steps in a staircase: a qualitative study of the perspectives of key stakeholders on the use of adaptive designs in confirmatory trials.

BackgroundDespite the promising benefits of adaptive designs (ADs), their routine use, especially in confirmatory trials, is lagging behind the prominence given to them in the statistical literature. Much of the previous research to understand barriers and potential facilitators to the use of ADs has been driven from a pharmaceutical drug development perspective, with little focus on trials in the public sector. In this paper, we explore key stakeholders’ experiences, perceptions and views on barriers and facilitators to the use of ADs in publicly funded confirmatory trials.MethodsSemi-structured, in-depth interviews of key stakeholders in clinical trials research (CTU directors, funding board and panel members, statisticians, regulators, chief investigators, data monitoring committee members and health economists) were conducted through telephone or face-to-face sessions, predominantly in the UK. We purposively selected participants sequentially to optimise maximum variation in views and experiences. We employed the framework approach to analyse the qualitative data.ResultsWe interviewed 27 participants. We found some of the perceived barriers to be: lack of knowledge and experience coupled with paucity of case studies, lack of applied training, degree of reluctance to use ADs, lack of bridge funding and time to support design work, lack of statistical expertise, some anxiety about the impact of early trial stopping on researchers’ employment contracts, lack of understanding of acceptable scope of ADs and when ADs are appropriate, and statistical and practical complexities. Reluctance to use ADs seemed to be influenced by: therapeutic area, unfamiliarity, concerns about their robustness in decision-making and acceptability of findings to change practice, perceived complexities and proposed type of AD, among others.ConclusionsThere are still considerable multifaceted, individual and organisational obstacles to be addressed to improve uptake, and successful implementation of ADs when appropriate. Nevertheless, inferred positive change in attitudes and receptiveness towards the appropriate use of ADs by public funders are supportive and are a stepping stone for the future utilisation of ADs by researchers.

An Investigation of the Shortcomings of the CONSORT 2010 Statement for the Reporting of Group Sequential Randomised Controlled Trials: A Methodological Systematic Review.

Background It can be argued that adaptive designs are underused in clinical research. We have explored concerns related to inadequate reporting of such trials, which may influence their uptake. Through a careful examination of the literature, we evaluated the standards of reporting of group sequential (GS) randomised controlled trials, one form of a confirmatory adaptive design. Methods We undertook a systematic review, by searching Ovid MEDLINE from the 1st January 2001 to 23rd September 2014, supplemented with trials from an audit study. We included parallel group, confirmatory, GS trials that were prospectively designed using a Frequentist approach. Eligible trials were examined for compliance in their reporting against the CONSORT 2010 checklist. In addition, as part of our evaluation, we developed a supplementary checklist to explicitly capture group sequential specific reporting aspects, and investigated how these are currently being reported. Results Of the 284 screened trials, 68(24%) were eligible. Most trials were published in “high impact” peer-reviewed journals. Examination of trials established that 46(68%) were stopped early, predominantly either for futility or efficacy. Suboptimal reporting compliance was found in general items relating to: access to full trials protocols; methods to generate randomisation list(s); details of randomisation concealment, and its implementation. Benchmarking against the supplementary checklist, GS aspects were largely inadequately reported. Only 3(7%) trials which stopped early reported use of statistical bias correction. Moreover, 52(76%) trials failed to disclose methods used to minimise the risk of operational bias, due to the knowledge or leakage of interim results. Occurrence of changes to trial methods and outcomes could not be determined in most trials, due to inaccessible protocols and amendments. Discussion and Conclusions There are issues with the reporting of GS trials, particularly those specific to the conduct of interim analyses. Suboptimal reporting of bias correction methods could potentially imply most GS trials stopping early are giving biased results of treatment effects. As a result, research consumers may question credibility of findings to change practice when trials are stopped early. These issues could be alleviated through a CONSORT extension. Assurance of scientific rigour through transparent adequate reporting is paramount to the credibility of findings from adaptive trials. Our systematic literature search was restricted to one database due to resource constraints.

Relative effectiveness of insulin pump treatment over multiple daily injections and structured education during flexible intensive insulin treatment for type 1 diabetes: cluster randomised trial (REPOSE)

Objective To compare the effectiveness of insulin pumps with multiple daily injections for adults with type 1 diabetes, with both groups receiving equivalent training in flexible insulin treatment. Design Pragmatic, multicentre, open label, parallel group, cluster randomised controlled trial (Relative Effectiveness of Pumps Over MDI and Structured Education (REPOSE) trial). Setting Eight secondary care centres in England and Scotland. Participants Adults with type 1 diabetes who were willing to undertake intensive insulin treatment, with no preference for pumps or multiple daily injections. Participants were allocated a place on established group training courses that taught flexible intensive insulin treatment (“dose adjustment for normal eating,” DAFNE). The course groups (the clusters) were then randomly allocated in pairs to either pump or multiple daily injections. Interventions Participants attended training in flexible insulin treatment (using insulin analogues) structured around the use of pump or injections, followed for two years. Main outcome measures The primary outcomes were a change in glycated haemoglobin (HbA1c) values (%) at two years in participants with baseline HbA1c value of ≥7.5% (58 mmol/mol), and the proportion of participants achieving an HbA1c value of <7.5%. Secondary outcomes included body weight, insulin dose, and episodes of moderate and severe hypoglycaemia. Ancillary outcomes included quality of life and treatment satisfaction. Results 317 participants (46 courses) were randomised (156 pump and 161 injections). 267 attended courses and 260 were included in the intention to treat analysis, of which 235 (119 pump and 116 injection) had baseline HbA1c values of ≥7.5%. Glycaemic control and rates of severe hypoglycaemia improved in both groups. The mean change in HbA1c at two years was −0.85% with pump treatment and −0.42% with multiple daily injections. Adjusting for course, centre, age, sex, and accounting for missing values, the difference was −0.24% (−2.7 mmol/mol) in favour of pump users (95% confidence interval −0.53 to 0.05, P=0.10). Most psychosocial measures showed no difference, but pump users showed greater improvement in treatment satisfaction and some quality of life domains (dietary freedom and daily hassle) at 12 and 24 months. Conclusions Both groups showed clinically relevant and long lasting decreases in HbA1c, rates of severe hypoglycaemia, and improved psychological measures, although few participants achieved glucose levels currently recommended by national and international guidelines. Adding pump treatment to structured training in flexible intensive insulin treatment did not substantially enhance educational benefits on glycaemic control, hypoglycaemia, or psychosocial outcomes in adults with type 1 diabetes. These results do not support a policy of providing insulin pumps to adults with poor glycaemic control until the effects of training on participants’ level of engagement in intensive self management have been determined. Trial registration Current Controlled Trials ISRCTN61215213.