5.1 Sample size calculation
The sample size calculation for this study has been based on data from the ABC trial conducted by our US collaborator Professor Ely. In this trial the median number of coma-delirium free days in the control group was 10. Because the primary outcome is expected to be bimodal (many participants will have zero or close to the maximum number) and hence cannot be transformed to a normal distribution, it is proposed to analyse the data using non-parametric statistics. This will require a higher sample size than a t-test to achieve the same power. The power-efficiency of the Wilcoxon rank sum test is expected to be about 95% compared to a t-test (Segal & Castellan 1988), and would be at worst 86.4% (Randles & Wolfe 1979) suggesting that the necessary sample size would be between 1.053 and 1.157 times that needed for a t-test.
To detect a true difference of 0.5 standard deviations using a t-test requires 64 participants per group (128 in total). Allowing for 1.053 times as many recruits because of the use of a Wilcoxon rank sum test (the best case scenario), and 5% loss to follow-up, the sample size required is 142. In the worst case scenario, this sample size would have equal power to a t-test using a sample size of 121, which would have 77.5% power to detect a detect a difference of 0.5 standard deviations.
5.2 Statistical analysis
Data analysis will be undertaken by the trial statistician. Analyses of effectiveness end-points will be on an intention-to-treat basis. The primary outcome (delirium-coma free days) is a heavily skewed distribution and (bimodal with peaks at 0 and 28 days) which cannot be reliably transformed to a normal distribution. The primary outcome will therefore be measured using the Wilcoxon Rank sum test. For dichotomous outcomes, risk ratios and 95% confidence intervals will be calculated. Continuous variables over time will be analysed by generalised linear modelling. Time to event outcomes such as duration of hospital stay will be analysed by survival methods and reported as hazard ratios and 95% CI’s. Primary analyses will be based on patients with outcome data (i.e. available case analysis) but we will carry out sensitivity analyses using methods such as multiple imputations to assess the impact of missing data due to withdrawal of consent or loss to follow-up. The randomisation process will ensure balance in baseline variables but in the unlikely event of a chance imbalance, we will conduct a secondary analysis by constructing a multiple logistic regression model to adjust for these differences. A detailed analysis plan will be developed during the trial and submitted to the DMEC for approval prior to commencement of analysis.
Plasma -amyloid 42/40 levels are being collected as part of an exploratory analysis and as such no formal power calculation is required, it is estimated that 60 samples would be adequate.
5.3 Economic evaluation
A within trial cost-effectiveness analysis, with results presented in terms of cost per quality adjusted life years. Results will include probabilistic sensitivity analysis as an expression of uncertainty, as well as appropriate one-way and scenario analysis to assess how results may be generalised to other settings. The primary analysis will take the perspective of the service provider including the costs of health and social care. Data will be collected over the course of the intervention at appropriate time points and at appropriate follow-up points. Resource use data associated with each group will be collected during the intervention to contribute to a health economics analysis of costs related to the intervention and the study. Unit costs for health and social services resources will be obtained from national sources such as the PSSRU, the BNF and NHS reference cost database along with other appropriate resources as required.
The analysis will use quality adjusted life years (QALYs) as the outcome measure. The estimation of QALYs requires the production of utility weights for each health state observed in the trial population. We will use the EQ-5D (Euroqol) for this purpose. The evaluation will also inform us about the responsiveness of the EQ-5D in this population. The EQ-5D is a simple instrument to complete and will be collected at the same time and using the same methods as the other outcome data, including at baseline and at follow-up. This will limit the need to interpolate quality of life between observation points and the associated inaccuracy in the estimation of the health related quality of life differences between the control and intervention group.
6 Trial Organisation
The West Hertfordshire Hospitals NHS Trust will act as sponsor for this trial.
6.2 Trial steering committee (TSC)
The trial will be guided by a group of respected and experienced critical care personnel and trialist as well as a lay representative from the Alzheimer’s Society. Meetings will be held at regular intervals determined by need but not less than twice a year. Routine business is conducted by e mail, post or teleconferencing.
The Steering committee, in the development of this protocol and throughout the trial will take responsibility for:
Major decisions such as a need to change the protocol for any reason
Montoring and supervising the progress of the trial
Reviewing relevant information from other sources
Considering recommendations from the DMEC
Informing and advising on all aspects of the trial
6.3 Data Monitoring and Ethics Committee (DMEC)
A DMEC will be appointed independent of the study team comprising of two clinicians with experience in undertaking clinical trials/caring for critically ill patients. The study statistician will provide a report on safety data.
The DMEC will reach agreement as to their conduct and remit in the setting of this trial. They will discuss trial progress as and when required but at least every 9 months. An interim analysis of efficacy is not planned although this can be requested by the DMEC as required.
The DMEC will function primarily as a check for safety reviewing adverse events. They will specifically review the incidence and severity of side effects, SAEs and SUSARs and produce a safety report following each meeting. Early termination of the study in response to safety issues will be addressed via the DMEC. They will report any issues pertaining to safety to the Chief Investigator. It will be the responsibility of the Chief Investigator to inform the sponsor who will take appropriate action to halt the trial if concerns exist about participant safety.
Chief Investigator (CI) will assume overall responsibility for ensuring the trial is run in accordance with Good Clinical Practice and to the highest ethical and scientific standards. She will have regular meetings with the Trust Research and Development (R&D) department.
West Hertfordshire hospitals NHS Trust R&D department, represented by Fiona Smith (manager) will be responsible for overseeing the financial management of the trial and as Sponsors for ensuring that statutory regulations and reporting requirements are fulfilled.
The senior research nurse will be based at Watford General Hospital and supervised on a day to day basis by the CI. The trial will be conducted according to Standard Operating Procedures agreed in advance. The senior nurse will be the main contact between the trial office, CLRN network and the Alzheimer Society representatives. The CI and the nurse will also support the intensive care clinicians in facilitating recruitment and data collection. During the working week there are 2 consultants working in critical care, one is responsible for the ICU patients, the second for patients outside the ICU and as a supporting consultant. For this study a second consultant or the on call consultant will be responsible for recruitment on a daily basis.
Patient confidentiality will be maintained at every stage and we comply with the Data Protection Act.
NHS indemnity covers NHS staff and those conducting the trial.
6.6 Monitoring and Safety Procedures
The West Hertfordshire Hospitals NHS Trust indemnifies the study. In the case of negligent harm the Trust will accept full financial responsibility. NHS bodies carry this risk themselves or spread it through the Clinical Negligence Scheme for Trusts, which provides unlimited cover for this risk. NHS indemnity covers NHS staff, medical academic staff with honorary contracts, and those conducting the trial.
6.7 Safety and well being of study subjects
Subject safety and well-being are protected by implementation of the sponsoring
organisation’s standard operating procedures (SOPs) as set out in the Research
Governance Framework and The Medicines for Human Use (Clinical Trials)
Systems are in place to ensure that all investigators are able to demonstrate that they are qualified by education, training or experience to fulfil their roles, and that systems and procedures are in place which can assure the quality of every aspect of the trial. If new safety information becomes available, then study subjects will be informed of this and asked if they wish to continue in the study. If a subject wishes to continue in the trial they will be formally asked to read a revised approved subject information sheet and sign a new consent form.
Early termination of trial in response to safety issues will be addressed via the Data
Monitoring and Ethics Committee (DMEC) as discussed below in 9.3.1.
Day to day management will be undertaken via a trials management group composed of the chief investigator and supporting staff. They will meet on a monthly basis.
6.8 Safety of investigators
West Hertfordshire Hospitals NHS Trust has Health and Safety Policies applicable to all employees. All personnel should also ensure they adhere to any other Health and
Safety regulations relating to their area of work. The Chief Investigator will ensure that all personnel have been trained appropriately to undertake their
As the study fits closely to standard practice, there are few risks identified which are
hazardous to the investigators. The study team will complete Good Clinical Practice
(GCP) and consent training prior to start up.
7. Ethics and regulatory approval.
The study will be conducted in accordance with the ethical principles that have their
origin in the Declaration of Helsinki. The study will be submitted for Research Ethics Committee and MHRA approval.
Following detailed discussion of the study, written, informed consent will be obtained
from each subject. In line with The Medicines for Human Use (Clinical Trials)
Regulations 2004 and to comply with the Research Governance Framework, consenting processes are standardised, and are reinforced via training prior to study
Clinical Trial Authorisation will be sought from the MHRA and the trial will be
registered with the International Standard Randomised Controlled Trial Number
Any amendments to the final protocol will be clearly documented and forwarded to
the Research Ethics Committee for approval prior to implementation.
The results of the trial will be reported first to trial collaborators. The trial office team will draft the main report. The final version will be agreed by the
Steering Committee then submitted for publication, on behalf of the collaboration.
At the end of the trial, all subjects will be written to thanking for their participation in
the study and provided with a short summary of the trial findings. Further details
about the trial results may be obtained by visiting the trial website or requesting a copy of the final report.
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Hope-ICU Version 8: 8th April 2012