Ana səhifə

# Hope-icu trial

Yüklə 171.5 Kb.
 səhifə 9/9 tarix 26.06.2016 ölçüsü 171.5 Kb.

## 5 Data analysis

#### 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:

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.
6.3.1 Safety:

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.

## 6.5 Indemnity

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)

Regulations 2004.

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

start-up.

Clinical Trial Authorisation will be sought from the MHRA and the trial will be

registered with the International Standard Randomised Controlled Trial Number

register.

#### 8. Protocol Amendments

Any amendments to the final protocol will be clearly documented and forwarded to

the Research Ethics Committee for approval prior to implementation.

## 9. Publication

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.

References

1. American Psychiatric Association (APA). Diagnostic and statistical manual of mental disorders. 4th edition, text revision. Washington DC: American Psychiatric Association, 2000.

2. D Meagher. Motor subtypes of delirium: Past, present and future International Review of Psychiatry. 2009; 21: 59-73

3. Ely EW, Gautam S, Margolin R et al. The impact of delirium in the intensive care unit on hospital length of stay. Intensive Care Medicine 2001; 27: 1892-1900

4. Spronk PE, Riekerk B, Hofhuis J, Rommes JH. (2009) Occurence of delirium is severely underestimated in the ICU during daily care. Intensive Care Med 35 (7): 1276 – 80

5. Page VJ, Navarange S, Gama S, McAuley DF. (2009) Routine delirium monitoring in a UK critical care unit. Crit Care, 13: R16
6. ## Maldonado J Pathoetiological Model of Delirium: a Comprehensive Understanding of the Neurobiology of Delirium and an Evidence-Based Approach to Prevention and Treatment. Critical Care Clinics 2008; 24: 789-856

7. MacLullich A, Ferguson K, Miller T et al. Unravelling the pathophysiology of delirium; A focus on the role of aberrant stress responses. Journal of Psychosomatic Research 2008; 65: 229-238

8. Trzepacz P. Is there a final common neural pathway in delirium? Focus on acetylcholine and dopamine. Seminars in Clinical Neuropsychiatry 2000; 5: 132-48
9. ## Hshieh T, Fong T, Marcantonio E, Inouye S. Cholinergic Deficiency Hypothesis in Delirium: A Synthesis of Current Evidence The Journals of Gerontology Series A: Biological Sciences and Medical Sciences 2008;63:764-772

10. McCusker J, Cole M, Abrahamowicz M et al. Delirium predicts 12-month mortality. Archives of Internal Medicine 2002; 162: 457-63

11. Pisani M, Kong S, Kasi S et al. Days of delirium are associated with 1-year mortality in an older intensive care unit population. American Journal of Respiratory and Critical Care Medicine 2009; 180: 1092-7.

12. Fong TG, Jones RN, Shi P et al. Delirium accelerates cognitive decline in

Alzheimer disease. Neurology 2009; 72 (18): 1570-75.

1. Jorm A. The Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE): a review. International Psychogeriatrics 2004; 16: 1-19

2. Marcantonio D, Simon S, Bergmann M et al. Delirium Symptoms in Post-Acute Care: Prevalent, Persistent, and Associated with Poor Functional Recovery. Journal of the American Geriatrics Society 2003; 51: 4-9

4. ## Balas M, Happ M, Yang W et al. Outcomes associated with delirium in older patients in surgical ICUs. Chest 2009; 135: 18-25.

5. Ely EW, Shintani A, Truman B, Speroff T, Gordon SM, Harrell FE, Inouye SK, Bernard GR, Dittus RS. Delirium as a predictor of mortality in mechanically ventilated patients in the intensive care unit. JAMA 2004; 29: 1753-1762.

6. Jones H, Pilowsky L. Dopamine and antipsychotic drug action revisited. British Journal of Psychiatry 2002; 181 ; 271-5.

7. Hu H, Dneg W, Yang Hui, Liu Y. Olanzapine and haloperidol for senile delirium: A randomized controlled observation. Chinese Journal of Clinical Rehabilitation 2006; 42: 188-90.

8. Siddiqui N, Stockdale R, Britton AM, Holmes J. Interventions for preventing delirium in hospitalised patients. Cochrane Database of Systematic Review 2007; 2: CD005563.

9. Lonergan E, Britton A, Luxenberg J. Antipsychotics for delirium. Cochrane Database of Systematic Review 2007; 2: CD005594

10. Kalisvaart K, De Jonghe J, Bogaards M et al. Haloperidol prophylaxis for elderly hip-surgery patients at risk of delirium: A randomised placebo-controlled study. Journal of the American Geriatrics Society 2005; 53: 1658-66

11. Kaneko T, Cai J, Ishikura T et al. Prophylactic consecutive administration of haloperidol can reduce the occurrence of postoperative delirium in gastrointestinal surgery. Yonago Acta medica 1999; 42: 179-84

12. Milbrandt EB, Kersten A, Kong L, Weissfeld L, Clermont G, Fink M, Angus D. Haloperidol is associated with lower hospital mortality in mechanically ventilated patients. Critical Care Medicine 2005; 33: 226-229.

13. Wang P, Schneeweiss S, Avorn J et al. Risk of death in elderly users of conventional vs. atypical antipsychotic medications. New England Journal of Medicine 2005; 353: 2335-2341.

14. Knol W, van Marum R, Jansen P et al. Antipsychotic drug use and risk of pneumonia in elderly people. Journal of the American Geriatric Society 2008; 56: 661-66.

15. Suh G, Shah A. Effects of antipsychotics on mortality in elderly patients with dementia: a 1-year prospective study in a nursing home. International Psychogeriatrics 2005; 17: 429-44.

16. Raivio M, Laurila JV, Standberg TE, Tilvis RS, Pitkala KH (2007) Neither atypical nor conventional antipsychotics increase mortality or hospital admissions among elderly patients with dementia: a two year prospective study American Journal Geriatric Psychiatry 15 (5): 416 – 24

17. Moots R, Al-Saffar Z, Hutchinson D. Old drug, new tricks: haloperidol inhibits secretion of proinflammatory cytokines. Annals of the Rheumatic Diseases 1999; 58: 585-7.

18. Woodward N, Purdon S, Meltzer H, Zald D. A meta-analysis of cognitive change with haloperidol in clinical trials of atypical antipsychotics: Dose effects and comparison to practice effects. Schizophrenia Research 2007; 89: 211-24.

19. MacSweeney R, Barber V, Page V et al. A national survey of the management of delirium in UK intensive care units. Quarterly Journal of Medicine in press.

20. Van den Boogaard M, Pickkers P, van der Hoeven et al Implementation of a delirium assessement tool in the ICU can influence haloperidol use Critical Care 2009; 13: R131

21. Girard T, Pandharipande P, Carson S et al. Feasibility, efficacy, and safety of antipsychotics for intensive care unit delirium: the MIND randomized, placebo-controlled trial. Critical Care Medicine 2010; 38: 428-437

22. Simpson GM, Angus JWS: A rating scale for extrapyramidal side effects. Acta Psychiatrica Scandinavica 1970; Supp 212:11–19

23. Hassaballa H, Balk R. Torsade de pointes associated with the administration of intravenous haloperidol: a review of the literature and practical guidelines for use. Expert Opinion on Drug Safety 2003; 2: 543-7

24. Giegling I, Drago A, Schafer M et al. Interaction of haloperidol plasma level and antipsychotic effect in early phases of acute psychosis treatment. Journal of Psychiatric Research 2009, doi; 10.1016/j.jpsychires.2009.11.004

25. Graff-Radford N, Crook J, Lucas J et al. Association of low plasma A 42/ A 40 ratios with increased imminent risk for mild cognitive impairment and Alzheimer’s Disease. Archives of Neurology 2007;64: 354-62.

26. Yaffe K, Weston A, Graff-Radford N et al. Association of plasma -amyloid level and cognitive reserve with subsequent cognitive decline. JAMA 2011; 305: 261-66.
27. ## Schoenfeld D, Bernard G; ARDS Network. Statistical evaluation of ventilator-free days as an efficacy measure in clinical trials of treatments for acute respiratory distress syndrome. Critical Care Medicine 2002; 30: 1772-7

28. Jager C, Budge M and Clarke R. Utility of the TICS-M for the assessment of cognitive function in older adults. International Journal of Geriatric Psychiatry 2003; 18: 318-24

Hope-ICU Version 8: 8th April 2012

Verilənlər bazası müəlliflik hüququ ilə müdafiə olunur ©atelim.com 2016
rəhbərliyinə müraciət