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PRECIOUS: PREvention of Complications to Improve OUtcome in elderly patients with acute Stroke-statistical analysis plan of a randomised, open, phase III, clinical trial with blinded outcome assessment.

ABSTRACT: RATIONALE:Aspiration, infections, and fever are common in the first days after stroke, especially in older patients. The occurrence of these complications has been associated with an increased risk of death or dependency. AIMS AND DESIGN:PREvention of Complications to Improve OUtcome in elderly patients with acute Stroke (PRECIOUS) is an international, multi-centre, 3?×?2 factorial, randomised, controlled, open-label clinical trial with blinded outcome assessment, which will assess whether prevention of aspiration, infections, or fever with metoclopramide, ceftriaxone, paracetamol, respectively, or any combination of these in the first 4 days after stroke onset improves functional outcome at 90?days in elderly patients with acute stroke. DISCUSSION:This statistical analysis plan provides a technical description of the statistical methodology and unpopulated tables and figures. The paper is written prior to data lock and unblinding of treatment allocation. TRIAL REGISTRATION:ISRCTN registry ISRCTN82217627 . Registered on 22 September 2015. The trial was prospectively registered.

SUBMITTER: de Jonge JC

PROVIDER: S-EPMC7586648 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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PRECIOUS: PREvention of Complications to Improve OUtcome in elderly patients with acute Stroke-statistical analysis plan of a randomised, open, phase III, clinical trial with blinded outcome assessment.

de Jonge Jeroen C JC Woodhouse Lisa J LJ Reinink Hendrik H van der Worp H Bart HB Bath Philip M PM

Trials 20201026 1

<h4>Rationale</h4>Aspiration, infections, and fever are common in the first days after stroke, especially in older patients. The occurrence of these complications has been associated with an increased risk of death or dependency.<h4>Aims and design</h4>PREvention of Complications to Improve OUtcome in elderly patients with acute Stroke (PRECIOUS) is an international, multi-centre, 3 × 2 factorial, randomised, controlled, open-label clinical trial with blinded outcome assessment, which will asses ...[more]

PMID: 33106180

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Project description:BackgroundInfections and fever after stroke are associated with poor functional outcome or death. We assessed whether prophylactic treatment with anti-emetic, antibiotic, or antipyretic medication would improve functional outcome in older patients with acute stroke.MethodsWe conducted an international, 2∗2∗2-factorial, randomised, controlled, open-label trial with blinded outcome assessment in patients aged 66 years or older with acute ischaemic stroke or intracerebral haemorrhage and a score on the National Institutes of Health Stroke Scale ≥ 6. Patients were randomly allocated (1:1) to metoclopramide (oral, rectal, or intravenous; 10 mg thrice daily) vs. no metoclopramide, ceftriaxone (intravenous; 2000 mg once daily) vs. no ceftriaxone, and paracetamol (oral, rectal, or intravenous; 1000 mg four times daily) vs. no paracetamol, started within 24 h after symptom onset and continued for four days. All participants received standard of care. The target sample size was 3800 patients. The primary outcome was the score on the modified Rankin Scale (mRS) at 90 days analysed with ordinal logistic regression and reported as an adjusted common odds ratio (an acOR < 1 suggests benefit and an acOR > 1 harm). This trial is registered (ISRCTN82217627).FindingsFrom April 2016 through June 2022, 1493 patients from 67 European sites were randomised to metoclopramide (n = 704) or no metoclopramide (n = 709), ceftriaxone (n = 594) or no ceftriaxone (n = 482), and paracetamol (n = 706) or no paracetamol (n = 739), of whom 1471 were included in the intention-to-treat analysis. Prophylactic use of study medication did not significantly alter the primary outcome at 90 days: metoclopramide vs. no metoclopramide (adjusted common odds ratio [acOR], 1.01; 95% CI 0.81-1.25), ceftriaxone vs. no ceftriaxone (acOR 0.99; 95% CI 0.77-1.27), paracetamol vs. no paracetamol (acOR 1.19; 95% CI 0.96-1.47). The study drugs were safe and not associated with an increased incidence of serious adverse events.InterpretationWe observed no sign of benefit of prophylactic use of metoclopramide, ceftriaxone, or paracetamol during four days in older patients with a moderately severe to severe acute stroke.FundingThis project has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement No: 634809.

Project description:IntroductionCoronary artery bypass grafting can be conducted using the radial artery as a bypass graft. However, it remains unclear which harvesting method is superior, i.e. endoscopic or open radial artery, and which site for proximal anastomosis of the radial artery has the greatest benefits?MethodsThe NEO Trial is a single site randomised clinical trial with a 2 × 2 factorial design. The first comparison assesses endoscopic versus open radial artery harvest with a primary outcome of hand function and secondary outcomes of neurological deficits through clinical exams and neurophysiological studies. The primary outcome is postoperatively hand function at three months. We anticipate a mean difference of 3 points with a standard deviation of 8 points, a power of 90%, and a type I error of 5%, resulting in a required sample size of 300 participants randomised 1:1. Secondary outcomes are neurological deficits (based on nerve conduction measurements, algometry test and von Frey hair test), clinical neurological examination of cutaneous sensibility, and registration of complications in the donor arm (haematoma formation, wound dehiscence, and/or infection). The second comparison assesses two different proximal anastomotic sites, i.e. aorto-radial anastomosis versus mammario-radial anastomosis. The primary outcome is a composite of cerebrovascular events and the secondary outcome is graft patency evaluation by multi-slice computer tomography-scan. These outcomes will be assessed at 1 year postoperatively, and the results of this comparison will be exploratory only. Both comparisons will be analysed using intention-to-treat and intervention groups will be compared using linear regression, logistic regression, or Mann-Whitney U test depending on data type. Two independent statisticians will follow the present plan and conduct the analyses which will hereafter be fused into a final analysis based on consensus.ConclusionThis detailed analysis plan will increase the validity of the NEO trial results by predefining the statistical analysis in detail.Trial registrationClinicalTrials.gov identifier: NCT01848886 . Registered 25 February 2013. Danish Ethics committee number: H-3-2012-116. Danish Data Protection Agency: 2007-58-0015/jr. n:30-0838.

Project description:IntroductionThe rising prevalence of modifiable risk factors (eg, obesity, hypertension and physical inactivity) is causing an increase in possible avoidable complications in patients undergoing cardiac surgery. This study aims to assess whether a combined preoperative and postoperative multidisciplinary cardiac rehabilitation (CR) programme (Heart-ROCQ programme) can improve functional status and reduce surgical complications, readmissions and major adverse cardiac events (MACE) as compared with standard care.Methods and analysisPatients (n=350) are randomised to the Heart-ROCQ programme or standard care. The Heart-ROCQ programme consists of a preoperative optimisation phase while waiting for surgery (three times per week, minimum of 3 weeks), a postoperative inpatient phase (3 weeks) and an outpatient CR phase (two times per week, 4 weeks). Patients receive multidisciplinary treatment (eg, physical therapy, dietary advice, psychological sessions and smoking cessation). Standard care consists of 6 weeks of postsurgery outpatient CR with education and physical therapy (two times per week). The primary outcome is a composite weighted score of functional status, surgical complications, readmissions and MACE, and is evaluated by a blinded endpoint committee. The secondary outcomes are length of stay, physical and psychological functioning, lifestyle risk factors, and work participation. Finally, an economic evaluation is performed. Data are collected at six time points: at baseline (start of the waiting period), the day before surgery, at discharge from the hospital, and at 3, 7 and 12 months postsurgery.Ethics and disseminationThis study will be conducted according to the principles of the Declaration of Helsinki (V.8, October 2013). The protocol has been approved by the Medical Ethical Review Board of the UMCG (no 2016/464). Results of this study will be submitted to a peer-reviewed scientific journal and can be presented at national and international conferences.Trial registration numberNCT02984449.

Project description:BackgroundPeople who sustain spinal cord injuries in low- and middle-income countries are vulnerable to life-threatening complications after discharge. The aim of this trial is to determine the effect on all-cause mortality of a sustainable model of community-based care provided over the first 2 years after discharge.Methods and analysisThe CIVIC trial is a single centre, parallel group trial with concealed and stratified randomisation. The protocol has been previously published (BMJ Open 2016;6:e010350). This paper provides the accompanying detailed statistical plan. In total, 410 people with recent spinal cord injury who are wheelchair dependent and about to be discharged from the Centre for the Rehabilitation of the Paralysed in Bangladesh are randomised to intervention or control groups. Participants assigned to the intervention group receive a model of community-based care in which a case manager provides ongoing telephone-based support and visits participants in their homes over a 2-year period. Participants assigned to the control group receive usual care which may involve a follow-up phone call or a home visit. The primary outcome is all-cause mortality at 2 years as determined by a blinded assessor (Bangladesh does not have a death registry). The primary effectiveness analysis will compare Kaplan-Meier survival curves (time from allocation to death) in the intervention and control groups using the log-rank test (two-tailed α = 0.05). Participants will be censored at the time they were last known to be alive or at the time of the follow-up assessment. Recruitment finished in March 2018 and the last assessment will be conducted in March 2020.DiscussionThe CIVIC trial will provide unbiased and precise estimates of the effectiveness of a model of community-based care for people with spinal cord injuries in Bangladesh. The results will have implications for provision of health services for people with spinal cord injuries and other conditions that cause serious disability in low-income and middle-income countries.Trial registrationANZCTR, ACTRN12615000630516, U1111-1171-1876. Registered on 17 June 2015.

Project description:Background and purposeBlinded outcome assessment in trials with prospective randomized open blinded end point design is challenging. Unblinding can result in misclassified outcomes and biased treatment effect estimates. An outcome adjudication committee assures blinded outcome assessment, but the added value for trials with prospective randomized open blinded end point design and subjective outcomes is unknown. We aimed to assess the degree of misclassification of modified Rankin Scale (mRS) scores by a central assessor and its impact on treatment effect estimates in a stroke trial with prospective randomized open blinded end point design.MethodsWe used data from the MR CLEAN (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands). The primary outcome was the mRS at 90 days. Standardized, algorithm-based telephone interviews to assess the mRS were conducted from a central location by an experienced research nurse, unaware but not formally blinded to treatment allocation (central assessor). Masked reports of these interviews were adjudicated by a blinded outcome committee. Misclassification was defined as an incorrect classification of the mRS by the central assessor. The effect of endovascular treatment on the mRS was assessed with multivariable ordinal logistic regression.ResultsIn MR CLEAN, 53/500 (10.6%) of the mRS scores were misclassified. The degree and direction of misclassification did not differ between treatment arms (P=0.59). Benefit of endovascular treatment was shown on the mRS when scored by the central assessor (adjusted common odds ratio, 1.60 [95% CI, 1.16-2.21]) and the outcome adjudication committee (adjusted common odds ratio, 1.67 [95% CI, 1.21-2.20]).ConclusionsMisclassification by the central assessor was small, randomly distributed over treatment arms, and did not affect treatment effect estimates. This study suggests that the added value of a blinded outcome adjudication committee is limited in a stroke trial with prospective randomized open blinded end point design applying standardized, algorithm-based outcome assessment by a central assessor, who is unaware but not formally blinded to treatment allocation. Registration: URL: https://www.isrctn.com; Unique identifier: ISRCTN10888758.

Dataset Information

PRECIOUS: PREvention of Complications to Improve OUtcome in elderly patients with acute Stroke-statistical analysis plan of a randomised, open, phase III, clinical trial with blinded outcome assessment.

Publications

PRECIOUS: PREvention of Complications to Improve OUtcome in elderly patients with acute Stroke-statistical analysis plan of a randomised, open, phase III, clinical trial with blinded outcome assessment.

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