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PACMAN trial protocol, Perioperative Administration of Corticotherapy on Morbidity and mortality After Non-cardiac major surgery: a randomised, multicentre, double-blind, superiority study.

ABSTRACT: INTRODUCTION:Postoperative complications are major healthcare problems and are associated with a reduced short-term and long-term survival after surgery. An excessive postoperative inflammatory response participates to the development of postoperative infection and mortality. The aim of the Perioperative Administration of Corticotherapy on Morbidity and mortality After Non-cardiac surgery (PACMAN) study is to assess the effectiveness of perioperative administration of corticosteroid to reduce postoperative morbidity and mortality in patients undergoing major non-cardiac surgery. METHODS AND ANALYSIS:The PACMAN is a multicentre, randomised, controlled, double-blind, superiority, two-arm trial of 1222 high-risk patients aged 50 years or older undergoing major non-cardiac surgery at 32 acute care hospital in France. Patients are randomly assigned to dexamethasone (0.2?mg/kg at the end of the surgical procedure and at day +1, n=611) or to placebo (n=611). The primary outcome is a composite of predefined 14-day major pulmonary complications and mortality. Secondary outcomes are surgical complications, infections, organ failures, critical care-free days, length of hospital stay and all-cause mortality at 28 days. ETHICS AND DISSEMINATION:The PACMAN trial protocol has been approved by the ethics committee of Sud Mediterranée V, and will be carried out according to the Good Clinical Practice guidelines and the principles of the Declaration of Helsinki. The PACMAN trial is a randomised controlled trial powered to investigate whether perioperative administration of corticosteroids in patients undergoing non-cardiac major surgery reduces postoperative complications. The results of this study will be disseminated through presentation at scientific conferences and publication in peer-reviewed journals. TRIAL REGISTRATION NUMBER:NCT03218553; Pre-results.

SUBMITTER: Asehnoune K

PROVIDER: S-EPMC6475215 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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PACMAN trial protocol, Perioperative Administration of Corticotherapy on Morbidity and mortality After Non-cardiac major surgery: a randomised, multicentre, double-blind, superiority study.

Asehnoune Karim K Futier Emmanuel E Feuillet Fanny F Roquilly Antoine A

BMJ open 20190323 3

<h4>Introduction</h4>Postoperative complications are major healthcare problems and are associated with a reduced short-term and long-term survival after surgery. An excessive postoperative inflammatory response participates to the development of postoperative infection and mortality. The aim of the Perioperative Administration of Corticotherapy on Morbidity and mortality After Non-cardiac surgery (PACMAN) study is to assess the effectiveness of perioperative administration of corticosteroid to r ...[more]

PMID: 30904834

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Project description:BackgroundThe use of electroconvulsive therapy (ECT) is limited by concerns about its cognitive adverse effects. Preliminary evidence suggests that administering the glutamate antagonist ketamine with ECT might alleviate cognitive adverse effects and accelerate symptomatic improvement; we tested this in a randomised trial of low-dose ketamine.MethodsIn this multicentre, randomised, parallel-group study in 11 ECT suites serving inpatient and outpatient care settings in seven National Health Service trusts in the North of England, we recruited severely depressed patients, who were diagnosed as having unipolar or bipolar depressive episodes defined as moderate or severe by DSM-IV criteria, aged at least 18 years, and were able and willing to provide written consent to participate in the study. Patients were randomly assigned (1:1) to ketamine (0·5 mg/kg intravenous bolus) or saline adjunctive to the anaesthetic for the duration of their ECT course. Patients and assessment and ECT treatment teams were masked to treatment allocation, although anaesthetists administering the study medication were not. We analysed the primary outcome, Hopkins Verbal Learning Test-Revised delayed verbal recall (HVLT-R-DR) after four ECT treatments, using a Gaussian repeated measures model in all patients receiving the first ECT treatment. In the same population, safety was assessed by adverse effect monitoring. This trial was registered with International Standard Randomised Controlled Trial Number, number ISRCTN14689382.FindingsBetween early December, 2012, and mid-June, 2015, 628 patients were screened for eligibility, of whom 79 were randomly assigned to treatment (40 in the ketamine group vs 39 in the saline group). Ketamine (mean 5·17, SD 2·92), when compared with saline (5·54, 3·42), had no benefit on the primary outcome (HVLT-R-DR; difference in means -0·43 [95% CI -1·73 to 0·87]). 15 (45%) of 33 ketamine-treated patients compared with 10 (27%) of 37 patients receiving saline experienced at least one adverse event which included two (6%) of 33 patients who had ketamine-attributable transient psychological effects. Psychiatric adverse events were the most common in both groups (six [27%] of 22 adverse events in the ketamine group vs seven [54%] of 13 in the saline group).InterpretationNo evidence of benefit for ketamine was found although the sample size used was small; however, the results excluded greater than a small to moderate benefit with 95% confidence. The results do not support the use of adjunctive low-dose ketamine in routine ECT treatment.FundingNational Institute for Health Research (NIHR) Efficacy and Mechanism Evaluation (EME) programme, an MRC and NIHR partnership.

Project description:INTRODUCTION:Psoriasis vulgaris is a common skin disease that is characterised by persistent localised erythematous scaly plaques. Yinxieling is a Chinese herbal formula for psoriasis that has been used for more than 20 years in China. To facilitate application, PSORI-CM01 was developed based on the optimisation and simplification of Yinxieling tablets performed in a previous study and in clinical practice. However, the scientific evidence regarding whether PSORI-CM01 is more effective for psoriasis than the original Yinxieling remains insufficient. Therefore, we designed a randomised clinical trial to investigate the effect, safety and cost-effectiveness of PSORI-CM01 granules compared with those of Yinxieling tablets for the treatment of patients with psoriasis. METHODS AND ANALYSIS:This ongoing study is a two-arm parallel, randomised, double-blind, double-dummy clinical trial. Five hundred and fifty-six participants with psoriasis will be recruited and then randomly allocated into two groups in a 1:1 ratio. Participants in PSORI-CM01 group will receive a 5.5?g granule of PSORI-CM01 two times daily and five placebo tablets three times daily for 12 weeks. The participants in the Yinxieling group will receive five Yinxieling tablets three times daily and a placebo granule two times daily for 12 weeks. The primary outcome is the reduction of the Psoriasis Area and Severity Index. The secondary outcomes include relapse rate, Visual Analogue Scale scores, body surface area and the Dermatology Life Quality Index. Cost-effectiveness analysis will be performed from a health and community care provider perspective. ETHICS AND DISSEMINATION:This research protocol had been reviewed and approved by the institutional review boards of three trial centres (Guangdong Provincial Hospital of Chinese Medicine (B2014-026-01), Affiliated Hospital of Tianjin Chinese Medicine Academy (2014-KY-001) and Third Hospital of Hangzhou (B2014-026-01)). The findings will be disseminated to the public through conference presentations and open-access journals. TRIAL REGISTRATION NUMBER:Chinese Clinical Trial Registry (ChiCTR-TRC-14005185); Pre-results.

Project description:IntroductionEarly childhood pneumonia is a common problem globally with long-term complications that include bronchiectasis and chronic obstructive pulmonary disease. It is biologically plausible that these long-term effects may be minimised in young children at increased risk of such sequelae if any residual lower airway infection and inflammation in their developing lungs can be treated successfully by longer antibiotic courses. In contrast, shortened antibiotic treatments are being promoted because of concerns over inducing antimicrobial resistance. Nevertheless, the optimal treatment duration remains unknown. Outcomes from randomised controlled trials (RCTs) on paediatric pneumonia have focused on short-term (usually <2 weeks) results. Indeed, no long-term RCT-generated outcome data are available currently. We hypothesise that a longer antibiotic course, compared with the standard treatment course, reduces the risk of chronic respiratory symptoms/signs or bronchiectasis 24 months after the original pneumonia episode.Methods and analysisThis multicentre, parallel, double-blind, placebo-controlled randomised trial involving seven hospitals in six cities from three different countries commenced in May 2016. Three-hundred-and-fourteen eligible Australian Indigenous, New Zealand Māori/Pacific and Malaysian children (aged 0.25 to 5 years) hospitalised for community-acquired, chest X-ray (CXR)-proven pneumonia are being recruited. Following intravenous antibiotics and 3 days of amoxicillin-clavulanate, they are randomised (stratified by site and age group, allocation-concealed) to receive either: (i) amoxicillin-clavulanate (80 mg/kg/day (maximum 980 mg of amoxicillin) in two-divided doses or (ii) placebo (equal volume and dosing frequency) for 8 days. Clinical data, nasopharyngeal swab, bloods and CXR are collected. The primary outcome is the proportion of children without chronic respiratory symptom/signs of bronchiectasis at 24 months. The main secondary outcomes are 'clinical cure' at 4 weeks, time-to-next respiratory-related hospitalisation and antibiotic resistance of nasopharyngeal respiratory bacteria.Ethics and disseminationThe Human Research Ethics Committees of all the recruiting institutions (Darwin: Northern Territory Department of Health and Menzies School of Health Research; Auckland: Starship Children's and KidsFirst Hospitals; East Malaysia: Likas Hospital and Sarawak General Hospital; Kuala Lumpur: University of Malaya Research Ethics Committee; and Klang: Malaysian Department of Health) have approved the research protocol version 7 (13 August 2018). The RCT and other results will be submitted for publication.Trial registrationACTRN12616000046404.

Project description:AIM:To investigate whether probiotic bacteria, given perioperatively, might adhere to the colonic mucosa, reduce concentration of pathogens in stools, and modulate the local immune function. METHODS:A randomized, double-blind clinical trial was carried out in 31 subjects undergoing elective colorectal resection for cancer. Patients were allocated to receive either a placebo (group A, n = 10), or a dose of 10(7) of a mixture of Bifidobacterium longum (BB536) and Lactobacillus johnsonii (La1) (group B, n = 11), or the same mixture at a concentration of 10(9) (group C, n = 10). Probiotics, or a placebo, were given orally 2 doses/d for 3 d before operation. The same treatment continued postoperatively from day two to day four. Stools were collected before treatment, during surgery (day 0) and 5 d after operation. During the operation, colonic mucosa samples were harvested to evaluate bacterial adherence and to assess the phenotype of dendritic cells (DCs) and lymphocyte subsets by surface antigen expression (flow cytometry). The presence of BB536 and La1 was evaluated by the random amplified polymorphism DNA method with specific polymerase chain reaction probes. RESULTS:The three groups were balanced for baseline and surgical parameters. BB536 was never found at any time-points studied. At day 0, La1 was present in 6/10 (60%) patients in either stools or by biopsy in group C, in 3/11 (27.2%) in group B, and none in the placebo group (P = 0.02, C vs A). There was a linear correlation between dose given and number of adherent La1 (P = 0.01). The rate of mucosal colonization by enterobacteriacae was 30% (3/10) in C, 81.8% (9/11) in B and 70% (7/10) in A (P = 0.03, C vs B). The Enterobacteriacae count in stools was 2.4 (log10 scale) in C, 4.6 in B, and 4.5 in A (P = 0.07, C vs A and B). The same trend was observed for colonizing enterococci. La1 was not found at day +5. We observed greater expression of CD3, CD4, CD8, and naive and memory lymphocyte subsets in group C than in group A with a dose response trend (C > B > A). Treatment did not affect DC phenotype or activation, but after ex vivo stimulation with lipopolysaccharides, groups C and B had a lower proliferation rate compared to group A (P = 0.04). Moreover, dendritic phenotypes CD83-123, CD83-HLADR, and CD83-11c (markers of activation) were significantly less expressed in patients colonized with La1 (P = 0.03 vs not colonized). CONCLUSION:La1, but not BB536, adheres to the colonic mucosa, and affects intestinal microbiota by reducing the concentration of pathogens and modulates local immunity.

Project description:ObjectiveTo assess the effect of dexamethasone on complications or all cause mortality after major non-cardiac surgery.DesignPhase III, randomised, double blind, placebo controlled trial.Setting34 centres in France, December 2017 to March 2019.Participants1222 adults (>50 years) requiring major non-cardiac surgery with an expected duration of more than 90 minutes. The anticipated time frame for recruitment was 24 months.InterventionsParticipants were randomised to receive either dexamethasone (0.2 mg/kg immediately after the surgical procedure, and on day 1) or placebo. Randomisation was stratified on the two prespecified criteria of cancer and thoracic procedure.Main outcomes measuresThe primary outcome was a composite of postoperative complications or all cause mortality within 14 days after surgery, assessed in the modified intention-to-treat population (at least one treatment administered).ResultsOf the 1222 participants who underwent randomisation, 1184 (96.9%) were included in the modified intention-to-treat population. 14 days after surgery, 101 of 595 participants (17.0%) in the dexamethasone group and 117 of 589 (19.9%) in the placebo group had complications or died (adjusted odds ratio 0.81, 95% confidence interval 0.60 to 1.08; P=0.15). In the stratum of participants who underwent non-thoracic surgery (n=1038), the primary outcome occurred in 69 of 520 participants (13.3%) in the dexamethasone group and 93 of 518 (18%) in the placebo group (adjusted odds ratio 0.70, 0.50 to 0.99). Adverse events were reported in 288 of 613 participants (47.0%) in the dexamethasone group and 296 of 609 (48.6%) in the placebo group (P=0.46).ConclusionsDexamethasone was not found to significantly reduce the incidence of complications and death in patients 14 days after major non-cardiac surgery. The 95% confidence interval for the main result was, however, wide and suggests the possibility of important clinical effectiveness.Trial registrationClinicalTrials.gov NCT03218553.

Project description:A systematic assessment of potential disease-modifying compounds for Parkinson's disease concluded that pioglitazone could hold promise for the treatment of patients with this disease. We assessed the effect of pioglitazone on the progression of Parkinson's disease in a multicentre, double-blind, placebo-controlled, futility clinical trial.Participants with the diagnosis of early Parkinson's disease on a stable regimen of 1 mg/day rasagiline or 10 mg/day selegiline were randomly assigned (1:1:1) to 15 mg/day pioglitazone, 45 mg/day pioglitazone, or placebo. Investigators were masked to the treatment assignment. Only the statistical centre and the central pharmacy knew the treatment name associated with the randomisation number. The primary outcome was the change in the total Unified Parkinson's Disease Rating Scale (UPDRS) score between the baseline and 44 weeks, analysed by intention to treat. The primary null hypothesis for each dose group was that the mean change in UPDRS was 3 points less than the mean change in the placebo group. The alternative hypothesis (of futility) was that pioglitazone is not meaningfully different from placebo. We rejected the null if there was significant evidence of futility at the one-sided alpha level of 0·10. The study is registered at ClinicalTrials.gov, number NCT01280123.210 patients from 35 sites in the USA were enrolled between May 10, 2011, and July 31, 2013. The primary analysis included 72 patients in the 15 mg group, 67 in the 45 mg group, and 71 in the placebo group. The mean total UPDRS change at 44 weeks was 4·42 (95% CI 2·55-6·28) for 15 mg pioglitazone, 5·13 (95% CI 3·17-7·08) for 45 mg pioglitazone, and 6·25 (95% CI 4·35-8·15) for placebo (higher change scores are worse). The mean difference between the 15 mg and placebo groups was -1·83 (80% CI -3·56 to -0·10) and the null hypothesis could not be rejected (p=0·19). The mean difference between the 45 mg and placebo groups was -1·12 (80% CI -2·93 to 0·69) and the null hypothesis was rejected in favour of futility (p=0·09). Planned sensitivity analyses of the primary outcome, using last value carried forward (LVCF) to handle missing data and using the completers' only sample, suggested that the 15 mg dose is also futile (p=0·09 for LVCF, p=0·09 for completers) but failed to reject the null hypothesis for the 45 mg dose (p=0·12 for LVCF, p=0·19 for completers). Six serious adverse events occurred in the 15 mg group, nine in the 45 mg group, and three in the placebo group; none were thought to be definitely or probably related to the study interventions.These findings suggest that pioglitazone at the doses studied here is unlikely to modify progression in early Parkinson's disease. Further study of pioglitazone in a larger trial in patients with Parkinson's disease is not recommended.National Institute of Neurological Disorders and Stroke.

Project description:IntroductionAcute pancreatitis (AP) is an inflammatory disease with no specific treatment. Mitochondrial injury followed by ATP depletion in both acinar and ductal cells is a recently discovered early event in its pathogenesis. Importantly, preclinical research has shown that intracellular ATP delivery restores the physiological function of the cells and protects from cell injury, suggesting that restoration of energy levels in the pancreas is therapeutically beneficial. Despite several high quality experimental observations in this area, no randomised trials have been conducted to date to address the requirements for energy intake in the early phase of AP.Methods/designThis is a randomised controlled two-arm double-blind multicentre trial. Patients with AP will be randomly assigned to groups A (30 kcal/kg/day energy administration starting within 24 hours of hospital admission) or B (low energy administration during the first 72 hours of hospital admission). Energy will be delivered by nasoenteric tube feeding with additional intravenous glucose supplementation or total parenteral nutrition if necessary. A combination of multiorgan failure for more than 48 hours and mortality is defined as the primary endpoint, whereas several secondary endpoints such as length of hospitalisation or pain will be determined to elucidate more detailed differences between the groups. The general feasibility, safety and quality checks required for high quality evidence will be adhered to.Ethics and disseminationThe study has been approved by the relevant organisation, the Scientific and Research Ethics Committee of the Hungarian Medical Research Council (55961-2/2016/EKU). This study will provide evidence as to whether early high energy nutritional support is beneficial in the clinical management of AP. The results of this trial will be published in an open access way and disseminated among medical doctors.Trial registrationThe trial has been registered at the ISRCTN (ISRTCN 63827758).

Dataset Information

PACMAN trial protocol, Perioperative Administration of Corticotherapy on Morbidity and mortality After Non-cardiac major surgery: a randomised, multicentre, double-blind, superiority study.

Publications

PACMAN trial protocol, Perioperative Administration of Corticotherapy on Morbidity and mortality After Non-cardiac major surgery: a randomised, multicentre, double-blind, superiority study.

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