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GI-REASONS: a novel 6-month, prospective, randomized, open-label, blinded endpoint (PROBE) trial.

ABSTRACT: Because of the limitations of randomized controlled trials (RCTs) and observational studies, a prospective, randomized, open-label, blinded endpoint (PROBE) study may be an appropriate alternative, as the design allows the assessment of clinical outcomes in clinical practice settings. The Gastrointestinal (GI) Randomized Event and Safety Open-Label Nonsteroidal Anti-inflammatory Drug (NSAID) Study (GI-REASONS) was designed to reflect standard clinical practice while including endpoints rigorously evaluated by a blinded adjudication committee. The objective of this study was to assess if celecoxib is associated with a lower incidence of clinically significant upper and/or lower GI events than nonselective NSAIDs (nsNSAIDs) in standard clinical practice.This was a PROBE study carried out at 783 centers in the United States, where a total of 8,067 individuals aged ? 55 years, requiring daily NSAIDs to treat osteoarthritis, participated. The participants were randomized to celecoxib or nsNSAIDs (1:1) for 6 months and stratified by Helicobacter pylori status. Treatment doses could be adjusted as per the United States prescribing information; patients randomized to nsNSAIDs could switch between nsNSAIDs; crossover between treatment arms was not allowed, and patients requiring aspirin at baseline were excluded. The primary outcome was the incidence of clinically significant upper and/or lower GI events.Significantly more nsNSAID users met the primary endpoint (2.4% (98/4,032) nsNSAID patients and 1.3% (54/4,035) celecoxib patients; odds ratio, 1.82 (95% confidence interval, 1.31-2.55); P = 0.0003). Moderate to severe abdominal symptoms were experienced by 94 (2.3%) celecoxib and 138 (3.4%) nsNSAID patients (P=0.0035). Other non-GI adverse events were similar between treatment groups. One limitation is the open-label design, which presents the possibility of interpretive bias.Celecoxib was associated with a lower risk of clinically significant upper and/or lower GI events than nsNSAIDs. Furthermore, this trial represents a successful execution of a PROBE study, where therapeutic options and management strategies available in clinical practice were incorporated into the rigor of a prospective RCT.

SUBMITTER: Cryer B

PROVIDER: S-EPMC3590424 | biostudies-literature | 2013 Mar

REPOSITORIES: biostudies-literature

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GI-REASONS: a novel 6-month, prospective, randomized, open-label, blinded endpoint (PROBE) trial.

Cryer Byron B Li Chunming C Simon Lee S LS Singh Gurkirpal G Stillman Martin J MJ Berger Manuela F MF

The American journal of gastroenterology 20130212 3

<h4>Objectives</h4>Because of the limitations of randomized controlled trials (RCTs) and observational studies, a prospective, randomized, open-label, blinded endpoint (PROBE) study may be an appropriate alternative, as the design allows the assessment of clinical outcomes in clinical practice settings. The Gastrointestinal (GI) Randomized Event and Safety Open-Label Nonsteroidal Anti-inflammatory Drug (NSAID) Study (GI-REASONS) was designed to reflect standard clinical practice while including ...[more]

PMID: 23399552

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Project description:BackgroundAngiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) prevent microalbuminuria in normoalbuminuric type 2 diabetic patients. We assessed whether combined therapy with the 2 medications may prevent microalbuminuria better than ACE inhibitor or ARB monotherapy.Methods and findingsVARIETY was a prospective, randomized, open-label, blinded endpoint (PROBE) trial evaluating whether, at similar blood pressure (BP) control, combined therapy with benazepril (10 mg/day) and valsartan (160 mg/day) would prevent microalbuminuria more effectively than benazepril (20 mg/day) or valsartan (320 mg/day) monotherapy in 612 type 2 diabetic patients with high-normal albuminuria included between July 2007 and April 2013 by the Istituto di Ricerche Farmacologiche Mario Negri IRCCS and 8 diabetology or nephrology units in Italy. Time to progression to microalbuminuria was the primary outcome. Analyses were intention to treat. Baseline characteristics were similar among groups. During a median [interquartile range, IQR] follow-up of 66 [42 to 83] months, 53 patients (27.0%) on combination therapy, 57 (28.1%) on benazepril, and 64 (31.8%) on valsartan reached microalbuminuria. Using an accelerated failure time model, the estimated acceleration factors were 1.410 (95% CI: 0.806 to 2.467, P = 0.229) for benazepril compared to combination therapy, 0.799 (95% CI: 0.422 to 1.514, P = 0.492) for benazepril compared to valsartan, and 1.665 (95% CI: 1.007 to 2.746, P = 0.047) for valsartan compared to combination therapy. Between-group differences in estimated acceleration factors were nonsignificant after adjustment for predefined confounders. BP control was similar across groups. All treatments were safe and tolerated well, with a slight excess of hyperkalemia and hypotension in the combination therapy group. The main study limitation was the lower than expected albuminuria at inclusion.ConclusionsRisk/benefit profile of study treatments was similar. Dual renin-angiotensin system (RAS) blockade is not recommended as compared to benazepril or valsartan monotherapy for prevention of microalbuminuria in normoalbuminuric type 2 diabetic patients.Trial registrationEudraCT 2006-005954-62; ClinicalTrials.gov NCT00503152.

Project description:BackgroundStandard diet with normal calcium and reduced animal proteins and salt content reduces stone recurrence in calcium oxalate nephrolithiasis. Whether lemon juice supplementation further reduces recurrence rate is unknown.MethodsIn this single-centre, prospective, randomised, open, blinded endpoint trial (Clinical Trials gov NCT01217372) we evaluated the effects of fresh lemon juice supplementation (60 mL twice daily) versus no supplementation, on time to stone recurrence in 203 patients with recurrent idiopathic calcium oxalate nephrolithiasis who were all prescribed a standard diet. Patients were included between July 2009 and March 2017 at the Nephrology Unit of the Papa Giovanni XXIII hospital in Bergamo, Italy. Time to stone recurrence at 2 years of follow-up was the primary outcome. Analyses were by intention-to-treat.FindingsDuring two years of follow-up 21 of 100 patients randomised to lemon juice supplementation and 32 of 103 controls randomised to no supplementation had stone recurrence [HR (95% CI): 0·62 (0·35-1·07), p = 0·089]. Patient adherence to lemon juice supplementation, however, progressively decreased from 68% at one-year to 48% at two-year follow-up. At explorative analyses restricted at one-year follow-up, ten patients with supplementation versus 22 controls had stone recurrence [0·43 (0·20-0·89), p = 0·028]. After adjustment by age, sex and normo or hypocitraturia, the HR (95%) was still significant [0·45 (0·20-0·93), p = 0·036]. At six months, 24 hour urinary sodium excretion decreased by 8·60±65·68 mEq/24 h in patients receiving lemon juice supplementation and increased by 3·88±64·78 mEq/24 h in controls. Changes significantly differed between groups (p = 0·031). This difference was subsequently lost. Treatment was safe. In patients with lemon juice supplementation gastrointestinal disorders were more frequent (p<0·001). Renal and urinary tract disorders were similar between groups (p = 0·103).InterpretationExplorative analyses suggest that fresh lemon juice supplementation to standard diet might prevent stone recurrence in patients with calcium-oxalate nephrolithiasis. However, treatment effect was likely reduced by progressively declining adherence to lemon juice supplementation.FundingThis study received no funding.

Project description:BackgroundOral and pharyngeal swallowing dysfunction are common complications in acute stroke patients. This primary aim of this study was to determine whether oral neuromuscular training improves swallowing function in participants with swallowing dysfunction after stroke. A secondary aim was to assess how well results of the timed water-swallow test (TWST) correspond with swallowing dysfunction diagnosed by videofluoroscopy (VFS).MethodsThis was an intention-to-treat two-centre prospective randomized open-label study with blinded-evaluators (PROBE) design. At 4 weeks after stroke onset, participants with swallowing dysfunction were randomized to 5 weeks of continued orofacial sensory-vibration stimulation with an electric toothbrush or additional oral neuromuscular training with an oral device (Muppy®). Participants were examined with TWST, a lip-force test, and VFS before (baseline), after 5 weeks' treatment (the end-of-treatment), and 12 months after treatment (follow-up). The baseline VFS results were compared with the TWST results. The primary endpoint was changes in swallowing rate assessed using TWST, from baseline to the end of training and from baseline to follow-up based on intention-to-treat analyses. The secondary endpoint was the corresponding changes in lip-force between baseline, the end of treatment, and follow-up.ResultsThe participants were randomly assigned as controls (n = 20) or for intervention with oral neuromuscular training (n = 20). After treatment, both groups had improved significantly (intervention, P < 0.001; controls, P = 0.001) in TWST but there was no significant between-group difference in swallowing rate. At the 12-month follow-up, the intervention group had improved further whereas the controls had deteriorated, and there were significant between-group differences in swallowing rate (P = 0.032) and lip force (P = 0.001). A TWST < 10 mL/sec at baseline corresponded to VFS-verified swallowing dysfunction in all assessed participants.ConclusionThe 5-week oral neuromuscular training improved swallowing function in participants with post-stroke dysphagia compared with the controls 12 months after intervention, but there was no between-group difference in improvement immediately after treatment. TWST results corresponded with VFS results, making TWST a feasible method for identifying persons with swallowing dysfunction after stroke. Larger randomized controlled trials are required to confirm our preliminary positive long-term results.Trial registrationRetrospectively registered at ClinicalTrials.gov : NCT04164420 . Registered on 15 November 2019.

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: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.

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GI-REASONS: a novel 6-month, prospective, randomized, open-label, blinded endpoint (PROBE) trial.

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GI-REASONS: a novel 6-month, prospective, randomized, open-label, blinded endpoint (PROBE) trial.

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