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Journal of Clinical Epidemiology Dec 2014The degree of bias in randomized clinical trials varies depending on whether the outcome is subjective or objective. Assessment of the risk of bias in a clinical trial... (Review)
Review
OBJECTIVES
The degree of bias in randomized clinical trials varies depending on whether the outcome is subjective or objective. Assessment of the risk of bias in a clinical trial will therefore often involve categorization of the type of outcome. Our primary aim was to examine how the concepts "subjective outcome" and "objective outcome" are defined in methodological publications and clinical trial reports. To put this examination into perspective, we also provide an overview of how outcomes are classified more broadly.
STUDY DESIGN AND SETTING
A systematic review of methodological publications providing a classification of clinical trial outcomes and a descriptive study of how outcomes were classified in 200 PubMed indexed clinical trial reports published in 2012.
RESULTS
We identified 90 methodological publications with some form of a classification of outcomes. Three distinct definitions were provided for subjective outcome: (1) dependent on assessor judgment, (2) patient-reported outcome, or (3) private phenomena (ie, phenomena only assessable by the patient). Of the 200 clinical trial reports, 12 used the term "subjective" and/or "objective" about outcomes, but no clinical trial reports explicitly defined the terms.
CONCLUSION
The terms "subjective" and "objective" are ambiguous when used to describe outcomes in randomized clinical trials. We suggest that the terms should be defined explicitly when used in connection with the assessment of risk of bias in a clinical trial, in metaepidemiological research, and generally in the reporting of clinical trials. We also suggest that adding an explicit clarification of the terms in future versions of the Cochrane Handbook might further strengthen its important role in guiding review authors.
Topics: Humans; Publication Bias; Randomized Controlled Trials as Topic; Research Design; Terminology as Topic; Treatment Outcome
PubMed: 25263546
DOI: 10.1016/j.jclinepi.2014.06.020 -
Clinical Breast Cancer Dec 2019Optimal treatment of breast cancer brain metastases (BCBM) is often hampered by limitations in diagnostic abilities. Developing innovative tools for BCBM diagnosis is...
Optimal treatment of breast cancer brain metastases (BCBM) is often hampered by limitations in diagnostic abilities. Developing innovative tools for BCBM diagnosis is vital for early detection and effective treatment. In this study we explored the advances in trial for the diagnosis of BCBM, with review of the literature. On May 8, 2019, we searched ClinicalTrials.gov for interventional and diagnostic clinical trials involving BCBM, without limiting for date or location. Information on trial characteristics, experimental interventions, results, and publications were collected and analyzed. In addition, a systematic review of the literature was conducted to explore published studies related to BCBM diagnosis. Only 9 diagnostic trials explored BCBM. Of these, 1 trial was withdrawn because of low accrual numbers. Three trials were completed; however, none had published results. Modalities in trial for BCBM diagnosis entailed magnetic resonance imaging (MRI), computed tomography (CT), positron emission tomography (PET), PET-CT, nanobodies, and circulating tumor cells (CTCs), along with a collection of novel tracers and imaging biomarkers. MRI continues to be the diagnostic modality of choice, whereas CT is best suited for acute settings. Advances in PET and PET-CT allow the collection of metabolic and functional information related to BCBM. CTC characterization can help reflect on the molecular foundations of BCBM, whereas cell-free DNA offers new genetic material for further exploration in trials. The integration of machine learning in BCBM diagnosis seems inevitable as we continue to aim for rapid and accurate detection and better patient outcomes.
Topics: Brain Neoplasms; Breast Neoplasms; Clinical Trials as Topic; Female; Humans; Magnetic Resonance Imaging; Neoplastic Cells, Circulating; Positron Emission Tomography Computed Tomography; Prognosis
PubMed: 31262686
DOI: 10.1016/j.clbc.2019.05.018 -
The Journal of Pathology. Clinical... May 2021The SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) 2013 Statement was developed to provide guidance for inclusion of key methodological... (Meta-Analysis)
Meta-Analysis
The SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) 2013 Statement was developed to provide guidance for inclusion of key methodological components in clinical trial protocols. However, these standards do not include guidance specific to pathology input in clinical trials. This systematic review aims to synthesise existing recommendations specific to pathology practice in clinical trials for implementation in trial protocol design. Articles were identified from database searches and deemed eligible for inclusion if they contained: (1) guidance and/or a checklist, which was (2) pathology-related, with (3) content relevant to clinical trial protocols or could influence a clinical trial protocol design from a pathology perspective and (4) were published in 1996 or later. The quality of individual papers was assessed using the AGREE-GRS (Appraisal of Guidelines for REsearch & Evaluation - Global Rating Scale) tool, and the confidence in cumulative evidence was evaluated using the GRADE-CERQual (Grading of Recommendations Assessment, Development and Evaluation-Confidence in Evidence from Reviews of Qualitative research) approach. Extracted recommendations were synthesised using the best fit framework method, which includes thematic analysis followed by a meta-aggregative approach to synthesis within the framework. Of the 10 184 records screened and 199 full-text articles reviewed, only 40 guidance resources met the eligibility criteria for inclusion. Recommendations extracted from 22 guidance documents were generalisable enough for data synthesis. Seven recommendation statements were synthesised as follows: (1) multidisciplinary collaboration in trial design with early involvement of pathologists, particularly with respect to the use of biospecimens and associated biomarker/analytical assays and in the evaluation of pathology-related parameters; (2) funding and training for personnel undertaking trial work; (3) selection of an accredited laboratory with suitable facilities to undertake scheduled work; (4) quality assurance of pathology-related parameters; (5) transparent reporting of pathology-related parameters; (6) policies regarding informatics and tracking biospecimens across trial sites; and (7) informed consent for specimen collection and retention for future research.
Topics: Biomarkers; Biopsy; Clinical Trials as Topic; Humans; Pathology, Clinical; Pathology, Molecular; Practice Guidelines as Topic; Predictive Value of Tests; Research Design; Treatment Outcome
PubMed: 33635586
DOI: 10.1002/cjp2.199 -
The Cochrane Database of Systematic... Sep 2018Impaired mucociliary clearance characterises lung disease in cystic fibrosis (CF). Hypertonic saline enhances mucociliary clearance and may lessen the destructive... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Impaired mucociliary clearance characterises lung disease in cystic fibrosis (CF). Hypertonic saline enhances mucociliary clearance and may lessen the destructive inflammatory process in the airways. This is an update of a previously published review.
OBJECTIVES
To investigate efficacy and tolerability of treatment with nebulised hypertonic saline on people with CF compared to placebo and or other treatments that enhance mucociliary clearance.
SEARCH METHODS
We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Cystic Fibrosis Trials Register, comprising references identified from comprehensive electronic database searches, handsearches of relevant journals and abstract books of conference proceedings. We also searched ongoing trials databases.Date of most recent searches: 08 August 2018.
SELECTION CRITERIA
Randomised and quasi-randomised controlled trials assessing hypertonic saline compared to placebo or other mucolytic therapy, for any duration or dose regimen in people with CF (any age or disease severity).
DATA COLLECTION AND ANALYSIS
Two authors independently reviewed all identified trials and data, and assessed trial quality. The quality of the evidence was assessed using GRADE.
MAIN RESULTS
A total of 17 trials (966 participants, aged 4 months to 63 years) were included; 19 trials were excluded, three trials are ongoing and 16 are awaiting classification. We judged 14 of the 17 included trials to have a high risk of bias due to participants ability to discern the taste of the solutions.Hypertonic saline 3% to 7% versus placeboAt four weeks, we found very low-quality evidence from three placebo-controlled trials (n = 225) that hypertonic saline (3% to 7%, 10 mL twice-daily) increased the mean change from baseline of the forced expiratory volume at one second (FEV) (% predicted) by 3.44% (95% confidence interval (CI) 0.67 to 6.21), but there was no difference between groups in lung clearance index in one small trial (n = 10). By 48 weeks the effect was slightly smaller in one trial (n = 134), 2.31% (95% CI -2.72 to 7.34) (low-quality evidence). No deaths occurred in the trials. Two trials reporting data on exacerbations were not combined as the age difference between the participants in the trials was too great. One trial (162 adults) found 0.5 fewer exacerbations requiring antibiotics per person in the hypertonic saline group; the second trial (243 children, average age of two years) found no difference between groups (low-quality evidence). There was insufficient evidence reported across the trials to determine the rate of different adverse events such as cough, chest tightness, tonsillitis and vomiting (very low-quality evidence). Four trials (n = 80) found very low-quality evidence that sputum clearance was better with hypertonic saline.A further trial was performed in adults with an acute exacerbation of lung disease (n = 132). The effects of hypertonic saline on short-term lung function, 5.10% higher (14.67% lower to 24.87% higher) and the time to the subsequent exacerbation post-discharge, hazard ratio 0.86 (95% CI 0.57 to 1.30) are uncertain (low-quality evidence). No deaths were reported. Cough and wheeze were reported but no serious adverse events (very low-quality evidence).Hypertonic saline versus mucus mobilising treatments Three trials compared a similar dose of hypertonic saline to recombinant deoxyribonuclease (rhDNase); two (61 participants) provided data for inclusion in the review. There was insufficient evidence from one three-week trial (14 participants) to determine the effects of hypertonic saline on FEV % predicted, mean difference (MD) 1.60% (95% CI -7.96 to 11.16) (very low-quality evidence). In the second trial, rhDNase led to a greater increase in FEV % predicted than hypertonic saline (5 mL twice daily) at 12 weeks in participants with moderate to severe lung disease, MD 8.00% (95% CI 2.00 to 14.00) (low-quality evidence). One cross-over trial (47 participants) reported 15 exacerbations during treatment with hypertonic saline and 18 exacerbations in the rhDNase group (low-quality evidence). Increased cough was reported in 13 participants using hypertonic saline and 17 on daily rhDNase in one cross-over trial of 47 people (low-quality evidence). There was insufficient evidence to assess rates of other adverse events reported. No deaths were reported.One trial (12 participants) compared hypertonic saline to amiloride and one (29 participants) to sodium-2-mercaptoethane sulphonate. Neither trial found a difference between treatments in any measures of sputum clearance; additionally the comparison of hypertonic saline and sodium-2-mercaptoethane sulphonate reported no differences in courses of antibiotics or adverse events (very low-quality evidence).One trial (12 participants) compared hypertonic saline to mannitol but did not report lung function at relevant time points for this review; there were no differences in sputum clearance, but mannitol was reported to be more 'irritating' (very low-quality evidence).
AUTHORS' CONCLUSIONS
Regular use of nebulised hypertonic saline by adults and children over the age of 12 years with CF results in an improvement in lung function after four weeks (very low-quality evidence from three trials), but this was not sustained at 48 weeks (low-quality evidence from one trial). The review did show that nebulised hypertonic saline reduced the frequency of pulmonary exacerbations (although we found insufficient evidence for this outcome in children under six years of age) and may have a small effect on improvement in quality of life in adults.Evidence from one small cross-over trial in children indicates that rhDNase may lead to better lung function at three months; qualifying this we highlight that while the study did demonstrate that the improvement in FEV was greater with daily rHDNase, there were no differences seen in any of the secondary outcomes.Hypertonic saline does appear to be an effective adjunct to physiotherapy during acute exacerbations of lung disease in adults. However, for the outcomes assessed, the quality of the evidence ranged from very low to at best moderate, according to the GRADE criteria.
Topics: Administration, Inhalation; Controlled Clinical Trials as Topic; Cystic Fibrosis; Forced Expiratory Volume; Humans; Mucociliary Clearance; Nebulizers and Vaporizers; Randomized Controlled Trials as Topic; Saline Solution, Hypertonic
PubMed: 30260472
DOI: 10.1002/14651858.CD001506.pub4 -
Revista Brasileira de Psiquiatria (Sao... 2014To conduct the first systematic literature review of clinical trials of N-acetylcysteine (NAC) for the treatment of substance abuse disorders and addictive behaviors. (Review)
Review
OBJECTIVE
To conduct the first systematic literature review of clinical trials of N-acetylcysteine (NAC) for the treatment of substance abuse disorders and addictive behaviors.
METHODS
A search of the MEDLINE, Embase and PsycINFO databases was conducted. The inclusion criteria for the review were clinical trials that used NAC in the treatment of a disorder related to substance use and/or addictive behaviors, limited to texts in English, Spanish, or French. The selected studies were evaluated with respect to type of trial, sample size, diagnostic input, intervention, length of follow-up, outcome variables, and results.
RESULTS
Nine studies analyzing a total of 165 patients met the eligibility criteria and were included in qualitative analysis. These studies evaluated the role of NAC in cocaine dependence (three studies), cannabis dependence (two studies), nicotine dependence (two studies), methamphetamine addiction (one study), and pathological gambling (one study). Five of these trials were double-blind, randomized, and placebo-controlled.
CONCLUSIONS
The studies analyzed suggest a potential role for NAC in the treatment of addiction, especially of cocaine and cannabis dependence. These results are concordant with the hypothesis of the involvement of glutamatergic pathways in the pathophysiology of addiction.
Topics: Acetylcysteine; Behavior, Addictive; Clinical Trials as Topic; Female; Glutamic Acid; Humans; Male; Substance-Related Disorders; Time Factors; Treatment Outcome
PubMed: 24676047
DOI: 10.1590/1516-4446-2013-1244 -
Journal of Clinical Epidemiology Dec 2023To inform clinical practice guidelines, randomized controlled trials (RCTs) of the management of pneumonia need to address the outcomes that are most important to...
OBJECTIVES
To inform clinical practice guidelines, randomized controlled trials (RCTs) of the management of pneumonia need to address the outcomes that are most important to patients and health professionals using consistent instruments, to enable results to be compared, contrasted, and combined as appropriate. This systematic review describes the outcomes reported in clinical trials of pneumonia management and the instruments used to measure these outcomes.
STUDY DESIGN AND SETTING
Based on a prospective protocol, we searched MEDLINE/PubMed, Cochrane CENTRAL and clinical trial registries for ongoing or completed clinical trials evaluating pneumonia management in adults in any clinical setting. We grouped reported outcomes thematically and classified them following the COMET Initiative's taxonomy. We describe instruments used for assessing each outcome.
RESULTS
We found 280 eligible RCTs of which 115 (41.1%) enrolled critically ill patients and 165 (58.9%) predominantly noncritically ill patients. We identified 43 distinct outcomes and 108 measurement instruments, excluding nonvalidated scores and questionnaires. Almost all trials reported clinical/physiological outcomes (97.5%). Safety (63.2%), mortality (56.4%), resource use (48.6%) and life impact (11.8%) outcomes were less frequently addressed. The most frequently reported outcomes were treatment success (60.7%), mortality (56.4%) and adverse events (41.1%). There was significant variation in the selection of measurement instruments, with approximately two-thirds used in less than 10 of the 280 RCTs. None of the patient-reported outcomes were used in 10 or more RCTs.
CONCLUSION
This review reveals significant variation in outcomes and measurement instruments reported in clinical trials of pneumonia management. Outcomes that are important to patients and health professionals are often omitted. Our findings support the need for a rigorous core outcome set, such as that being developed by the European Respiratory Society.
Topics: Adult; Humans; Pneumonia; Treatment Outcome; Clinical Trials as Topic
PubMed: 37898460
DOI: 10.1016/j.jclinepi.2023.10.011 -
Journal of Clinical Pharmacology Nov 2016During drug development, matching adult systemic exposures of drugs is a common approach for dose selection in pediatric patients when efficacy is partially or fully... (Review)
Review
During drug development, matching adult systemic exposures of drugs is a common approach for dose selection in pediatric patients when efficacy is partially or fully extrapolated. This is a systematic review of approaches used for matching adult systemic exposures as the basis for dose selection in pediatric trials submitted to the US Food and Drug Administration (FDA) between 1998 and 2012. The trial design of pediatric pharmacokinetic (PK) studies and the pediatric and adult systemic exposure data were obtained from FDA publicly available databases containing reviews of pediatric trials. Exposure-matching approaches that were used as the basis for pediatric dose selection were reviewed. The PK data from the adult and pediatric populations were used to quantify exposure agreement between the 2 patient populations. The main measures were the pediatric PK studies' trial design elements and drug systemic exposures (adult and pediatric). There were 31 products (86 trials) with full or partial extrapolation of efficacy with an available PK assessment. Pediatric exposures had a range of mean C and AUC ratios (pediatric/adult) of 0.63 to 4.19 and 0.36 to 3.60, respectively. Seven of the 86 trials (8.1%) had a predefined acceptance boundary used to match adult exposures. The key PK parameter was consistently predefined for antiviral and anti-infective products. Approaches to match exposure in children and adults varied across products. A consistent approach for systemic exposure matching and evaluating pediatric PK studies is needed to guide future pediatric trials.
Topics: Adult; Age Factors; Child; Clinical Trials as Topic; Dose-Response Relationship, Drug; Drug Discovery; Humans; Pharmaceutical Preparations; Treatment Outcome; United States; United States Food and Drug Administration
PubMed: 27040726
DOI: 10.1002/jcph.744 -
Bone Marrow Transplantation Apr 2009Opinions are divided regarding the best prophylactic regimen for GVHD. The aim of this study was to evaluate potential survival benefit of different prophylactic... (Meta-Analysis)
Meta-Analysis Review
Opinions are divided regarding the best prophylactic regimen for GVHD. The aim of this study was to evaluate potential survival benefit of different prophylactic regimens for acute GVHD (aGVHD). We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) including patients undergoing Allo-SCT. We included trials that assessed the addition of MTX, compared CsA and tacrolimus and evaluated the addition of steroids. Outcomes assessed were all-cause mortality (ACM) at the longest follow-up, aGVHD, chronic GVHD, TRM, relapse rate and regimen-specific adverse events. Relative risks (RRs) with 95% confidence intervals (CIs) were estimated and pooled. The regimen of MTX-CsA vs CsA alone (four trials) yielded no statistically significant difference in ACM (RR=0.84 (0.61-1.14)), but a significant decrease in aGVHD (RR=0.52 (0.39-0.7)). There was no difference in ACM for the comparison of MTX-CsA and MTX-tacrolimus (three trials); however, MTX-tacrolimus was superior to MTX-CsA in the reduction of aGVHD (RR=0.62 (0.52-0.75)) and severe aGVHD (RR=0.67 (0.47-0.95)). The addition of steroids did not affect the outcomes (four trials). We conclude that MTX-CsA and MTX-tacrolimus are both acceptable alternatives for GVHD prophylaxis, although MTX-tacrolimus may be superior in terms of aGVHD reduction.
Topics: Adolescent; Adult; Child; Child, Preschool; Clinical Trials as Topic; Graft vs Host Disease; Hematologic Diseases; Humans; Immunosuppressive Agents; Methotrexate; Middle Aged; Randomized Controlled Trials as Topic; Recurrence; Risk; Tacrolimus; Treatment Outcome
PubMed: 18997826
DOI: 10.1038/bmt.2008.373 -
Annals of Internal Medicine Sep 2000The optimal management of chronic abacterial prostatitis is not known. A systematic review of the literature was done to answer the following questions: Are there... (Review)
Review
PURPOSE
The optimal management of chronic abacterial prostatitis is not known. A systematic review of the literature was done to answer the following questions: Are there accurate, reliable tests to diagnose chronic abacterial prostatitis? Are there effective therapies for it?
DATA SOURCES
Studies were identified by searching MEDLINE (1966 to 1999), the Cochrane Library, and bibliographies of identified articles and reviews and by contacting an expert
STUDY SELECTION
Diagnostic test articles were included if they reported on controlled studies; treatment articles were included if they reported on randomized or controlled trials. No language restrictions were applied.
DATA EXTRACTION
For each selected article, two investigators independently extracted key data on study design, patient characteristics, diagnostic test or treatment characteristics, and outcomes.
DATA SYNTHESIS
19 diagnostic test articles and 14 treatment trials met the inclusion criteria The disparity among studies in design, interventions, and other factors precluded quantitative analysis or pooling of the findings. Diagnostic test articles included 1384 men (mean age, 33 to 67 years) and evaluated infection; inflammation, immunology, and biochemistry; psychological factors; and ultrasonography. Treatment trials included 570 men (mean age, 38 to 45 years) and evaluated medications used to treat benign prostatic hyperplasia, anti-inflammatory drugs, antibiotics, thermotherapy, and miscellaneous medications. No trial was done in the United States.
CONCLUSIONS
There is no gold-standard diagnostic test for chronic abacterial prostatitis, and the methodologic quality of available studies of diagnostic tests is low. The few treatment trials are methodologically weak and involved small samples. The routine use of antibiotics and alpha-blockers to treat chronic abacterial prostatitis is not supported by the existing evidence.
Topics: Adult; Aged; Chronic Disease; Controlled Clinical Trials as Topic; Humans; Male; Middle Aged; Practice Guidelines as Topic; Prostatitis; Randomized Controlled Trials as Topic
PubMed: 10979882
DOI: 10.7326/0003-4819-133-5-200009050-00013 -
Regional Anesthesia and Pain Medicine 2016We summarized the evidence for ultrasound (US) guidance for truncal blocks in 2010 by performing a systematic literature review and rating the strength of evidence for... (Review)
Review
UNLABELLED
We summarized the evidence for ultrasound (US) guidance for truncal blocks in 2010 by performing a systematic literature review and rating the strength of evidence for each block using a system developed by the United States Agency for Health Care Policy and Research. Since then, numerous studies of US guidance for truncal blocks have been published. In addition, 3 novel US-guided blocks have been described since our last review. To provide updated recommendations, we performed another systematic search of the literature to identify studies pertaining to US guidance for the following blocks: paravertebral, intercostal, transversus abdominis plane, rectus sheath, ilioinguinal/iliohypogastric, as well as the Pecs, quadratus lumborum, and transversalis fascia blocks. We rated the methodologic quality of each of the identified studies and then graded the strength of evidence supporting the use of US for each block based on the number and quality of available studies for that block.
WHAT'S NEW
Since our last review, numerous studies have been published, especially for the paravertebral and transversus abdominis plane blocks, and 3 novel US-guided blocks (Pecs, quadratus lumborum, and transversalis fascia blocks) have been described. Although some of these studies support the use of US for performing these blocks, others do not. Additional studies have used US to improve our understanding of the anatomy pertinent to these blocks and evaluated the effect on patient outcomes and risk of complications.
Topics: Abdominal Muscles; Clinical Trials as Topic; Evidence-Based Medicine; Humans; Nerve Block; Pain, Postoperative; Ultrasonography, Interventional
PubMed: 26866299
DOI: 10.1097/AAP.0000000000000372