-
Annals of Internal Medicine Feb 2013The protocol of a clinical trial serves as the foundation for study planning, conduct, reporting, and appraisal. However, trial protocols and existing protocol...
The protocol of a clinical trial serves as the foundation for study planning, conduct, reporting, and appraisal. However, trial protocols and existing protocol guidelines vary greatly in content and quality. This article describes the systematic development and scope of SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) 2013, a guideline for the minimum content of a clinical trial protocol.The 33-item SPIRIT checklist applies to protocols for all clinical trials and focuses on content rather than format. The checklist recommends a full description of what is planned; it does not prescribe how to design or conduct a trial. By providing guidance for key content, the SPIRIT recommendations aim to facilitate the drafting of high-quality protocols. Adherence to SPIRIT would also enhance the transparency and completeness of trial protocols for the benefit of investigators, trial participants, patients, sponsors, funders, research ethics committees or institutional review boards, peer reviewers, journals, trial registries, policymakers, regulators, and other key stakeholders.
Topics: Checklist; Clinical Protocols; Clinical Trials as Topic; Humans
PubMed: 23295957
DOI: 10.7326/0003-4819-158-3-201302050-00583 -
BMJ Open Sport & Exercise Medicine 2018To review existing biomechanical and clinical evidence regarding postoperative weight-bearing and range of motion restrictions for patients following meniscal repair...
OBJECTIVE
To review existing biomechanical and clinical evidence regarding postoperative weight-bearing and range of motion restrictions for patients following meniscal repair surgery.
METHODS AND DATA SOURCES
Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guideline, we searched MEDLINE using following search strategy: (((("Weight-Bearing/physiology"[Mesh]) OR "Range of Motion, Articular"[Mesh]) OR "Rehabilitation"[Mesh])) AND ("Menisci, Tibial"[Mesh]). Additional articles were derived from previous reviews. Eligible studies were published in English and reported a rehabilitation protocol following meniscal repair on human. We summarised rehabilitation protocols and patients' outcome among original studies.
RESULTS
Seventeen clinical studies were included in this systematic review. There was wide variation in rehabilitation protocols among clinical studies. Biomechanical evidence from small cadaveric studies suggests that higher degrees of knee flexion and weight-bearing may be safe following meniscal repair and may not compromise the repair. An accelerated protocol with immediate weight-bearing at tolerance and early motion to non-weight-bearing with immobilising up to 6 weeks postoperatively is reported. Accelerated rehabilitation protocols are not associated with higher failure rates following meniscal repair.
CONCLUSIONS
There is a lack of consensus regarding the optimal postoperative protocol following meniscal repair. Small clinical studies support rehabilitation protocols that allow early motion. Additional studies are needed to better clarify the interplay between tear type, repair method and optimal rehabilitation protocol.
PubMed: 29682310
DOI: 10.1136/bmjsem-2016-000212 -
BMJ (Clinical Research Ed.) Jan 2013High quality protocols facilitate proper conduct, reporting, and external review of clinical trials. However, the completeness of trial protocols is often inadequate. To...
High quality protocols facilitate proper conduct, reporting, and external review of clinical trials. However, the completeness of trial protocols is often inadequate. To help improve the content and quality of protocols, an international group of stakeholders developed the SPIRIT 2013 Statement (Standard Protocol Items: Recommendations for Interventional Trials). The SPIRIT Statement provides guidance in the form of a checklist of recommended items to include in a clinical trial protocol. This SPIRIT 2013 Explanation and Elaboration paper provides important information to promote full understanding of the checklist recommendations. For each checklist item, we provide a rationale and detailed description; a model example from an actual protocol; and relevant references supporting its importance. We strongly recommend that this explanatory paper be used in conjunction with the SPIRIT Statement. A website of resources is also available (www.spirit-statement.org). The SPIRIT 2013 Explanation and Elaboration paper, together with the Statement, should help with the drafting of trial protocols. Complete documentation of key trial elements can facilitate transparency and protocol review for the benefit of all stakeholders.
Topics: Checklist; Clinical Protocols; Clinical Trials Data Monitoring Committees; Clinical Trials as Topic; Computer Security; Data Collection; Ethics, Medical; Humans; Medical Audit; Patient Selection; Practice Guidelines as Topic; Professional Role; Quality Control; Random Allocation; Research Design; Research Personnel; Research Support as Topic; Sample Size; Social Responsibility; Statistics as Topic; Time Factors; Treatment Outcome
PubMed: 23303884
DOI: 10.1136/bmj.e7586 -
Nature Protocols Sep 2016High-throughput sequencing of mRNA (RNA-seq) has become the standard method for measuring and comparing the levels of gene expression in a wide variety of species and...
High-throughput sequencing of mRNA (RNA-seq) has become the standard method for measuring and comparing the levels of gene expression in a wide variety of species and conditions. RNA-seq experiments generate very large, complex data sets that demand fast, accurate and flexible software to reduce the raw read data to comprehensible results. HISAT (hierarchical indexing for spliced alignment of transcripts), StringTie and Ballgown are free, open-source software tools for comprehensive analysis of RNA-seq experiments. Together, they allow scientists to align reads to a genome, assemble transcripts including novel splice variants, compute the abundance of these transcripts in each sample and compare experiments to identify differentially expressed genes and transcripts. This protocol describes all the steps necessary to process a large set of raw sequencing reads and create lists of gene transcripts, expression levels, and differentially expressed genes and transcripts. The protocol's execution time depends on the computing resources, but it typically takes under 45 min of computer time. HISAT, StringTie and Ballgown are available from http://ccb.jhu.edu/software.shtml.
Topics: Gene Expression Profiling; Molecular Sequence Annotation; RNA, Messenger; Sequence Analysis, RNA; Software; Statistics as Topic; User-Computer Interface
PubMed: 27560171
DOI: 10.1038/nprot.2016.095 -
Nature Protocols Mar 2012Recent advances in high-throughput cDNA sequencing (RNA-seq) can reveal new genes and splice variants and quantify expression genome-wide in a single assay. The volume...
Recent advances in high-throughput cDNA sequencing (RNA-seq) can reveal new genes and splice variants and quantify expression genome-wide in a single assay. The volume and complexity of data from RNA-seq experiments necessitate scalable, fast and mathematically principled analysis software. TopHat and Cufflinks are free, open-source software tools for gene discovery and comprehensive expression analysis of high-throughput mRNA sequencing (RNA-seq) data. Together, they allow biologists to identify new genes and new splice variants of known ones, as well as compare gene and transcript expression under two or more conditions. This protocol describes in detail how to use TopHat and Cufflinks to perform such analyses. It also covers several accessory tools and utilities that aid in managing data, including CummeRbund, a tool for visualizing RNA-seq analysis results. Although the procedure assumes basic informatics skills, these tools assume little to no background with RNA-seq analysis and are meant for novices and experts alike. The protocol begins with raw sequencing reads and produces a transcriptome assembly, lists of differentially expressed and regulated genes and transcripts, and publication-quality visualizations of analysis results. The protocol's execution time depends on the volume of transcriptome sequencing data and available computing resources but takes less than 1 d of computer time for typical experiments and ∼1 h of hands-on time.
Topics: DNA, Complementary; Gene Expression Profiling; Genetic Association Studies; Genomics; Sequence Analysis, DNA; Software
PubMed: 22383036
DOI: 10.1038/nprot.2012.016 -
Human Reproduction Update May 2023Several GnRH antagonist protocols are currently used during COS in the context of ART treatments; however, questions remain regarding whether these protocols are...
BACKGROUND
Several GnRH antagonist protocols are currently used during COS in the context of ART treatments; however, questions remain regarding whether these protocols are comparable in terms of efficacy and safety.
OBJECTIVE AND RATIONALE
A systematic review followed by a pairwise and network meta-analyses were performed. The systematic review and pairwise meta-analysis of direct comparative data according to the PRISMA guidelines evaluated the effectiveness of different GnRH antagonist protocols (fixed Day 5/6 versus flexible, ganirelix versus cetrorelix, with or without hormonal pretreatment) on the probability of live birth and ongoing pregnancy after COS during ART treatment. A frequentist network meta-analysis combining direct and indirect comparisons (using the long GnRH agonist protocol as the comparator) was also performed to enhance the precision of the estimates.
SEARCH METHODS
The systematic literature search was performed using Embase (Ovid), MEDLINE (Ovid), Cochrane Central Register of Trials (CENTRAL), SCOPUS and Web of Science (WOS), from inception until 23 November 2021. The search terms comprised three different MeSH terms that should be present in the identified studies: GnRH antagonist; assisted reproduction treatment; randomized controlled trial (RCT). Only studies published in English were included.
OUTCOMES
The search strategy resulted in 6738 individual publications, of which 102 were included in the systematic review (corresponding to 75 unique studies) and 73 were included in the meta-analysis. Most studies were of low quality. One study compared a flexible protocol with a fixed Day 5 protocol and the remaining RCTs with a fixed Day 6 protocol. There was a lack of data regarding live birth when comparing the flexible and fixed GnRH antagonist protocols or cetrorelix and ganirelix. No significant difference in live birth rate was observed between the different pretreatment regimens versus no pretreatment or between the different pretreatment protocols. A flexible GnRH antagonist protocol resulted in a significantly lower OPR compared with a fixed Day 5/6 protocol (relative risk (RR) 0.76, 95% CI 0.62 to 0.94, I2 = 0%; 6 RCTs; n = 907 participants; low certainty evidence). There were insufficient data for a comparison of cetrorelix and ganirelix for OPR. OCP pretreatment was associated with a lower OPR compared with no pretreatment intervention (RR 0.79, 95% CI 0.69 to 0.92; I2 = 0%; 5 RCTs, n = 1318 participants; low certainty evidence). Furthermore, in the network meta-analysis, a fixed protocol with OCP resulted in a significantly lower OPR than a fixed protocol with no pretreatment (RR 0.84, 95% CI 0.71 to 0.99; moderate quality evidence). The surface under the cumulative ranking (SUCRA) scores suggested that the fixed protocol with no pretreatment is the antagonist protocol most likely (84%) to result in the highest OPR. There was insufficient evidence of a difference between fixed/flexible or OCP pretreatment/no pretreatment interventions regarding other outcomes, such as ovarian hyperstimulation syndrome and miscarriage rates.
WIDER IMPLICATIONS
Available evidence, mostly of low quality and certainty, suggests that different antagonist protocols should not be considered as equivalent for clinical decision-making. More trials are required to assess the comparative effectiveness of ganirelix versus cetrorelix, the effect of different pretreatment interventions (e.g. progestins or oestradiol) or the effect of different criteria for initiation of the antagonist in the flexible protocol. Furthermore, more studies are required examining the optimal GnRH antagonist protocol in women with high or low response to ovarian stimulation.
Topics: Pregnancy; Female; Humans; Network Meta-Analysis; Pregnancy Rate; Ovulation Induction; Ovarian Hyperstimulation Syndrome; Gonadotropin-Releasing Hormone; Meta-Analysis as Topic; Systematic Reviews as Topic
PubMed: 36594696
DOI: 10.1093/humupd/dmac040 -
JAMA Nov 2018In adults in whom weaning from invasive mechanical ventilation is difficult, noninvasive ventilation may facilitate early liberation, but there is uncertainty about its... (Comparative Study)
Comparative Study Randomized Controlled Trial
Effect of Protocolized Weaning With Early Extubation to Noninvasive Ventilation vs Invasive Weaning on Time to Liberation From Mechanical Ventilation Among Patients With Respiratory Failure: The Breathe Randomized Clinical Trial.
IMPORTANCE
In adults in whom weaning from invasive mechanical ventilation is difficult, noninvasive ventilation may facilitate early liberation, but there is uncertainty about its effectiveness in a general intensive care patient population.
OBJECTIVE
To investigate among patients with difficulty weaning the effects of protocolized weaning with early extubation to noninvasive ventilation on time to liberation from ventilation compared with protocolized invasive weaning.
DESIGN, SETTING, AND PARTICIPANTS
Randomized, allocation-concealed, open-label, multicenter clinical trial enrolling patients between March 2013 and October 2016 from 41 intensive care units in the UK National Health Service. Follow-up continued until April 2017. Adults who received invasive mechanical ventilation for more than 48 hours and in whom a spontaneous breathing trial failed were enrolled.
INTERVENTIONS
Patients were randomized to receive either protocolized weaning via early extubation to noninvasive ventilation (n = 182) or protocolized standard weaning (continued invasive ventilation until successful spontaneous breathing trial, followed by extubation) (n = 182).
MAIN OUTCOMES AND MEASURES
Primary outcome was time from randomization to successful liberation from all forms of mechanical ventilation among survivors, measured in days, with the minimal clinically important difference defined as 1 day. Secondary outcomes were duration of invasive and total ventilation (days), reintubation or tracheostomy rates, and survival.
RESULTS
Among 364 randomized patients (mean age, 63.1 [SD, 14.8] years; 50.5% male), 319 were evaluable for the primary effectiveness outcome (41 died before liberation, 2 withdrew, and 2 were discharged with ongoing ventilation). The median time to liberation was 4.3 days in the noninvasive group vs 4.5 days in the invasive group (adjusted hazard ratio, 1.1; 95% CI, 0.89-1.40). Competing risk analysis accounting for deaths had a similar result (adjusted hazard ratio, 1.1; 95% CI, 0.86-1.34). The noninvasive group received less invasive ventilation (median, 1 day vs 4 days; incidence rate ratio, 0.6; 95% CI, 0.47-0.87) and fewer total ventilator days (median, 3 days vs 4 days; incidence rate ratio, 0.8; 95% CI, 0.62-1.0). There was no significant difference in reintubation, tracheostomy rates, or survival. Adverse events occurred in 45 patients (24.7%) in the noninvasive group compared with 47 (25.8%) in the invasive group.
CONCLUSIONS AND RELEVANCE
Among patients requiring mechanical ventilation in whom a spontaneous breathing trial had failed, early extubation to noninvasive ventilation did not shorten time to liberation from any ventilation.
TRIAL REGISTRATION
ISRCTN Identifier: ISRCTN15635197.
Topics: Aged; Airway Extubation; Female; Hospital Mortality; Humans; Intensive Care Units; Male; Middle Aged; Noninvasive Ventilation; Respiration, Artificial; Respiratory Insufficiency; Time Factors; Ventilator Weaning
PubMed: 30347090
DOI: 10.1001/jama.2018.13763 -
Therapeutic Innovation & Regulatory... Jul 2022Little to no data exist quantifying and benchmarking the magnitude of protocol deviation experience.
BACKGROUND
Little to no data exist quantifying and benchmarking the magnitude of protocol deviation experience.
METHODS
Nearly two-dozen companies provided the Tufts Center for the Study of Drug Development (Tufts CSDD) with data on the design and the performance of 187 protocols.
RESULTS
The results of this working group study show that phase II and III protocols have a mean total of 75 and 119 protocol deviations, respectively, involving nearly one-third of all patients enrolled in each clinical trial. Oncology clinical trials have the highest relative mean number of protocol deviations affecting more than 40% of patients enrolled in each trial. The number of endpoints, the number of procedures per visit, and the number of countries were modestly positively associated with and predictive of, the incidence of deviations per protocol. A strong positive relationship was shown between the number of investigative sites and the number of protocol deviations.
CONCLUSION
The results of this initial study provide useful measures that sponsor companies can use to benchmark their own protocol deviation experience, identify factors most associated with protocol deviations, and determine whether remediation is warranted.
Topics: Benchmarking; Humans
PubMed: 35378712
DOI: 10.1007/s43441-022-00401-4 -
Therapeutic Innovation & Regulatory... Jan 2023Benchmark data characterizing protocol design practices and performance informs clinical trial design decisions and serves as important baseline measures for assessing...
BACKGROUND
Benchmark data characterizing protocol design practices and performance informs clinical trial design decisions and serves as important baseline measures for assessing protocol design behaviors and their impact during and post-pandemic.
METHODS
Tufts CSDD, in collaboration with a working group of 20 major and mid-sized pharmaceutical companies and CROs, gathered phase I-III data from protocols completed just prior to the start of the global pandemic.
RESULTS
Data for 187 protocols were analyzed to derive benchmarks overall and for two primary subgroups: oncology vs. non-oncology protocols and rare disease vs. non-rare disease protocols. The results show a continuing upward trend across all protocol design variables. Phase II and III protocols average more endpoints, eligibility criteria, protocol pages; investigative sites; countries and datapoints collected. Oncology and rare disease protocols' enrolled-to-completion rates are much lower, involve a much higher average number of countries and investigative sites, require more planned patient visits and generate considerably more clinical research data. As such, oncology and rare disease clinical trial cycle times are longer-most notably at time periods occurring after study startup and prior to database lock-due to intense patient recruitment and retention challenges.
CONCLUSIONS
The results of this study present valuable design insights and comparative baseline measures. The implications of these results and the expected impact of decentralized clinical trials on protocol design practices and performance is discussed.
Topics: Humans; Benchmarking; Pandemics; Patient Selection; Clinical Trials as Topic
PubMed: 35960455
DOI: 10.1007/s43441-022-00438-5 -
Heliyon Apr 2022In this study, we investigated a mathematical model for chemoimmunotherapy (a combination of chemotherapy and immunotherapy) for brain cancer. In most cases, the...
In this study, we investigated a mathematical model for chemoimmunotherapy (a combination of chemotherapy and immunotherapy) for brain cancer. In most cases, the standard protocol for cancer treatment is fixed in terms of treatment time intervals and dosages. We offer a wide range of non-fixed protocols, which essentially vary in terms of time intervals and dosages (i.e., personalised medicine). The functions that describe this treatment are explicit and analytical. Hence, the parameters of the function can be easily changed and a new protocol can be obtained. We compared different protocols and obtained an optimal solution. In addition, we applied the singular perturbed vector field (SPVF) method to determine the hierarchy of the system of equations, which enabled us to identify the equilibrium points of the mathematical model and investigate their stability.
PubMed: 35520602
DOI: 10.1016/j.heliyon.2022.e09288