The fragility index: how robust are the outcomes of head and neck cancer randomised, controlled trials?

BACKGROUND: The fragility index represents the minimum number of patients required to convert an outcome from statistically significant to insignificant. This report assesses the fragility index of head and neck cancer randomised, controlled trials. METHODS: Studies were extracted from PubMed/Medline, Scopus, Embase and Cochrane databases. RESULTS: Overall, 123 randomised, controlled trials were included. The sample size and fragility index medians (interquartile ranges) were 103 (56-213) and 2 (0-5), respectively. The fragility index exceeded the number of patients lost to follow up in 42.3 per cent (n = 52) of studies. A higher fragility index correlated with higher sample size (r = 0.514, p < 0.001), number of events (r = 0.449, p < 0.001) and statistical significance via p-value (r = -0.367, p < 0.001). CONCLUSION: Head and neck cancer randomised, controlled trials demonstrated low fragility index values, in which statistically significant results could be nullified by altering the outcomes of just two patients, on average. Future head and neck oncology randomised, controlled trials should report the fragility index in order to provide insight into statistical robustness.

Improving care for elderly patients living with polypharmacy: protocol for a pragmatic cluster randomized trial in community-based primary care practices in Canada.

BACKGROUND: Elders living with polypharmacy may be taking medications that do not benefit them. Polypharmacy can be associated with elevated risks of poor health, reduced quality of life, high care costs, and persistently complex care needs. While many medications could be problematic, this project targets medications that should be deprescribed for most elders and for which guidelines and evidence-based deprescribing tools are available. These are termed potentially inappropriate prescriptions (PIPs) and are as follows: proton pump inhibitors, benzodiazepines, antipsychotics, and sulfonylureas. Implementation strategies for deprescribing PIPs in complex older patient populations are needed. METHODS: This will be a pragmatic cluster randomized controlled trial in community-based primary care practices across Canada. Eligible practices provide comprehensive primary care and have at least one physician that consents to participate. Community-dwelling patients aged 65 years and older with ten or more unique medication prescriptions in the past year will be included. The objective is to assess whether the intervention reduces targeted PIPs for these patients compared with usual care. The intervention, Structured Process Informed by Data, Evidence and Research (SPIDER), is a collaboration between quality improvement (QI) and research programs. Primary care teams will form interprofessional Learning Collaboratives and work with QI coaches to review electronic medical record data provided by their regional Practice Based Research Networks (PBRNs), identify areas of improvement, and develop and implement changes. The study will be tested for feasibility in three PBRNs (Toronto, Montreal, and Edmonton) using prospective single-arm mixed methods. Findings will then guide a pragmatic cluster randomized controlled trial in five PBRNs (Calgary, Winnipeg, Ottawa, Montreal, and Halifax). Seven practices per PBRN will be recruited for each arm. The analysis will be by intention to treat. Ten percent of patients who have at least one PIP at baseline will be randomly selected to participate in the assessment of patient experience and self-reported outcomes. Qualitative methods will be used to explore patient and physician experience and evaluate SPIDER's processes. CONCLUSION: We are testing SPIDER in a primary care population with complex care needs. This could provide a widely applicable model for care improvement. TRIAL REGISTRATION: Clinicaltrials.gov NCT03689049 ; registered September 28, 2018.

Accuracy of the ABC/2 Score for Intracerebral Hemorrhage: Systematic Review and Analysis of MISTIE, CLEAR-IVH, and CLEAR III.

BACKGROUND AND PURPOSE: The ABC/2 score estimates intracerebral hemorrhage (ICH) volume, yet validations have been limited by small samples and inappropriate outcome measures. We determined accuracy of the ABC/2 score calculated at a specialized reading center (RC-ABC) or local site (site-ABC) versus the reference-standard computed tomography-based planimetry (CTP). METHODS: In Minimally Invasive Surgery Plus Recombinant Tissue-Type Plasminogen Activator for Intracerebral Hemorrhage Evacuation-II (MISTIE-II), Clot Lysis Evaluation of Accelerated Resolution of Intraventricular Hemorrhage (CLEAR-IVH) and CLEAR-III trials. ICH volume was prospectively calculated by CTP, RC-ABC, and site-ABC. Agreement between CTP and ABC/2 was defined as an absolute difference up to 5 mL and relative difference within 20%. Determinants of ABC/2 accuracy were assessed by logistic regression. RESULTS: In 4369 scans from 507 patients, CTP was more strongly correlated with RC-ABC (r(2)=0.93) than with site-ABC (r(2)=0.87). Although RC-ABC overestimated CTP-based volume on average (RC-ABC, 15.2 cm(3); CTP, 12.7 cm3), agreement was reasonable when categorized into mild, moderate, and severe ICH (κ=0.75; P<0.001). This was consistent with overestimation of ICH volume in 6 of 8 previous studies. Agreement with CTP was greater for RC-ABC (84% within 5 mL; 48% of scans within 20%) than for site-ABC (81% within 5 mL; 41% within 20%). RC-ABC had moderate accuracy for detecting ≥5 mL change in CTP volume between consecutive scans (sensitivity, 0.76; specificity, 0.86) and was more accurate with smaller ICH, thalamic hemorrhage, and homogeneous clots. CONCLUSIONS: ABC/2 scores at local or central sites are sufficiently accurate to categorize ICH volume and assess eligibility for the CLEAR-III and MISTIE III studies and moderately accurate for change in ICH volume. However, accuracy decreases with large, irregular, or lobar clots. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: MISTIE-II NCT00224770; CLEAR-III NCT00784134.

The effects of propofol cardioplegia on blood and myocardial biomarkers of stress and injury in patients with isolated coronary artery bypass grafting or aortic valve replacement using cardiopulmonary bypass: protocol for a single-center randomized controlled trial.

BACKGROUND: Despite improved myocardial protection strategies, cardioplegic arrest and ischemia still result in reperfusion injury. We have previously published a study describing the effects of propofol (an anesthetic agent commonly used in cardiac surgery) on metabolic stress, cardiac function, and injury in a clinically relevant animal model. We concluded that cardioplegia supplementation with propofol at a concentration relevant to the human clinical setting resulted in improved hemodynamic function, reduced oxidative stress, and reduced reperfusion injury when compared to standard cardioplegia. OBJECTIVE: The Propofol cardioplegia for Myocardial Protection Trial (ProMPT) aims to translate the successful animal intervention to the human clinical setting. We aim to test the hypothesis that supplementation of the cardioplegic solution with propofol will be cardioprotective for patients undergoing isolated coronary artery bypass graft or aortic valve replacement surgery with cardiopulmonary bypass. METHODS: The trial is a single-center, placebo-controlled, randomized trial with blinding of participants, health care staff, and the research team. Patients aged between 18 and 80 years undergoing nonemergency isolated coronary artery bypass graft or aortic valve replacement surgery with cardiopulmonary bypass at the Bristol Heart Institute are being invited to participate. Participants are randomly assigned in a 1:1 ratio to either cardioplegia supplementation with propofol (intervention) or cardioplegia supplementation with intralipid (placebo) using a secure, concealed, Internet-based randomization system. Randomization is stratified by operation type and minimized by diabetes mellitus status. Biomarkers of cardiac injury and metabolism are being assessed to investigate any cardioprotection conferred. The primary outcome is myocardial injury, studied by measuring myocardial troponin T. The trial is designed to test hypotheses about the superiority of the intervention within each surgical stratum. The sample size of 96 participants has been chosen to achieve 80% power to detect standardized differences of 0.5 at a significance level of 5% (2-tailed) assuming equal numbers in each surgical stratum. RESULTS: A total of 96 patients have been successfully recruited over a 2-year period. Results are to be published in late 2014. CONCLUSIONS: Designing a practicable method for delivering a potentially protective dose of propofol to the heart during cardiac surgery was challenging. If our approach confirms the potential of propofol to reduce damage during cardiac surgery, we plan to design a larger multicenter trial to detect differences in clinical outcomes. TRIAL REGISTRATION: International Standard Randomized Controlled Trial Number (ISRCTN): 84968882; http://www.controlled-trials.com/ISRCTN84968882/ProMPT (Archived by WebCite at http://www.webcitation.org/6Qi8A51BS).

Rol del estado en los ensayos clínicos / Role of government in clinical trials

La regulación de los ensayos clínicos por el Estado es un proceso en constante cambio y adecuación, cuyo reto actual consiste en salvaguardar la seguridad de los participantes y equilibrar la carga administrativa. El desarrollo y la regulación de los ensayos clínicos en los distintos países varían según la realidad, el contexto, su ejecución nacional o multinacional, condicionando que la regulación puramente nacional resulte insuficiente y se precise conocer parte de la regulación internacional. El objetivo de esta publicación es mostrar una visión global del rol de Estado en la regulación de los ensayos clínicos en distintas realidades. Para ello, se ha realizado una revisión de la regulación en la Unión Europea, Estados Unidos de Norteamérica y algunos países de Latinoamérica, para llegar finalmente al Perú. La tendencia actual en la regulación de los ensayos clínicos, se caracteriza por el incremento en los estándares de calidad, el garantizar la seguridad de los participantes, promover la transparencia, la disminución de los procesos burocráticos y el fortalecimiento de los comités de ética, en el marco de procesos democráticos abiertos, que convoquen e integren a todos los interesados en procesos dinámicos basados en el conocimiento actual y los cambios que se suceden. El reto actual es promover el desarrollo de ensayos clínicos desde el Estado (universidades, centros de investigación, institutos especializados, hospitales, etc.) para los aspectos que el país necesita, incluidos medicamentos huérfanos, enfermedades prevalentes y abandonadas, y el uso terapéutico de los principios activos originarios.

The regulation of clinical trials by the Government is a process of continuous change and adaptation, current challenge is to ensure the safety of participants and get balance of administrative procedures. Development and regulation of clinical trials in different countries vary according to the situation, context national or international execution, determining the insufficiency of national regulation requiring review of international regulation. The aim of this publication is to present a comprehensive overview of the role of Government in the regulation of clinical trials in different realities. It includes a review of the regulation in The European Union, The United States and some Latin American countries and finally the regulation in Peru. Contemporary trends in the regulation of clinical trials, are characterized by increasing standards of quality, ensuring the safety of the participants, promote transparency, lower bureaucratic processes and strengthening ethics IRB committees in the framework of open democratic processes, involving all stakeholders in dynamic processes based on current knowledge and changing tendencies. The challenge is to promote the development of clinical trials from the government institutions (universities, research centers, institutes, hospitals, etc.) priorizing local needs including orphan drugs, prevalent and neglected diseases, and therapeutic use of active components of local native plants.

¿Contribuyen los ensayos clínicos al desarrollo de la investigación en el Perú? ¿Cómo lograrlo? / Do clinical trials contribute to research development in Peru? How can that be achieved?

La participación del Instituto Nacional de Salud como ente rector en la evaluación ética, metodológica y, por consiguiente, a cargo de la aprobación de la ejecución de estudios, data del año 1995. Desde entonces ha existido un gran incremento de ensayos clínicos hasta el 2009, por lo que se realizó un análisis preliminar para evaluar si este incremento ha repercutido en la producción de ensayos clínicos sobre tópicos endémicos o problemas de carga de enfermedad que deben ser investigados y resueltos por los peruanos. Para ello, se realizó una búsqueda en SCOPUS Y MEDLINE, pudiendo identificar 102 ensayos clínicos en humanos, diseñados, ejecutados y realizados en el Perú sobre problemas endémicos o propios del Perú. La apreciación en el tiempo no permite afirmar que haya ocurrido un incremento en paralelo, ni que se hayan incluido a nuevos grupos de investigación o nuevos investigadores, no se investiga sobre problemas endémicos de nuestro país, no se ha realizado por ejemplo ningún ensayo clínico sobre la enfermedad de Carrión, son muy pocos los ensayos clínicos promovidos durante este tiempo por instituciones académicas y de la sociedad civil. Teniendo en cuenta ello, podemos afirmar que no se aprecia una influencia positiva en la generación de ensayos clínicos autóctonos, sobre problemas locales que a los peruanos les corresponde resolver.

The participation of the National Institute of Health as a leader in ethical and methodological assessment and its responsibility to approve the implementation of studies dates back to 1995. Since then, clinical trials have increased significantly until 2009; for this reason, a preliminary analysis was made to assess whether this increase has had an impact in the production of clinical trials on endemic topics or disease burden problems that must be researched and resolved by Peruvian people. For this purpose, a search in SCOPUS and MEDLINE was conducted, with 102 clinical trials in humans found, all of them designed, implemented and carried out in Peru on endemic or domestic health issues. Observation over time does not reveal any parallel increase or the inclusion of new research groups or researchers, no research on endemic problems has been carried out in our country; for example, clinical trials on the “Carrion’s Disease” have not been conducted. Very few clinical trials have been promoted during this period by academic institutions and the civil society. Taking this into consideration, we can affirm that there is no positive influence in the generation of native clinical trials on local problems that Peruvian people need to resolve.

The importance of growth factors for the treatment of chronic wounds in the case of diabetic foot ulcers.

INTRODUCTION: Ulcers as a result of diabetes mellitus are a serious problem with an enormous impact on the overall global disease burden due to the increasing prevalence of diabetes. Because of long hospital stays, rehabilitation, often required home care and the use of social services diabetic foot complications are costly. Therapy with growth factors could be an effective and innovative add-on to standard wound care. RESEARCH QUESTIONS: What is the benefit of therapies with growth factors alone or in combination with other technologies in the treatment of diabetic foot ulcer assessed regarding medical, economical, social, ethical and juridical aspects? METHODS: We systematically searched relevant databases limited to English and German language and publications since 1990. Cost values were adjusted to the price level of 2008 and converted into Euro. A review and an assessment of the quality of publications were conducted following approved methodical standards conforming to evidence-based medicine and health economics. RESULTS: We identified 25 studies (14 randomized controlled trials (RCT), nine cost-effectiveness analyses, two meta-analyses). The RCT compared an add-on therapy to standard wound care with standard wound care/placebo alone or extracellular wound matrix: in six studies becaplermin, in two rhEGF, in one bFGF, and in five studies the metabolically active skin grafts Dermagraft and Apligraf. The study duration ranged from twelve to 20 weeks and the study population included between 17 to 382 patients, average 130 patients. The treatment with becaplermin, rhEGF and skin implants Dermagraft and Apligraf showed in eight out of 13 studies an advantage concerning complete wound closure and the time to complete wound healing. Evidence for a benefit of treatment with bFGF could not be found. In four out of 14 studies the proportion of adverse events was 30% per study group with no difference between the treatment groups. The methodological quality of the studies was affected by significant deficiencies. The results showed becaplermin being cost-effective whereas no obvious statement can be made regarding Dermagraft and Apligraf because of diverging cost bases and incremental cost-effectiveness ratios. DISCUSSION: Differences in standard wound care are complicating the comparison of study results. Taking into consideration the small to very small sample sizes and other methodological flaws with high potential of bias, the validity of the results with regard to effectiveness and cost-effectiveness has to be considered limited. The duration of treatment and follow-up examinations is not long enough to assess the sustainability of the intervention and the surveillance of ulcer recurrences or treatment related adverse events like the development of malignancy. CONCLUSIONS: There are indications of an advantage for the add-on therapy with growth factors in diabetic foot ulcers concerning complete wound closure and the time to complete wound healing. Further more studies of high methodological quality with adequate sample sizes and sufficient follow-up periods are necessary also investigating patient-relevant parameters like the health-related quality of life, the acceptance and tolerance of the intervention in addition to clinical outcomes.