Antimalarials and macrolides: a review of off-label pharmacotherapies during the first wave of the SARS-CoV-2 pandemic

Abstract We critically analyzed clinical trials performed with chloroquine (CQ) and hydroxychloroquine (HCQ) with or without macrolides during the first wave of COVID-19 and discussed the design and limitations of peer-reviewed studies from January to July 2020. Seventeen studies were eligible for the discussion. CQ and HCQ did not demonstrate clinical advantages that justified their inclusion in therapeutic regimens of free prescription for treatment or prophylactic purposes, as suggested by health authorities, including in Brazil, during the first wave. Around August 2020, robust data had already indicated that pharmacological effects of CQ, HCQ and macrolides as anti-SARS-CoV-2 molecules were limited to in vitro conditions and largely based on retrospective trials with low quality and weak internal validity, which made evidence superficial for decision-making. Up to that point, most randomized and nonrandomized clinical trials did not reveal beneficial effects of CQ or HCQ with or without macrolides to reduce lethality, rate of intubation, days of hospitalization, respiratory support/mechanical ventilation requirements, duration, type and number of symptoms, and death and were unsuccessful in increasing virus elimination and/or days alive in hospitalized or ambulatory patients with COVID-19. In addition, many studies have demonstrated that side effects are more common in CQ-or HCQ-treated patients.

Association of Remote Technology Use and Other Decentralization Tools With Patient Likelihood to Enroll in Cancer Clinical Trials.

Importance: Logistical challenges such as travel time and distance to a clinical trial site can be a barrier to patient participation. The association of remote technology use and other decentralization tools that can reduce these barriers with likelihood to enroll in cancer trials is not well understood. Objective: To assess the association of remote technology and other decentralization tools used to reduce participation-related time and travel with the likelihood to enroll in cancer clinical trials. Design, Setting, and Participants: Between July 6 and September 8, 2021, a 41-question, cross-sectional, internet-based survey was administered to patients with cancer and survivors of cancer in the US who had been diagnosed with or treated for cancer in the past 7 years. Main Outcomes and Measures: Increase in self-reported likelihood to enroll in cancer clinical trials that use remote technology and other decentralization tools to decrease the need for travel to the trial site. Results: There were 1183 survey respondents, with a mean (SD) age of 58.2 (12.5) years. Respondents self-reported their gender, race and ethnicity, cancer type, and treatment status. Of the 1183 respondents, 848 (72%) were female, 296 (25%) were male, 8 (1%) were other/nonbinary, and 31 (3%) declined to answer. With regard to race, 28 respondents (3%) were American Indian or Alaska Native, 25 (2%) were Asian, 234 (20%) were Black or African American, 20 (2%) were Native Hawaiian or Other Pacific Islander, 825 (70%) were White, and 51 (4%) declined to answer. With regard to ethnicity, 115 respondents (10%) were Hispanic, Latino/Latina, or of Spanish origin, whereas 1017 (86%) were not and 51 (4%) declined to answer. Regarding cancer type and treatment status, 483 respondents (41%) either had or had survived breast cancer and 325 (28%) were being treated for cancer during the survey period. Individuals older than 55 years were more likely to say that they would only participate in trials no farther from their home than their regular care health care practitioner compared with younger respondents (26% vs 16%, respectively; P = .02). Higher-income earners (ie, those in households earning >$125 000/y) were significantly more likely than lower-income earners (ie, those in households earning <$70 000/y) to say they would participate in trials requiring additional effort (62% vs 41%, respectively; P = .03). If given the opportunity to enroll in a cancer clinical trial that required travel farther than their regular care, a majority of respondents (range, 60%-85%) indicated that they would be more likely to participate if the trial used remote technology and other tools to decrease the need for travel to a trial site. Conclusions and Relevance: In this cross-sectional study, the survey findings suggest that cancer clinical trials leveraging remote technology and decentralization tools to reduce patient time and travel burden associated with participation may increase the patient consent rate.

Implementation of Mobile Health Technologies in Clinical Trials of Movement Disorders: Underutilized Potential.

Mobile health technologies (mHealth) are patient-worn or portable devices aimed at increasing the granularity and relevance of clinical measurements. The implementation of mHealth has the potential to decrease sample size, duration, and cost of clinical trials. We performed a review of the ClinicalTrials.gov database using a standardized approach to identify adoption in and usefulness of mHealth in movement disorders interventional clinical trials. Trial phase, geographical area, availability of data captured, constructs of interest, and outcome priority were collected. Eligible trials underwent quality appraisal using an ad hoc 5-point checklist to assess mHealth feasibility, acceptability, correlation with patient-centered outcome measures, and clinical meaningfulness. A total of 29% (n = 54/184) registered trials were using mHealth, mainly in Parkinson's disease and essential tremor (59.3% and 27.8%). In most cases, mHealth were used in phase 2 trials (83.3%) as secondary outcome measures (59.3%). Only five phase 3 trials, representing 9.3% of the total, used mHealth (1 as primary outcome measure, 3 as secondary, and 1 as tertiary). Only 3.7% (n = 2/54) of all trials used mHealth for measuring both motor and non-motor symptoms, and 23.1% (n = 12/52) used mHealth for unsupervised, ecologic outcomes. Our findings suggest that mHealth remain underutilized and largely relegated to phase 2 trials for secondary or tertiary outcome measures. Efforts toward greater alignment of mHealth with patient-centered outcomes and development of a universal, common-language platform to synchronize data from one or more devices will assist future efforts toward the integration of mHealth into clinical trials.

Evaluation of intervention reporting in published emergency medicine clinical trials.

OBJECTIVE: The extent of intervention reporting in emergency medicine journals remains unclear. The primary objective is to assess overall completion of the Template for Intervention Description and Replication (TIDieR) checklist described in emergency medicine randomized clinical trials (RCTs). The secondary outcomes were to (1) compare reporting before and after TIDieR publication; (2) evaluate factors associated with intervention reporting. METHODS: Our cross-sectional study used Google Scholar's metrics to identify seven emergency medicine journals; of which, we randomly sampled 300 articles. Using two PubMed searches, we extracted 150 RCTs before and after publications of TIDieR. Two investigators independently extracted data. The primary analysis to measure overall completion included descriptive statistics for each checklist item. Our secondary analysis used an interrupted time series analysis and generalized estimating equations to determine the effect of TIDieR publication on intervention reporting. RESULTS: Our initial search yielded 635 articles; from which, we randomly sampled 300 articles. We excluded 67 articles, leaving 233 for analysis. The mean number of TIDieR items reported was 5.4 (standard deviation = 1.18). Of the 233 trials, 42.9% provided information about materials, 67% provided intervention procedures, and 99.1% provided intervention delivery. The least reported items were intervention modifications (2.6%), intervention adherence assessment methods (3.4%), and intervention adherence assessment outcomes (2.2%). CONCLUSIONS: The completeness of intervention reporting is suboptimal in emergency medicine journals, necessitating improvement. The current state of adherence could be improved through the combined efforts of journal editors, major editorial organizations, and authors.

Determine what to measure and how to measure in clinical trials for the treatment of pressure injury: A protocol for the development of a core outcome set.

BACKGROUND: A core outcome set (COS) is an agreed minimum set of outcomes that should be reported in all clinical trials in specific areas of health care. A considerable amount of trials did not report essential outcomes or outcomes measurement methods, which makes it challenging to evaluate the efficacy and safety of treatment strategies for pressure injury (PI) and produced significant heterogeneity of reported outcomes. It is necessary to develop a COS, which can be used for clinical trials in PI treatment. METHODS/DESIGN: The development of this COS will be guided by an advisory group composed of clinicians, senior nurses, patients, and methodologists. We will search six databases and 2 registry platforms to identify currently reported PI treatment outcomes and outcome measurement instruments in randomized controlled trials, meta-analysis, and systematic reviews. We will also conduct a semi-structured interview with clinicians, nurses, and adult PI patients to collect their opinions on important outcomes. Each outcome of the initial list generated from systematic review and interviews will be scored and reach a consensus through two rounds of international Delphi survey with all key stakeholders. A face-to-face consensus meeting with key stakeholders will be conducted to finish a final COS and recommend measurement instruments for each outcome. RESULTS: We will develop a COS that should be reported in future clinical trials to evaluate the effectiveness of PI treatment. DISCUSSION: The COS will follow current guidance to develop a high-quality COS in the field of PI treatment to reduce heterogeneity in trial reporting, facilitate valid comparisons of new therapies, and improve the quality of clinical trials.

Evaluación comparativa, mediante ensayos biomecánicos, de dispositivos de ostomía de dos piezas / Comparative evaluation through biomechanical tests of two-piece ostomy systems

OBJETIVO: comparar las propiedades mecánicas de los dispositivos de ostomía de dos piezas más empleados en España (Coloplast -o Fabricante I- y Fabricante II), mediante la realización de ensayos mecánicos. MÉTODO: los ensayos se realizaron en el Instituto de Biomecánica de Valencia (IBV), empleándose una máquina universal de ensayos MTS INSIGHT/468, con unas condiciones ambientales controladas de temperatura (22-24 ºC) y de humedad (39-41%). El tamaño de la muestra para cada uno de los ensayos fue de 10 unidades para cada tipo de sistema. Se llevaron a cabo tres pruebas: 1) Ensayo de resistencia a la degradación del adhesivo en solución salina; 2) Ensayo de resistencia al estallido del canal de vaciado de las bolsas abiertas; 3) Ensayo de resistencia a la separación entre el disco y la bolsa. RESULTADOS: en el ensayo de resistencia a la degradación del adhesivo en solución salina, los dos adhesivos, sometidos a periodos de degradación de 6 y 12 horas en solución salina a 37 ºC, presentaron diferencias significativas a favor del Fabricante I (Coloplast) para los dos periodos. En el ensayo de resistencia al estallido del canal de vaciado de las bolsas abiertas, con las bolsas llenas de agua, cerradas y pegadas sobre una plancha lisa, después de aplicar cargas de compresión hasta el estallido del canal, los dos sistemas no mostraron diferencias significativas. En el ensayo de resistencia a la separación entre el disco y la bolsa, ensamblada cada bolsa a su disco correspondiente y aplicadas cargas de tracción hasta la separación, también hubo diferencias significativas a favor del Fabricante I (Coloplast). CONCLUSIÓN: se puede afirmar que ambos sistemas son seguros, pero el sistema Coloplast presenta mayor durabilidad ante la degradación por el efluente y mayor coeficiente de seguridad frente a la separación entre la bolsa y el disco

OBJECTIVE: to compare the mechanical characteristics of the two-piece ostomy systems most widely used in Spain: (Coloplast or Manufacturer I and Manufacturer II), through mechanical tests. METHOD: tests were conducted in the Instituto de Biomecánica de Valencia (IBV), using a MTS INSIGHT/468 universal test machine, under environmental conditions of controlled temperature (22-24 ºC) and humidity (39-41%). The sample size for each test was 10 units per each type of system. Three tests were conducted: 1) Resistance test to degradation of the adhesive in saline solution; 2) Resistance test to burst of the outlet in open pouches; 3) Resistance test for the separation between the disc and the pouch. RESULTS: in the test of resistance to degradation of the adhesive in saline solution, both adhesives were submitted to 6 and 12-hour degradation periods in saline solution at 37 ºC, and significant differences were presented in favour of Manufacturer 1 (Coloplast) for both time periods. In the resistance test for the burst of the outlet in open pouches, the pouches were filled with water, closed and stuck on a flat plate; after applying compression charges until the outlet burst, both systems did not show any significant differences. In the resistance test for the separation between disc and pouch, each pouch was assembled with its disc, and traction charges were applied until their separation; there were significant differences in favour of Manufacturer I (Coloplast). CONCLUSION: it can be stated that both systems are safe, but the Coloplast system shows higher durability in terms of degradation by effluent, and a higher safety coefficient regarding the separation between pouch and disc

Seizure detection devices for use in antiseizure medication clinical trials: A systematic review.

OBJECTIVE: This study characterizes the current capabilities of seizure detection device (SDD) technology and evaluates the fitness of these devices for use in anti-seizure medication (ASM) clinical trials. METHODS: Through a systematic literature review, 36 wireless SDDs featured in published device validation studies were identified. Each device's seizure detection capabilities that addressed ASM clinical trial primary endpoint measurement needs were cataloged. RESULTS: The two most common types of seizures targeted by ASMs in clinical trials are generalized tonic-clonic (GTC) seizures and focal with impaired awareness (FIA) seizures. The Brain Sentinel SPEAC achieved the highest performance for the detection of GTC seizures (F1-score = 0.95). A non-commercial wireless EEG device achieved the highest performance for the detection of FIA seizures (F1-score = 0.88). DISCUSSION: A preliminary assessment of device capabilities for measuring selected ASM clinical trial secondary endpoints was performed. The need to address key limitations in validation studies is highlighted in order to support future assessments of SDD fitness for ASM clinical trial use. In tandem, a stepwise framework to streamline device testing is put forth. These suggestions provide a starting point for establishing SDD reporting requirements before device integration into ASM clinical trials.

Use of nonintrusive sensor-based information and communication technology for real-world evidence for clinical trials in dementia.

Cognitive function is an important end point of treatments in dementia clinical trials. Measuring cognitive function by standardized tests, however, is biased toward highly constrained environments (such as hospitals) in selected samples. Patient-powered real-world evidence using information and communication technology devices, including environmental and wearable sensors, may help to overcome these limitations. This position paper describes current and novel information and communication technology devices and algorithms to monitor behavior and function in people with prodromal and manifest stages of dementia continuously, and discusses clinical, technological, ethical, regulatory, and user-centered requirements for collecting real-world evidence in future randomized controlled trials. Challenges of data safety, quality, and privacy and regulatory requirements need to be addressed by future smart sensor technologies. When these requirements are satisfied, these technologies will provide access to truly user relevant outcomes and broader cohorts of participants than currently sampled in clinical trials.

Incorporating Digital Tools to Improve Clinical Trial Infrastructure: A White Paper From the Digital Engagement Committee of SWOG.

Progress toward improvement in cancer therapy relies on clinical trials. Yet, only a minority of eligible patients with cancer enroll as a result of multiple barriers at the patient, investigator, center, and national level. However, the rise of the Internet and mobile technology has created a slew of tools with medical applications, from Web sites to apps to social media platforms, all of which may aide clinicians in our quest to improve the clinical research enterprise. SWOG is one of five members in the National Cancer Institute's National Clinical Trials Network-the nation's oldest and largest publicly funded cancer research network-and is taking a leadership role in exploring and testing the promise of digital engagement through the empaneling of the Digital Engagement Committee. This article outlines the mission, principles, and priorities of the Digital Engagement Committee and proposes how this work may inform the use of digital tools for the cancer research community and, hopefully, translate to improved outcomes for our patients.

Use of Wearable, Mobile, and Sensor Technology in Cancer Clinical Trials.

As the availability and sophistication of mobile health (mHealth) technology (wearables, mobile technology, and sensors) continues to increase, there is great promise that these tools will be transformative for clinical trials and drug development. This review provides an overview of the current landscape of potential measurement options, including the various types of data collected, methods/tools for collecting them, and a crosswalk of available options. The opportunities and potential drawbacks of mHealth in cancer clinical trials are discussed. Specific concerns related to data accuracy, provenance, and regulatory issues are highlighted, with suggestions for how to address these in future research. Next steps for establishing mHealth methods and tools as legitimate and accepted measures in oncology clinical trials include continuation of regulatory definition by the FDA; establishment of security standards and protocols; refinement and implementation of methods to establish and document data accuracy; and finally, creation of feedback loops wherein regulators receive updates from researchers with better and more timely data, which should decrease trial times and lessen drug development costs. Implementing mHealth technologies into cancer clinical trials has the potential to transform and propel oncology drug development and precision medicine to keep pace with the rapidly increasing developments in genomics and immunology.

Sleep devices: wearables and nearables, informational and interventional, consumer and clinical.

The field of sleep is in many ways ideally positioned to take full advantage of advancements in technology and analytics that is fueling the mobile health movement. Combining hardware and software advances with increasingly available big datasets that contain scored data obtained under gold standard sleep laboratory conditions completes the trifecta of this perfect storm. This review highlights recent developments in consumer and clinical devices for sleep, emphasizing the need for validation at multiple levels, with the ultimate goal of using personalized data and advanced algorithms to provide actionable information that will improve sleep health.

Review of a commercially available hybrid closed-loop insulin-delivery system in the treatment of Type 1 diabetes.

Type 1 diabetes is an important medical condition causing significant burden and morbidity to those persons affected by it. Improvements in insulin products, insulin delivery and glucose monitoring technology have all contributed to reductions in long-term complications and hypoglycemia. This article reviews the Medtronic 670G device and summarizes the data supporting how this product reduces the burden and increases the safety of insulin dosing in Type 1 diabetes.

Quality assurance guidelines for superficial hyperthermia clinical trials : II. Technical requirements for heating devices.

Quality assurance (QA) guidelines are essential to provide uniform execution of clinical trials with uniform quality hyperthermia treatments. This document outlines the requirements for appropriate QA of all current superficial heating equipment including electromagnetic (radiative and capacitive), ultrasound, and infrared heating techniques. Detailed instructions are provided how to characterize and document the performance of these hyperthermia applicators in order to apply reproducible hyperthermia treatments of uniform high quality. Earlier documents used specific absorption rate (SAR) to define and characterize applicator performance. In these QA guidelines, temperature rise is the leading parameter for characterization of applicator performance. The intention of this approach is that characterization can be achieved with affordable equipment and easy-to-implement procedures. These characteristics are essential to establish for each individual applicator the specific maximum size and depth of tumors that can be heated adequately. The guidelines in this document are supplemented with a second set of guidelines focusing on the clinical application. Both sets of guidelines were developed by the European Society for Hyperthermic Oncology (ESHO) Technical Committee with participation of senior Society of Thermal Medicine (STM) members and members of the Atzelsberg Circle.

How do researchers decide early clinical trials?

Launch of clinical investigation represents a substantial escalation in commitment to a particular clinical translation trajectory; it also exposes human subjects to poorly understood interventions. Despite these high stakes, there is little to guide decision-makers on the scientific and ethical evaluation of early phase trials. In this article, we review policies and consensus statements on human protections, drug regulation, and research design surrounding trial launch, and conclude that decision-making is largely left to the discretion of research teams and sponsors. We then review what is currently understood about how research teams exercise this discretion, and close by laying out a research agenda for characterizing the way investigators, sponsors, and reviewers approach decision-making in early phase research.

An improved electrical impedance myography (EIM) tongue array for use in clinical trials.

OBJECTIVES: Electrical impedance myography (EIM) measurements of the tongue could provide valuable information about bulbar dysfunction in amyotrophic lateral sclerosis (ALS). A prototype tongue depressor EIM array produced gag reflexes. The objectives of this study were to determine the reliability, mean phase values, and tolerability of tongue EIM measurements using a smaller electrode array. METHODS: Tongue EIM measurements were performed in a total of 31 healthy individuals and four neuromuscular patients with lingual abnormalities. Reliability was assessed by calculating the intraclass correlation coefficient (ICC) and percent difference in addition to performing Bland-Altman analyses. Standard descriptive statistics, including results of a Mann-Whitney test, were also determined. RESULTS: At the 50 kHz frequency, the ICCs for intra- and inter-rater reliability were 0.76 with 5.17% difference and 0.78 with 5.34% difference respectively. The mean EIM phase values of healthy participants (11.61° ± 1.00°) and patients (9.87° ± 1.28°) were significantly different (p=0.0051). None of the participants experienced gag reflexes or discomfort. CONCLUSIONS: The small tongue array provided good inter- and intra-rater reliability, could preliminarily distinguish between healthy and diseased muscle, and was well-tolerated. SIGNIFICANCE: Biomarker information about tongue health could be more comfortably obtained with a smaller EIM array.

La cara oculta del estudio 329 y la manipulación de la evidencia científica / Study's 329 hiddens face and scientifics evidence manipulation

El emblemático ensayo clínico 329, financiado por Smith Kline Beecham (actualmente GlaxoSmith-Kline) y publicado en2001, permitió posicionar a la paroxetina como un tratamiento efectivo y seguro para la depresión mayor en adolescentes. En la presente editorial el autor describe los sucesos ocurridos luego de su publicación, partiendo de los cuestionamientos iniciales respecto de su eficacia, hasta llegar a los resultados de su reciente reanálisis (llevando adelante por la iniciativa internacional RIAT), el cual concluyo que dicho fármaco no solo no provee un beneficio adicional al placebo para la condición y población utilizada, sino que además se asocia a efectos adversos sustanciales que no habían sido reportados en el informe original. Se exploran además las repercusiones de este suceso en la comunidad científica y se hace un señalamiento de la necesidad de permitir el acceso a las bases de datos originales que sustentan los resultados y conclusiones de las investigaciones publicadas, como mecanismo de transparencia superador a la revisión por pares. (AU)

The emblematic 329 study, funded by Smith Kline Beecham (now GlaxoSmith-Kline) and published in 2001, allowed to position paroxetine as an effective and safe treatment for major depression in adolescents. In this editorial, the author describes the events after its publication, from the initial concerns about its effectiveness, to the results of its recent reanalysis (accounted by the international RIAT initiative), which concluded that the drug not only does not provide an additional benefit than placebo, but is also associated with significant adverse effects that were not reported in the original report. It also explores the repercussions generated in the scientific community by this event, pointing out the need to allow access to original databases that support the findings and conclusions of published research, as an overcoming mechanism for transparency to the traditional peerreview. Agustín Ciapponi Study's 329 hiddens face and scientifics evidence manipulation. (AU)

Using e-technologies in clinical trials.

Clinical trials have been slow to incorporate e-technology (digital and electronic technology that utilizes mobile devices or the Internet) into the design and execution of studies. In the meantime, individuals and corporations are relying more on electronic platforms and most have incorporated such technology into their daily lives. This paper provides a general overview of the use of e-technologies in clinical trials research, specifically within the last decade, marked by rapid growth of mobile and Internet-based tools. Benefits of and challenges to the use of e-technologies in data collection, recruitment and retention, delivery of interventions, and dissemination are provided, as well as a description of the current status of regulatory oversight of e-technologies in clinical trials research. As an example of ways in which e-technologies can be used for intervention delivery, a summary of e-technologies for treatment of substance use disorders is presented. Using e-technologies to design and implement clinical trials has the potential to reach a wide audience, making trials more efficient while also reducing costs; however, researchers should be cautious when adopting these tools given the many challenges in using new technologies, as well as threats to participant privacy/confidentiality. Challenges of using e-technologies can be overcome with careful planning, useful partnerships, and forethought. The role of web- and smartphone-based applications is expanding, and the increasing use of those platforms by scientists and the public alike make them tools that cannot be ignored.

El receptor del factor de crecimiento epidérmico (EGFR) en el glioblastoma: mecanismo de tumorigénesis y papel como diana terapéutica / Epidermic growth factor receptor (EGFR) in glioblastomas: the mechanism of tumorigenesis and its role as a therapeutic target

El glioblastoma es un tumor cerebral primario muy agresivo y resistente al tratamiento convencional con quimio y radioterapia. Dado que el receptor del factor de crecimiento epidérmico (EGFR) se encuentra alterado en el 50% de los glioblastomas, representa actualmente una de las dianas terapéuticas más prometedoras en este tipo de tumores. Sin embargo, los inhibidores de la actividad cinasa del EGFR han generado escasos resultados en ensayos clínicos con pacientes con glioblastoma. En esta revisión se analiza la función del EGFR en el glioblastoma y se describen las aproximaciones terapéuticas dirigidas frente a dicho receptor en este tipo de tumores. Este tipo de análisis podría constituir un punto de partida para mejorar el diseño de futuras terapias para los glioblastomas, basadas en la inhibición de la función del EGFR (AU)

A glioblastoma is a primary brain tumour that is very aggressive and resistant to conventional treatment with chemo- or radiotherapy. Given that epidermic growth factor receptor (EGFR) is altered in 50% of glioblastomas, it is currently one of the most promising therapeutic targets in this kind of tumour. Yet, inhibitors of the kinase activity of EGFR have yielded poor results in clinical trials with patients with glioblastomas. In this review we analyse the function of EGFR in glioblastomas and outline the therapeutic approaches aimed against this receptor in this kind of tumour. This sort of analysis could be a starting point for improving the design of future therapies for glioblastomas, based on inhibiting the EGFR function (AU)

Más allá de compartir los datos / Beyond "data sharing"

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