How to write a research study protocol

A study protocol is an important document that specifies the research plan for a clinical study. Many funders such as the NHS Health Research Authority encourage researchers to publish their study protocols to create a record of the methodology and reduce duplication of research effort. In this paper, we will describe how to write a research study protocol.

Stopping rules for phase I clinical trials with dose expansion cohorts

Many clinical trials incorporate stopping rules to terminate early if the clinical question under study can be answered with a high degree of confidence. While common in later-stage trials, these rules are rarely implemented in dose escalation studies, due in part to the relatively smaller sample size of these designs. However, even with a small sample size, this paper shows that easily implementable stopping rules can terminate dose-escalation early with minimal loss to the accuracy of maximum tolerated dose estimation. These stopping rules are developed when the goal is to identify one or two dose levels, as the maximum tolerated dose and co-maximum tolerated dose. In oncology, this latter goal is frequently considered when the study includes dose-expansion cohorts, which are used to further estimate and compare the safety and efficacy of one or two dose levels. As study protocols do not typically halt accrual between escalation and expansion, early termination is of clinical importance as it either allows for additional patients to be treated as part of the dose expansion cohort to obtain more precise estimates of the study endpoints or allows for an overall reduction in the total sample size.

Exploring Tobacco and E-Cigarette Use among Queer Adults during the Early Days of the COVID-19 Pandemic

The purpose of this narrative study is to describe the vaping and smoking characteristics of Queer people ages 18–34 before March of 2020 and to better understand how the COVID-19 pandemic has impacted those behaviors since March of 2020. In total, 31 participants were screened. Thirteen participants were screened prior to the emergence of COVID-19, and 18 were screened when study protocols transitioned to a remote setting (pre and during). Of the 27 eligible participants, a total of 25 participants completed the study. Most participants (n = 13) self-identified as male, followed by five identified as female, four self-identified as gender non-binary, and three identified as transgender. The most common sexual orientation amongst participants was gay (n = 10), with bisexual being the second-most reported. Approximately 20 Queer participants reported using cigarettes, 14 participants self-reported using electronic devices, and 11 reported using hookah. Twenty participants reported smoking ten or less, and four self-reported using 11–20 cigarettes per day. Approximately, 92% of participants (n = 23) indicate that they are using an e-cigarette and regular cigarettes, and 57% of participants (n = 12) report using one pod or cartridge per day. The three themes that emerged in this study are: (1) Queer people during COVID-19 are experiencing heightened minority stress; (2) Queer people are unfamiliar with smoking cessation; and (3) vaping and smoking are attributed to stress and anxiety. Queer participants are likely to be dual users of cigarette and vaping products. This present study provides increasing evidence that Queer people are experiencing heightened stress and anxiety and using cigarette smoking and vaping to cope during the COVID-19 pandemic.

A COMPREHENSIVE GUIDE TO MEGA-PRESS FOR GABA MEASUREMENT

Background: The aim of this guideline is to provide a series of evidence-based recommendations that allow those new to the field of MEGA-PRESS to produce high-quality data for the measurement of GABA levels using edited magnetic resonance spectroscopy with the MEGA-PRESS sequence at 3T. GABA is the main inhibitory neurotransmitter of the central nervous system and has been increasingly studied due to its relevance in many clinical disorders of the central nervous system. MEGA-PRESS is the most widely used method for quantification of GABA at 3T, but is technically challenging and operates at a low signal-to-noise ratio. Therefore, the acquisition of high-quality MRS data relies on avoiding numerous pitfalls and observing important caveats. Methods: The guideline was developed by a working party that consisted of experts in MRS and experts in guideline development and implementation, together with key stakeholders. Strictly following a translational framework, we first identified evidence using a systematically conducted scoping literature review, then synthesised and graded the quality of evidence that formed recommendations. These recommendations were then sent to a panel of 21 world leaders in MRS for feedback and approval using a modified-Delphi process across two rounds. Results: The final guideline consists of 23 recommendations across six domains essential for GABA MRS acquisition (Parameters, Practicalities, Data acquisition, Confounders, Quality/reporting, Post-processing). Overall, 78% of recommendations were formed from high-quality evidence, and 91% received agreement from over 80% of the expert panel. Conclusion: These 23 expert-reviewed recommendations and accompanying extended documentation form a readily usable guideline to allow those new to the field of MEGA-PRESS to design appropriate MEGA-PRESS study protocols and generate high-quality data.

Building a National Reassessment Process for Oncology Drugs: Lessons Learned by the Canadian Real-World Evidence for Value of Cancer Drugs (CanREValue) Collaboration through a Simulated Reassessment Exercise

The CanREValue Collaboration established the Reassessment & Uptake Working Group to develop a preliminary process to reassess funded cancer drugs in Canada. A simulated exercise was conducted to evaluate the proposed reassessment process using a real-world case. We invited 32 attendees including representatives from Health Canada and Health Technology Assessment (HTA) agencies, along with payers, clinicians, academics, and patient representatives. A case was developed using a real-world study on a publicly funded cancer drug. In facilitated group sessions, participants were asked to deliberate upon the evidence presented in the case to issue reassessment recommendations. Several themes were identified through the deliberation discussions. While the generalizability of real-world evidence (RWE) is perceived as a strength, trust in the RWE depends largely on the source of the real-world data. The attendees suggested several improvements to the proposed reassessment process including evidence requirement for reassessment, recommendation categories, and a priori study protocols. This exercise generated important insights on the evidence required for conducting reassessment and considerations for improvements of the proposed reassessment process. Building upon lessons from this exercise, future work would continue to refine the reassessment process as part of the overall CanREValue framework.

Cohort profile: the Mâncio Lima cohort study of urban malaria in Amazonian Brazil

PurposeThis population-based open cohort study aims to investigate biological and sociodemographic drivers of malaria transmission in the main urban hotspot of Amazonian Brazil.ParticipantsNearly 20% of the households in the northwestern town of Mâncio Lima were randomly selected and 2690 participants were enrolled since April 2018. Sociodemographic, housing quality, occupational, behavioural and morbidity information and travel histories were collected during consecutive study visits. Blood samples from participants>3 months old were used for malaria diagnosis and human genetic studies; samples from participants with laboratory-confirmed malaria have been cryopreserved for genetic and phenotypic characterisation of parasites. Serology was introduced in 2020 to measure the prevalence and longevity of SARS-CoV-2 IgG antibodies.Findings to dateMalaria prevalence rates were low (up to 1.0% for Plasmodium vivax and 0.6% for P. falciparum) during five consecutive cross-sectional surveys between April–May 2018 and October–November 2020; 63% of infections diagnosed by microscopy were asymptomatic. Malaria risk is heterogeneously distributed, with 20% study participants contributing 86% of the overall burden of P. vivax infection. Adult males are at greatest risk of infection and human mobility across the urban–rural interface may contribute to sustained malaria transmission. Local P. vivax parasites are genetically diverse and fragmented into discrete inbred lineages that remain stable across space and time.Future plansTwo follow-up visits, with similar study protocols, are planned in 2021. We aim to identify high-risk individuals that fuel onwards malaria transmission and represent a priority target for more intensive and effective control interventions.Trial registration numberNCT03689036.

662 Dissecting the CD226 immune axis in the tumor microenvironment using CyTOF-based high-dimensional immunophenotyping

BackgroundIn recent years, a regulatory network involving nectin/nectin-like immune receptors has emerged as a potential point of manipulation for cancer immunotherapy. Central to this axis, CD226 (DNAM-1) is a T and NK cell co-stimulatory receptor that competes for ligand (CD155 and CD112) binding with multiple inhibitory receptors (TIGIT, CD96, and PVRIG [CD112R]). Despite a large body of literature for TIGIT, detailed cellular characterization of the entire axis is still lacking. Therefore, we used mass cytometry (CyTOF) to systematically evaluate expression of the CD226 axis in tumors from a range of indications.MethodsTo thoroughly characterize the CD226 axis in the tumor microenvironment, we immunophenotyped approximately 100 tumor samples derived from a variety of cancer types using a bespoke 46-parameter CyTOF panel. Human biological samples were sourced ethically and their research use was in accord with the terms of the informed consents under an IRB/EC approved protocol. Using a suite of high-dimensional analytical tools, including FlowSOM, UMAP, and tSNE, we revealed distinct expression profiles for each receptor; a finding that was previously obscured due to a lack of sufficient resolution.ResultsWe observed a notable divergence in expression profiles between the CD226 axis members across tumor indications. For example, TIGIT expression was found to be highest on activated CD4+ regulatory T (Treg) cells, where its expression correlated strongly with ICOS, FoxP3, CD25, and CCR8. By contrast, CD96 and PVRIG exhibited broad expression across intratumoral T and NK cell populations. Other receptors (e.g., CD226) demonstrated variegated expression profiles across T and NK cell subsets. Finally, despite relatively consistent expression profiles of certain CD226 axis (i.e., TIGIT on Treg cells) across tumors, we also found several cell subsets/clusters unique to specific indications.ConclusionsUsing high-parameter CyTOF analysis, we were able to thoroughly characterize the CD226 axis (CD226, TIGIT, CD96, PVRIG) and related immune receptors across a range of tumor indications. These analyses revealed divergent expression profiles for each CD226 axis member, suggesting distinct/contextual biological role(s) for each receptor. However, future studies will need to dissect the importance of the distinct cellular representation for each CD226 axis member.Ethics ApprovalAll samples were purchased from Discovery Life Sciences (DLS). DLS represents and warrants that it has ownership of all Products available for sale and has properly obtained, where required under HHS/OHRP 45 CFR 46.102 (d) (f), IRB approval (or appropriate research approval for institutions outside the U.S.) for study protocols and informed consent documents for all human subject derived biological materials.

Remote Delivery of Motor Function Assessment and Training for Clinical Trials in Neuromuscular Disease: A Response to the COVID-19 Global Pandemic

Clinical outcome assessments of function or strength, assessed by physical therapists, are commonly used as primary endpoints in clinical trials, natural history studies and within clinics for individuals with neuromuscular disorders. These evaluations not only inform the efficacy of investigational agents in clinical trials, but also importantly track disease trajectory to prospectively advise need for equipment, home and work modifications, and other assistive devices. The COVID-19 pandemic had a global impact on the safety and feasibility of in-person visits and assessments, necessitating rapid development of mitigation strategies to ensure ongoing collection of key clinical trial endpoints and access to expert clinical care despite travel restrictions. Physical therapists who are expert in neuromuscular disorders working across clinics, countries, and clinical trials developed initial guidelines and methods for the suitability and feasibility of performing remote evaluations. A number of Sponsors introduced amendments to their study protocols to enable remote evaluations, supported by live video streaming of the assessment to their local clinical evaluators. Similarly, application of these techniques to clinical telemedicine enabled objective evaluations for use in payer discussions, equipment procurement, and general access to expert physical therapy services. Here we report on our methodology for adapting current practices to remote testing and considerations for remote evaluations.