Emerging drugs in randomized controlled trials for sickle cell disease: are we on the brink of a new era in research and treatment?

ABSTRACT Introduction: Sickle cell disease (SCD) is caused by a mutation in the HBB gene which is key for making a component of hemoglobin. The mutation leads to the formation of an abnormal hemoglobin molecule called sickle hemoglobin (HbS). SCD is a chronic, complex disease with a multiplicity of pathophysiological targets; it has high morbidity and mortality. Hydroxyurea has for many years been the only approved drug for SCD; hence, the development of new therapeutics is critical. Areas covered: This article offers an overview of the key studies of new therapeutic options for SCD. We searched the PubMed database and Cochrane Database of Systemic Reviews for agents in early phase clinic trials and preclinical development. Expert opinion: Although knowledge of SCD has progressed, patient survival and quality of life must be improved. Phase II and phase III clinical trials investigating pathophysiology-based novel agents show promising results in the clinical management of SCD acute events. The design of longterm clinical studies is necessary to fully understand the clinical impact of these new therapeutics on the natural history of the disease. Furthermore, the building of global collaborations will enhance the clinical management of SCD and the design of primary outcomes of future clinical trials

Glucagon like peptide-1 receptor agonists as neuroprotective agents for ischemic stroke: a systematic scoping review

Stroke mortality and morbidity is expected to rise. Despite considerable recent advances within acute ischemic stroke treatment, scope remains for development of widely applicable neuroprotective agents. Glucagon like peptide-1 receptor agonists (GLP-1RAs), originally licensed for the management of Type 2 Diabetes Mellitus, have demonstrated pre-clinical neuroprotective efficacy in a range of neurodegenerative conditions. This systematic scoping review reports the pre-clinical basis of GLP-1RAs as neuroprotective agents in acute ischemic stroke and their translation into clinical trials. We included 35 pre-clinical studies, 11 retrospective database studies, 7 cardiovascular outcome trials and 4 prospective clinical studies. Pre-clinical neuroprotection was demonstrated in normoglycemic models when administration was delayed by up to 24-hours following stroke induction. Outcomes included reduced infarct volume, apoptosis, oxidative stress and inflammation alongside increased neurogenesis, angiogenesis and cerebral blood flow. Improved neurological function and a trend towards increased survival were also reported. Cardiovascular outcomes trials reported a significant reduction in stroke incidence with semaglutide and dulaglutide. Retrospective database studies show a trend towards neuroprotection. Prospective interventional clinical trials are on-going, but initial indicators of safety and tolerability are favourable. Ultimately, we propose that repurposing GLP-1RAs is potentially advantageous but appropriately designed trials are needed to determine clinical efficacy and cost-effectiveness

Changing platforms without stopping the train: experiences of data management and data management systems when adapting platform protocols by adding and closing comparisons.

Background There is limited research and literature on the data management challenges encountered in multi-arm, multi-stage platform and umbrella protocols. These trial designs allow both (1) seamless addition of new research comparisons and (2) early stopping of accrual to individual comparisons that do not show sufficient activity. FOCUS4 (colorectal cancer) and STAMPEDE (prostate cancer), run from the Medical Research Council Clinical Trials Unit (CTU) at UCL, are two leading UK examples of clinical trials implementing adaptive platform protocol designs. To date, STAMPEDE has added five new research comparisons, closed two research comparisons following pre-planned interim analysis (lack of benefit), adapted the control arm following results from STAMPEDE and other relevant trials, and completed recruitment to six research comparisons. FOCUS4 has closed one research comparison following pre-planned interim analysis (lack of benefit) and added one new research comparison, with a number of further comparisons in the pipeline. We share our experiences from the operational aspects of running these adaptive trials, focusing on data management.Methods We held discussion groups with STAMPEDE and FOCUS4 CTU data management staff to identify data management challenges specific to adaptive platform protocols. We collated data on a number of case report form (CRF) changes, database amendments and database growth since each trial began.Discussion We found similar adaptive protocol-specific challenges in both trials. Adding comparisons to and removing them from open trials provides extra layers of complexity to CRF and database development. At the start of an adaptive trial, CRFs and databases must be designed to be flexible and scalable in order to cope with the continuous changes, ensuring future data requirements are considered where possible. When adding or stopping a comparison, the challenge is to incorporate new data requirements while ensuring data collection within ongoing comparisons is unaffected. Some changes may apply to all comparisons; others may be comparison-specific or applicable only to patients recruited during a specific time period. We discuss the advantages and disadvantages of the different approaches to CRF and database design we implemented in these trials, particularly in relation to use and maintenance of generic versus comparison-specific CRFs and databases. The work required to add or remove a comparison, including the development and testing of changes, updating of documentation, and training of sites, must be undertaken alongside data management of ongoing comparisons. Adequate resource is required for these competing data management tasks, especially in trials with long follow-up. A plan is needed for regular and pre-analysis data cleaning for multiple comparisons that could recruit at different rates and periods of time. Data-cleaning activities may need to be split and prioritised, especially if analyses for different comparisons overlap in time.Conclusions Adaptive trials offer an efficient model to run randomised controlled trials, but setting up and conducting the data management activities in these trials can be operationally challenging. Trialists and funders must plan for scalability in data collection and the resource required to cope with additional competing data management tasks

Development of the Lymphoma Enterprise Architecture Database: A caBIG(tm) Silver level compliant System

Lymphomas are the fifth most common cancer in United States with numerous histological subtypes. Integrating existing clinical information on lymphoma patients provides a platform for understanding biological variability in presentation and treatment response and aids development of novel therapies. We developed a cancer Biomedical Informatics Grid™ (caBIG™) Silver level compliant lymphoma database, called the Lymphoma Enterprise Architecture Data-system™ (LEAD™), which integrates the pathology, pharmacy, laboratory, cancer registry, clinical trials, and clinical data from institutional databases. We utilized the Cancer Common Ontological Representation Environment Software Development Kit (caCORE SDK) provided by National Cancer Institute’s Center for Bioinformatics to establish the LEAD™ platform for data management. The caCORE SDK generated system utilizes an n-tier architecture with open Application Programming Interfaces, controlled vocabularies, and registered metadata to achieve semantic integration across multiple cancer databases. We demonstrated that the data elements and structures within LEAD™ could be used to manage clinical research data from phase 1 clinical trials, cohort studies, and registry data from the Surveillance Epidemiology and End Results database. This work provides a clear example of how semantic technologies from caBIG™ can be applied to support a wide range of clinical and research tasks, and integrate data from disparate systems into a single architecture. This illustrates the central importance of caBIG™ to the management of clinical and biological data

A systematic review of non-pharmacological interventions for primary Sjögren’s syndrome

The objective of this systematic review was to assess the efficacy of non-pharmacological interventions for the management of primary Sjögren’s syndrome. We searched the following databases from inception to September 2014; Cochrane Database of Systematic Reviews; Medline; Embase; PsychINFO; Cinahl and clinical trials registers. We included randomised controlled trials of any non-pharmacological interventions. Two review authors independently reviewed titles and abstracts against the inclusion/exclusion criteria and independently assessed trial quality and extracted data. 1463 studies were identified of which 17 full text articles were screened and 5 studies were included in the review with a total of 130 participants randomised. The included studies investigated effectiveness of an oral lubricating device for dry mouth, acupuncture for dry mouth, lacrimal punctum plugs for dry eyes and psychodynamic group therapy for coping with symptoms. Overall the studies were of low quality and at high risk of bias. Although one study showed punctum plugs to improve dry eyes it was too small for the findings to be conclusive. Overall we identified no evidence to support any non-pharmacological interventions to improve PSS. The area needs quality large randomised controlled trials that are reported according to CONSORT guidelines and address important issues to patients

Effectiveness and efficiency of primary care based case management for chronic diseases: rationale and design of a systematic review and meta-analysis of randomized and non-randomized trials [CRD32009100316]

Contains fulltext : 88751.pdf (publisher's version ) (Open Access)BACKGROUND: Case management is an important component of structured and evidence-based primary care for chronically ill patients. Its effectiveness and efficiency has been evaluated in numerous clinical trials. This protocol describes aims and methods of a systematic review of research on the effectiveness and efficiency of case management in primary care. METHODS/DESIGN: According to this protocol Medline, Embase, CINAHL, PsychInfo, the Cochrane Central Register of Controlled trials, DARE, NHS EED, Science Citation Index, The Royal College of Nursing Database, Dissertation Abstracts, registers of clinical trials and the reference lists of retrieved articles will be searched to identify reports on randomized and non-randomized controlled trials of case management interventions in a primary care setting without limitations on language or publication date. We will further ask experts in the field to avoid missing relevant evidence. Study inclusion and data extraction will be performed independently by two reviewers. After assessing risk of bias according to predefined standards, included studies will be described qualitatively. Subgroup analyses are planned for different chronic diseases and intervention strategies. If appropriate, a quantitative synthesis of data will be performed to provide conclusive evidence about the effectiveness and efficiency of primary care based case management in chronic care. REVIEW REGISTRATION: Centre for Reviews and Dissemination (University of York): CRD32009100316

Study protocol: differential effects of diet and physical activity based interventions in pregnancy on maternal and fetal outcomes--individual patient data (IPD) meta-analysis and health economic evaluation.

© 2014 Ruifrok et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.BACKGROUND: Pregnant women who gain excess weight are at risk of complications during pregnancy and in the long term. Interventions based on diet and physical activity minimise gestational weight gain with varied effect on clinical outcomes. The effect of interventions on varied groups of women based on body mass index, age, ethnicity, socioeconomic status, parity, and underlying medical conditions is not clear. Our individual patient data (IPD) meta-analysis of randomised trials will assess the differential effect of diet- and physical activity-based interventions on maternal weight gain and pregnancy outcomes in clinically relevant subgroups of women. METHODS/DESIGN: Randomised trials on diet and physical activity in pregnancy will be identified by searching the following databases: MEDLINE, EMBASE, BIOSIS, LILACS, Pascal, Science Citation Index, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, Database of Abstracts of Reviews of Effects, and Health Technology Assessment Database. Primary researchers of the identified trials are invited to join the International Weight Management in Pregnancy Collaborative Network and share their individual patient data. We will reanalyse each study separately and confirm the findings with the original authors. Then, for each intervention type and outcome, we will perform as appropriate either a one-step or a two-step IPD meta-analysis to obtain summary estimates of effects and 95% confidence intervals, for all women combined and for each subgroup of interest. The primary outcomes are gestational weight gain and composite adverse maternal and fetal outcomes. The difference in effects between subgroups will be estimated and between-study heterogeneity suitably quantified and explored. The potential for publication bias and availability bias in the IPD obtained will be investigated. We will conduct a model-based economic evaluation to assess the cost effectiveness of the interventions to manage weight gain in pregnancy and undertake a value of information analysis to inform future research. SYSTEMATIC REVIEW REGISTRATION: PROSPERO 2013: CRD42013003804.This study was funded by the National Institute for Health Research (NIHR) HTA (Health Technology Assessment) UK programme 12/01

Is remdesivir the therapeutic answer for COVID-19: a review of current knowledge

As the world races to find the solution to the COVID-19 pandemic, an investigational agent which has triggered worldwide interest is remdesivir. Though failing clinical trials for treatment of Ebola virus disease, remdesivir has shown efficacy in numerous viral studies involving SARS-CoV-2. Reports from compassionate use of remdesivir in hospitalized patients of COVID-19 have been promising. But the real picture about the safety and efficacy of remdesivir can only be known after completion of randomized clinical trials. In this review, we aim to highlight the salient features of pharmacokinetics and pharmacodynamics of remdesivir known so far and its plausible role in management of COVID-19. We searched the PubMed database and Google Scholar for published literature using the key words: remdesivir, human coronavirus, novel coronavirus, COVID-19, SARS-CoV 2, mechanism of action, pharmacokinetics, pharmacodynamics and compassionate use till 1st May 2020. The U. S. national library of medical trials registry was searched for ongoing trials with remdesivir among patients of COVID-19. Remdesivir is a prodrug of a nucleoside Analog that inhibits RNA replication by binding to viral RNA dependent RNA polymerase. It is being employed in many global phase-3 clinical trials for evaluating the efficacy and safety of the drug in patients of COVID-19

The effects of multi-component weight management interventions on weight loss in adults with intellectual disabilities and obesity: a systematic review and meta-analysis of randomised controlled trials

Background: Adults with intellectual disabilities have been shown to experience higher rates of obesity in comparison to the general population. Aim: To examine the effectiveness of randomised controlled trials of multi-component weight management interventions for adults with intellectual disabilities and overweight/obesity. Methods and procedures: A systematic search of six electronic databases was conducted from database inception to January 2016. Risk of bias was assessed by the Cochrane Collaboration tool. Behavioural change techniques were defined by coding against the Coventry Aberdeen LOndon REfined (CALO-RE) taxonomy. Meta-analyses were conducted as Weighted Mean Difference (WMD) between intervention and control/comparator intervention. Outcomes and results: Six randomised controlled trials were included. The interventions did not adhere to clinical recommendations [the inclusion of an energy deficit diet (EDD), physical activity, and behaviour change techniques]. Meta-analysis revealed that current multi-component weight management interventions are not more effective than no treatment (WMD: −0.38 kg; 95% CI −1.34 kg to 0.58 kg; p = 0.44). Conclusion and implications: There is a paucity of randomised controlled trials of multi-component weight management interventions for adults with intellectual disabilities and overweight/ obesity. Current interventions, based on a health education approach are ineffective. Future longterm interventions that include an EDD and adhere to clinical recommendations on the management of obesity are warranted

Can guidelines improve referral to elective surgical specialties for adults? A systematic review

Aim To assess effectiveness of guidelines for referral for elective surgical assessment. Method Systematic review with descriptive synthesis. Data sources Medline, EMBASE, CINAHL and Cochrane database up to 2008. Hand searches of journals and websites. Selection of studies Studies evaluated guidelines for referral from primary to secondary care, for elective surgical assessment for adults. Outcome measures Appropriateness of referral (usually measured as guideline compliance) including clinical appropriateness, appropriateness of destination and of pre-referral management (eg, diagnostic investigations), general practitioner knowledge of referral appropriateness, referral rates, health outcomes and costs. Results 24 eligible studies (5 randomised control trials, 6 cohort, 13 case series) included guidelines from UK, Europe, Canada and the USA for referral for musculoskeletal, urological, ENT, gynaecology, general surgical and ophthalmological conditions. Interventions varied from complex (“one-stop shops”) to simple guidelines. Four randomized control trials reported increases in appropriateness of pre-referral care (diagnostic investigations and treatment). No evidence was found for effects on practitioner knowledge. Mixed evidence was reported on rates of referral and costs (rates and costs increased, decreased or stayed the same). Two studies reported on health outcomes finding no change. Conclusions Guidelines for elective surgical referral can improve appropriateness of care by improving prereferral investigation and treatment, but there is no strong evidence in favour of other beneficial effects