Publications by authors named "Gareth Griffiths"

245 Publications

Programmed cell death (PCD) processes begin extremely early in Alstroemeria petal senescence.

New Phytol 2003 Oct;160(1):49-59

Cardiff School of Biosciences, Cardiff University, Main Building, Cardiff University, PO Box 915, Cardiff CF10 3TL, UK.

•  In the Liliaceous species Alstroemeria, petal senescence is characterized by wilting and inrolling, terminating in abscission 8-10 d after flower opening. •  In many species, flower development and senescence involves programmed cell death (PCD). PCD in Alstroemeria petals was investigated by light (LM) and transmission electron microscopy (TEM) (to study nuclear degradation and cellular integrity), DNA laddering and the expression programme of the DAD-1 gene. •  TEM showed nuclear and cellular degradation commenced before the flowers were fully open and that epidermal cells remained intact whilst the mesophyll cells degenerated completely. DNA laddering increased throughout petal development. Expression of the ALSDAD-1 partial cDNA was shown to be downregulated after flower opening. •  We conclude that some PCD processes are started extremely early and proceed throughout flower opening and senescence, whereas others occur more rapidly between stages 4-6 (i.e. postanthesis). The spatial distribution of PCD across the petals is discussed. Several molecular and physiological markers of PCD are present during Alstroemeria petal senescence.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1046/j.1469-8137.2003.00853.xDOI Listing
October 2003

Clonal architecture in mesothelioma is prognostic and shapes the tumour microenvironment.

Nat Commun 2021 03 19;12(1):1751. Epub 2021 Mar 19.

Department of Genetics and Genome Biology, University of Leicester, Leicester, UK.

Malignant Pleural Mesothelioma (MPM) is typically diagnosed 20-50 years after exposure to asbestos and evolves along an unknown evolutionary trajectory. To elucidate this path, we conducted multi-regional exome sequencing of 90 tumour samples from 22 MPMs acquired at surgery. Here we show that exomic intratumour heterogeneity varies widely across the cohort. Phylogenetic tree topology ranges from linear to highly branched, reflecting a steep gradient of genomic instability. Using transfer learning, we detect repeated evolution, resolving 5 clusters that are prognostic, with temporally ordered clonal drivers. BAP1/-3p21 and FBXW7/-chr4 events are always early clonal. In contrast, NF2/-22q events, leading to Hippo pathway inactivation are predominantly late clonal, positively selected, and when subclonal, exhibit parallel evolution indicating an evolutionary constraint. Very late somatic alteration of NF2/22q occurred in one patient 12 years after surgery. Clonal architecture and evolutionary clusters dictate MPM inflammation and immune evasion. These results reveal potentially drugable evolutionary bottlenecking in MPM, and an impact of clonal architecture on shaping the immune landscape, with potential to dictate the clinical response to immune checkpoint inhibition.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-021-21798-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7979861PMC
March 2021

Palliative radiotherapy after oesophageal cancer stenting (ROCS): a multicentre, open-label, phase 3 randomised controlled trial.

Lancet Gastroenterol Hepatol 2021 04 19;6(4):292-303. Epub 2021 Feb 19.

Centre for Trials Research, Cardiff University, Cardiff, UK.

Background: Patients with advanced oesophageal cancer have a median survival of 3-6 months, and most require intervention for dysphagia. Self-expanding metal stent (SEMS) insertion is the most typical form of palliation in these patients, but dysphagia deterioration and re-intervention are common. This study examined the efficacy of adjuvant external beam radiotherapy (EBRT) compared with usual care alone in preventing dysphagia deterioration and reducing service use after SEMS insertion.

Methods: This was a multicentre, open-label, phase 3 randomised controlled trial based at cancer centres and acute care hospitals in England, Scotland, and Wales. Patients (aged ≥16 years) with incurable oesophageal carcinoma receiving stent insertion for primary management of dysphagia were randomly assigned (1:1) to receive usual care alone or EBRT (20 Gy in five fractions or 30 Gy in ten fractions) plus usual care after stent insertion. Usual care was implemented according to need as identified by the local multidisciplinary team (MDT). Randomisation was via the method of minimisation stratified by treating centre, stage at diagnosis (I-III vs IV), histology (squamous or non-squamous), and MDT intent to give chemotherapy (yes vs no). The primary outcome was difference in proportions of participants with dysphagia deterioration (>11 point decrease on patient-reported European Organisation for Research and Treatment of Cancer quality of life questionnaire-oesophagogastric module [QLQ-OG25], or a dysphagia-related event consistent with such a deterioration) or death by 12 weeks in a modified intention-to-treat (ITT) population, which excluded patients who did not have a stent inserted and those without a baseline QLQ-OG25 assessment. Secondary outcomes included survival, quality of life (QoL), morbidities (including time to first bleeding event or hospital admission for bleeding event and first dysphagia-related stent complications or re-intervention), and cost-effectiveness. Safety analysis was undertaken in the modified ITT population. The study is registered with the International Standard Randomised Controlled Trial registry, ISRCTN12376468, and ClinicalTrials.gov, NCT01915693, and is completed.

Findings: 220 patients were randomly assigned between Dec 16, 2013, and Aug 24, 2018, from 23 UK centres. The modified ITT population (n=199) comprised 102 patients in the usual care group and 97 patients in the EBRT group. Radiotherapy did not reduce dysphagia deterioration, which was reported in 36 (49%) of 74 patients receiving usual care versus 34 (45%) of 75 receiving EBRT (adjusted odds ratio 0·82 [95% CI 0·40-1·68], p=0·59) in those with complete data for the primary endpoint. No significant difference was observed in overall survival: median overall survival was 19·7 weeks (95% CI 14·4-27·7) with usual care and 18·9 weeks (14·7-25·6) with EBRT (adjusted hazard ratio 1·06 [95% CI 0·78-1·45], p=0·70; n=199). Median time to first bleeding event or hospital admission for a bleeding event was 49·0 weeks (95% CI 33·3-not reached) with usual care versus 65·9 weeks (52·7-not reached) with EBRT (adjusted subhazard ratio 0·52 [95% CI 0·28-0·97], p=0·038; n=199). No time versus treatment interaction was observed for prespecified QoL outcomes. We found no evidence of differences between trial group in time to first stent complication or re-intervention event. The most common (grade 3-4) adverse event was fatigue, reported in 19 (19%) of 102 patients receiving usual care alone and 22 (23%) of 97 receiving EBRT. On cost-utility analysis, EBRT was more expensive and less efficacious than usual care.

Interpretation: Patients with advanced oesophageal cancer having SEMS insertion for the primary management of their dysphagia did not gain additional benefit from concurrent palliative radiotherapy and it should not be routinely offered. For a minority of patients clinically considered to be at high risk of tumour bleeding, concurrent palliative radiotherapy might reduce bleeding risk and the need for associated interventions.

Funding: National Institute for Health Research Health Technology Assessment Programme.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S2468-1253(21)00004-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7955283PMC
April 2021

Supporting self-care for eczema: protocol for two randomised controlled trials of ECO (Eczema Care Online) interventions for young people and parents/carers.

BMJ Open 2021 Feb 5;11(2):e045583. Epub 2021 Feb 5.

School of Primary Care, Population Health and Medical Education, University of Southampton, Southampton, UK.

Introduction: Eczema care requires management of triggers and various treatments. We developed two online behavioural interventions to support eczema care called ECO (Eczema Care Online) for young people and ECO for families. This protocol describes two randomised controlled trials (RCTs) aimed to evaluate clinical and cost-effectiveness of the two interventions. METHODS AND ANALYSIS: : Two independent, pragmatic, unmasked, parallel group RCTs with internal pilots and nested health economic and process evaluation studies. : Participants will be recruited from general practitioner practices in England. : Young people aged 13-25 years with eczema and parents and carers of children aged 0-12 years with eczema, excluding inactive or very mild eczema (five or less on Patient-Oriented Eczema Measure (POEM)). : Participants will be randomised to online intervention plus usual care or to usual eczema care alone. : Primary outcome is eczema severity over 24 weeks measured by POEM. Secondary outcomes include POEM 4-weekly for 52 weeks, quality of life, eczema control, itch intensity (young people only), patient enablement, health service and treatment use. Process measures include treatment adherence, barriers to adherence and intervention usage. Our sample sizes of 303 participants per trial are powered to detect a group difference of 2.5 (SD 6.5) in monthly POEM scores over 24 weeks (significance 0.05, power 0.9), allowing for 20% loss to follow-up. Cost-effectiveness analysis will be from a National Health Service and personal social service perspective. Qualitative and quantitative process evaluation will help understand the mechanisms of action and participant experiences and inform implementation.

Ethics And Dissemination: The study has been approved by South Central Oxford A Research Ethics Committee (19/SC/0351). Recruitment is ongoing, and follow-up will be completed by mid-2022. Findings will be disseminated to participants, the public, dermatology and primary care journals, and policy makers.

Trial Registration Number: ISRCTN79282252.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/bmjopen-2020-045583DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7925854PMC
February 2021

Pelargonium sidoides root extract for the treatment of acute cough due to lower respiratory tract infection in adults: a feasibility double-blind, placebo-controlled randomised trial.

BMC Complement Med Ther 2021 Jan 29;21(1):48. Epub 2021 Jan 29.

School of Primary Care, Population Sciences and Medical Education, University of Southampton, Aldermoor Health Centre, Aldermoor Close, Southampton, SO16 5ST, UK.

Background: Pelargonium sidoides DC (Geraniaceae) root extract, EPs®7630 or "Kaloba®", is a widely used herbal remedy for respiratory infections, with some evidence of effectiveness for acute bronchitis. However, it is not yet widely recommended by medical professionals in the UK. There is a need to undertake appropriately designed randomised trials to test its use as an alternative to antibiotics. The aim was to assess the feasibility of conducting a double-blind randomised controlled trial of Pelargonium sidoides root extract for treatment of acute bronchitis in UK primary care, investigating intervention compliance, patient preference for dosage form and acceptability of patient diaries.

Study Design: Feasibility double-blind randomised placebo-controlled clinical trial.

Methods: We aimed to recruit 160 patients with cough (≤ 21 days) caused by acute bronchitis from UK general practices. Practices were cluster-randomised to liquid or tablet preparations and patients were individually randomised to Kaloba® or placebo. We followed participants up for 28 days through self-reported patient diaries with telephone support and reviewed medical records at one month. Outcomes included recruitment, withdrawal, safety, reconsultation and symptom diary completion rates. We also assessed treatment adherence, antibiotic prescribing and consumption, mean symptom severity (at days 2-4 after randomisation) and time to symptom resolution. We interviewed 29 patients and 11 health professionals to identify barriers and facilitators to running such a randomised trial.

Results: Of 543 patients screened, 261 were eligible, of whom 134 (51%) were recruited and 103 (77%) returned a completed diary. Overall, 41% (41/100) of patients took antibiotics (Kaloba® liquid group: 48% [15/31]; placebo liquid group: 23% [6/26]; Kaloba® tablet group: 48% [9/21]; placebo tablet group: 50% [11/22]). Most patients adhered to the study medication (median 19 out of 21 doses taken in week 1, IQR 18-21 - all arms combined). There were no serious adverse events relating to treatment. Most patients interviewed found study recruitment to be straightforward, but some found the diary too complex.

Conclusions: It was feasible and acceptable to recruit patients from UK primary care to a double-blind placebo-controlled trial of herbal medicine (Kaloba®) for the treatment of acute bronchitis, with good retention and low data attrition.

Trial Registration: HATRIC was registered on the ISRCTN registry ( ISRCTN17672884 ) on 16 August 2018, retrospectively registered. The record can be found at http://www.isrctn.com/ISRCTN17672884 .
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12906-021-03206-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7845084PMC
January 2021

Phase I Trial of DNA Methyltransferase Inhibitor Guadecitabine Combined with Cisplatin and Gemcitabine for Solid Malignancies Including Urothelial Carcinoma (SPIRE).

Clin Cancer Res 2021 Apr 20;27(7):1882-1892. Epub 2021 Jan 20.

Southampton Clinical Trials Unit, University of Southampton, Southampton, England, United Kingdom.

Purpose: Preclinical data indicate that DNA methyltransferase inhibition will circumvent cisplatin resistance in various cancers.

Patient And Methods: SPIRE comprised a dose-escalation phase for incurable metastatic solid cancers, followed by a randomized dose expansion phase for neoadjuvant treatment of T2-4a N0 M0 bladder urothelial carcinoma. The primary objective was a recommended phase II dose (RP2D) for guadecitabine combined with gemcitabine and cisplatin. Treatment comprised 21-day gemcitabine and cisplatin cycles (cisplatin 70 mg/m, i.v., day 8 and gemcitabine 1,000 mg/m, i.v., days 8 + 15). Guadecitabine was injected subcutaneously on days 1-5, within escalation phase cohorts, and to half of 20 patients in the expansion phase. Registration ID: ISRCTN 16332228.

Results: Within the escalation phase, dose-limiting toxicities related predominantly to myelosuppression requiring G-CSF prophylaxis from cohort 2 (guadecitabine 20 mg/m, days 1-5). The most common grade ≥3 adverse events in 17 patients in the dose-escalation phase were neutropenia (76.5%), thrombocytopenia (64.7%), leukopenia (29.4%), and anemia (29.4%). Addition of guadecitabine to gemcitabine and cisplatin in the expansion phase resulted in similar rates of severe hematologic adverse events, similar cisplatin dose intensity, but modestly reduced gemcitabine dose intensity. Radical treatment options after chemotherapy were not compromised. Pharmacodynamics evaluations indicated guadecitabine maximal target effect at the point of cisplatin administration. Pharmacokinetics were consistent with prior data. No treatment-related deaths occurred.

Conclusions: The guadecitabine RP2D was 20 mg/m, days 1-5, in combination with gemcitabine and cisplatin and required GCSF prophylaxis. Gene promoter methylation pharmacodynamics are optimal with this schedule. Addition of guadecitabine to gemcitabine and cisplatin was tolerable, despite some additional myelosuppression, and warrants further investigation to assess efficacy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1078-0432.CCR-20-3946DOI Listing
April 2021

Biodistribution of surfactant-free poly(lactic-acid) nanoparticles and uptake by endothelial cells and phagocytes in zebrafish: Evidence for endothelium to macrophage transfer.

J Control Release 2021 Mar 11;331:228-245. Epub 2021 Jan 11.

CNRS, University Lyon 1, UMR 5305, Laboratory of Tissue Biology and Therapeutic Engineering, IBCP, 7 Passage du Vercors, 69367 Lyon Cedex 07, France.

In the development of therapeutic nanoparticles (NP), there is a large gap between in vitro testing and in vivo experimentation. Despite its prominence as a model, the mouse shows severe limitations for imaging NP and the cells with which they interact. Recently, the transparent zebrafish larva, which is well suited for high-resolution live-imaging, has emerged as a powerful alternative model to investigate the in vivo behavior of NP. Poly(D,L lactic acid) (PLA) is widely accepted as a safe polymer to prepare therapeutic NP. However, to prevent aggregation, many NP require surfactants, which may have undesirable biological effects. Here, we evaluate 'safe-by-design', surfactant-free PLA-NP that were injected intravenously into zebrafish larvae. Interaction of fluorescent NPs with different cell types labelled in reporter animals could be followed in real-time at high resolution; furthermore, by encapsulating colloidal gold into the matrix of PLA-NP we could follow their fate in more detail by electron microscopy, from uptake to degradation. The rapid clearance of fluorescent PLA-NP from the circulation coincided with internalization by endothelial cells lining the whole vasculature and macrophages. After 30 min, when no NP remained in circulation, we observed that macrophages continued to internalize significant amounts of NP. More detailed video-imaging revealed a new mechanism of NP transfer where NP are transmitted along with parts of the cytoplasm from endothelial cells to macrophages.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jconrel.2021.01.006DOI Listing
March 2021

Pan-AKT Inhibitor Capivasertib With Docetaxel and Prednisolone in Metastatic Castration-Resistant Prostate Cancer: A Randomized, Placebo-Controlled Phase II Trial (ProCAID).

J Clin Oncol 2021 Jan 16;39(3):190-201. Epub 2020 Dec 16.

University of Glasgow, Beatson West of Scotland Cancer Centre, Glasgow, United Kingdom.

Purpose: Capivasertib is a pan-AKT inhibitor. Preclinical data indicate activity in metastatic castration-resistant prostate cancer (mCRPC) and synergism with docetaxel.

Patients And Methods: ProCAID was a placebo controlled randomized phase II trial in mCRPC. Patients received up to ten 21-day cycles of docetaxel (75 mg/m intravenous, day 1) and prednisolone (5 mg twice daily, oral, day 1-21) and were randomly assigned (1:1) to oral capivasertib (320 mg twice daily, 4 days on/3 days off, from day 2 each cycle), or placebo, until disease progression. Treatment allocation used minimization factors: bone metastases; visceral metastases; investigational site; and prior abiraterone or enzalutamide. The primary objective, by intention to treat, determined if the addition of capivasertib prolonged a composite progression-free survival (cPFS) end point that included prostate-specific antigen progression events. cPFS and overall survival (OS) were also assessed by composite biomarker subgroup for PI3K/AKT/PTEN pathway activation status.

Results: One hundred and fifty patients were enrolled. Median cPFS was 7.03 (95% CI, 6.28 to 8.25) and 6.70 months (95% CI, 5.52 to 7.36) with capivasertib and placebo respectively (hazard ratio [HR], 0.92; 80% CI, 0.73 to 1.16; one-sided = .32). Median OS was 31.15 (95% CI, 20.07 to not reached) and 20.27 months (95% CI, 17.51 to 24.18), respectively (HR, 0.54; 95% CI, 0.34 to 0.88; two-sided = .01). cPFS and OS results were consistent irrespective of PI3K/AKT/PTEN pathway activation status. Grade III-IV adverse events were equivalent between arms (62.2%). The most common adverse events of any grade deemed related to capivasertib were diarrhea, fatigue, nausea, and rash.

Conclusion: The addition of capivasertib to chemotherapy did not extend cPFS in mCRPC irrespective of PI3K/AKT/PTEN pathway activation status. The observed OS result (a secondary end point) will require prospective validation in future studies to address potential for bias.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/JCO.20.01576DOI Listing
January 2021

The Active Brains Digital Intervention to Reduce Cognitive Decline in Older Adults: Protocol for a Feasibility Randomized Controlled Trial.

JMIR Res Protoc 2020 Nov 20;9(11):e18929. Epub 2020 Nov 20.

Centre for Community and Clinical Applications of Health Psychology, University of Southampton, Southampton, United Kingdom.

Background: Increasing physical activity, improving diet, and performing brain training exercises are associated with reduced cognitive decline in older adults.

Objective: In this paper, we describe a feasibility trial of the Active Brains intervention, a web-based digital intervention developed to support older adults to make these 3 healthy behavior changes associated with improved cognitive health. The Active Brains trial is a randomized feasibility trial that will test how accessible, acceptable, and feasible the Active Brains intervention is and the effectiveness of the study procedures that we intend to use in the larger, main trial.

Methods: In the randomized controlled trial (RCT), we use a parallel design. We will be conducting the intervention with 2 populations recruited through GP practices (family practices) in England from 2018 to 2019: older adults with signs of cognitive decline and older adults without any cognitive decline. Trial participants were randomly allocated to 1 of 3 study groups: usual care, the Active Brains intervention, or the Active Brains website plus brief support from a trained coach (over the phone or by email). The main outcomes are performance on cognitive tasks, quality of life (using EuroQol-5D 5 level), Instrumental Activities of Daily Living, and diagnoses of dementia. Secondary outcomes (including depression, enablement, and health care costs) and process measures (including qualitative interviews with participants and supporters) will also be collected. The trial has been approved by the National Health Service Research Ethics Committee (reference 17/SC/0463).

Results: Results will be published in peer-reviewed journals, presented at conferences, and shared at public engagement events. Data collection was completed in May 2020, and the results will be reported in 2021.

Conclusions: The findings of this study will help us to identify and make important changes to the website, the support received, or the study procedures before we progress to our main randomized phase III trial.

Trial Registration: International Standard Randomized Controlled Trial Number 23758980; http://www.isrctn.com/ISRCTN23758980.

International Registered Report Identifier (irrid): DERR1-10.2196/18929.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2196/18929DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7718093PMC
November 2020

Factors Associated with Attrition and Performance Throughout Surgical Training: A Systematic Review and Meta-Analysis.

World J Surg 2021 Feb 26;45(2):429-442. Epub 2020 Oct 26.

Division of Epidemiology and Public Health, Nottingham Digestive Diseases Centre, School of Medicine, University of Nottingham, Nottingham, UK.

Background: Attrition within surgical training is a challenge. In the USA, attrition rates are as high as 20-26%. The factors predicting attrition are not well known. The aim of this systematic review is to identify factors that influence attrition or performance during surgical training.

Method: The review was performed in line with PRISMA guidelines and registered with the Open Science Framework (OSF). Medline, EMBASE, PubMed and the Cochrane Central Register of Controlled Trials were searched for articles. Risk of bias was assessed using the Newcastle-Ottawa scale. Pooled estimates were calculated using random effects meta-analyses in STATA version 15 (Stata Corp Ltd). A sensitivity analysis was performed including only multi-institutional studies.

Results: The searches identified 3486 articles, of which 31 were included, comprising 17,407 residents. Fifteen studies were based on multi-institutional data and 16 on single-institutional data. Twenty-nine of the studies are based on US residents. The pooled estimate for overall attrition was 17% (95% CI 14-20%). Women had a significantly higher pooled attrition than men (24% vs 16%, p < 0.001). Some studies reported Hispanic residents had a higher attrition rate than non-Hispanic residents. There was no increased risk of attrition with age, marital or parental status. Factors reported to affect performance were non-white ethnicity and faculty assessment of clinical performance. Childrearing was not associated with performance.

Conclusion: Female gender is associated with higher attrition in general surgical residency. Longitudinal studies of contemporary surgical cohorts are needed to investigate the complex multi-factorial reasons for failing to complete surgical residency.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00268-020-05844-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7773620PMC
February 2021

ACCEPT - combining acalabrutinib with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP) for Diffuse Large B-cell Lymphoma (DLBCL): study protocol for a Phase Ib/II open-label non-randomised clinical trial.

F1000Res 2020 7;9:941. Epub 2020 Aug 7.

Southampton Clinical Trials Unit, University of Southampton and University Hospital Southampton NHS Foundation Trust, Southampton, UK.

Over 13,000 new cases of non-Hodgkin's lymphoma (NHL) are diagnosed in the UK, with approximately 4,900 attributable deaths each year. Diffuse Large B-cell Lymphoma (DLBCL) is the most common NHL comprising one third of adult NHL cases. R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone) is accepted as the international standard first-line regimen, but improvement in first line treatment is needed. Dysregulated B-cell receptor (BCR) signalling has been identified as a feature of DLBCL. Inhibition of Bruton's tyrosine kinase (Btk), downstream of the BCR has proven efficacious in other B-cell malignancies and in combination with R-CHOP. The second generation Btk inhibitor, acalabrutinib, may have improved target potency and specificity, and therefore better efficacy and tolerability. ACCEPT is an open-label non-randomised Phase Ib/II trial testing the addition of acalabrutinib to conventional R-CHOP therapy. ACCEPT incorporates an initial 6+6 modified Phase I design of up to 24 participants followed by 15 participant single arm Phase II expansion cohort in treatment naive patients with histologically confirmed DLBCL expressing CD20. Participants are recruited from UK secondary care sites. Phase I will establish the recommended Phase II dose (RP2D, primary endpoint) of acalabrutinib in combination with R-CHOP. Phase II will gain additional information on safety and efficacy on the RP2D. The primary endpoints of Phase II are overall response rate and toxicity profile. Secondary endpoints include duration of response (progression-free survival and overall survival OS) in relation to cell of origin. Analyses are not powered for formal statistical comparisons; descriptive statistics will describe rates of toxicity, efficacy and translational endpoints.  ACCEPT will provide evidence for whether acalabrutinib in combination with R-CHOP is safe and biologically effective prior to future Phase II/III trials in patients with previously untreated CD20 positive DLBCL. EudraCT Number: 2015-003213-18 (issued 16 July 2015); ISRCTN 13626902 (registered 07 March 2017).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.12688/f1000research.22318.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7551525PMC
August 2020

Evaluating prophylactic heparin in ambulatory patients with solid tumours: a systematic review and individual participant data meta-analysis.

Lancet Haematol 2020 Oct;7(10):e746-e755

Department of Internal Medicine, American University of Beirut, Beirut, Lebanon.

Background: Study-level meta-analyses provide high-certainty evidence that heparin reduces the risk of symptomatic venous thromboembolism for patients with cancer; however, whether the benefits and harms associated with heparin differ by cancer type is unclear. This individual participant data meta-analysis of randomised controlled trials examines the effect of heparin on survival, venous thromboembolism, and bleeding in patients with cancer in general and by type.

Methods: In this systematic review and meta-analysis we searched MEDLINE, Embase, and The Cochrane Library for randomised controlled trials comparing parenteral anticoagulants with placebo or standard care in ambulatory patients with solid tumours and no indication for anticoagulation published from the inception of each database to January 14, 2017, and updated it on May 14, 2020, without language restrictions. We calculated the effect of parenteral anticoagulant administration on all-cause mortality, venous thromboembolism occurrence, and bleeding related outcomes through multivariable hierarchical models with patient-level variables as fixed effects and a categorical trial variable as a random effect, adjusting for age, cancer type, and metastatic status. Interaction terms were tested to investigate effects in predefined subgroups. This study is registered with PROSPERO, CRD42013003526.

Findings: We obtained individual participant data from 14 of 20 eligible randomised controlled trials (8278 [79%] of 10 431 participants; 4139 included in the low-molecular-weight heparin group and 4139 in the control group). Meta-analysis showed an adjusted relative risk (RR) of mortality at 1 year of 0·99 (95% CI 0·93-1·06) and a hazard ratio of 1·01 (95% CI 0·96-1·07). The number of patients with venous thromboembolic events was 158 (4·0%) of 3958 with available data in the low-molecular-weight heparin group compared with 279 (7·1%) of 3957 in the control group. Major bleeding events occurred in 71 (1·7%) of 4139 patients in the control population and 88 (2·1%) in the low-molecular-weight heparin group, and minor bleeding events in 478 (12·1%) of 3945 patients with available data in the control group and 652 (16·6%) of 3937 patients in the low-molecular-weight heparin group. The adjusted RR was 0·58 (95% CI 0·47-0·71) for venous thromboembolism, 1·27 (0·92-1·74) for major bleeding, and 1·34 (1·19-1·51) for minor bleeding. Prespecified subgroup analysis of venous thromboembolism occurrence by cancer type identified the most certain benefit from heparin treatment in patients with lung cancer (RR 0·59 [95% CI 0·42-0·81]), which dominated the overall reduction in venous thromboembolism. Certainty of the evidence for the outcomes ranged from moderate to high.

Interpretation: Low-molecular-weight heparin reduces risk of venous thromboembolism without increasing risk of major bleeding compared with placebo or standard care in patients with solid tumours, but it does not improve survival.

Funding: Canadian Institutes of Health Research.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S2352-3026(20)30293-3DOI Listing
October 2020

Supporting self-management of low back pain with an internet intervention in primary care: a protocol for a randomised controlled trial of clinical and cost-effectiveness (SupportBack 2).

BMJ Open 2020 08 20;10(8):e040543. Epub 2020 Aug 20.

Primary Care, Population Sciences and Medical Education, University of Southampton, Southampton, Hampshire, UK.

Introduction: Self-management and remaining physically active are first-line recommendations for the care of patients with low back pain (LBP). With a lifetime prevalence of up to 85%, novel approaches to support behavioural self-management are needed. Internet interventions may provide accessible support for self-management of LBP in primary care. The aim of this randomised controlled trial is to determine the clinical and cost-effectiveness of the 'SupportBack' internet intervention, with or without physiotherapist telephone support in reducing LBP-related disability in primary care patients.

Methods And Analysis: A three-parallel arm, multicentre randomised controlled trial will compare three arms: (1) usual primary care for LBP; (2) usual primary care for LBP and an internet intervention; (3) usual primary care for LBP and an internet intervention with additional physiotherapist telephone support. Patients with current LBP and no indicators of serious spinal pathology are identified and invited via general practice list searches and mailouts or opportunistic recruitment following LBP consultations. Participants undergo a secondary screen for possible serious spinal pathology and are then asked to complete baseline measures online after which they are randomised to an intervention arm. Follow-ups occur at 6 weeks, 3, 6 and 12 months. The primary outcome is physical function (using the Roland and Morris Disability Questionnaire) over 12 months (repeated measures design). Secondary outcomes include pain intensity, troublesome days in pain over the last month, pain self-efficacy, catastrophising, kinesophobia, health-related quality of life and cost-related measures for a full health economic analysis. A full mixed-methods process evaluation will be conducted.

Ethics And Dissemination: This trial has been approved by a National Health Service Research Ethics Committee (REC Ref: 18/SC/0388). Results will be disseminated through peer-reviewed journals, conferences, communication with practices and patient groups. Patient representatives will support the implementation of our full dissemination strategy.

Trial Registration Number: ISRCTN14736486.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/bmjopen-2020-040543DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7440707PMC
August 2020

ACCORD: A Multicentre, Seamless, Phase 2 Adaptive Randomisation Platform Study to Assess the Efficacy and Safety of Multiple Candidate Agents for the Treatment of COVID-19 in Hospitalised Patients: A structured summary of a study protocol for a randomised controlled trial.

Trials 2020 Jul 31;21(1):691. Epub 2020 Jul 31.

University of Manchester, Manchester, UK.

Objectives: Stage 1: To evaluate the safety and efficacy of candidate agents as add-on therapies to standard of care (SoC) in patients hospitalised with COVID-19 in a screening stage. Stage 2: To confirm the efficacy of candidate agents selected on the basis of evidence from Stage 1 in patients hospitalised with COVID-19 in an expansion stage.

Trial Design: ACCORD is a seamless, Phase 2, adaptive, randomised controlled platform study, designed to rapidly test candidate agents in the treatment of COVID-19. Designed as a master protocol with each candidate agent being included via its own sub-protocol, initially randomising equally between each candidate and a single contemporaneous SoC arm (which can adapt into 2:1). Candidate agents currently include bemcentinib, MEDI3506, acalabrutinib, zilucoplan and nebulised heparin. For each candidate a total of 60 patients will be recruited in Stage 1. If Stage 1 provides evidence of efficacy and acceptable safety the candidate will enter Stage 2 where a total of approximately 126 patients will be recruited into each study arm sub-protocol. Enrollees and outcomes will not be shared across the Stages; the endpoint, analysis and sample size for Stage 2 may be adjusted based on evidence from Stage 1. Additional arms may be added as new potential candidate agents are identified via candidate agent specific sub-protocols.

Participants: The study will include hospitalised adult patients (≥18 years) with confirmed SARS-CoV-2 infection, the virus that causes COVID-19, that clinically meet Grades 3 (hospitalised - mild disease, no oxygen therapy), Grades 4 (hospitalised, oxygen by mask or nasal prongs) and 5 (hospitalised, non-invasive ventilation or high flow oxygen) of the WHO Working Group on the Clinical Characteristics of COVID-19 9-point category ordinal scale. Participants will be recruited from England, Northern Ireland, Wales and Scotland.

Intervention And Comparator: Comparator is current standard of care (SoC) for the treatment of COVID-19. Current candidate experimental arms include bemcentinib, MEDI3506, acalabrutinib, zilucoplan and nebulised heparin with others to be added over time. Bemcentinib could potentially reduce viral infection and blocks SARS-CoV-2 spike protein; MEDI3506 is a clinic-ready anti-IL-33 monoclonal antibody with the potential to treat respiratory failure caused by COVID; acalabrutinib is a BTK inhibitor which is anti-viral and anti-inflammatory; zilucoplan is a complement C5 inhibitor which may block the severe inflammatory response in COVID-19 and; nebulised heparin has been shown to bind with the spike protein. ACCORD is linked with the UK national COVID therapeutics task force to help prioritise candidate agents.

Main Outcomes: Time to sustained clinical improvement of at least 2 points (from randomisation) on the WHO 9-point category ordinal scale, live discharge from the hospital, or considered fit for discharge (a score of 0, 1, or 2 on the ordinal scale), whichever comes first, by Day 29 (this will also define the "responder" for the response rate analyses).

Randomisation: An electronic randomization will be performed by Cenduit using Interactive Response Technology (IRT). Randomisation will be stratified by baseline severity grade. Randomisation will proceed with an equal allocation to each arm and a contemporaneous SoC arm (e.g. 1:1 if control and 1 experimental arm; 1:1:1 if two experimental candidate arms etc) but will be reviewed as the trial progresses and may be changed to 2:1 in favour of the candidate agents.

Blinding (masking): The trial is open label and no blinding is currently planned in the study.

Numbers To Be Randomised (sample Size): This will be in the order of 60 patients per candidate agent for Stage 1, and 126 patients for Stage 2. However, sample size re-estimation may be considered after Stage 1. It is estimated that up to 1800 patients will participate in the overall study.

Trial Status: Master protocol version ACCORD-2-001 - Master Protocol (Amendment 1) 22 April 2020, the trial has full regulatory approval and recruitment is ongoing in the bemcentinib (first patient recruited 6/5/2020), MEDI3506 (first patient recruited 19/5/2020), acalabrutinib (first patient recruited 20/5/2020) and zilucoplan (first patient recruited 19/5/2020) candidates (and SoC). The recruitment dates of each arm will vary between candidate agents as they are added or dropped from the trial, but will have recruited and reported within a year.

Trial Registration: EudraCT 2020-001736-95 , registered 28 April 2020.

Full Protocol: The full protocol (Master Protocol with each of the candidate sub-protocols) is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13063-020-04584-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7393340PMC
July 2020

Real-time imaging of polymersome nanoparticles in zebrafish embryos engrafted with melanoma cancer cells: Localization, toxicity and treatment analysis.

EBioMedicine 2020 Aug 21;58:102902. Epub 2020 Jul 21.

University of Oslo, Department of Biosciences, Blindernveien 31, 0371 Oslo, Norway. Electronic address:

Background: The developing zebrafish is an emerging tool in nanomedicine, allowing non-invasive live imaging of the whole animal at higher resolution than is possible in the more commonly used mouse models. In addition, several transgenic fish lines are available endowed with selected cell types expressing fluorescent proteins; this allows nanoparticles to be visualized together with host cells.

Methods: Here, we introduce the zebrafish neural tube as a robust injection site for cancer cells, excellently suited for high resolution imaging. We use light and electron microscopy to evaluate cancer growth and to follow the fate of intravenously injected nanoparticles.

Findings: Fluorescently labelled mouse melanoma B16 cells, when injected into this structure proliferated rapidly and stimulated angiogenesis of new vessels. In addition, macrophages, but not neutrophils, selectively accumulated in the tumour region. When injected intravenously, nanoparticles made of Cy5-labelled poly(ethylene glycol)-block-poly(2-(diisopropyl amino) ethyl methacrylate) (PEG-PDPA) selectively accumulated in the neural tube cancer region and were seen in individual cancer cells and tumour associated macrophages. Moreover, when doxorubicin was released from PEG-PDPA, in a pH dependant manner, these nanoparticles could strongly reduce toxicity and improve the treatment outcome compared to the free drug in zebrafish xenotransplanted with mouse melanoma B16 or human derived melanoma cells.

Interpretation: The zebrafish has the potential of becoming an important intermediate step, before the mouse model, for testing nanomedicines against patient-derived cancer cells.

Funding: We received funding from the Norwegian research council and the Norwegian cancer society.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ebiom.2020.102902DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7381511PMC
August 2020

Jasmonates: biosynthesis, perception and signal transduction.

Authors:
Gareth Griffiths

Essays Biochem 2020 09;64(3):501-512

Energy and Bioproducts Research Institute, Chemical Engineering and Applied Chemistry, Aston University, Birmingham B4 7ET, UK.

Jasmonates (JAs) are physiologically important molecules involved in a wide range of plant responses from growth, flowering, senescence to defence against abiotic and biotic stress. They are rapidly synthesised from α-linolenic acid (ALA; C18:3 ∆9,12,15) by a process of oxidation, cyclisation and acyl chain shortening involving co-operation between the chloroplast and peroxisome. The active form of JA is the isoleucine conjugate, JA-isoleucine (JA-Ile), which is synthesised in the cytoplasm. Other active metabolites of JA include the airborne signalling molecules, methyl JA (Me-JA) and cis-jasmone (CJ), which act as inter-plant signalling molecules activating defensive genes encoding proteins and secondary compounds such as anthocyanins and alkaloids. One of the key defensive metabolites in many plants is a protease inhibitor that inactivates the protein digestive capabilities of insects, thereby, reducing their growth. The receptor for JA-Ile is a ubiquitin ligase termed as SCFCoi1 that targets the repressor protein JA Zim domain (JAZ) for degradation in the 26S proteasome. Removal of JAZ allows other transcription factors (TFs) to activate the JA response. The levels of JA-Ile are controlled through catabolism by hydroxylating enzymes of the cytochrome P450 (CYP) family. The JAZ proteins act as metabolic hubs and play key roles in cross-talk with other phytohormone signalling pathways in co-ordinating genome-wide responses. Specific subsets of JAZ proteins are involved in regulating different response outcomes such as growth inhibition versus biotic stress responses. Understanding the molecular circuits that control plant responses to pests and pathogens is a necessary pre-requisite to engineering plants with enhanced resilience to biotic challenges for improved agricultural yields.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1042/EBC20190085DOI Listing
September 2020

AGILE-ACCORD: A Randomized, Multicentre, Seamless, Adaptive Phase I/II Platform Study to Determine the Optimal Dose, Safety and Efficacy of Multiple Candidate Agents for the Treatment of COVID-19: A structured summary of a study protocol for a randomised platform trial.

Trials 2020 Jun 19;21(1):544. Epub 2020 Jun 19.

University of Liverpool, Liverpool, UK.

Objectives: Phase I - To determine the optimal dose of each candidate (or combination of candidates) entered into the platform. Phase II - To determine the efficacy and safety of each candidate entered into the platform, compared to the current Standard of Care (SoC), and recommend whether it should be evaluated further in a later phase II & III platforms.

Trial Design: AGILE-ACCORD is a Bayesian multicentre, multi-arm, multi-dose, multi-stage open-label, adaptive, seamless phase I/II randomised platform trial to determine the optimal dose, activity and safety of multiple candidate agents for the treatment of COVID-19. Designed as a master protocol with each candidate being evaluated within its own sub-protocol (Candidate Specific Trial (CST) protocol), randomising between candidate and SoC with 2:1 allocation in favour of the candidate (N.B the first candidate has gone through regulatory approval and is expected to open to recruitment early summer 2020). Each dose will be assessed for safety sequentially in cohorts of 6 patients. Once a phase II dose has been identified we will assess efficacy by seamlessly expanding into a larger cohort.

Participants: Patient populations can vary between CSTs, but the main eligibility criteria include adult patients (≥18 years) who have laboratory-confirmed infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We will include both severe and mild-moderate patients defined as follows: Group A (severe disease) - patients with WHO Working Group on the Clinical Characteristics of COVID-19 infection 9-point ordinal scale of Grades 4 (hospitalised, oxygen by mask or nasal prongs), 5 (hospitalised, non-invasive ventilation or high flow oxygen), 6 (hospitalised, intubation and mechanical ventilation) or 7 (hospitalised, ventilation and additional organ support); Group B (mild-moderate disease) - ambulant or hospitalised patients with peripheral capillary oxygen saturation (SpO) >94% RA. If any CSTs are included in the community setting, the CST protocol will clarify whether patients with suspected SARS-CoV-2 infection are also eligible. Participants will be recruited from England, North Ireland, Wales and Scotland.

Intervention And Comparator: Comparator is the current standard of care (SoC), in some CSTs plus placebo. Candidates that prevent uncontrolled cytokine release, prevention of viral replication, and other anti-viral treatment strategies are at various stages of development for inclusion into AGILE-ACCORD. Other CSTs will be added over time. There is not a set limit on the number of CSTs we can include within the AGILE-ACCORD Master protocol and we will upload each CST into this publication as each opens to recruitment.

Main Outcomes: Phase I: Dose limiting toxicities using Common Terminology Criteria for Adverse Events v5 Grade ≥3 adverse events. Phase II: Agreed on a CST basis depending on mechanism of action of the candidate and patient population. But may include; time to clinical improvement of at least 2 points on the WHO 9-point category ordinal scale [measured up to 29 days from randomisation], progression of disease (oxygen saturation (SaO <92%) or hospitalization or death, or change in time-weighted viral load [measured up to 29 days from randomisation].

Randomisation: Varies with CST, but default is 2:1 allocation in favour of the candidate to maximise early safety data.

Blinding (masking): For the safety phase open-label although for some CSTs may include placebo or SoC for the efficacy phase.

Numbers To Be Randomised (sample Size): Varies between CSTs. However simulations have shown that around 16 participants are necessary to determine futility or promise of a candidate at a given dose (in efficacy evaluation alone) and between 32 and 40 participants are required across the dose-finding and efficacy evaluation when capping the maximum number of participants contributing to the evaluation of a treatment at 40.

Trial Status: Master protocol version number v5 07 May 2020, trial is in setup with full regulatory approval and utilises several digital technology solutions, including Medidata's Rave EDC [electronic data capture], RTSM for randomisation and patient eConsent on iPads via Rave Patient Cloud. The recruitment dates will vary between CSTs but at the time of writing no CSTs are yet open for recruitment.

Trial Registration: EudraCT 2020-001860-27 14 March 2020 FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13063-020-04473-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7303573PMC
June 2020

Digital tools for the recruitment and retention of participants in randomised controlled trials: a systematic map.

Trials 2020 Jun 5;21(1):478. Epub 2020 Jun 5.

Wessex Institute, Faculty of Medicine, University of Southampton, Alpha House, Southampton Science Park, Southampton, SO16 7NS, UK.

Background: Recruiting and retaining participants in randomised controlled trials (RCTs) is challenging. Digital tools, such as social media, data mining, email or text-messaging, could improve recruitment or retention, but an overview of this research area is lacking. We aimed to systematically map the characteristics of digital recruitment and retention tools for RCTs, and the features of the comparative studies that have evaluated the effectiveness of these tools during the past 10 years.

Methods: We searched Medline, Embase, other databases, the Internet, and relevant web sites in July 2018 to identify comparative studies of digital tools for recruiting and/or retaining participants in health RCTs. Two reviewers independently screened references against protocol-specified eligibility criteria. Included studies were coded by one reviewer with 20% checked by a second reviewer, using pre-defined keywords to describe characteristics of the studies, populations and digital tools evaluated.

Results: We identified 9163 potentially relevant references, of which 104 articles reporting 105 comparative studies were included in the systematic map. The number of published studies on digital tools has doubled in the past decade, but most studies evaluated digital tools for recruitment rather than retention. The key health areas investigated were health promotion, cancers, circulatory system diseases and mental health. Few studies focussed on minority or under-served populations, and most studies were observational. The most frequently-studied digital tools were social media, Internet sites, email and tv/radio for recruitment; and email and text-messaging for retention. One quarter of the studies measured efficiency (cost per recruited or retained participant) but few studies have evaluated people's attitudes towards the use of digital tools.

Conclusions: This systematic map highlights a number of evidence gaps and may help stakeholders to identify and prioritise further research needs. In particular, there is a need for rigorous research on the efficiency of the digital tools and their impact on RCT participants and investigators, perhaps as studies-within-a-trial (SWAT) research. There is also a need for research into how digital tools may improve participant retention in RCTs which is currently underrepresented relative to recruitment research.

Registration: Not registered; based on a pre-specified protocol, peer-reviewed by the project's Advisory Board.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13063-020-04358-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7273688PMC
June 2020

Patient-reported outcome measures for monitoring primary care patients with depression (PROMDEP): study protocol for a randomised controlled trial.

Trials 2020 May 29;21(1):441. Epub 2020 May 29.

Institute of Psychology Health and Society, University of Liverpool, Liverpool, L69 3GL, UK.

Background: Benefits to patients from reduced depression have been shown from monitoring progress with patient-reported outcome measures (PROMs) in psychological therapy and mental health settings. This approach has not yet been researched in the United Kingdom for primary care, which is where most people with depression are treated in the United Kingdom.

Methods: This is a parallel-group cluster randomised trial with 1:1 allocation to intervention and control. Patients who are age 18+ years, with a new episode of depressive disorder/symptoms, meet the inclusion criteria. Patients with current depression treatment, comorbid dementia/psychosis/substance misuse/suicidal ideas are excluded. The intervention includes the Administration of Patient Health Questionnaire (PHQ-9) as a PROM within 2 weeks of diagnosis and at follow-up 4 weeks later. General practitioners are trained in interpreting scores and asked to take them into account in their treatment decisions. Patients are given written feedback on scores and suggested treatments. The primary outcome measure is Depression on the Beck Depression Inventory BDI-II at 12 weeks. Secondary outcomes include BDI-II at 26 weeks, changes in drug treatments and referrals, social functioning (Work & Social Adjustment Scale) and quality of life (EQ-5D) at 12 and 26 weeks, service use over 26 weeks (modified Client Services Receipt Inventory) to calculate NHS costs, and patient satisfaction at 26 weeks (Medical Informant Satisfaction Scale). The sample includes 676 total participants from 113 practices across three centres. Randomisation is achieved by computerised sequence generation. Blinding is impossible given the nature of the intervention (self-report outcome measures prevent rating bias). Differences at 12 and 26 weeks between intervention and controls in depression, social functioning and quality of life are analysed using linear mixed models, adjusted for socio-demographics, baseline depression, anxiety, and clustering, while including practice as a random effect. Patient satisfaction, quality of life (QALYs) and costs over 26 weeks will be compared between arms. Qualitative process analysis includes interviews with 15-20 GP/NPs and 15-20 patients per arm to reflect trial results and implementation issues, using Normalization Process Theory as a theoretical framework.

Discussion: If PROMs are helpful in improving patient outcomes for depression even to a small extent, then they are likely to be good value for money, given their low cost. The benefits could be considerable, given that depression is common, disabling, and costly.

Trial Registration: ISRCTN no: 17299295. Registered 1st October 2018.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13063-020-04344-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7257549PMC
May 2020

Effectiveness of nurse-led group CBT for hot flushes and night sweats in women with breast cancer: Results of the MENOS4 randomised controlled trial.

Psychooncology 2020 10 24;29(10):1514-1523. Epub 2020 Jul 24.

Department of Psychology, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.

Objective: Troublesome hot flushes and night sweats (HFNS) are experienced by many women after treatment for breast cancer, impacting significantly on sleep and quality of life. Cognitive behavioural therapy (CBT) is known to be effective for the alleviation of HFNS. However, it is not known if it can effectively be delivered by specialist nurses. We investigated whether group CBT, delivered by breast care nurses (BCNs), can reduce the impact of HFNS.

Methods: We recruited women with primary breast cancer following primary treatment with seven or more HFNS/week (including 4/10 or above on the HFNS problem rating scale), from six UK hospitals to an open, randomised, phase 3 effectiveness trial. Participants were randomised to Group CBT or usual care (UC). The primary endpoint was HFNS problem rating at 26 weeks after randomisation. Secondary outcomes included sleep, depression, anxiety and quality of life.

Results: Between 2017 and 2018, 130 participants were recruited (CBT:63, control:67). We found a 46% (6.9-3.7) reduction in the mean HFNS problem rating score from randomisation to 26 weeks in the CBT arm and a 15% (6.5-5.5) reduction in the UC arm (adjusted mean difference -1.96, CI -3.68 to -0.23, P = .039). Secondary outcomes, including frequency of HFNS, sleep, anxiety and depression all improved significantly.

Conclusion: Our results suggest that specialist nurses can be trained to deliver CBT effectively to alleviate troublesome menopausal hot flushes in women following breast cancer in the NHS setting.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/pon.5432DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7590063PMC
October 2020

REDUCE (Reviewing long-term antidepressant use by careful monitoring in everyday practice) internet and telephone support to people coming off long-term antidepressants: protocol for a randomised controlled trial.

Trials 2020 May 24;21(1):419. Epub 2020 May 24.

Institute of Psychology Health and Society, University of Liverpool, Liverpool, UK.

Background: Around one in ten adults take antidepressants for depression in England, and their long-term use is increasing. Some need them to prevent relapse, but 30-50% could possibly stop them without relapsing and avoid adverse effects and complications of long-term use. However, stopping is not always easy due to withdrawal symptoms and a fear of relapse of depression. When general practitioners review patients on long-term antidepressants and recommend to those who are suitable to stop the medication, only 6-8% are able to stop. The Reviewing long-term antidepressant use by careful monitoring in everyday practice (REDUCE) research programme aims to identify safe and cost-effective ways of helping patients taking long-term antidepressants taper off treatment when appropriate.

Methods: Design: REDUCE is a two-arm, 1:1 parallel group randomised controlled trial, with randomisation clustered by participating family practices.

Setting: England and north Wales.

Population: patients taking antidepressants for longer than 1 year for a first episode of depression or longer than 2 years for repeated episodes of depression who are no longer depressed and want to try to taper off their antidepressant use.

Intervention: provision of 'ADvisor' internet programmes to general practitioners or nurse practitioners and to patients designed to support antidepressant withdrawal, plus three patient telephone calls from a psychological wellbeing practitioner. The control arm receives usual care. Blinding of patients, practitioners and researchers is not possible in an open pragmatic trial, but statistical and health economic data analysts will remain blind to allocation.

Outcome Measures: the primary outcome is self-reported nine-item Patient Health Questionnaire at 6 months for depressive symptoms.

Secondary Outcomes: depressive symptoms at other follow-up time points, anxiety, discontinuation of antidepressants, social functioning, wellbeing, enablement, quality of life, satisfaction, and use of health services for costs.

Sample Size: 402 patients (201 intervention and 201 controls) from 134 general practices recruited over 15-18 months, and followed-up at 3, 6, 9 and 12 months. A qualitative process evaluation will be conducted through interviews with 15-20 patients and 15-20 practitioners in each arm to explore why the interventions were effective or not, depending on the results.

Discussion: Helping patients reduce and stop antidepressants is often challenging for practitioners and time-consuming for very busy primary care practices. If REDUCE provides evidence showing that access to internet and telephone support enables more patients to stop treatment without increasing depression we will try to implement the intervention throughout the National Health Service, publishing practical guidance for professionals and advice for patients to follow, publicised through patient support groups.

Trial Registration: ISRCTN:12417565. Registered on 7 October 2019.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13063-020-04338-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7245840PMC
May 2020

A Novel Chemically Differentiated Mouse Embryonic Stem Cell-Based Model to Study Liver Stages of Plasmodium berghei.

Stem Cell Reports 2020 06 21;14(6):1123-1134. Epub 2020 May 21.

Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK; Molecular Infection Medicine Sweden and Molecular Biology Department, Umeå University, 90187 Umeå, Sweden. Electronic address:

Asymptomatic and obligatory liver stage (LS) infection of Plasmodium parasites presents an attractive target for antimalarial vaccine and drug development. Lack of robust cellular models to study LS infection has hindered the discovery and validation of host genes essential for intrahepatic parasite development. Here, we present a chemically differentiated mouse embryonic stem cell (ESC)-based LS model, which supports complete development of Plasmodium berghei exoerythrocytic forms (EEFs) and can be used to define new host-parasite interactions. Using our model, we established that host Pnpla2, coding for adipose triglyceride lipase, is dispensable for P. berghei EEF development. In addition, we also evaluated in-vitro-differentiated human hepatocyte-like cells (iHLCs) to study LS of P. berghei and found it to be a sub-optimal infection model. Overall, our results present a new mouse ESC-based P. berghei LS infection model that can be utilized to study the impact of host genetic variation on parasite development.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.stemcr.2020.04.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7355138PMC
June 2020

Obtaining and managing data sets for individual participant data meta-analysis: scoping review and practical guide.

BMC Med Res Methodol 2020 05 12;20(1):113. Epub 2020 May 12.

Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada.

Background: Shifts in data sharing policy have increased researchers' access to individual participant data (IPD) from clinical studies. Simultaneously the number of IPD meta-analyses (IPDMAs) is increasing. However, rates of data retrieval have not improved. Our goal was to describe the challenges of retrieving IPD for an IPDMA and provide practical guidance on obtaining and managing datasets based on a review of the literature and practical examples and observations.

Methods: We systematically searched MEDLINE, Embase, and the Cochrane Library, until January 2019, to identify publications focused on strategies to obtain IPD. In addition, we searched pharmaceutical websites and contacted industry organizations for supplemental information pertaining to recent advances in industry policy and practice. Finally, we documented setbacks and solutions encountered while completing a comprehensive IPDMA and drew on previous experiences related to seeking and using IPD.

Results: Our scoping review identified 16 articles directly relevant for the conduct of IPDMAs. We present short descriptions of these articles alongside overviews of IPD sharing policies and procedures of pharmaceutical companies which display certification of Principles for Responsible Clinical Trial Data Sharing via Pharmaceutical Research and Manufacturers of America or European Federation of Pharmaceutical Industries and Associations websites. Advances in data sharing policy and practice affected the way in which data is requested, obtained, stored and analyzed. For our IPDMA it took 6.5 years to collect and analyze relevant IPD and navigate additional administrative barriers. Delays in obtaining data were largely due to challenges in communication with study sponsors, frequent changes in data sharing policies of study sponsors, and the requirement for a diverse skillset related to research, administrative, statistical and legal issues.

Conclusions: Knowledge of current data sharing practices and platforms as well as anticipation of necessary tasks and potential obstacles may reduce time and resources required for obtaining and managing data for an IPDMA. Sufficient project funding and timeline flexibility are pre-requisites for successful collection and analysis of IPD. IPDMA researchers must acknowledge the additional and unexpected responsibility they are placing on corresponding study authors or data sharing administrators and should offer assistance in readying data for sharing.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12874-020-00964-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7218569PMC
May 2020

The Khorana score for prediction of venous thromboembolism in cancer patients: An individual patient data meta-analysis.

J Thromb Haemost 2020 08 8;18(8):1940-1951. Epub 2020 Jul 8.

Michael G. DeGroote Cochrane Canada and McGRADE Centres, Department of Health Research Methods, Evidence and Impact, Faculty of Health Sciences, McMaster University, Hamilton, Canada.

Background: Oncology guidelines suggest using the Khorana score to select ambulatory cancer patients receiving chemotherapy for primary venous thromboembolism (VTE) prevention, but its performance in different cancers remains uncertain.

Objective: To examine the performance of the Khorana score in assessing 6-month VTE risk, and the efficacy and safety of low-molecular-weight heparin (LMWH) among high-risk Khorana score patients.

Methods: This individual patient data meta-analysis evaluated (ultra)-LMWH in patients with solid cancer using data from seven randomized controlled trials.

Results: A total of 3293 patients from the control groups with an available Khorana score had lung (n = 1913; 58%), colorectal (n = 452; 14%), pancreatic (n = 264; 8%), gastric (n = 201; 6%), ovarian (n = 184; 56%), breast (n = 164; 5%), brain (n = 84; 3%), or bladder cancer (n = 31; 1%). The 6-month VTE incidence was 9.8% among high-risk Khorana score patients and 6.4% among low-to-intermediate-risk patients (odds ratio [OR], 1.6; 95% confidence interval [CI], 1.1-2.2). The dichotomous Khorana score performed differently in lung cancer patients (OR 1.1; 95% CI, 0.72-1.7) than in the group with other cancer types (OR 3.2; 95% CI, 1.8-5.6; P  = .002). Among high-risk patients, LMWH decreased the risk of VTE by 64% compared with controls (OR 0.36; 95% CI, 0.22-0.58), without increasing the risk of major bleeding (OR 1.1; 95% CI, 0.59-2.1).

Conclusion: The Khorana score was unable to stratify patients with lung cancer based on their VTE risk. Among those with other cancer types, a high-risk score was associated with a three-fold increased risk of VTE compared with a low-to-intermediate risk score. Thromboprophylaxis was effective and safe in patients with a high-risk Khorana score.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/jth.14824DOI Listing
August 2020

A randomised Phase II trial of carboplatin and gemcitabine ± vandetanib in first-line treatment of patients with advanced urothelial cell cancer not suitable to receive cisplatin.

BJU Int 2020 08 19;126(2):292-299. Epub 2020 May 19.

Southampton Clinical Trials Unit, University of Southampton, Southampton, UK.

Objectives: To assess the efficacy and tolerability of the dual epidermal growth factor receptor/vascular endothelial growth factor receptor inhibitor, vandetanib, in combination with carboplatin and gemcitabine in the first-line treatment of patients with advanced transitional cell carcinoma urothelial cancer (UC) who were unsuitable for cisplatin.

Patients And Methods: From 2011 to 2014, 82 patients were randomised from 16 hospitals across the UK into the TOUCAN double-blind, placebo-controlled randomised Phase II trial, receiving six 21-day cycles of intravenous carboplatin (target area under the concentration versus time curve 4.5, day 1) and gemcitabine (1000 mg/m days 1 and 8) combined with either oral vandetanib 100 mg or placebo (once daily). Progression-free survival (PFS; primary endpoint), adverse events, tolerability and feasibility of use, objective response rate and overall survival (OS) were evaluated. Intention-to-treat and per-protocol analyses were used to analyse the primary endpoint.

Results: The 82 patients were randomised 1:1 to vandetanib (n = 40) or placebo (n = 42), and 25 patients (30%) completed six cycles of all allocated treatment. Toxicity Grade ≥3 was experienced in 80% (n = 32) and 76% (n = 32) of patients in the vandetanib and placebo arms, respectively. The median PFS was 6.8 and 8.8 months for the vandetanib and placebo arms, respectively (hazard ratio [HR] 1.07, 95% confidence interval [CI] 0.65-1.76; P = 0.71); the median OS was 10.8 vs 13.8 months (HR 1.41, 95% CI 0.79-2.52; P = 0.88); and radiological response rates were 50% and 55%.

Conclusion: There is no evidence that vandetanib improves clinical outcome in this setting. Our present data do not support its adoption as the regimen of choice for first-line treatment in patients with UC who were unfit for cisplatin.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/bju.15096DOI Listing
August 2020

Using digital tools in the recruitment and retention in randomised controlled trials: survey of UK Clinical Trial Units and a qualitative study.

Trials 2020 Apr 3;21(1):304. Epub 2020 Apr 3.

Southampton Clinical Trials Unit, University of Southampton and University Hospital Southampton NHS Foundation Trust, Southampton General Hospital, Southampton, SO16 6YD, UK.

Background: Recruitment and retention of participants in randomised controlled trials (RCTs) is a key determinant of success but is challenging. Trialists and UK Clinical Research Collaboration (UKCRC) Clinical Trials Units (CTUs) are increasingly exploring the use of digital tools to identify, recruit and retain participants. The aim of this UK National Institute for Health Research (NIHR) study was to identify what digital tools are currently used by CTUs and understand the performance characteristics required to be judged useful.

Methods: A scoping of searches (and a survey with NIHR funding staff), a survey with all 52 UKCRC CTUs and 16 qualitative interviews were conducted with five stakeholder groups including trialists within CTUs, funders and research participants. A purposive sampling approach was used to conduct the qualitative interviews during March-June 2018. Qualitative data were analysed using a content analysis and inductive approach.

Results: Responses from 24 (46%) CTUs identified that database-screening tools were the most widely used digital tool for recruitment, with the majority being considered effective. The reason (and to whom) these tools were considered effective was in identifying potential participants (for both Site staff and CTU staff) and reaching recruitment target (for CTU staff/CI). Fewer retention tools were used, with short message service (SMS) or email reminders to participants being the most reported. The qualitative interviews revealed five themes across all groups: 'security and transparency'; 'inclusivity and engagement'; 'human interaction'; 'obstacles and risks'; and 'potential benefits'. There was a high level of stakeholder acceptance of the use of digital tools to support trials, despite the lack of evidence to support them over more traditional techniques. Certain differences and similarities between stakeholder groups demonstrated the complexity and challenges of using digital tools for recruiting and retaining research participants.

Conclusions: Our studies identified a range of digital tools in use in recruitment and retention of RCTs, despite the lack of high-quality evidence to support their use. Understanding the type of digital tools in use to support recruitment and retention will help to inform funders and the wider research community about their value and relevance for future RCTs. Consideration of further focused digital tool reviews and primary research will help to reduce gaps in the evidence base.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13063-020-04234-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7118862PMC
April 2020

Salicylic acid and aspirin stimulate growth of Chlamydomonas and inhibit lipoxygenase and chloroplast desaturase pathways.

Plant Physiol Biochem 2020 Apr 15;149:256-265. Epub 2020 Feb 15.

Chemical Engineering and Applied Chemistry, Energy and Bioproducts Research Institute, Aston University, B4 7ET, Birmingham, United Kingdom. Electronic address:

Chemical stimulants, used to enhance biomass yield, are highly desirable for the commercialisation of algal products for a wide range of applications in the food, pharma and biofuels sectors. In the present study, phenolic compounds, varying in substituents and positional isomers on the arene ring have been evaluated to determine structure-activity relationship and growth. The phenols, catechol, 4-methylcatechol and 2, 4-dimethyl phenol were generally inhibitory to growth as were the compounds containing an aldehyde function. By contrast, the phenolic acids, salicylic acid, aspirin and 4-hydroxybenzoate markedly stimulated cell proliferation enhancing cell numbers by 20-45% at mid-log phase. The order of growth stimulation was ortho > para > meta with respect to the position of the OH group. Both SA and aspirin reduced 16:3 in chloroplast galactolipids. In addition, both compounds inhibited lipoxygenase activity and lowered the levels of lipid hydroperoxides and malondialdehydes in the cells. The present study has demonstrated the possibility of using SA or aspirin to promote algal growth through the manipulation of lipid metabolising enzymes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.plaphy.2020.02.019DOI Listing
April 2020

Systemic chemotherapy with or without cetuximab in patients with resectable colorectal liver metastasis (New EPOC): long-term results of a multicentre, randomised, controlled, phase 3 trial.

Lancet Oncol 2020 03 31;21(3):398-411. Epub 2020 Jan 31.

Department of Surgery, University of Southampton, Southampton, UK. Electronic address:

Background: The interim analysis of the multicentre New EPOC trial in patients with resectable colorectal liver metastasis showed a significant reduction in progression-free survival in patients allocated to cetuximab plus chemotherapy compared with those given chemotherapy alone. The focus of the present analysis was to assess the effect on overall survival.

Methods: New EPOC was a multicentre, open-label, randomised, controlled, phase 3 trial. Adult patients (aged ≥18 years) with KRAS wild-type (codons 12, 13, and 61) resectable or suboptimally resectable colorectal liver metastases and a WHO performance status of 0-2 were randomly assigned (1:1) to receive chemotherapy with or without cetuximab before and after liver resection. Randomisation was done centrally with minimisation factors of surgical centre, poor prognosis cancer, and previous adjuvant treatment with oxaliplatin. Chemotherapy consisted of oxaliplatin 85 mg/m administered intravenously over 2 h, l-folinic acid (175 mg flat dose administered intravenously over 2 h) or d,l-folinic acid (350 mg flat dose administered intravenously over 2 h), and fluorouracil bolus 400 mg/m administered intravenously over 5 min, followed by a 46 h infusion of fluorouracil 2400 mg/m repeated every 2 weeks (regimen one), or oxaliplatin 130 mg/m administered intravenously over 2 h and oral capecitabine 1000 mg/m twice daily on days 1-14 repeated every 3 weeks (regimen two). Patients who had received adjuvant oxaliplatin could receive irinotecan 180 mg/m intravenously over 30 min with fluorouracil instead of oxaliplatin (regimen three). Cetuximab was given intravenously, 500 mg/m every 2 weeks with regimen one and three or a loading dose of 400 mg/m followed by a weekly infusion of 250 mg/m with regimen two. The primary endpoint of progression-free survival was published previously. Secondary endpoints were overall survival, preoperative response, pathological resection status, and safety. Trial recruitment was halted prematurely on the advice of the Trial Steering Committee on Nov 1, 2012. All analyses (except safety) were done on the intention-to-treat population. Safety analyses included all randomly assigned patients. This trial is registered with ISRCTN, number 22944367.

Findings: Between Feb 26, 2007, and Oct 12, 2012, 257 eligible patients were randomly assigned to chemotherapy with cetuximab (n=129) or without cetuximab (n=128). This analysis was carried out 5 years after the last patient was recruited, as defined in the protocol, at a median follow-up of 66·7 months (IQR 58·0-77·5). Median progression-free survival was 22·2 months (95% CI 18·3-26·8) in the chemotherapy alone group and 15·5 months (13·8-19·0) in the chemotherapy plus cetuximab group (hazard ratio [HR] 1·17, 95% CI 0·87-1·56; p=0·304). Median overall survival was 81·0 months (59·6 to not reached) in the chemotherapy alone group and 55·4 months (43·5-71·5) in the chemotherapy plus cetuximab group (HR 1·45, 1·02-2·05; p=0·036). There was no significant difference in the secondary outcomes of preoperative response or pathological resection status between groups. Five deaths might have been treatment-related (one in the chemotherapy alone group and four in the chemotherapy plus cetuximab group). The most common grade 3-4 adverse events reported were: neutrophil count decreased (26 [19%] of 134 in the chemotherapy alone group vs 21 [15%] of 137 in the chemotherapy plus cetuximab group), diarrhoea (13 [10%] vs 14 [10%]), skin rash (one [1%] vs 22 [16%]), thromboembolic events (ten [7%] vs 11 [8%]), lethargy (ten [7%] vs nine [7%]), oral mucositis (three [2%] vs 14 [10%]), vomiting (seven [5%] vs seven [5%]), peripheral neuropathy (eight [6%] vs five [4%]), and pain (six [4%] vs six [4%]).

Interpretation: Although the addition of cetuximab to chemotherapy improves the overall survival in some studies in patients with advanced, inoperable metastatic disease, its use in the perioperative setting in patients with operable disease confers a significant disadvantage in terms of overall survival. Cetuximab should not be used in this setting.

Funding: Cancer Research UK.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S1470-2045(19)30798-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7052737PMC
March 2020

Unusual dual-emissive heteroleptic iridium complexes incorporating TADF cyclometalating ligands.

Dalton Trans 2020 Feb 31;49(7):2190-2208. Epub 2020 Jan 31.

Department of Chemistry, Durham University, Durham DH1 3LE, UK.

Five new neutral heteroleptic iridium(iii) complexes IrL(pic) (2-6) based on the archetypical blue emitter FIrpic have been synthesised. The cyclometallating ligands L are derived from 2-(2,6-F-3-pyridyl)-4-mesitylpyridine (7), 2-(3-cyano-2,6-F-phenyl)-4-mesitylpyridine (8), 2-(2,6-F-phenyl)-4-[2,7-(HexO)-9H-carbazol-9-yl]pyridine (9), 2-(2,6-F-3-pyridyl)-4-[2,7-(HexO)-9H-carbazol-9-yl]pyridine (10) and 2-(3-cyano-2,6-F-phenyl)-4-[2,7-(HexO)-9H-carbazol-9-yl]pyridine (11) for complexes 2, 3, 4, 5 and 6, respectively. The carbazole-functionalised ligands 9-11 show weak thermally activated delayed fluorescence (TADF) in solution. Complexes 5 and 6 reveal dual emission in polar solvents. A broad charge transfer (CT) band appears and increases in intensity relative to the higher energy emission band as solvent polarity is increased. The dual emission occurs when the energy of the ligand CT state is comparable to that of the MLCT state of the complex, resulting in fast interconversion between the two. Assignment of the ligand TADF and dual emission properties is supported by hybrid density functional theory (DFT) and time dependent DFT (TD-DFT) calculations. Phosphorescent organic light emitting devices (PhOLEDs) have been fabricated using these complexes as sky-blue emitters, and their performance is compared to devices using FIrpic and the previously reported complex IrL(pic) 1 (L from the 2-(2,6-F-phenyl)-4-mesitylpyridine ligand). For identical device structures, the device containing the carbazole complex 4 performs best out of the seven complexes. The dual emission observed in solution for complexes 5 and 6 is not observed in their devices.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1039/c9dt04672kDOI Listing
February 2020

HATRIC: a study of root extract EPs®7630 (Kaloba®) for the treatment of acute cough due to lower respiratory tract infection in adults-study protocol for a double blind, placebo-controlled randomised feasibility trial.

Pilot Feasibility Stud 2019 31;5:98. Epub 2019 Jul 31.

2Primary Care and Population Science, Faculty of Medicine, University of Southampton, Aldermoor Health Centre, Southampton, SO16 5ST UK.

Background: Acute lower respiratory tract infection is a common acute infection managed in primary care. The current dominant management strategy in the UK is antibiotics, despite widespread publicity regarding antimicrobial resistance and evidence that the small benefits of antibiotics do not outweigh the harms. There is a need to address the rising problem of antibiotic resistance by providing credible alternative strategies, which reduce symptom burden. There is sufficient evidence to recommend the use of root extract in order to warrant undertaking an independent clinical trial.We propose a feasibility study to demonstrate our ability to recruit and retain patients and conduct a placebo-controlled trial of extract EPs®7630 in lower respiratory tract infection where pneumonia is not suspected. Both the tablet and liquid formulations will be included.

Methods: The HATRIC trial is a double-blind randomised placebo-controlled feasibility study aiming to determine the potential to conduct a fully powered trial of root extract as an alternative to the inappropriate use of antibiotics for acute bronchitis in UK primary care.Primary care sites will be equally randomised to one of two formulation groups (tablet or liquid preparation). Additionally, within each site, patients will be evenly randomised to active or placebo treatment. Antibiotic consumption will be monitored during the trial, but the use of a delayed prescription strategy is encouraged. The target sample size for this study is 160 patients overall or 40 per arm, recruited from approximately 20 primary care sites. The analysis will be descriptive focusing on estimation with no formal comparison of groups taking place.

Discussion: If this trial demonstrates the feasibility of recruitment and delivery, we will seek funding for a fully powered placebo-controlled trial of root extract for the treatment of lower respiratory tract infections in primary care.

Trial Registration: HATRIC was registered on the ISRCTN registry (ISRCTN17672884) on 16 August 2018.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s40814-019-0478-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6668164PMC
July 2019