Exploristics (United Kingdom)

Complex socio-cultural, psychological, geographical, and service-related challenges are faced when recruiting people with dementia for clinical trials. The aim of Phase 1 of the Dementia PersonAlised Care Team (D-PACT) project was to assess the feasibility of recruiting (identifying, approaching and consenting) people with dementia, including those without capacity to consent, to a cluster randomized controlled trial of a primary care-based personalized dementia support intervention in England. COVID-19 necessitated a shift to remote working, creating the opportunity to compare recruitment strategies before and under lockdown constraints. This paper shares the adaptations made to enable remote consent and capacity judgement with people with dementia, as well as lessons learned. Consent was conducted in person from September 2019 to March 2020. Remote consent was implemented from September 2020 to March 2021 after an enforced pause. Both quantitative and qualitative data were collected. Recruitment rates (proportion consented from eligible patients approached), mean monthly consent rates, and time spent on consent-related activities (tasks before and after consent/capacity-judgment meetings, miscellaneous tasks, travel) were compared. Participant experiences with remote recruitment were examined through thematic analysis of qualitative interviews. Pre-COVID-19, 22 participants (9.9%) out of 228 approached were consented in person. During the pandemic, 19 participants (9.6%) out of 198 were consented remotely, excluding 15 participants initially approached pre-pandemic and later consented via remote means. Mean monthly consent rates increased from 3.6 (in person) to 5.6 (remote). However, remote consent required more time (mean 14 researcher-hours per participant vs. 9 in person), with 75% of time spent on consent-related tasks compared to 20% in person. Travel accounted for 40% of in-person consent time. Interviews (n = 13) showed general acceptability of remote processes. However pre-consent information was perceived as excessive and led some participants to skim materials, potentially reducing understanding. While remote consent is time-intensive, it achieves comparable rates (proportion consented/total approached) to in-person methods and higher monthly consent rates. A flexible, hybrid approach can enhance participation, offer choice, and increase person-centredness. Realistic planning for time and resources is crucial for inclusive dementia research. Funders should support these needs to ensure effective recruitment. ISRCTN80204146.

Background: Prinflammatory extracellular chromatin from neutrophil extracellular traps (NETs) and other cellular sources is found in COVID-19 patients and may promote pathology. We determined whether pulmonary administration of the endonuclease dornase alfa reduced systemic inflammation by clearing extracellular chromatin. Methods: Eligible patients were randomized (3:1) to the best available care including dexamethasone (R-BAC) or to BAC with twice-daily nebulized dornase alfa (R-BAC + DA) for seven days or until discharge. A 2:1 ratio of matched contemporary controls (CC-BAC) provided additional comparators. The primary endpoint was the improvement in C-reactive protein (CRP) over time, analyzed using a repeated-measures mixed model, adjusted for baseline factors. Results: We recruited 39 evaluable participants: 30 randomized to dornase alfa (R-BAC +DA), 9 randomized to BAC (R-BAC), and included 60 CC-BAC participants. Dornase alfa was well tolerated and reduced CRP by 33% compared to the combined BAC groups (T-BAC). Least squares (LS) mean post-dexamethasone CRP fell from 101.9 mg/L to 23.23 mg/L in R-BAC +DA participants versus a 99.5 mg/L to 34.82 mg/L reduction in the T-BAC group at 7 days; p=0.01. The anti-inflammatory effect of dornase alfa was further confirmed with subgroup and sensitivity analyses on randomised participants only, mitigating potential biases associated with the use of CC-BAC participants. Dornase alfa increased live discharge rates by 63% (HR 1.63, 95% CI 1.01–2.61, p=0.03), increased lymphocyte counts (LS mean: 1.08 vs 0.87, p=0.02) and reduced circulating cf-DNA and the coagulopathy marker D-dimer (LS mean: 570.78 vs 1656.96 μg/mL, p=0.004). Conclusions: Dornase alfa reduces pathogenic inflammation in COVID-19 pneumonia, demonstrating the benefit of cost-effective therapies that target extracellular chromatin. Funding: LifeArc, Breathing Matters, The Francis Crick Institute (CRUK, Medical Research Council, Wellcome Trust). Clinical trial number: NCT04359654 .

11168 Background: Precision medicine is a paradigm shift in healthcare: 24% of all FDA approvals are precision medicines, with 67% of new approvals relying on companion or complementary testing or on diagnostics prior to clinical use. Yet a recent publication indicates that approximately 64% of potentially eligible patients could be lost due to various clinical practice gaps along patient journey (Sadik et al JCO 2022). Low prevalence biomarker testing is proven to be one of the critical determinants of missed therapy, potentially due to poor physician awareness. The increasingly advanced machine learning (ML) and natural language processing (NLP)-based ability to label, analyze, and segment data can be utilized to monitor and influence testing behavior in real-time. We hypothesize that a real-time data-driven physician-targeted digital engagement can increase biomarker testing rate and in turn enhance patient identification for precision therapies. Methods: Unstructured real-world, real-time biomarker testing reports were collected from 494 laboratories across the US. These testing reports were first curated, labeled and extracted via ML and NLP-based technologies to allow data analysis and reveal testing behavior. Suboptimal testing behavior was defined as no requisition of the selected novel biomarker as part of the diagnostic workups. Physicians who identified as having suboptimal testing behavior were selected as candidates to receive a personalized digital engagement over a 4-week period. The digital engagement's purpose was to raise clinical awareness towards the novel biomarker testing. The follow-up testing behavior was analyzed again over laboratory reports collected from 26-weeks’ time after the initial engagement. Results: 822 physicians were identified with suboptimal testing behavior and selected to receive 4 weeks' follow-up digital engagement. 271 out of 822 (33%) recipients were successfully engaged shown as open and read the digital communication. 42 (~15%) physicians reacted to the communications and ordered the new test at least once during this period. The initial 4 weeks' engagement was observed to be the most impactful, when 23 out of the 42 (~55%) physicians ordered the novel biomarker test for the first time.71 new therapy-eligible patients were identified via data-driven targeted physician digital engagement during the 26 weeks’ follow-up period. Conclusions: This study illustrates the value of data in influencing or reinforcing testing behaviors and emphasizes the value of data-driven physician-targeted digital engagement in addressing clinical practice gaps which in turn, drive patient identification to match potential eligible precision therapies.

The mean age of patients undergoing total knee arthroplasty (TKA) has reduced with time. Younger patients have increased expectations following TKA. Aseptic loosening of the tibial component is the most common cause of failure of TKA in the UK. Interest in cementless TKA has re-emerged due to its encouraging results in the younger patient population. We review a large series of tantalum trabecular metal cementless implants in patients who are at the highest risk of revision surgery. A total of 454 consecutive patients who underwent cementless TKA between August 2004 and December 2021 were reviewed. The mean follow-up was ten years. Plain radiographs were analyzed for radiolucent lines. Patients who underwent revision TKA were recorded, and the cause for revision was determined. Data from the National Joint Registry for England, Wales, Northern Island, the Isle of Man and the States of Guernsey (NJR) were compared with our series. No patients in our series had evidence of radiolucent lines on their latest radiological assessment. Only eight patients out of 454 required revision arthroplasty, and none of these revisions were indicated for aseptic loosening of the tibial baseplate. When compared to data from the NJR annual report, Kaplan-Meier estimates from our series (2.94 (95% confidence interval (CI) 1.24 to 5.87)) show a significant reduction in cumulative estimates of revision compared to all cemented (4.82 (95% CI 4.69 to 4.96)) or cementless TKA (5.65 (95% CI 5.23 to 6.10)). Our data (2.94 (95% CI 1.24 to 5.87)) also show lower cumulative revision rates compared to the most popular implant (PFC Sigma Cemented Knee implant fixation, 4.03 (95% CI 3.75 to 4.33)). The prosthesis time revision rate (PTIR) estimates for our series (2.07 (95% CI 0.95 to 3.83)) were lower than those of cemented cases (4.53 (95% CI 4.49 to 4.57)) from NJR. The NexGen trabecular (tantalum) cementless implant has lower revision rates in our series compared to all cemented implants and other types of cementless implants, and its use in younger patients should be encouraged.

Abstract Background SARS-CoV2 infection causes severe, life-threatening pneumonia. Hyper-inflammation, coagulopathy and lymphopenia are associated with pathology and poor outcomes in these patients. Cell-free (cf) DNA is prominent in COVID-19 patients, amplifies inflammation and promotes coagulopathy and immune dysfunction. We hypothesized that cf-DNA clearance by nebulised dornase alfa may reduce inflammation and improve disease outcomes. Here, we evaluated the efficacy of nebulized dornase alfa in patients hospitalised with severe COVID-19 pneumonia. Methods In this randomised controlled single-centre phase 2 proof-of-concept trial, we recruited adult patients admitted to hospital that exhibited stable oxygen saturation (≥94%) on supplementary oxygen and a C-reactive protein (CRP) level ≥30mg/L post dexamethasone treatment. Participants were randomized at a 3:1 ratio to receive twice-daily nebulised dornase alfa in addition to best available care (BAC) or BAC alone for seven days or until hospital discharge. A 2:1 ratio of historical controls to treated individuals (HC, 2:1) were included as the primary endpoint comparators. The primary outcome was a reduction in systemic inflammation measured by blood CRP levels over 7 days post-randomisation, or to discharge if sooner. Secondary and exploratory outcomes included time to discharge, time on oxygen, D-dimer levels, lymphocyte counts and levels of circulating cf-DNA. Results We screened 75 patients and enrolled 39 participants out of which 30 in dornase alfa arm, and 9 in BAC group. We also matched the recruited patients in the treated group (N=30) to historical controls in the BAC group (N=60). For the the primary outcome, 30 patients in the dornase alfa were compared to 69 patients in the BAC group. Dornase alfa treatment reduced CRP by 33% compared to the BAC group at 7-days (P=0.01). The dornase alfa group least squares mean CRP was 23.23 mg/L (95% CI 17.71 to 30.46) and the BAC group 34.82 mg/L (95% CI 28.55 to 42.47). A significant difference was also observed when only randomised participants were compared. Furthermore, compared to the BAC group, the chance of live discharge was increased by 63% in the dornase alfa group (HR 1.63, 95% CI 1.01 to 2.61, P=0.03), lymphocyte counts were improved (least-square mean: 1.08 vs 0.87, P=0.02) and markers of coagulopathy such as D-dimer were diminished (least-square mean: 570.78 vs 1656.96μg/mL, P=0.004). Moreover, the dornase alfa group exhibited lower circulating cf-DNA levels that correlated with CRP changes over the course of treatment. No differences were recorded in the rates and length of stay in the ICU or the time on oxygen between the groups. Dornase alfa was well-tolerated with no serious adverse events reported. Conclusions In this proof-of-concept study in patients with severe COVID-19 pneumonia, treatment with nebulised dornase alfa resulted in a significant reduction in inflammation, markers of immune pathology and time to discharge. The effectiveness of dornase alfa in patients with acute respiratory infection and inflammation should be investigated further in larger trials.

IntroductionSEL-212 is a developmental treatment for uncontrolled gout characterized by serum uric acid (sUA) levels ≥ 6 mg/dl despite treatment. It comprises a novel PEGylated uricase (SEL-037; also called pegadricase) co-administered with tolerogenic nanoparticles containing sirolimus (rapamycin) (SEL-110; also called ImmTOR®), which mitigates the formation of anti-drug antibodies (ADAs) against uricase and SEL-037 (PEGylated uricase), thereby enabling sustained sUA control (sUA < 6 mg/dl). The aim of this study was to identify appropriate dosing for SEL-037 and SEL-110 for use in phase 3 clinical trials.MethodsThis open-label phase 2 study was conducted in adults with symptomatic gout and sUA ≥ 6 mg/dl. Participants received five monthly infusions of SEL-037 (0.2 or 0.4 mg/kg) alone or in combination with three or five monthly infusions of SEL-110 (0.05–0.15 mg/kg). Safety, tolerability, sUA, ADAs, and tophi were monitored for 6 months.ResultsA total of 152 adults completed the study. SEL-037 alone resulted in rapid sUA reductions that were not sustained beyond 30 days in most participants due to ADA formation and loss of uricase activity. Levels of ADAs decreased with increasing doses of SEL-110 up to 0.1 mg/kg, with anti-uricase titers < 1080 correlating with sustained sUA control and reductions in tophi. Overall, 66% of evaluable participants achieved sUA control at week 20 following five monthly doses of SEL-037 0.2 mg/kg + SEL-110 0.1–0.15 mg/kg, whereas only 26% achieved sUA control at week 20 when SEL-110 was withdrawn after week 12. Compared to other dose combinations, SEL-037 0.2 mg/kg + SEL-110 0.15 mg/kg achieved the greatest sUA control at week 12 and was well-tolerated with no safety concerns.ConclusionResults provide continued support for the use of multiple monthly administrations of SEL-037 0.2 mg/kg + SEL-110 0.1-0.15 mg/kg in clinical trials for SEL-212.Trial RegistrationClinicalTrials.gov identifier, NCT02959918.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40744-023-00546-0.

BackgroundPC786 is a nebulized nonnucleoside respiratory syncytial virus (RSV) polymerase inhibitor designed to treat RSV, which replicates in the superficial layer of epithelial cells lining the airways.MethodsFifty-six healthy volunteers inoculated with RSV-A (Memphis 37b) were randomly dosed with either nebulized PC786 (5 mg) or placebo, twice daily for 5 days, from either 12 hours after confirmation of RSV infection or 6 days after virus inoculation. Viral load (VL), disease severity, pharmacokinetics, and safety were assessed until discharge. RSV infection was confirmed by reverse-transcription quantitative polymerase chain reaction with any positive value (intention-to-treat infected [ITT-I] population) or RSV RNA ≥1 log10 plaque-forming unit equivalents (PFUe)/mL (specific intention-to-treat infection [ITT-IS] population) in nasal wash samples.ResultsIn the ITT-I population, the mean VL area under the curve (AUC) was lower in the PC786 group than the placebo group (274.1 vs 406.6 log10 PFUe/mL × hour; P = .0359). PC786 showed a trend toward reduction of symptom score and mucous weight. In ITT-IS (post hoc analysis), the latter was statistically significant as well as VL AUC (P = .0126). PC786 showed an early time to maximum plasma concentration, limited systemic exposure, and long half-life and consequently a 2-fold accumulation over the 5-day dosing period. PC786 was well tolerated.ConclusionsNebulized PC786 demonstrated a significant antiviral effect against RSV, warranting further clinical study.Clinical Trials RegistrationClinicalTrials.gov: NCT03382431; EudraCT: 2017-002563-18.