Antibody persistence and safety of a live-attenuated chikungunya virus vaccine up to 2 years after single-dose administration in adults in the USA: a single-arm, multicentre, phase 3b study.

Chikungunya virus infection can lead to long-term debilitating symptoms. A precursor phase 3 clinical study showed high seroprotection (defined as a 50% plaque reduction of chikungunya virus-specific neutralising antibodies on a micro plaque reduction neutralisation test [μPRNT] titre of ≥150 in baseline seronegative participants) up to 6 months after a single vaccination of the chikungunya virus vaccine VLA1553 (Valneva Austria, Vienna, Austria) and a good safety profile. Here we report antibody persistence and safety up to 2 years. In this single-arm, multicentre, phase 3b study, we recruited participants from the precursor phase 3 trial from professional vaccine trial sites in the USA. Participants (aged ≥18 years) were eligible if they had completed the previous study and received VLA1553. Chikungunya virus-specific neutralising antibodies were evaluated at 28 days, 6 months, and 1 year and 2 years after vaccination. The primary outcome was the proportion of seroprotected participants (ie, μPRNT50 titre of ≥150) at 1 and 2 years, assessed in all eligible participants who had at least one post-vaccination immunogenicity sample available, overall and by age group at the time of vaccination (18-64 years and ≥65 years). Adverse events of special interest at the time of transition from the previous study to the current study (ie, at 6 months) and serious adverse events during the current study were recorded (ie, between 6 months and 2 years). All analyses were descriptive. This study is registered with ClinicalTrials.gov, NCT04838444, and immunogenicity follow-up is ongoing. In the precursor study, participants were screened between Sept 17, 2020, and April 10, 2021; data cutoff for this analysis was March 31, 2023. Of 2724 participants in the precursor study who received one dose of VLA1553, 363 participants were analysed in this study (310 [85%] aged 18-64 years and 53 [15%] aged ≥65 years at enrolment in the precursor study; mean age 47·7 years [SD 14·2], 207 [57%] of 363 participants were female, 156 [43%] were male, 280 [77%] were White, and 314 [87%] were not Hispanic or Latino). Strong seroprotection was observed at 1 year (98·9% [356 of 360 assessable participants; 97·2-99·7]) and 2 years (96·8% [306 of 316; 94·3-98·5]) after vaccination, and was very similar between those aged 18-64 years (at 1 year: 98·7% [303 of 307; 96·7-99·6]; at 2 years: 96·6% [256 of 265; 93·7-98·4]) and those aged 65 years and older (at 1 year: 100% [53 of 53; 93·3-100]; at 2 years: 98·0% [50 of 51; 89·6-100]) at each timepoint. No adverse events of special interest were ongoing at the time of transition. Ten serious adverse events occurred in nine (2%) participants between the 6-month and 2-year timepoints, including one death (due to drug overdose) that was determined to not be related to VLA1553. After a single VLA1553 vaccination, chikungunya virus-neutralising antibodies above the threshold considered to be protective persisted up to 2 years and there were no long-term serious adverse events related to vaccination. VLA1553 is an efficient and safe intervention that offers high seroprotection against chikungunya virus infection, a virus likely to spread globally with an urgent demand for long-lasting prophylaxis. Valneva Austria, Coalition for Epidemic Preparedness Innovation, and EU Horizon 2020.

McMahon R ，Toepfer S ，Sattler N ，Schneider M ，Narciso-Abraham M ，Hadl S ，Hochreiter R ，Kosulin K ，Mader R ，Zoihsl O ，Wressnigg N ，Dubischar K ，Buerger V ，Eder-Lingelbach S ，Jaramillo JC ... -  《-》

Early high-dose cryoprecipitate to reduce mortality in adult patients with traumatic haemorrhage: the CRYOSTAT-2 RCT with cost-effectiveness analysis.

Curry N ，Davenport R ，Thomas H ，Fox E ，Lucas J ，Evans A ，Massou E ，Sharma R ，Shanmugaranjan S ，Rourke C ，Newton A ，Deary A ，Dallas N ，Fitzpatrick-Creamer C ，Podbielski JM ，Wade CE ，Edwards A ，Benger J ，Morris S ，Cotton BA ，Piercy J ，Green L ，Brohi K ，Stanworth S ... -  《-》

Falls prevention interventions for community-dwelling older adults: systematic review and meta-analysis of benefits, harms, and patient values and preferences.

About 20-30% of older adults (≥ 65 years old) experience one or more falls each year, and falls are associated with substantial burden to the health care system, individuals, and families from resulting injuries, fractures, and reduced functioning and quality of life. Many interventions for preventing falls have been studied, and their effectiveness, factors relevant to their implementation, and patient preferences may determine which interventions to use in primary care. The aim of this set of reviews was to inform recommendations by the Canadian Task Force on Preventive Health Care (task force) on fall prevention interventions. We undertook three systematic reviews to address questions about the following: (i) the benefits and harms of interventions, (ii) how patients weigh the potential outcomes (outcome valuation), and (iii) patient preferences for different types of interventions, and their attributes, shown to offer benefit (intervention preferences). We searched four databases for benefits and harms (MEDLINE, Embase, AgeLine, CENTRAL, to August 25, 2023) and three for outcome valuation and intervention preferences (MEDLINE, PsycINFO, CINAHL, to June 9, 2023). For benefits and harms, we relied heavily on a previous review for studies published until 2016. We also searched trial registries, references of included studies, and recent reviews. Two reviewers independently screened studies. The population of interest was community-dwelling adults ≥ 65 years old. We did not limit eligibility by participant fall history. The task force rated several outcomes, decided on their eligibility, and provided input on the effect thresholds to apply for each outcome (fallers, falls, injurious fallers, fractures, hip fractures, functional status, health-related quality of life, long-term care admissions, adverse effects, serious adverse effects). For benefits and harms, we included a broad range of non-pharmacological interventions relevant to primary care. Although usual care was the main comparator of interest, we included studies comparing interventions head-to-head and conducted a network meta-analysis (NMAs) for each outcome, enabling analysis of interventions lacking direct comparisons to usual care. For benefits and harms, we included randomized controlled trials with a minimum 3-month follow-up and reporting on one of our fall outcomes (fallers, falls, injurious fallers); for the other questions, we preferred quantitative data but considered qualitative findings to fill gaps in evidence. No date limits were applied for benefits and harms, whereas for outcome valuation and intervention preferences we included studies published in 2000 or later. All data were extracted by one trained reviewer and verified for accuracy and completeness. For benefits and harms, we relied on the previous review team's risk-of-bias assessments for benefit outcomes, but otherwise, two reviewers independently assessed the risk of bias (within and across study). For the other questions, one reviewer verified another's assessments. Consensus was used, with adjudication by a lead author when necessary. A coding framework, modified from the ProFANE taxonomy, classified interventions and their attributes (e.g., supervision, delivery format, duration/intensity). For benefit outcomes, we employed random-effects NMA using a frequentist approach and a consistency model. Transitivity and coherence were assessed using meta-regressions and global and local coherence tests, as well as through graphical display and descriptive data on the composition of the nodes with respect to major pre-planned effect modifiers. We assessed heterogeneity using prediction intervals. For intervention-related adverse effects, we pooled proportions except for vitamin D for which we considered data in the control groups and undertook random-effects pairwise meta-analysis using a relative risk (any adverse effects) or risk difference (serious adverse effects). For outcome valuation, we pooled disutilities (representing the impact of a negative event, e.g. fall, on one's usual quality of life, with 0 = no impact and 1 = death and ~ 0.05 indicating important disutility) from the EQ-5D utility measurement using the inverse variance method and a random-effects model and explored heterogeneity. When studies only reported other data, we compared the findings with our main analysis. For intervention preferences, we used a coding schema identifying whether there were strong, clear, no, or variable preferences within, and then across, studies. We assessed the certainty of evidence for each outcome using CINeMA for benefit outcomes and GRADE for all other outcomes. A total of 290 studies were included across the reviews, with two studies included in multiple questions. For benefits and harms, we included 219 trials reporting on 167,864 participants and created 59 interventions (nodes). Transitivity and coherence were assessed as adequate. Across eight NMAs, the number of contributing trials ranged between 19 and 173, and the number of interventions ranged from 19 to 57. Approximately, half of the interventions in each network had at least low certainty for benefit. The fallers outcome had the highest number of interventions with moderate certainty for benefit (18/57). For the non-fall outcomes (fractures, hip fracture, long-term care [LTC] admission, functional status, health-related quality of life), many interventions had very low certainty evidence, often from lack of data. We prioritized findings from 21 interventions where there was moderate certainty for at least some benefit. Fourteen of these had a focus on exercise, the majority being supervised (for > 2 sessions) and of long duration (> 3 months), and with balance/resistance and group Tai Chi interventions generally having the most outcomes with at least low certainty for benefit. None of the interventions having moderate certainty evidence focused on walking. Whole-body vibration or home-hazard assessment (HHA) plus exercise provided to everyone showed moderate certainty for some benefit. No multifactorial intervention alone showed moderate certainty for any benefit. Six interventions only had very-low certainty evidence for the benefit outcomes. Two interventions had moderate certainty of harmful effects for at least one benefit outcome, though the populations across studies were at high risk for falls. Vitamin D and most single-component exercise interventions are probably associated with minimal adverse effects. Some uncertainty exists about possible adverse effects from other interventions. For outcome valuation, we included 44 studies of which 34 reported EQ-5D disutilities. Admission to long-term care had the highest disutility (1.0), but the evidence was rated as low certainty. Both fall-related hip (moderate certainty) and non-hip (low certainty) fracture may result in substantial disutility (0.53 and 0.57) in the first 3 months after injury. Disutility for both hip and non-hip fractures is probably lower 12 months after injury (0.16 and 0.19, with high and moderate certainty, respectively) compared to within the first 3 months. No study measured the disutility of an injurious fall. Fractures are probably more important than either falls (0.09 over 12 months) or functional status (0.12). Functional status may be somewhat more important than falls. For intervention preferences, 29 studies (9 qualitative) reported on 17 comparisons among single-component interventions showing benefit. Exercise interventions focusing on balance and/or resistance training appear to be clearly preferred over Tai Chi and other forms of exercise (e.g., yoga, aerobic). For exercise programs in general, there is probably variability among people in whether they prefer group or individual delivery, though there was high certainty that individual was preferred over group delivery of balance/resistance programs. Balance/resistance exercise may be preferred over education, though the evidence was low certainty. There was low certainty for a slight preference for education over cognitive-behavioral therapy, and group education may be preferred over individual education. To prevent falls among community-dwelling older adults, evidence is most certain for benefit, at least over 1-2 years, from supervised, long-duration balance/resistance and group Tai Chi interventions, whole-body vibration, high-intensity/dose education or cognitive-behavioral therapy, and interventions of comprehensive multifactorial assessment with targeted treatment plus HHA, HHA plus exercise, or education provided to everyone. Adding other interventions to exercise does not appear to substantially increase benefits. Overall, effects appear most applicable to those with elevated fall risk. Choice among effective interventions that are available may best depend on individual patient preferences, though when implementing new balance/resistance programs delivering individual over group sessions when feasible may be most acceptable. Data on more patient-important outcomes including fall-related fractures and adverse effects would be beneficial, as would studies focusing on equity-deserving populations and on programs delivered virtually. Not registered.

Pillay J ，Gaudet LA ，Saba S ，Vandermeer B ，Ashiq AR ，Wingert A ，Hartling L ... -  《Systematic Reviews》

Safety, pharmacokinetics, and pharmacodynamics of LBP-EC01, a CRISPR-Cas3-enhanced bacteriophage cocktail, in uncomplicated urinary tract infections due to Escherichia coli (ELIMINATE): the randomised, open-label, first part of a two-part phase 2 trial.

The rate of antibiotic resistance continues to grow, outpacing small-molecule-drug development efforts. Novel therapies are needed to combat this growing threat, particularly for the treatment of urinary tract infections (UTIs), which are one of the largest contributors to antibiotic use and associated antibiotic resistance. LBP-EC01 is a novel, genetically enhanced, six-bacteriophage cocktail developed by Locus Biosciences (Morrisville, NC, USA) to address UTIs caused by Escherichia coli, regardless of antibiotic resistance status. In this first part of the two-part phase 2 ELIMINATE trial, we aimed to define a dosing regimen of LBP-EC01 for the treatment of uncomplicated UTIs that could advance to the second, randomised, controlled, double-blinded portion of the study. This first part of ELIMINATE is a randomised, uncontrolled, open-label, phase 2 trial that took place in six private clinical sites in the USA. Eligible participants were female by self-identification, aged between 18 years and 70 years, and had an uncomplicated UTI at the time of enrolment, as well as a history of at least one drug-resistant UTI caused by E coli within the 12 months before enrolment. Participants were initially randomised in a 1:1:1 ratio into three treatment groups, but this part of the trial was terminated on the recommendation of the safety review committee after a non-serious tolerability signal was observed based on systemic drug exposure. A protocol update was then implemented, comprised of three new treatment groups. Groups A to C were dosed with intraurethral 2 × 1012 plaque-forming units (PFU) of LBP-EC01 on days 1 and 2 by catheter, plus one of three intravenous doses daily on days 1-3 of LBP-EC01 (1 mL of 1 × 1010 PFU intravenous bolus in group A, 1 mL of 1 × 109 PFU intravenous bolus in group B, and a 2 h 1 × 1011 PFU intravenous infusion in 100 mL of sodium lactate solution in group C). In all groups, oral trimethoprim-sulfamethoxazole (TMP-SMX; 160 mg and 800 mg) was given twice daily on days 1-3. The primary outcome was the level of LBP-EC01 in urine and blood across the treatment period and over 48 h after the last dose and was assessed in patients in the intention-to-treat (ITT) population who received at least one dose of LBP-EC01 and had concentration-time data available throughout the days 1-3 dosing period (pharmacokinetic population). Safety, a secondary endpoint, was assessed in enrolled patients who received at least one dose of study drug (safety population). As exploratory pharmacodynamic endpoints, we assessed E coli levels in urine and clinical symptoms of UTI in patients with at least 1·0 × 105 colony-forming units per mL E coli in urine at baseline who took at least one dose of study drug and completed their day 10 test-of-cure assessment (pharmacodynamic-evaluable population). This trial is registered with ClinicalTrials.gov, NCT05488340, and is ongoing. Between Aug 22, 2022, and Aug 28, 2023, 44 patients were screened for eligibility, and 39 were randomly assigned (ITT population). Initially, eight participants were assigned to the first three groups. After the protocol was updated, 31 participants were allocated into groups A (11 patients), B (ten patients), and C (ten patients). One patient in group C withdrew consent on day 2 for personal reasons, but as she had received the first dose of the study drug was included in the modified ITT population. Maximum urine drug concentrations were consistent across intraurethral dosing, with a maximum mean concentration of 6·3 × 108 PFU per mL (geometric mean 8·8 log10 PFU per mL and geometric SD [gSD] 0·3). Blood plasma level of bacteriophages was intravenous dose-dependent, with maximum mean concentrations of 4·0 × 103 (geometric mean 3·6 log10 PFU per mL [gSD 1·5]) in group A, 2·5 × 103 (3·4 log10 PFU per mL [1·7]) in group B, and 8·0 × 105 (5·9 log10 PFU per mL [1·4]) in group C. No serious adverse events were observed. 44 adverse events were reported across 18 (46%) of the 39 participants in the safety population, with more adverse events seen with higher intravenous doses. Three patients in groups 1 to 3 and one patient in group C, all of whom received 1 × 1011 LBP-EC01 intravenously, had non-serious tachycardia and afebrile chills after the second intravenous dose. A rapid reduction of E coli in urine was observed by 4 h after the first treatment and maintained at day 10 in all 16 evaluable patients; these individuals had complete resolution of UTI symptoms by day 10. A regimen consisting of 2 days of intraurethral LBP-EC01 and 3 days of concurrent intravenous LBP-EC01 (1 × 1010 PFU) and oral TMP-SMX twice a day was well tolerated, with consistent pharmacokinetic profiles in urine and blood. LBP-EC01 and TMP-SMX dosing resulted in a rapid and durable reduction of E coli, with corresponding elimination of clinical symptoms in evaluable patients. LBP-EC01 holds promise in providing an alternative therapy for uncomplicated UTIs, with further testing of the group A dosing regimen planned in the controlled, double-blind, second part of ELIMINATE. Federal funds from the US Department of Health and Human Services, Administration for Strategic Preparedness and Response, and Biomedical Advanced Research and Development Authority (BARDA).

Kim P ，Sanchez AM ，Penke TJR ，Tuson HH ，Kime JC ，McKee RW ，Slone WL ，Conley NR ，McMillan LJ ，Prybol CJ ，Garofolo PM ... -  《-》

Tamoxifen for adults with hepatocellular carcinoma.

Hepatocellular carcinoma is the most common type of liver cancer, accounting for 70% to 85% of individuals with primary liver cancer. Tamoxifen has been evaluated in randomised clinical trials in people with hepatocellular cancer. The reported results have been inconsistent. To evaluate the benefits and harms of tamoxifen or tamoxifen plus any other anticancer drugs compared with no intervention, placebo, any type of standard care, or alternative treatment in adults with hepatocellular carcinoma, irrespective of sex, administered dose, type of formulation, and duration of treatment. We searched the Cochrane Hepato-Biliary Group Controlled Trials Register, CENTRAL, MEDLINE, Embase, three other databases, and major trials registries, and handsearched reference lists up to 26 March 2024. Parallel-group randomised clinical trials including adults (aged 18 years and above) diagnosed with advanced or unresectable hepatocellular carcinoma. Had we found cross-over trials, we would have included only the first trial phase. We did not consider data from quasi-randomised trials for analysis. Our critical outcomes were all-cause mortality, serious adverse events, and health-related quality of life. Our important outcomes were disease progression, and adverse events considered non-serious. We assessed risk of bias using the RoB 2 tool. We used standard Cochrane methods and Review Manager. We meta-analysed the outcome data at the longest follow-up. We presented the results of dichotomous outcomes as risk ratios (RR) and continuous data as mean difference (MD), with 95% confidence intervals (CI) using the random-effects model. We summarised the certainty of evidence using GRADE. We included 10 trials that randomised 1715 participants with advanced, unresectable, or terminal stage hepatocellular carcinoma. Six were single-centre trials conducted in Hong Kong, Italy, and Spain, while three were conducted as multicentre trials in single countries (France, Italy, and Spain), and one trial was conducted in nine countries in the Asia-Pacific region (Australia, Hong Kong, Indonesia, Malaysia, Myanmar, New Zealand, Singapore, South Korea, and Thailand). The experimental intervention was tamoxifen in all trials. The control interventions were no intervention (three trials), placebo (six trials), and symptomatic treatment (one trial). Co-interventions were best supportive care (three trials) and standard care (one trial). The remaining six trials did not provide this information. The number of participants in the trials ranged from 22 to 496 (median 99), mean age was 63.7 (standard deviation 4.18) years, and mean proportion of men was 74.7% (standard deviation 42%). Follow-up was three months to five years. Ten trials evaluated oral tamoxifen at five different dosages (ranging from 20 mg per day to 120 mg per day). All trials investigated one or more of our outcomes. We performed meta-analyses when at least two trials assessed similar types of tamoxifen versus similar control interventions. Eight trials evaluated all-cause mortality at varied follow-up points. Tamoxifen versus the control interventions (i.e. no treatment, placebo, and symptomatic treatment) results in little to no difference in mortality between one and five years (RR 0.99, 95% CI 0.92 to 1.06; 8 trials, 1364 participants; low-certainty evidence). In total, 488/682 (71.5%) participants died in the tamoxifen groups versus 487/682 (71.4%) in the control groups. The separate analysis results for one, between two and three, and five years were comparable to the analysis result for all follow-up periods taken together. The evidence is very uncertain about the effect of tamoxifen versus no treatment on serious adverse events at one-year follow-up (RR 0.44, 95% CI 0.19 to 1.06; 1 trial, 36 participants; very low-certainty evidence). A total of 5/20 (25.0%) participants in the tamoxifen group versus 9/16 (56.3%) participants in the control group experienced serious adverse events. One trial measured health-related quality of life at baseline and at nine months' follow-up, using the Spitzer Quality of Life Index. The evidence is very uncertain about the effect of tamoxifen versus no treatment on health-related quality of life (MD 0.03, 95% CI -0.45 to 0.51; 1 trial, 420 participants; very low-certainty evidence). A second trial found no appreciable difference in global health-related quality of life scores. No further data were provided. Tamoxifen versus control interventions (i.e. no treatment, placebo, or symptomatic treatment) results in little to no difference in disease progression between one and five years' follow-up (RR 1.02, 95% CI 0.91 to 1.14; 4 trials, 720 participants; low-certainty evidence). A total of 191/358 (53.3%) participants in the tamoxifen group versus 198/362 (54.7%) participants in the control group had progression of hepatocellular carcinoma. Tamoxifen versus control interventions (i.e. no treatment or placebo) may have little to no effect on adverse events considered non-serious during treatment, but the evidence is very uncertain (RR 1.17, 95% CI 0.45 to 3.06; 4 trials, 462 participants; very low-certainty evidence). A total of 10/265 (3.8%) participants in the tamoxifen group versus 6/197 (3.0%) participants in the control group had adverse events considered non-serious. We identified no trials with participants diagnosed with early stages of hepatocellular carcinoma. We identified no ongoing trials. Based on the low- and very low-certainty evidence, the effects of tamoxifen on all-cause mortality, disease progression, serious adverse events, health-related quality of life, and adverse events considered non-serious in adults with advanced, unresectable, or terminal stage hepatocellular carcinoma when compared with no intervention, placebo, or symptomatic treatment could not be established. Our findings are mostly based on trials at high risk of bias with insufficient power (fewer than 100 participants), and a lack of trial data on clinically important outcomes. Therefore, firm conclusions cannot be drawn. Trials comparing tamoxifen administered with any other anticancer drug versus standard care, usual care, or alternative treatment as control interventions were lacking. Evidence on the benefits and harms of tamoxifen in participants at the early stages of hepatocellular carcinoma was also lacking. This Cochrane review had no dedicated funding. Protocol available via DOI: 10.1002/14651858.CD014869.

Naing C ，Ni H ，Aung HH 《Cochrane Database of Systematic Reviews》