Placebo Recipients Research Articles

The effect of lyophilised oral faecal microbial transplantation on functional outcomes in dogs with diabetes mellitus.

We aimed to determine if oral faecal microbiota transplantation improves indices of glycaemic control, changes the faecal dysbiosis indices, alters faecal short-chain fatty acid and bile acid profiles and increases serum glucagon-like-peptide 1 concentrations in diabetic dogs. In this prospective randomised, placebo-controlled, double-blinded pilot study, we recruited nine diabetic dogs (five faecal microbiota transplantation and four placebo) and nine healthy controls. Compared to healthy dogs, diabetic dogs had altered faecal short-chain fatty acid and bile acid profiles. In the first 30 days, the faecal microbiota transplantation group had a more rapid decline in interstitial glucose; however, the mean interstitial glucose of the faecal microbiota transplantation recipients did not differ from the placebo recipients at the end of the study. Compared with placebo, faecal microbiota transplantation recipients had a decreased 24-hour water intake at day 60 and increased faecal abundance of Faecalibacterium. This study provides a proof of concept for faecal microbiota transplantation in canine diabetes, and its data could inform the design of future large-scale studies. Further investigation is required to determine whether faecal microbiota transplantation would have any role as an adjunctive therapy in canine diabetes and to elucidate the mechanisms by which faecal microbiota transplantation may provide a beneficial clinical effect in canine diabetes.

Impact of RSV Prevention in Infancy on Prevalence of Asthma Among 9-14-Year-old Native American Children in the Southwest United States.

The impact of respiratory syncytial virus (RSV) prevention on persistent childhood asthma is unknown. We revisited Native American children 9-14 years old who participated as infants in a phase III, randomized, placebo-controlled trial of an efficacious monoclonal antibody (motavizumab) for prevention of RSV to quantify asthma prevalence and investigate relationships between RSV prevention and subsequent asthma. Families that participated in the phase III RSV prevention trial were contacted. Following informed consent, data were collected by parental questionnaire and medical record review to assess respiratory health. Composite outcomes for asthma were defined using a combination of questionnaire and chart review data. Relative risk reductions (RRRs) for asthma-related outcomes were stratified by motavizumab and placebo recipients. Of the 2127 original trial participants, 97% were eligible for enrollment in this follow-up study, of which 1773 (86%) were enrolled at a median age of 11 years (range: 9-14). The composite measure of asthma prevalence was 18.2% (95% confidence interval: 16.5, 20). The point estimate for persistent asthma was lower in motavizumab recipients [17.5% (15.4, 19.7)] compared with placebo recipients [19.7% (16.6, 23.1)], but this difference was not statistically significant [RRR: 11.1% (-9.1, 27.6)]. Asthma-related outcomes occurred less frequently among children who received motavizumab compared with placebo in infancy; however, these findings were not statistically significant, related to insufficient study power. The potential for reduction in asthma related to the prevention of RSV should be further evaluated in larger studies, especially given the elevated asthma prevalence observed in Native American children in this study.

Brief Report: Associations Between Gender and Solicited Adverse Events After Passive Infusion of VRC01 or Placebo in HVTN 704/HPTN 085.

Realizing the potential of HIV prevention options requires understanding product tolerability across diverse groups vulnerable to HIV acquisition. Gender minority (GM) individuals are understudied in clinical trials. HVTN 704/HIV Prevention Trials Network 085, a phase 2b randomized HIV prevention trial, enrolled MSM and transgender participants from Brazil, Peru, Switzerland, and the United States to receive an infusion every 8 weeks (10 total) of VRC01 30 mg/kg, VRC01 10 mg/kg, or placebo. Solicited adverse events (AEs) were recorded for 3 days after each infusion. Gender was defined by self-report and sex assigned-at-birth. Multivariate mixed logistic models were used to estimate the association between gender (cisgender men [CM] vs. GM participants [transgender women, transgender men, or another gender]) and solicited AE frequency and severity. GM participants reported more solicited AEs than CM among all participants (adjusted OR 1.59, 95% CI: 1.20 to 2.10, P = 0.001) and among placebo recipients (1.72, 1.05 to 2.81, P = 0.031). The severity of solicited AEs (occurrence of grade 2 and higher event) did not significantly differ overall (1.83, 0.79 to 4.20, P = 0.174) or among placebo recipients (3.05, 0.76 to 12.32, P = 0.112). Grade 2 events were reported after 1% and 2% of total infusions among CM and GM participants, respectively. Grade 3-4 events were rare overall (<0.1%). Completion of 10 infusions was high (78.6%) and slightly higher in CM (79.2%) than GM participants (73%). This is the first report of associations between gender and solicited AEs after monoclonal antibody infusion. GM participants reported more events; severity was low. HIV prevention trials must engage and support GM individuals to best evaluate tolerability of novel agents.

Efficacy, safety, and immunogenicity of the AS01E-adjuvanted respiratory syncytial virus prefusion F protein vaccine (RSVPreF3 OA) in older adults over three respiratory syncytial virus seasons (AReSVi-006): a multicentre, randomised, observer-blinded, placebo-controlled, phase 3 trial.

Efficacy, safety, and immunogenicity of the AS01E-adjuvanted respiratory syncytial virus prefusion F protein vaccine (RSVPreF3 OA) in older adults over three respiratory syncytial virus seasons (AReSVi-006): a multicentre, randomised, observer-blinded, placebo-controlled, phase 3 trial.

Summary of the National Advisory Committee on Immunization (NACI) Statement on the Prevention of Respiratory Syncytial Virus (RSV) in Infants.

Immunization programs for the prevention of respiratory syncytial virus (RSV) in infants have been available in Canada since the authorization of palivizumab in 2002. However, these programs have been limited to only those infants at highest risk for severe RSV disease. The authorization of new passive immunizing products to prevent RSV, including a new monoclonal antibody (nirsevimab) and a vaccine administered in pregnancy (RSV pre-fusion stabilized F protein; RSVpreF) offers the opportunity to prevent RSV in more Canadian infants. The objective of this article is to summarize guidance from the National Advisory Committee on Immunization (NACI) on the prevention of RSV in infants. NACI established key policy questions and performed an evidence review and synthesis. NACI made evidence-based recommendations in consideration of the burden of illness to be prevented, safety and efficacy of the new immunizing products, economic evidence and ethics, equity, feasibility, and acceptability. Nirsevimab and RSVpreF offer protection against severe outcomes of RSV disease, including hospitalization and intensive care unit admission. Nirsevimab protection may be slightly higher and may last longer than protection offered by RSVpreF. Nirsevimab and RSVpreF also have a similar frequency of adverse reactions for both pregnant and infant participants. The RSVpreF vaccine may increase the risk of severe local adverse events compared to placebo for pregnant recipients. In RSVpreF clinical trials, an imbalance was observed in late preterm birth between RSVpreF and placebo recipients. It is unclear whether there is a causal relation with the vaccine as the currently available data is inconclusive. Based on new evidence, NACI recommends building towards a universal RSV immunization program for all infants. Currently, nirsevimab is preferred over RSVpreF. Program introduction could occur in stages depending on access to supply, cost effectiveness, and affordability of available options.

Efficacy and Safety of WXSH0208 Tablets in Treatment of Acute Uncomplicated Influenza Infection in Adults: A Multicenter Randomized, Double-Blind, Placebo-Controlled Phase 2 Trial.

WXSH0208 is a selective inhibitor of influenza RNA polymerase subunit, demonstrating antiviral activity in preclinical studies against influenza A and B virus infections. The purpose of this study was to investigate the efficacy and safety of WXSH0208 in adult outpatients with uncomplicated influenza. We conducted a multicenter phase 2 trial based on a randomized, double-blind, placebo-controlled design at 23 research centers in China from November 2023 to March 2024. Participants were randomized 1:1:1:1 to receive one of the following treatments within 48 hours of symptom onset: WXSH0208 10 mg once daily for 5 days, 20 mg once daily for 5 days, 30 mg once daily for 3 days, or placebo. The primary outcome was the time to negative detection of viral load by reverse transcriptase quantitative polymerase chain reaction in the intention-to-treat infected population. Of 240 randomized patients, 209 were included in the intention-to-treat infected analysis. The median time to negative detection of viral load was 49.3 hours in the WXSH0208 10 mg group, 48.0 hours in the 20 mg group, and 48.2 hours in the 30 mg group, as compared with 95.6 hours in the placebo group (P < .001). Time to alleviation of influenza symptoms was comparable among all groups. Treatment-emergent adverse events were reported in 48.3% to 51.7% of WXSH0208 recipients and 58.3% of placebo recipients, with most being mild or moderate in severity. WXSH0208 showed no evident safety concerns and was superior to placebo in reducing viral load in adult outpatients with uncomplicated influenza. Clinical Trials Registration. CTR20233250 (www.chinadrugtrials.org.cn).

Protective targets of PfSPZ vaccines identified from whole-genome sieve analysis of isolates from malaria vaccine efficacy trials in West Africa.

Identification of antigens targeted by a protective response is a central quest in malaria vaccinology. Whole-genome sieve analysis (SA WG ) in samples collected from placebo-controlled field trials of Plasmodium falciparum (Pf) sporozoite (SPZ) vaccines may enable identification of Pf pre-erythrocytic antigens. We applied SA WG to genomic data generated from Pf isolates collected during two field trials measuring the efficacy, in malaria-exposed African adults, of two PfSPZ vaccines. These randomized, double-blind, placebo-controlled trials were conducted in regions of Mali and Burkina Faso characterized by high seasonal transmission, where parasite genetic diversity is high. Genomic sites in which the vaccine allelic state was significantly underrepresented among breakthrough infections in vaccinees relative to placebo recipients were termed "target sites". Protein-coding loci containing target sites that changed amino acids were termed "target loci". The SA WG conducted on clinical trial samples from the Burkina Faso and Mali trials identified 138 and 80 single-copy protein-coding target loci in the Burkinabe and Malian data sets, respectively, with twelve common to both, a number significantly higher than expected ( E = 3.9; 99%CI = [0, 9]). Among these was the thrombospondin-related anonymous protein locus, which encodes PfSSP2|TRAP, one of the most abundant and well-characterized pre-erythrocytic stage antigen as well as other genes encoding membrane-associated proteins of unknown function. These results identify SA WG as a potentially powerful tool for identifying protective vaccine antigens in recombining pathogens with large genome size and reveals potential new protective Pf antigens.

Safety, immunogenicity and effect on viral rebound of HTI vaccines combined with a TLR7 agonist in early-treated HIV-1 infection: a randomized, placebo-controlled phase 2a trial

Building on results from the AELIX-002 trial with HIVACAT T-cell immunogen (HTI)-based vaccines, the AELIX-003 (NCT04364035) trial tested the safety of the combination of ChAdOx1.HTI (C) and MVA.HTI (M), with the TLR7 agonist vesatolimod (VES), in a double-blind, placebo-controlled, randomized clinical trial in 50 virally suppressed early-treated men with HIV-1 infection. Secondary objectives included immunogenicity and effects on viral rebound kinetics during a 24-week antiretroviral treatment interruption (ATI). The most common treatment-related adverse events were mild-to-moderate injection-site pain, influenza-like illness, headache, and fatigue. Strong, broad, and HTI-focused T-cell responses were induced by vaccination. All participants experienced viral rebound in ATI; 33.3% and 23.5% (P = 0.4494) of CCMM + VES and placebo recipients, respectively, remained off antiretroviral therapy for 24 weeks. Post hoc analysis confirmed a correlation between levels of HTI-specific T cells and prolonged time off antiretroviral therapy. The combination of HTI vaccines and VES was safe and elicited robust T-cell responses.

Immune response and safety of the adjuvanted recombinant zoster vaccine in adults 50years of age and older in India: A randomized phase 3 trial.

Reactivation of latent varicella-zoster virus can cause herpes zoster (shingles) and associated complications, such as post-herpetic neuralgia. The adjuvanted recombinant zoster vaccine (RZV) was shown to be efficacious in preventing herpes zoster and have an acceptable safety profile in adults ≥50years of age. However, no clinical data on RZV were available in an Indian population. The aim of the current study was to assess the immunogenicity and safety of RZV in adults ≥50years of age in India. In this randomized, placebo-controlled, observer-blind, multi-center trial, conducted between February 2022 and March 2023, participants ≥50years of age received two doses (with a two-month interval) of RZV (N=143) or placebo (N=145). Blood samples were collected pre-dose 1 and one month post-dose 2 to quantify anti-glycoprotein E (gE) antibody concentrations. Solicited adverse events (AEs) with onset within seven days and unsolicited AEs with onset within 30days following any RZV or placebo dose were recorded. Serious AEs (SAEs) and potential immune-mediated diseases (pIMDs) were recorded until trial end (six months post-dose 2). At one month post-dose 2, vaccine response rate in the RZV group was 85.7% (95% confidence interval [CI]: 78.4%-91.3%), meeting the primary objective's success criterion (lower limit of 95% CI ≥60%). The adjusted geometric mean anti-gE antibody concentration ratio between the RZV and placebo groups was 19.8 (95% CI, 14.1-27.8), meeting the secondary objective's success criterion (lower limit of 95% CI ≥3). Solicited AEs were reported by 103 (72.0%) RZV and 86 (59.3%) placebo recipients; most had mild-to-moderate severity. No intervention-related unsolicited AE or SAE and no pIMD or death were reported. Two doses of RZV induced a robust antibody response, comparable to that reported in other populations, and had a safety profile similar to the known RZV safety profile. gov: NCT05219253.

Tixagevimab/cilgavimab or placebo for COVID-19 in ACTIV-2: Safety, pharmacokinetics and neutralizing and anti-drug antibodies.

Monoclonal antibodies have potential as rapidly developable agents for treatment and prevention of emerging viruses. The ACTIV-2 trial randomized persons with mild-moderate COVID-19 to the monoclonal antibody combination tixagevimab/cilgavimab via intramuscular injection (600mg IM) or infusion (300mg IV) versus placebo. We present final safety and laboratory outcomes; primary outcomes were previously reported. The analyzed IM group included 214 participants, and the IV group, 106 participants. Adverse events were not different between treatment and placebo. The half-life of both components was >90days for IM or 75days for IV. New anti-drug antibodies were about 3 times more likely in active vs. placebo recipients. SARS-CoV-2 neutralizing antibodies increased 157-fold at 7days and 127-fold at 1month (IM-treated) but were less robust in IV participants. These data can inform future development of monoclonal antibodies against SARS-CoV-2 and other viruses, even if this intervention is of low utility for contemporary SARS-CoV-2 variants.

Long-term hepatitis B surface antigen response after finite treatment of ARC-520 or JNJ-3989

Background and aimsRNA interference has been extensively explored in patients with chronic hepatitis B (CHB) infection. We aimed to characterise the long-term efficacy of small interfering RNA (siRNA) on hepatitis...

Single-dose suraxavir marboxil for acute uncomplicated influenza in adults and adolescents: a multicenter, randomized, double-blind, placebo-controlled phase 3 trial.

Suraxavir marboxil (GP681) is an antiviral drug inhibiting the polymerase acidic protein (PA) of RNA polymerase, of influenza. It has shown therapeutic activity against influenza A and B virus infections in preclinical studies. In this multicenter randomized, double-blind, placebo-controlled, phase 3 trial, we aimed to investigate the efficacy and safety of single-dose suraxavir marboxil (40-mg oral dose) in otherwise healthy outpatients aged 5-65 years with uncomplicated influenza unaccompanied by severe issues. From 28 July 2022 to 31 October 2023, 591 outpatients aged 5-65 years with uncomplicated influenza underwent randomization in 46 research centers in China and were randomly assigned in a 2:1 ratio to receive suraxavir marboxil (40 mg) or placebo within 2 days of symptom onset. The primary outcome was time to alleviation of influenza symptoms (TTAS) (from the start of treatment until body temperature returned to 37.2 °C or less and all seven influenza symptoms (cough, sore throat, headache, nasal congestion, feverishness or chills, muscle or joint pain, and fatigue) resolved for at least 21.5 h) within 15 days by treatment. The secondary endpoints included virological indicators, system and respiratory symptoms, PA variant mutation and adverse events. The median TTAS was significantly shorter in the group that received suraxavir marboxil compared to the placebo group (42.0 h versus 63.0 h, P = 0.002). Suraxavir marboxil was associated with more rapid decrease in viral load from baseline than placebo by 1 day after administration, with a mean change of -2.2 ± 1.3 compared to -1.3 ± 1.7 log10 copies per ml (P < 0.001) in the placebo group. Adverse events were reported in 28.4% (112 of 395) of suraxavir marboxil recipients and 23.3% (45 of 193) of placebo recipients, most of which were mild or moderate. The incidences of PA variants with the I38T mutation in the H1N1pdm and H3N2 subtypes were 0.7% (1 of 138) and 0.9% (2 of 213), respectively. Low acquired drug resistance was observed. In this trial, timely single-dose suraxavir marboxil was effective in shortening TTAS and reducing the influenza viral load in patients aged 5-65 years with uncomplicated influenza safely. ClinicalTrials.gov registration: NCT05474755 .

Preterm Birth Frequency and Associated Outcomes From the MATISSE (Maternal Immunization Study for Safety and Efficacy) Maternal Trial of the Bivalent Respiratory Syncytial Virus Prefusion F Protein Vaccine.

To describe preterm birth frequency and newborn and infant outcomes overall and among preterm children in the MATISSE (Maternal Immunization Study for Safety and Efficacy) trial of maternal vaccination with bivalent respiratory syncytial virus (RSV) prefusion F protein-based vaccine (RSVpreF) to protect infants against severe RSV-associated illness. MATISSE was a global, phase 3, randomized, double-blind trial. Pregnant individuals received single injections of RSVpreF or placebo. Adverse events of special interest, including preterm birth (gestational age less than 37 weeks) and low birth weight (2,500 g or less), were collected through 6 months after delivery (pregnant participants) and from birth through age 12 or 24 months (pediatric participants). Overall, 7,386 pregnant participants received RSVpreF (n=3,698) or placebo (n=3,688); 7,305 newborns and infants were included in the analysis. Most children in both groups were born full term (more than 93%) with normal birth weight (95% or higher). Newborn and infant outcomes, including rates of low birth weight and neonatal hospitalization, were favorable and comparable between groups. Preterm birth rates were 5.7% in the RSVpreF arm and 4.7% in the placebo arm (relative risk [RR] 1.20, 95% CI, 0.98-1.46); most were late preterm. Newborn and infant outcomes, including rates of low birth weight and neonatal hospitalization, were comparable between groups. Twenty-two newborn or infant deaths occurred during the study (RSVpreF n=8, placebo n=14). When stratified by income region, preterm birth rates in RSVpreF and placebo recipients were both 5.0% in high-income countries. Rates in non-high-income countries were 7.0% and 4.0% in the RSVpreF and placebo groups, respectively, and 8.3% and 4.0% in South Africa (RR 2.06, 95% CI, 1.21-3.51). In this study of maternal RSVpreF vaccination, no clinically significant increase in adverse events of special interest, including preterm birth, low birth weight, or neonatal hospitalization, was observed among pregnant people in the overall analysis. In subgroup analysis of non-high-income countries, an elevated risk of preterm birth was observed. More research is needed to better ascertain preterm delivery risk factors, particularly aimed at minimizing disparities among geographic regions. This study was sponsored by Pfizer. ClinicalTrials.gov , NCT04424316.

A phase I, randomized, placebo-controlled trial to evaluate the pharmacokinetics, safety, and tolerability of nirsevimab in healthy Chinese adults.

Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract infection (LRTI) in infants worldwide. Nirsevimab, an extended half-life monoclonal antibody against RSV, is approved in China for the prevention of RSV lower respiratory tract disease in infants; however, global nirsevimab trials did not enroll Chinese infants. To inform the investigation of nirsevimab for the prevention of RSV LRTI in Chinese infants, this Phase I, randomized, placebo-controlled trial evaluated the pharmacokinetics (PK) and safety of nirsevimab in healthy Chinese adults. Participants were randomized 3:1 to a single 300 mg intramuscular dose of nirsevimab or placebo and were followed through 150 days post-dose. Serum nirsevimab concentrations were measured and PK parameters of maximum serum concentration (Cmax), time to maximum concentration (tmax), and area under the concentration-time curve from time 0 to Day 150 (AUC0-150) were estimated. Treatment emergent adverse events (AEs), clinical laboratory data, and vital signs were evaluated. Overall, 24 participants were randomized to nirsevimab (n = 18) or placebo (n = 6). Nirsevimab geometric mean (coefficient of variation [%CV]) Cmax was 46.9 (21.7) μg/mL, median (range) tmax was 7.0 (4.9, 29.9) days, and geometric mean (%CV) AUC0-150 was 4210.6 (13.6) μg·day/mL. Treatment-emergent AEs (all Grade 1 or Grade 2 in severity) were reported in 5/18 (27.8%) nirsevimab recipients and 2/6 (33.3%) placebo recipients. No serious AEs, new onset chronic disease, or deaths were reported. Overall, safety and PK outcomes were consistent with those observed in healthy adults in the USA, with no new safety concerns.

Evaluation of the Safety and Impact of Heat-Treated Lactiplantibacillus plantarum KM2 Fermentation on Gut Microbiome Architecture.

Postbiotics, bioactive compounds from the fermentation process by probiotics, are gaining attention for their potential health benefits as safer alternatives to live probiotic microbes. Lactiplantibacillus plantarum is a well-studied probiotic species known for promoting gut health and immune modulation. However, the safety and effects of its postbiotic formulations on the gut microbiome structure remain less explored. This study presents a randomized, double-blind, placebo-controlled human study of KLP-KM2, a postbiotic consisting of heat-treated L. plantarum KM2 fermentation complex, in elderly participants. Over 12 weeks, KLP-KM2 consumption did not result in noticeable adverse reaction cases compared to the placebo. Nevertheless, the gut microbial diversity and taxonomic architecture of the KLP-KM2 recipients were differentiated from those of the placebo recipients after 12 weeks. A notable outcome was the increase in the number of subjects carrying Veillonella spp., which contributed to the distinct gut microbiome profiles observed between the two groups. Interestingly, KLP-KM2 facilitated the de novo colonization of Veillonella spp. in subjects who had not harbored these bacteria at the baseline. These results suggest the potential of KLP-KM2 as a safe and effective postbiotic intervention to enhance energy metabolism and mobility in older adults.

Immunogenicity and safety following a homologous booster dose of a SARS-CoV-2 recombinant spike protein vaccine with Matrix-MTM adjuvant (NVX-CoV2373) versus a primary series in people living with and without HIV-1 infection in South Africa: A randomized crossover phase 2a/2b trial

ABSTRACT COVID-19 remains a global public health issue and an improved understanding of vaccine performance in immunocompromised individuals, including people living with HIV (PLWH), is needed. Initial data from the present study’s pre-crossover/booster phase were previously reported. This phase 2a/b clinical trial in South Africa (2019nCoV-501/NCT04533399) revisits 1:1 randomly assigned HIV-negative adults (18–84 years) and medically stable PLWH (18–64 years) who previously received two NVX-CoV2373 doses (5 μg recombinant Spike protein with 50 μg Matrix-M™ adjuvant) or placebo. During the 6-month blinded crossover/booster phase, NVX-CoV2373 recipients could receive a single NVX-CoV2373 booster dose and placebo recipients a 2-dose NVX-CoV2373 primary series. NVX-CoV2373 safety and immunogenicity were assessed according to prior SARS-CoV-2 infection and HIV status. Post-crossover, 1900/3793 NVX-CoV2373 recipients were assigned another dose, and 1893/3793 placebo recipients were assigned NVX-CoV2373 primary series. Approximately 56% of the participants were SARS-CoV-2–seropositive (“seropositive”) at crossover (6% PLWH). In seropositive participants (HIV-negative and PLWH), booster-dose anti-spike IgG, MN50 and hACE2 inhibition responses increased to similar levels, exceeding those in seronegative participants. In primary-series and booster cohorts, seronegative PLWH showed higher neutralizing responses (4.9- to 5.5-fold, respectively) versus peak pre-crossover primary-series responses. The safety profile was similar among the pre-crossover/booster phase groups; solicited and unsolicited adverse events were infrequent in all groups. A single NVX-CoV2373 booster dose substantially increased antibodies. All baseline seropositive participants showed higher immune responses than seronegative participants. These findings support use of NVX-CoV2373, including in immunocompromised individuals.

Amlodipine in the HRT cycle for frozen embryo transfer to correct uterine artery resistance in women with prior implantation failure: a randomized controlled trial

For successful embryo implantation in women with high pulsatility, uterine vascular resistance and pulsatility must be reduced. We examined the effects of amlodipine on uterine pulsatility index (PI), resistance index (RI), and embryo transfer (ET) outcomes in women with prior implantation failure and at least one elevated uterine PI measurement (especially higher than 3). Between February and November 2023, our reproductive facility conducted a single-center randomized clinical trial, enrolling 100 patients with previous implantation failure and at least one uterine PI measurement exceeding 3. Participants were randomly assigned to receive either amlodipine (5 mg) or placebo (n=50 per group). Hormone replacement therapy was the predominant method for endometrial preparation. Transvaginal ultrasonography was used to measure uterine artery resistance and pulsatility on day 1 or 2 of menstruation. Women in the amlodipine group received 5 mg nightly. Following repeat transvaginal ultrasound to assess PI and RI, ET was performed. If a positive pregnancy test was obtained, treatment continued for a total of 7 weeks. Amlodipine reduced blood flow indices in the uterine artery. Among placebo recipients, 18% tested positive for beta-human chorionic gonadotropin, compared to 26% of medication recipients. However, this difference was statistically insignificant (p=0.472). Gestational sacs were observed in 12% of the placebo group and 22% of the medication group, but this difference was also insignificant (p=0.28). Amlodipine appears to reduce uterine pulsatility and resistance during ET. Despite the absence of significant differences in pregnancy outcomes, this promising drug merits further study in women with implantation failure.

Phase III KEYNOTE-789 Study of Pemetrexed and Platinum With or Without Pembrolizumab for Tyrosine Kinase Inhibitor‒Resistant, EGFR-Mutant, Metastatic Nonsquamous Non-Small Cell Lung Cancer.

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are standard first-line therapy for EGFR-mutant, metastatic non-small cell lung cancer (NSCLC); however, most patients experience disease progression. We report results from the randomized, double-blind, phase III KEYNOTE-789 study of pemetrexed and platinum-based chemotherapy with or without pembrolizumab for TKI-resistant, EGFR-mutant, metastatic nonsquamous NSCLC (ClinicalTrials.gov identifier: NCT03515837). Adults with pathologically confirmed stage IV nonsquamous NSCLC, documented DEL19 or L858R EGFR mutation, and progression after EGFR-TKI treatment were randomly assigned 1:1 to 35 cycles of pembrolizumab 200 mg or placebo once every 3 weeks plus four cycles of pemetrexed and carboplatin or cisplatin once every 3 weeks and then maintenance pemetrexed. Dual primary end points were progression-free survival (PFS) and overall survival (OS). Final PFS testing was completed at the second interim analysis (IA2; data cutoff, December 3, 2021); OS was tested at final analysis (FA; data cutoff, January 17, 2023). Efficacy boundaries were one-sided P = .0117 for PFS and OS. Four hundred ninety-two patients were randomly assigned to pembrolizumab plus chemotherapy (n = 245) or placebo plus chemotherapy (n = 247). At IA2, the median PFS was 5.6 months for pembrolizumab plus chemotherapy versus 5.5 months for placebo plus chemotherapy (hazard ratio [HR], 0.80 [95% CI, 0.65 to 0.97]; P = .0122). At FA, the median OS was 15.9 versus 14.7 months, respectively (HR, 0.84 [95% CI, 0.69 to 1.02]; P = .0362). Grade ≥3 treatment-related adverse events occurred in 43.7% of pembrolizumab plus chemotherapy recipients versus 38.6% of placebo plus chemotherapy recipients. Addition of pembrolizumab to chemotherapy in patients with TKI-resistant, EGFR-mutant, metastatic nonsquamous NSCLC did not significantly prolong PFS or OS versus placebo plus chemotherapy in KEYNOTE-789.

Therapeutic BCG vaccine protects against long COVID: The BATTLE randomized clinical trial.

Bacillus Calmette-Guérin (BCG) injected during the COVID-19 convalescence period was safe and enhanced recovery from anosmia and dysgeusia in the acute phase. To report the long-term results of the BATTLE trial, BCG vaccine in adults with mild COVID-19. Design: Double-blind, placebo-controlled, randomized (1:1) clinical trial. BCG intradermal vaccine and placebo. A total of 157 BCG and 142 placebo recipients participated in the 6-month follow-up, and 97 BCG and 95 placebo recipients participated in the 12-month follow-up. Long COVID symptoms and mechanistic analyses. BCG reduced hearing problems at 6 months (odds ratio [OR]=0.26) and sleeping, concentration, memory, and vision problems at 12 months (OR=0.45, 0.36, 0.38, and 0.36, respectively). Sensitivity analyses confirmed that long COVID-19 symptoms were reduced at the 6- and 12-month follow-ups (p=0.010 and 0.031, respectively). BCG's crossover interaction paradoxically increased hair loss in women and decreased it in men at 6 months (p=0.032). BCG immunomodulation is likely mediated through inhibition of Fas ligand expression in the blood and increased induction of IL6, IL10, interferon-induced transmembrane protein 3, and angiotensin-converting enzyme 2 in cultured human macrophages. Long-term follow-up of the BATTLE trial participants revealed that BCG protects against long COVID development if administered within the COVID-19 convalescence period. The response to BCG was subject-specific, including a paradoxical crossover interaction based on sex. Not tested for previous mycobacterial exposure; loss to follow-up, particularly at 12 months.

Bivalent RSVpreF Vaccine in Adults 18 to

Older individuals and adults with certain chronic or immunocompromising health conditions are at increased risk of severe RSV disease. In this phase 3 randomized trial of RSVpreF safety and immunogenicity in 18-59-year-olds at high-risk of severe RSV disease, participants were randomized 2:1 to 1 RSVpreF (120 µg) or placebo dose. Primary safety endpoints included reactogenicity events and adverse events (AEs) through 7 days and 1 month after vaccination, respectively, and serious AEs (SAEs) and newly diagnosed chronic medical conditions (NDCMCs) throughout the study. In primary analyses, immunogenicity elicited 1 month after RSVpreF was bridged to a randomly selected subset of ≥60-year-olds receiving RSVpreF from the immunogenicity subset in the pivotal phase 3 RENOIR trial, which demonstrated RSVpreF efficacy. Noninferiority was declared if 95% CI lower bounds were >0.667 (neutralizing titer adjusted geometric mean ratios) and >-10% (seroresponse rate differences) for RSV-A and RSV-B. Overall, 678 participants received RSVpreF (n=453) or placebo (n=225). Most reactogenicity events were mild/moderate; severe events occurred in ≤2.0% of participants overall. AE frequencies were similar in RSVpreF (7.1%) and placebo recipients (7.6%). No vaccine-related SAEs or NDCMCs were reported. One month after RSVpreF administration, noninferiority criteria were met in 18-59-year-olds versus ≥60-year-olds for RSV-A and RSV-B neutralizing titers and seroresponse rates. RSVpreF was well tolerated with no safety concerns and demonstrated immunobridging to efficacy in 18-59-year-olds at high-risk of severe RSV disease versus ≥60-year-olds in whom efficacy was previously demonstrated, supporting use of RSVpreF to prevent RSV-associated disease in this population. NCT05842967.