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BACKGROUND: Cervical cancer is the fourth most frequently diagnosed cancer and the fourth leading cause of cancer death in women, The standard treatment recommendation for women with early cervical cancer is radical hysterectomy with pelvic lymph node dissection, however, articles published in recent years have concluded that the treatment outcome of laparoscopic surgery for cervical cancer is inferior to that of open surgery. Thus, we choose a surgically new approach; the laparoscopic cervical cancer surgery in the open state is compared with the traditional open cervical cancer surgery, and we hope that patients can still have a good tumor outcome and survival outcome. This trial will investigate the effectiveness of laparoscopic cervical cancer surgery in the open-state treatment of early-stage cervical cancer. METHOD AND DESIGN: This will be an open-label, 2-armed, randomized, phase-III single-center trial of comparing laparoscopic radical hysterectomy based on open state with abdominal radical hysterectomy in patients with early-stage cervical cancer. A total of 740 participants will be randomly assigned into 2 treatment arms in a 1:1 ratio. Clinical, laboratory, ultrasound, and radiology data will be collected at baseline, and then at the study assessments and procedures performed at baseline and 1 week, 6 weeks, and 3 months, and follow-up visits begin at 3 months following surgery and continue every 3 months thereafter for the first 2 years and every 6 months until year 4.5. The primary aim is the rate of disease-free survival at 4.5 years. The secondary aims include treatment-related morbidity, costs and cost-effectiveness, patterns of recurrence, quality of life, pelvic floor function, and overall survival. CONCLUSIONS: This prospective trial aims to show the equivalence of the laparoscopic cervical cancer surgery in the open state versus the transabdominal radical hysterectomy approach for patients with early-stage cervical cancer following a 2-phase protocol. TRIAL REGISTRATION: ChiCTR2300075118. Registered on August 25, 2023.

Asunto(s)

Histerectomía , Laparoscopía , Estadificación de Neoplasias , Ensayos Clínicos Controlados Aleatorios como Asunto , Neoplasias del Cuello Uterino , Humanos , Neoplasias del Cuello Uterino/cirugía , Neoplasias del Cuello Uterino/mortalidad , Neoplasias del Cuello Uterino/patología , Femenino , Histerectomía/métodos , Histerectomía/efectos adversos , Laparoscopía/efectos adversos , Laparoscopía/métodos , Resultado del Tratamiento , Ensayos Clínicos Fase III como Asunto , Adulto , Persona de Mediana Edad , Escisión del Ganglio Linfático/efectos adversos , Escisión del Ganglio Linfático/métodos , Calidad de Vida

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BACKGROUND & AIMS: Bulevirtide (BLV), a first-in-class entry inhibitor, is approved in Europe for the treatment of chronic hepatitis delta (CHD). BLV monotherapy was superior to delayed treatment at week (W) 48, the primary efficacy endpoint, in the MYR301 study (NCT03852719). Here, we assessed if continued BLV therapy until W96 would improve virologic and biochemical response rates, particularly among patients who did not achieve virologic response at W24. METHODS: In this ongoing, open-label, randomized phase III study, patients with CHD (N = 150) were randomized (1:1:1) to treatment with BLV 2 mg/day (n = 49) or 10 mg/day (n = 50), each for 144 weeks, or to delayed treatment for 48 weeks followed by BLV 10 mg/day for 96 weeks (n = 51). Combined response was defined as undetectable hepatitis delta virus (HDV) RNA or a decrease in HDV RNA by ≥2 log10 IU/ml from baseline and alanine aminotransferase (ALT) normalization. Other endpoints included virologic response, ALT normalization, and change in HDV RNA. RESULTS: Of 150 patients, 143 (95%) completed 96 weeks of the study. Efficacy responses were maintained and/or improved between W48 and W96, with similar combined, virologic, and biochemical response rates between BLV 2 and 10 mg. Of the patients with a suboptimal early virologic response at W24, 43% of non-responders and 82% of partial responders achieved virologic response at W96. Biochemical improvement often occurred independently of virologic response. Adverse events were mostly mild, with no serious adverse events related to BLV. CONCLUSIONS: Virologic and biochemical responses were maintained and/or increased with longer term BLV therapy, including in those with suboptimal early virologic response. BLV monotherapy for CHD was safe and well tolerated through W96. IMPACT AND IMPLICATIONS: In July 2023, bulevirtide was fully approved for the treatment of chronic hepatitis delta (CHD) in Europe based on clinical study results from up to 48 weeks of treatment. Understanding the efficacy and safety of bulevirtide over the longer term is important for healthcare providers. In this analysis, we demonstrate that bulevirtide monotherapy for 96 weeks in patients with CHD was associated with continued improvements in combined, virologic, and biochemical responses as well as liver stiffness from week 48 at both the 2 mg and 10 mg doses. Patients with suboptimal virologic responses to bulevirtide at week 24 also benefited from continued therapy, with the majority achieving virologic response or biochemical improvement by week 96. GOV IDENTIFIER: NCT03852719.

Asunto(s)

Antivirales , Hepatitis D Crónica , Virus de la Hepatitis Delta , Humanos , Masculino , Femenino , Persona de Mediana Edad , Antivirales/uso terapéutico , Antivirales/efectos adversos , Antivirales/administración & dosificación , Adulto , Hepatitis D Crónica/tratamiento farmacológico , Virus de la Hepatitis Delta/efectos de los fármacos , Virus de la Hepatitis Delta/genética , Resultado del Tratamiento , ARN Viral/sangre , Alanina Transaminasa/sangre , Anciano , Carga Viral/efectos de los fármacos

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OBJECTIVE: Investigate racial disparities in outcomes and molecular features in Black and White patients with endometrioid endometrial carcinoma (EEC). METHODS: Black and White patients diagnosed with EEC who underwent hysterectomy ± adjuvant treatment in SEER, National Cancer Database (NCDB), the Genomics Evidence Neoplasia Information Exchange (GENIE) project (v.13.0), and eight NCI-sponsored randomized phase III clinical trials (RCTs) were studied. Hazard ratio (HR) and 95% confidence interval (CI) were estimated for cancer-related death (CRD), non-cancer death (NCD), and all-cause death. RESULTS: Black (n = 4397) vs. White (n = 47,959) patients in SEER had a HR (95% CI) of 2.04 (1.87-2.23) for CRD and 1.22 (1.09-1.36) for NCD. In NCDB, the HR (95% CI) for death in Black (n = 13,468) vs. White (n = 155,706) patients was 1.52 (1.46-1.58) dropping to 1.29 (1.23-1.36) after propensity-score matching for age, comorbidity, income, insurance, grade, stage, LVSI, and treatment. In GENIE, Black (n = 109) vs. White (n = 1780) patients had fewer PTEN, PIK3R1, FBXW7, NF1, mTOR, CCND1, and PI3K-pathway-related gene mutations. In contrast, TP53 and DNA-repair-related gene mutation frequency as well as tumor mutational burden-high status were similar in Black and White patients. In RCTs, Black (n = 187) vs. White (n = 2877) patients were more likely to have advanced or recurrent disease, higher grade, worse performance status and progressive disease. Risk of death in Black vs. White patients in RCTs was 2.19 (1.77-2.71) persisting to 1.32 (1.09-1.61) after matching for grade, stage, and treatment arm while balancing age and performance status. CONCLUSIONS: Differences exist in clinical presentation, outcomes, and molecular features in Black vs. White patients with EEC in real-world registries and RCTs. Targeted-drug development, strategies to modify social determinants, and diverse inclusion in RCTs are approaches to reduce disparities.

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Negro o Afroamericano , Carcinoma Endometrioide , Progresión de la Enfermedad , Neoplasias Endometriales , Población Blanca , Humanos , Femenino , Población Blanca/estadística & datos numéricos , Carcinoma Endometrioide/genética , Carcinoma Endometrioide/terapia , Carcinoma Endometrioide/patología , Carcinoma Endometrioide/etnología , Carcinoma Endometrioide/mortalidad , Neoplasias Endometriales/genética , Neoplasias Endometriales/terapia , Neoplasias Endometriales/etnología , Neoplasias Endometriales/mortalidad , Neoplasias Endometriales/patología , Persona de Mediana Edad , Negro o Afroamericano/estadística & datos numéricos , Anciano , Ensayos Clínicos Controlados Aleatorios como Asunto , Estados Unidos/epidemiología , Programa de VERF , Sistema de Registros , Ensayos Clínicos Fase III como Asunto , Adulto

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Background: We conducted a phase III, non-inferiority trial comparing safety and efficacy of RCP recombinant spike protein Covid-19 vaccine to BBIBP (Sinopharm). Methods: Adult Iranian population received RCP or BBIBP in a randomized, double blind and an additional non-randomized open labeled trial arms. Eligible participants signed a written informed consent and received two intramuscular injections three weeks apart. In the randomized arm, an intranasal dose of vaccine or adjuvant-only preparation were given to the RCP and BBIBP recipients at day 51 respectively. Participants were actively followed for up to 4 months for safety and efficacy outcomes. Primary outcome was PCR + symptomatic Covid-19 disease two weeks after the second dose. The non-inferiority margin was 10% of reported BBIBP vaccine efficacy (HR = 1.36). Results: We recruited 23,110 participants (7224 in the randomized and 15,886 in the non-randomized arm). We observed 604 primary outcome events during 4 months of active follow-up including 121 and 133 in the randomized and 157 and 193 cases in the non-randomized arms among recipients of RCP and BBIBP respectively. Adjusted hazard ratios for the primary outcome in those receiving RCP compared with BBIBP interval were 0.91 (0.71-1.16) and 0.62 (0.49-0.77) in the randomized and non-randomized arms respectively. The upper boundary of 99.1% confidence interval of HR = 0.91 (0.67-1.22) remained below the margin of non-inferiority in the randomized arm after observing the early stopping rules using O'Brien Fleming method. Conclusion: Our study showed that the RCP efficacy is non-inferior and its safety profile is comparable to the BBIBP.

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Typhoid fever is a significant public health concern with most of the sufferers between 15 and 25 y of age in Nepal. We undertook this study to demonstrate Vi polysaccharide conjugated with diphtheria toxoid (Vi-DT) conjugate vaccine which is non-inferior to Typbar typhoid conjugate vaccine, a Vi polysaccharide vaccine conjugated with tetanus toxoid (Vi-TT) with a focus on the adult population from Dhulikhel Hospital which was one of the total four sites in Nepal. In this study, we assigned the eligible participants in 1:1:1:1 ratio by block randomization, and stratified into three age groups (6 months to less than 2 y, 2 y to less than 18 y, and 18 y to 45 y), allotted to Group A, B, C, and D. Group A, B, and C received 25 µg (0.5 mL) of Vi-DT study vaccine and participants in Group D received 25 µg (0.5 mL) Vi-TT vaccine. We descriptively analyzed safety in all the participants receiving one dose of the investigational vaccine. The anti-Vi-IgG seroconversion rate in Vi-DT recipients was 99.71% (97.5% CI 98.04-99.96; 344 of 345 participants) and 99.13% (94.27-99.87; 114 of 115) in Vi-TT recipients which indicates that Vi-DT vaccine is non-inferior to Vi-TT vaccine. In safety aspect, 16.81% of total subject had at least one solicited adverse reaction and 22.61% of the Vi-TT participants experienced at least one solicited adverse reaction with most of them being local adverse reactions. None of the enrolled participants reported serious adverse events. Our study shows that a single dose of the Vi-DT vaccine is immunogenic, safe to administer and non-inferior to the Vi-TT vaccine four weeks after vaccination.

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Fiebre Tifoidea , Vacunas Tifoides-Paratifoides , Adolescente , Adulto , Niño , Preescolar , Lactante , Persona de Mediana Edad , Adulto Joven , Vacuna contra Difteria y Tétanos , Voluntarios Sanos , Polisacáridos , Fiebre Tifoidea/prevención & control , Vacunas Tifoides-Paratifoides/efectos adversos , Vacunas Conjugadas/efectos adversos , Humanos

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Background/Aims: H2 receptor antagonists (H2RA) have been used to treat gastritis by inhibiting gastric acid. Proton pump inhibitors (PPIs) are more potent acid suppressants than H2RA. However, the efficacy and safety of low-dose PPI for treating gastritis remain unclear. The aim was to investigate the efficacy and safety of low-dose PPI for treating gastritis. Methods: A double-blind, noninferiority, multicenter, phase 3 clinical trial randomly assigned 476 patients with endoscopic erosive gastritis to a group using esomeprazole 10 mg (DW1903) daily and a group using famotidine 20 mg (DW1903R1) daily for 2 weeks. The full-analysis set included 319 patients (DW1903, n=159; DW1903R1, n=160) and the per-protocol set included 298 patients (DW1903, n=147; DW1903R1, n=151). The primary endpoint (erosion improvement rate) and secondary endpoint (erosion and edema cure rates, improvement rates of hemorrhage, erythema, and symptoms) were assessed after the treatment. Adverse events were compared. Results: According to the full-analysis set, the erosion improvement rates in the DW1903 and DW1903R1 groups were 59.8% and 58.8%, respectively. According to the per-protocol analysis, the erosion improvement rates in the DW1903 and DW1903R1 groups were 61.9% and 59.6%, respectively. Secondary endpoints were not significantly different between two groups except that the hemorrhagic improvement rate was higher in DW1903 with statistical tendency. The number of adverse events were not statistically different. Conclusions: DW1903 of a low-dose PPI was not inferior to DW1903R1 of H2RA. Thus, lowdose PPI can be a novel option for treating gastritis (ClinicalTrials.gov Identifier: NCT05163756).

Asunto(s)

Famotidina , Gastritis , Humanos , Famotidina/uso terapéutico , Antagonistas de los Receptores H2 de la Histamina/uso terapéutico , Gastritis/tratamiento farmacológico , Inhibidores de la Bomba de Protones/uso terapéutico , Método Doble Ciego

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Glioblastoma (GBM) is the most common primary central nervous system tumor, whose prognosis remains poor under the sequential standard of care, such as neurosurgery followed by concurrent temozolomide radiochemotherapy and adjuvant temozolomide chemotherapy in the presence or absence of tumor treating fields. Accordingly, the advent of molecular targeted therapy and immunotherapy has opened a new era of tumor management. A diverse range of targeted drugs have been tested in patients with GBM in phase III clinical trials. However, these drugs are ineffective for all patients, as evidenced by the fact that only a minority of patients in these trials showed prolonged survival. Furthermore, there are several published phase III clinical trials that involve immune checkpoint inhibitors, peptide vaccines, dendritic cell vaccines, and virotherapy. Accordingly, this review comprehensively overviews existing studies of targeted drugs and immunotherapy for glioma and discusses the challenge and perspective of targeted drugs and immunotherapy for glioma to clarify future directions.

RESUMEN

BACKGROUND: The randomized clinical trial ESO-SPARE investigates if oesophagus-sparing radiotherapy (RT) can reduce dysphagia in patients with metastatic spinal cord compression (MSCC). Patient-reported outcome (PRO) is the only follow-up measure. Due to the fragile patient population, low respondent compliance was anticipated. We performed a planned interim analysis of dosimetry and respondent compliance, to ensure that the protocol requirements were met. METHODS: Patients >18 years referred for cervical/thoracic MSCC radiotherapy in 1-10 fractions were included from two centres. Patients were randomized (1:1) to standard RT or oesophagus-sparing RT, where predefined oesophageal dose constraints were prioritized over target coverage. Patients completed a trial diary with daily reports of dysphagia for 5 weeks (PRO-CTC-AE) and weekly quality of life reports for 9 weeks (QLQ-C30, EQ-5D-5L). According to power calculation, 124 patients are needed for primary endpoint analysis. The sample size was inflated to 200 patients to account for the fragile patient population. The co-primary endpoints, peak patient-reported dysphagia, and preserved ability to walk (EQ-5D-5L), are analysed at 5 and 9 weeks, respectively. The interim analysis was conducted 90 days after the inclusion of patient no 100. Respondent compliance was assessed at 5 and 9 weeks. In all RT plans, oesophagus and target doses were evaluated regarding adherence to protocol constraints. RESULTS: From May 2021 to November 2022, 100 patients were included. Fifty-two were randomized to oesophagus-sparing RT. In 23% of these plans, oesophagus constraints were violated. Overall, the dose to both target and oesophagus was significantly lower in the oesophagus-sparing plans. Only 51% and 41% of the patients were evaluable for co-primary endpoint analysis at five and nine weeks, respectively. Mortality and hospitalization rates were significantly larger in patients who completed <4 days PRO questionnaires. CONCLUSION: Compliance was lower than anticipated and interventions to maintain study power are needed.

Asunto(s)

Trastornos de Deglución , Compresión de la Médula Espinal , Humanos , Calidad de Vida , Compresión de la Médula Espinal/radioterapia , Medición de Resultados Informados por el Paciente

RESUMEN

Background/Aims: Fexuprazan is a novel potassium-competitive acid blocker that could be of benefit to patients with gastric mucosal injury. The aim of this study was to assess the 2-week efficacy and safety of fexuprazan in patients with acute or chronic gastritis. Methods: In this study, 327 patients with acute or chronic gastritis who had one or more gastric erosions on endoscopy and subjective symptoms were randomized into three groups receiving fexuprazan 20 mg once a day (q.d.), fexuprazan 10 mg twice a day (b.i.d.), or placebo for 2 weeks. The posttreatment assessments were the primary endpoint (erosion improvement rate), secondary endpoints (cure rates of erosion and edema and improvement rates of redness, hemorrhage, and subjective symptoms), and drug-related adverse events. Results: Among the patients, 57.8% (59/102), 65.7% (67/102), and 40.6% (39/96) showed erosion improvement 2 weeks after receiving fexuprazan 20 mg q.d., fexuprazan 10 mg b.i.d., and placebo, respectively. Both fexuprazan 20 mg q.d. and 10 mg b.i.d. showed superior efficacy to the placebo (p=0.017 and p<0.001, respectively). Likewise, both fexuprazan 20 mg q.d. and 10 mg b.i.d. also showed higher erosion healing rates than the placebo (p=0.033 and p=0.010, respectively). No difference was noted in the edema healing rate and the improvement rates for redness, hemorrhage, and subjective symptoms between the fexuprazan and placebo groups. No significant difference was noted in the incidence of adverse drug reactions. Conclusions: Fexuprazan 20 mg q.d. and 10 mg b.i.d. for 2 weeks showed therapeutic efficacy superior to that of placebo in patients with acute or chronic gastritis (ClinicalTrials.gov identifier NCT04341454).

Asunto(s)

Aminas , Gastritis , Humanos , Aminas/uso terapéutico , Gastritis/tratamiento farmacológico , Hemorragia , Edema , Método Doble Ciego , Resultado del Tratamiento

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BACKGROUND: Uncomplicated urinary tract infections (uUTIs) are among the most common community-acquired infections for women worldwide. Treatment options are increasingly limited by antibiotic resistance; novel oral antibiotics are urgently needed. Gepotidacin is a novel, bactericidal, first-in-class triazaacenaphthylene antibiotic that inhibits bacterial deoxyribonucleic acid (DNA) replication by a distinct mechanism of action, which confers activity against most strains of target pathogens, such as Escherichia coli and Staphylococcus saprophyticus, including those resistant to current antibiotics. Here, we describe the designs of two near-identical phase III clinical trials (EAGLE-2 and EAGLE-3) evaluating gepotidacin for the treatment of uUTI. METHODS: These are phase III, randomized, multicenter, parallel-group, double-blind, double-dummy, comparator-controlled, noninferiority studies, comparing the efficacy and safety of gepotidacin to nitrofurantoin in the treatment of uUTI. Eligible participants are women aged ≥ 12 years with ≥ 2 uUTI symptoms, randomized (1:1) to receive oral gepotidacin (1500 mg) plus placebo or nitrofurantoin (100 mg) plus placebo, twice daily for 5 days. The primary therapeutic endpoint is composite clinical and microbiological efficacy, with noninferiority comparisons made in individuals with a qualifying (≥ 105 colony-forming units/mL urine) nitrofurantoin-susceptible uropathogen. RESULTS: These trials were designed in accordance with US Food and Drug Administration (2019) and European Medicines Agency (2018) guidance, particularly the composite endpoint and microbiological evaluability requirements. Across the trials ~ 5000 participants are planned to be enrolled from > 200 centers globally. CONCLUSIONS: Gepotidacin represents an important potential treatment option being evaluated to address the need for novel oral antibiotics to treat uUTI. These trials are registered at ClinicalTrials.gov ( https://clinicaltrials.gov/ ) where the full protocols can be accessed under trial IDs: NCT04020341 (EAGLE-2) and NCT04187144 (EAGLE-3).

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CoronaVac is an inactivated SARS-CoV-2 vaccine approved by the World Health Organization (WHO). Previous studies reported increased levels of neutralizing antibodies and specific T cells 2 and 4 weeks after two doses of CoronaVac; these levels were significantly reduced at 6 to 8 months after the two doses. Here, we report the effect of a booster dose of CoronaVac on the anti-SARS-CoV-2 immune response generated against the variants of concern (VOCs), Delta and Omicron, in adults participating in a phase III clinical trial in Chile. Volunteers immunized with two doses of CoronaVac in a 4-week interval received a booster dose of the same vaccine between 24 and 30 weeks after the second dose. Neutralization capacities and T cell activation against VOCs Delta and Omicron were assessed 4 weeks after the booster dose. We observed a significant increase in neutralizing antibodies 4 weeks after the booster dose. We also observed a rise in anti-SARS-CoV-2-specific CD4+ T cells over time, and these cells reached a peak 4 weeks after the booster dose. Furthermore, neutralizing antibodies and SARS-CoV-2-specific T cells induced by the booster showed activity against VOCs Delta and Omicron. Our results show that a booster dose of CoronaVac increases adults' humoral and cellular anti-SARS-CoV-2 immune responses. In addition, immunity induced by a booster dose of CoronaVac is active against VOCs, suggesting adequate protection. IMPORTANCE CoronaVac is an inactivated vaccine against SARS-CoV-2 that has been approved by WHO for emergency use. Phase III clinical trials are in progress in several countries, including China, Brazil, Turkey, and Chile, and have shown safety and immunogenicity after two doses of the vaccine. This report characterizes immune responses induced by two doses of CoronaVac followed by a booster dose 5 months after the second dose in healthy Chilean adults. The data reported here show that a booster dose increased the immune responses against SARS-CoV-2, enhancing levels of neutralizing antibodies against the ancestral strain and VOCs. Similarly, anti-SARS-CoV-2 CD4+ T cell responses were increased following the booster dose. In contrast, levels of gamma interferon secretion and T cell activation against the VOCs Delta and Omicron were not significantly different from those for the ancestral strain. Therefore, a third dose of CoronaVac in a homologous vaccination schedule improves its immunogenicity in healthy volunteers.

Asunto(s)

COVID-19 , Vacunas Virales , Adulto , Anticuerpos Neutralizantes , Anticuerpos Antivirales , COVID-19/prevención & control , Vacunas contra la COVID-19 , Humanos , SARS-CoV-2 , Linfocitos T

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BACKGROUND: C-reactive protein (CRP) is an important prognostic and predictive factor in advanced renal cell carcinoma (aRCC). We report the association of CRP levels at baseline and early after treatment with efficacy of avelumab plus axitinib or sunitinib from the phase III JAVELIN Renal 101 trial. PATIENTS AND METHODS: Patients were categorized into normal (baseline CRP <10 mg/l), normalized (baseline CRP ≥10 mg/l and ≥1 CRP value decreased to <10 mg/l during 6-week treatment), and non-normalized (CRP ≥10 mg/l at baseline and during 6-week treatment) CRP groups. Progression-free survival and best overall response from the second interim analysis and overall survival (OS) from the third interim analysis were assessed. RESULTS: In the avelumab plus axitinib and sunitinib arms, respectively, 234, 51, and 108 patients and 232, 36, and 128 patients were categorized into normal, normalized, and non-normalized CRP groups. In respective CRP groups, objective response rates [95% confidence interval (CI)] were 56.0% (49.4% to 62.4%), 66.7% (52.1% to 79.2%), and 45.4% (35.8% to 55.2%) with avelumab plus axitinib and 30.6% (24.7% to 37.0%), 41.7% (25.5% to 59.2%), and 19.5% (13.1% to 27.5%) with sunitinib; complete response rates were 3.8%, 11.8%, and 0.9% and 3.0%, 0%, and 1.6%, respectively. Median progression-free survival (95% CI) was 15.2 months (12.5-21.0 months), not reached (NR) [11.1 months-not estimable (NE)], and 7.0 months (5.6-9.9 months) with avelumab plus axitinib and 11.2 months (8.4-13.9 months), 11.2 months (6.7-13.8 months), and 4.2 months (2.8-5.6 months) with sunitinib; median OS (95% CI) was NR (42.2 months-NE), NR (30.4 months-NE), and 23.0 months (18.4-33.1 months) and NR (39.0 months-NE), 39.8 months (21.7-NE), and 19.1 months (16.3-25.3 months), respectively. Multivariate analyses demonstrated that normalized or non-normalized CRP levels were independent factors for the prediction of objective response rate or OS, respectively, with avelumab plus axitinib. CONCLUSIONS: In patients with aRCC, CRP levels at baseline and early after treatment may predict efficacy with avelumab plus axitinib.

Asunto(s)

Carcinoma de Células Renales , Neoplasias Renales , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica , Axitinib/farmacología , Axitinib/uso terapéutico , Proteína C-Reactiva , Carcinoma de Células Renales/tratamiento farmacológico , Estudios de Seguimiento , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/patología , Sunitinib/farmacología , Sunitinib/uso terapéutico

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Several vaccines have been developed to control the COVID-19 pandemic. CoronaVac®, an inactivated SARS-CoV-2 vaccine, has demonstrated safety and immunogenicity, preventing severe COVID-19 cases. We investigate the safety and non-inferiority of two immunization schedules of CoronaVac® in a non-inferiority trial in healthy adults. A total of 2302 healthy adults were enrolled at 8 centers in Chile and randomly assigned to two vaccination schedules, receiving two doses with either 14 or 28 days between each. The primary safety and efficacy endpoints were solicited adverse events (AEs) within 7 days of each dose, and comparing the number of cases of SARS-CoV-2 infection 14 days after the second dose between the schedules, respectively. The most frequent local AE was pain at the injection site, which was less frequent in participants aged ≥60 years. Other local AEs were reported in less than 5% of participants. The most frequent systemic AEs were headache, fatigue, and myalgia. Most AEs were mild and transient. There were no significant differences for local and systemic AEs between schedules. A total of 58 COVID-19 cases were confirmed, and all but 2 of them were mild. No differences were observed in the proportion of COVID-19 cases between schedules. CoronaVac® is safe, especially in ≥60-year-old participants. Both schedules protected against COVID-19 hospitalization.

RESUMEN

BACKGROUND: Alzheimer's disease is a neurodegenerative disease characterized by progressive cognitive decline and dysfunction of independent living ability, with huge economic and healthy burden worldwide. However, there is still a lack of effective long-term drugs to improve cognitive function and reduce or halt disease progression. Phase III clinical trials of anti-AD drugs based on different hypotheses were in the pipeline, and this protocol for a systematic review and meta-analysis aims to determine what is the most effective direction for the development of drugs on cognitive improvement. METHODS/DESIGN: We will search the following literature databases for eligible studies from inception to December 2021: Ovid MEDLINE, Ovid Embase, PubMed MEDLINE, and Cochrane Central Register of Controlled Trials. Google Scholar, ClinicalTrials.gov registration platform, and the AlzForum website will also be searched for additional studies. Studies will be included irrespective of publication status or language. Phase III clinical trials reporting on the effect of anti-AD drugs on participants with AD will be included. Two independent reviewers will screen the hit articles and identify phase III clinical trials, extract data, and assess the quality of each study individually. The Cochrane Risk of Bias tool 2 (RoB 2) will be used to assess the risk of bias. For each kind of drugs based on the corresponding hypothesis, we will compare the study design and demographic features of the clinical trials and include appropriate studies in the network meta-analysis. The primary outcomes will be the indicators of cognitive improvement. The secondary outcomes will be activities of daily living, neuroimaging changes, biomarkers, and safety. Through network meta-analysis, we will suggest the hypothesis that most likely to improve cognitive function and provide the ranks of all kinds of drugs. We will give recommendation grade of each comparison using the Confidence In Network Meta-Analysis (CINeMa) tool. DISCUSSION: This study will provide helpful evidence for further drug development and clinical practice for treating Alzheimer's disease. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42021251507.

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Enfermedad de Alzheimer , Enfermedades Neurodegenerativas , Actividades Cotidianas , Enfermedad de Alzheimer/tratamiento farmacológico , Cognición , Humanos , Metaanálisis como Asunto , Metaanálisis en Red , Revisiones Sistemáticas como Asunto

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OBJECTIVES: To assess health-related quality of life (HRQoL) with first-line pembrolizumab, pembrolizumab-chemotherapy, or cetuximab-chemotherapy in recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) in the phase 3 KEYNOTE-048 trial (NCT02358031). MATERIALS AND METHODS: HRQoL was measured using the European Organisation for Research and Treatment of Cancer 30-question quality-of-life (EORTC QLQ-C30), the EORTC 35-question quality-of-life head and neck cancer-specific module (EORTC QLQ-H&N35), and the EuroQol 5-dimension 3-level instruments (EQ-5D-3L). Secondary endpoints included mean change from baseline in EORTC QLQ-C30 global health status/quality of life (GHS/QoL) at week 15 and time to deterioration (TTD) in EORTC QLQ-C30 GHS/QoL and EORTC QLQ-H&N35 pain and swallowing. RESULTS: Of 882 enrolled participants, 844 received ≥ 1 dose of study treatment and completed ≥ 1 HRQoL assessment; adherence was ≥ 79% at week 15 across treatment groups. At week 15, EORTC QLQ-C30 GHS/QoL scores remained stable; no clinically meaningful between-group differences were observed (least squares mean difference, pembrolizumab vs cetuximab-chemotherapy, 0.24; 95% CI, -3.34 to 3.82; pembrolizumab-chemotherapy vs cetuximab-chemotherapy, 0.40; 95% CI, -3.46 to 4.26). Median TTD in EORTC QLQ-C30 GHS/QoL and EORTC QLQ-H&N35 pain and swallowing scores was not reached over 51 weeks across groups, showing stable HRQoL. TTD was similar between groups for EORTC QLQ-C30 GHS/QoL (pembrolizumab vs cetuximab-chemotherapy: HR, 1.38; 95% CI, 0.95-2.00; pembrolizumab-chemotherapy vs cetuximab-chemotherapy: HR, 1.37; 95% CI, 0.94-2.00), as was TTD in EORTC QLQ-H&N35 pain and swallowing scores. CONCLUSIONS: Pembrolizumab monotherapy and pembrolizumab-chemotherapy extended OS while maintaining HRQoL, further supporting first-line use for R/M HNSCC.

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Neoplasias de Cabeza y Cuello , Calidad de Vida , Anticuerpos Monoclonales Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Cetuximab/uso terapéutico , Enfermedad Crónica , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Humanos , Recurrencia Local de Neoplasia/tratamiento farmacológico , Dolor/tratamiento farmacológico , Carcinoma de Células Escamosas de Cabeza y Cuello/tratamiento farmacológico , Encuestas y Cuestionarios

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BACKGROUND: Positron emission tomography targeting the prostate specific membrane antigen (PSMA PET/CT) has demonstrated unparalleled performance as a staging examination for prostate cancer resulting in substantial changes in management. However, the impact of altered management on patient outcomes is largely unknown. This study aims to assess the impact of intensified radiotherapy or surgery guided by PSMA PET/CT in patients at risk of advanced prostate cancer. METHODS: This pan-Canadian phase III randomized controlled trial will enroll 776 men with either untreated high risk prostate cancer (CAPRA score 6-10 or stage cN1) or biochemically recurrent prostate cancer post radical prostatectomy (PSA > 0.1 ng/mL). Patients will be randomized 1:1 to either receive conventional imaging or conventional plus PSMA PET imaging, with intensification of radiotherapy or surgery to newly identified disease sites. The primary endpoint is failure free survival at 5 years. Secondary endpoints include rates of adverse events, time to next-line therapy, as well as impact on health-related quality of life and cost effectiveness as measured by incremental cost per Quality Adjusted Life Years gained. DISCUSSION: This study will help create level 1 evidence needed to demonstrate whether or not intensification of radiotherapy or surgery based on PSMA PET findings improves outcomes of patients at risk of advanced prostate cancer in a manner that is cost-effective. TRIAL REGISTRATION: This trial was prospectively registered in ClinicalTrials.gov as NCT04557501 on September 21, 2020.

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Antígenos de Neoplasias/metabolismo , Proteínas de Neoplasias/metabolismo , Tomografía Computarizada por Tomografía de Emisión de Positrones , Neoplasias de la Próstata/terapia , Radioterapia Guiada por Imagen/métodos , Cirugía Asistida por Computador/métodos , Adulto , Canadá , Ensayos Clínicos Fase III como Asunto , Estudios de Equivalencia como Asunto , Radioisótopos de Flúor , Proteínas Ligadas a GPI/metabolismo , Humanos , Análisis de Intención de Tratar , Masculino , Recurrencia Local de Neoplasia/diagnóstico por imagen , Recurrencia Local de Neoplasia/metabolismo , Recurrencia Local de Neoplasia/terapia , Estadificación de Neoplasias/métodos , Ensayos Clínicos Pragmáticos como Asunto , Estudios Prospectivos , Prostatectomía/métodos , Neoplasias de la Próstata/diagnóstico por imagen , Neoplasias de la Próstata/metabolismo , Radiofármacos , Radioterapia de Intensidad Modulada/métodos , Ensayos Clínicos Controlados Aleatorios como Asunto , Resultado del Tratamiento

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BACKGROUND: This study was a multicenter, randomized, double-blinded, placebo-controlled phase III clinical trial to investigate the efficacy and safety of an olmesartan/amlodipine single pill plus rosuvastatin combination treatment for patients with concomitant hypertension and dyslipidemia. METHODS: Patients with both hypertension and dyslipidemia aged 20-80 were enrolled from 36 tertiary hospitals in Korea from January 2017 to April 2018. Patients were randomized to three groups in a 1:1:0.5 ratio, olmesartan/amlodipine single pill plus rosuvastatin (olme/amlo/rosu) or olmesartan plus rosuvastatin (olme/rosu) or olmesartan/amlodipine single pill (olme/amlo) combination. The primary endpoints were change of sitting systolic blood pressure (sitSBP) from baseline in the olme/amlo/rosu vs. olme/rosu groups and the percentage change of low-density lipoprotein cholesterol (LDL-C) from baseline in the olme/amlo/rosu vs. olme/amlo groups after 8 weeks of treatment. RESULTS: A total of 265 patients were randomized, 106 to olme/amlo/rosu, 106 to olme/rosu and 53 to olme/amlo groups. Baseline characteristics among the three groups did not differ. The mean sitSBP change was significantly larger in the olme/amlo/rosu group with -24.30 ± 12.62 mmHg (from 153.58 ± 10.90 to 129.28 ± 13.58) as compared to the olme/rosu group, -9.72 ± 16.27 mmHg (from 153.71 ± 11.10 to 144.00 ± 18.44 mmHg). The difference in change of sitSBP between the two groups was -14.62± 1.98 mmHg with significance (95% CI -18.51 to -10.73, p < 0.0001). The mean LDL-C reduced significantly in the olme/amlo/rosu group, -52.31 ± 16.63% (from 154.52 ± 30.84 to 72.72 ± 26.08 mg/dL) as compared to the olme/amlo group with no change, -2.98 ± 16.16% (from 160.42 ± 32.05 to 153.81 ± 31.57 mg/dL). Significant difference in change was found in LDL-C between the two groups with -50.10 ± 2.73% (95% CI -55.49 to -44.71, p < 0.0001). Total adverse drug reaction rates were 10.48%, 5.66% and 3.7% in the olme/amlo/rosu, olme/rosu and olme/amlo groups, respectively with no statistical significance among the three groups. Serious adverse drug reactions did not occur. CONCLUSIONS: Olmesartan/amlodipine single pill plus rosuvastatin combination treatment for patients with both hypertension and dyslipidemia is effective and safe as compared to either olmesartan plus rosuvastatin or olmesartan plus amlodipine treatment.

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Objective: The occurrence, development, and prognosis of serious adverse events (SAEs) associated with anticancer drugs in clinical trials have important guiding significance for real-world clinical applications. However, to date, there have been no studies investigating SAEs reporting in randomized clinical trials of colorectal cancer treatments. This article systematically reviewed the SAEs reporting of phase III randomized clinical trials of colorectal cancer treatments and analyzed the influencing factors. Methods: We reviewed all articles about phase III randomized clinical trials of colorectal cancer treatments published in the PubMed, Embase, Medline, and New England Journal of Medicine databases from January 1, 1993, to December 31, 2018, and searched the registration information of clinical trials via the internet sites such as "clinicaltrials.gov". We analyzed the correlation between the reported proportion (RP) of SAEs in the literature and nine elements, including the clinical trial sponsor and the publication time. Chi-square tests and binary logistic regression were used to identify the factors associated with improved SAEs reports. This study was registered on PROSPERO. Results: Of 1560 articles identified, 160 were eligible, with an RP of SAEs of 25.5% (41/160). In forty-one publications reporting SAEs, only 14.6% (6/41) described the pattern of SAEs in detail. In clinical trials sponsored by pharmaceutical companies, the RP of SAEs was significantly higher than that in those sponsored by investigators (57.6 versus 20.7%, p < 0.001). From 1993 to 2018, the RP of SAEs gradually increased (none (0/6) before 2000, 17.1% (12/70) from 2000 to 2009, and 34.5% (29/84) after 2009). The average RP of SAEs published in the New England Journal of Medicine (N Engl J Med), the Lancet, the Journal of the American Medical Association (JAMA), the Lancet Oncology (Lancet Oncol), and the Journal of Clinical Oncology (J Clin Oncol) was significantly higher than that published in other journals (31.9 versus 16.7%, p = 0.030). In the clinical trials referenced by clinical guidelines, the RP of SAEs was higher than that in non-referenced clinical trials (32.0 versus 15.9%, p = 0.023). Binary logistic regression analysis showed that pharmaceutical company sponsorship, new drug research, and sample size greater than 1000 were positive influencing factors for SAEs reporting. Conclusion: Although the RP of SAEs increased over time, SAEs reporting in clinical trials needs to be further improved. The performance, outcomes and prognosis of SAEs should be reported in detail to guide clinical practice in the real world.

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BACKGROUND: In the TAX 323 (EORTC 24971) phase III trial enrolling patients with unresectable locoregionally advanced squamous cell carcinoma of the head and neck (LA-SCCHN), the addition of docetaxel (T) to cisplatin and 5-fluorouracil (PF)-based induction chemotherapy prior to definite radiotherapy significantly improved progression-free survival (PFS) and overall survival (OS). METHODS: The data were updated for PFS, OS and treatment-related long-term side-effects. Baseline clinical and laboratory data of 17 variables were collected and subjected to univariate and multivariate prognostic factor analyses for OS. RESULTS: All 358 patients randomised between 1999 and 2002 were included in the long-term analysis with a median follow-up of 8.6 years. The primary end-point of PFS remained significantly improved with TPF compared with PF (adjusted hazard ratio [HR], 0.70; 95% CI, 0.56-0.88, p = 0.002), translating into a persisting benefit in OS (adjusted HR, 0.75; 95% CI, 0.60-0.95, p = 0.015). Long-term side-effects in the TPF/PF arms comprised tracheostomy (7%/5%), feeding tube dependency (3%/6%) and gastrostomy (11%/11%). Second malignancy occurred in 8%/3%, respectively. Out of 177 patients randomised to the TPF arm, 160 were included in the multivariate analysis. Grade 2 or more dysphagia (p = 0.002) and grade 2 or more pain (p = 0.004) at baseline were identified as independent negative prognostic factors. In addition, OS differed across primary tumour sites (p = 0.027) and was worse in patients with a higher N-stage (p = 0.025). CONCLUSIONS: In LA-SCCHN patients treated with sequential chemoradiotherapy, TPF induction chemotherapy demonstrated long-lasting efficacy, superior to the PF regimen. Higher-grade dysphagia and pain are unfavourable prognosticators.

Asunto(s)

Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Carcinoma de Células Escamosas de Cabeza y Cuello/tratamiento farmacológico , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Cisplatino/uso terapéutico , Ensayos Clínicos Fase III como Asunto , Bases de Datos Factuales , Progresión de la Enfermedad , Docetaxel/uso terapéutico , Europa (Continente) , Femenino , Fluorouracilo/uso terapéutico , Neoplasias de Cabeza y Cuello/mortalidad , Neoplasias de Cabeza y Cuello/patología , Humanos , Masculino , Persona de Mediana Edad , Supervivencia sin Progresión , Estudios Retrospectivos , Medición de Riesgo , Factores de Riesgo , Carcinoma de Células Escamosas de Cabeza y Cuello/mortalidad , Carcinoma de Células Escamosas de Cabeza y Cuello/patología , Factores de Tiempo

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INTRODUCTION: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of coronavirus disease 2019 (COVID-19), is an enveloped, single-stranded RNA virus. Favipiravir is an orally administrable antiviral drug whose mechanism of action is to selectively inhibit RNA-dependent RNA polymerase. A preliminary trial in COVID-19 patients reported significant improvements across a multitude of clinical parameters, but these findings have not been confirmed in an adequate well-controlled trial. We conducted a randomized, single-blind, placebo-controlled Phase III trial assessing the efficacy and safety of favipiravir in patients with moderate pneumonia not requiring oxygen therapy. METHODS: COVID-19 patients with moderate pneumonia (SpO2 ≥ 94%) within 10 days of onset of fever (temperature ≥ 37.5 °C) were assigned to receive either placebo or favipiravir (1800 mg twice a day on Day 1, followed by 800 mg twice a day for up to 13 days) in a ratio of 1:2. An adaptive design was used to re-estimate the sample size. The primary endpoint was a composite outcome defined as the time to improvement in temperature, oxygen saturation levels (SpO2), and findings on chest imaging, and recovery to SARS-CoV-2-negative. This endpoint was re-examined by the Central Committee under blinded conditions. RESULTS: A total of 156 patients were randomized. The median time of the primary endpoint was 11.9 days in the favipiravir group and 14.7 days in the placebo group, with a significant difference (p = 0.0136). Favipiravir-treated patients with known risk factors such as obesity or coexisting conditions provided better effects. Furthermore, patients with early-onset in the favipiravir group showed higher odds ratio. No deaths were documented. Although adverse events in the favipiravir group were predominantly transient, the incidence was significantly higher. CONCLUSIONS: The results suggested favipiravir may be one of options for moderate COVID-19 pneumonia treatment. However, the risk of adverse events, including hyperuricemia, should be carefully considered. TRIAL REGISTRATION: Clinicaltrials.jp number: JapicCTI-205238.