Noninferiority trials have recently gained importance for the clinical trials of drugs and medical devices. In these trials, most statistical methods have been used from a frequentist perspective, ...and historical data have been used only for the specification of the noninferiority margin Δ>0. In contrast, Bayesian methods, which have been studied recently are advantageous in that they can use historical data to specify prior distributions and are expected to enable more efficient decision making than frequentist methods by borrowing information from historical trials. In the case of noninferiority trials for response probabilities π1,π2, Bayesian methods evaluate the posterior probability of H1:π1>π2−Δ being true. To numerically calculate such posterior probability, complicated Appell hypergeometric function or approximation methods are used. Further, the theoretical relationship between Bayesian and frequentist methods is unclear. In this work, we give the exact expression of the posterior probability of the noninferiority under some mild conditions and propose the Bayesian noninferiority test framework which can flexibly incorporate historical data by using the conditional power prior. Further, we show the relationship between Bayesian posterior probability and the P value of the Fisher exact test. From this relationship, our method can be interpreted as the Bayesian noninferior extension of the Fisher exact test, and we can treat superiority and noninferiority in the same framework. Our method is illustrated through Monte Carlo simulations to evaluate the operating characteristics, the application to the real HIV clinical trial data, and the sample size calculation using historical data.
Purpose
This randomized phase II trial compared tegafur–uracil/leucovorin (UFT/LV) plus oxaliplatin (TEGAFOX) to UFT/LV as adjuvant chemotherapy for patients with high-risk stage II/III colorectal ...cancer.
Methods
From 2010 to April 2015, 159 patients who underwent curative resection were randomly assigned to receive TEGAFOX (85 mg/m
2
oxaliplatin on days 1 and 15, 300 mg/m
2
/day UFT and 75 mg/day LV on days 1–28, every 35 days for five cycles) or UFT/LV. The primary study endpoint was disease-free survival.
Results
The 3-year disease-free survival rate was 84.2% in the TEGAFOX arm, versus 62.1% for UFT/LV. The stratified hazard ratio for disease-free survival for TEGAFOX compared to UFT/LV was 0.338 (
P
< 0.01). The incidence of any-grade adverse events was significantly higher in the TEGAFOX arm (96.1%) than in the UFT/LV arm (76.6%;
P
< 0.01). The rates of any-grade neutropenia, thrombocytopenia, aspartate aminotransferase/alanine aminotransferase elevation, and peripheral sensory neuropathy were higher in the TEGAFOX group, whereas the incidence of grade ≥ 3 adverse events did not differ between the groups.
Conclusions
TEGAFOX is an additional adjuvant chemotherapy option for high-risk stage II/III colorectal cancer.
Trial registration
UMIN ID: 000007696, date of registration: April 10, 2012
Abstract
To compare the efficacy and safety of intravitreal aflibercept with three loading doses + pro re nata regimen combined with subthreshold laser application to that of IVA monotherapy on eyes ...with diabetic macular edema. This was a phase 4 clinical trial with a prospective, randomized, and parallel investigator-driven protocol. Patients with DME were randomly assigned to the IVA monotherapy group (n = 25) or the IVA + SL combination therapy group (n = 26). The main outcome measures were the number of IVA injections and the changes in the best-corrected visual acuity (BCVA) and the central retinal thickness (CRT) at the final evaluation at 96 weeks. The mean number of IVA injections in the monotherapy group was 5.86 ± 2.43 and it was 6.05 ± 2.73 in the IVA + SL group at 96 weeks, and this difference was not significant
(P
= 0.83). The differences in the mean changes of the CRT (
P
= 0.17) and the BCVA (
P
= 0.31) were also not significant between the two groups throughout the follow-up period. We conclude that adjunct of SL to anti-VEGF therapy does not reduce the number of necessary intravitreal injections.
•Body weight increases among Asian people living with human immunodeficiency virus following the initiation of antiretroviral therapy (ART).•Long-term weight gain following ART initiation depends on ...drug combination•The combination of dolutegravir plus tenofovir alafenamide (TAF)/emtricitabine is associated with the greatest weight gain.•TAF-containing regimens are associated with the greatest weight gain.
To investigate changes in weight following the initiation of antiretroviral therapy in treatment-naïve Asian people living with human immunodeficiency virus (PLWH).
This retrospective observational study evaluated adult treatment-naïve Asian PLWH who started antiretroviral therapy based on an integrase strand transfer inhibitor, a protease inhibitor or a non-nucleoside reverse transcriptase inhibitor at the AIDS Clinical Centre, Tokyo between January 2005 and February 2019. Patients were followed-up until October 2019. Multi-variate linear mixed-effects models were used to generate marginal predictions of weight over time. Predicted weight was reported at 3-month intervals until censoring or for 5 years after treatment initiation.
Five years after treatment initiation, average weight gain in PLWH who started on dolutegravir-, darunavir- and elvitegravir-based treatment was 5.3 kg, 4.1 kg and 4.6 kg, respectively, while those who started on raltegravir-, lopinavir- and atazanavir-based treatment gained an average of 1.9 kg, 2.1 kg and 2.3 kg, respectively. Average weight gain in PLWH who started treatment with the backbone drugs, tenofovir alafenamide, abacavir and tenofovir disproxil fumarateb was 4.1 kg, 3.0 kg and 3.0 kg, respectively, and those treated with dolutegravir plus tenofovir alafenamide/emtricitabine gained an average of 6.7 kg.
Antiretroviral-therapy-associated weight gain continued to increase for 5 years following treatment initiation. A combination of dolutegravir and tenofovir alafenamide/emtricitabine was associated with the greatest weight gain.
Green stem disorder (GSD) of soybean is characterized by delayed leaf and stem maturation despite normal pod maturation. Previous studies have suggested that GSD occurrence is promoted by a high ...source-sink ratio, which is produced by thinning or shade removal at the R5 growth stage (the beginning of seed filling). Here the effects of different times and durations of shade removal after the R5 stage on GSD severity were analyzed. First, shade removal for more than 28 days after R5 increased GSD severity by more than 0.4 point in GSD score. Thinning treatment at R5 increased specific leaf weight by 23%, suppressed stem dry weight reduction, and upregulated 19 genes including those encoding vegetative storage proteins at R5 + 28d, indicating excess source ability relative to sink size. On the contrary, shade removal for 14 days after R5 decreased GSD severity by 0.5 point in GSD score. In this treatment, seed size was smaller, while seed number was significantly larger than control, suggesting that shortage of source ability relative to sink size. These results implied that soybean plants regulate GSD occurrences either positively or negatively according to a source-sink ratio during the R5 to R5 + 28d growth stages.
IntroductionProgestin therapy is the only fertility-sparing treatment option for patients with atypical endometrial hyperplasia (AEH) and endometrial cancer (EC). However, the results of three ...meta-analyses revealed a high remission rate, as well as an association with a high rate of relapse. We previously conducted a phase II of medroxyprogesterone acetate (MPA) plus metformin as a fertility-sparing treatment for AEH and EC patients, and reported that metformin inhibited disease relapse after remission.Methods and analysisA randomised, open, blinded-endpoint design phase IIb dose response trial was planned to commence in July 2019. The trial aims to identify the appropriate dose of metformin to be combined with MPA therapy for fertility-sparing treatment of patients with AEH and EC. The primary endpoint of the trial is the 3-year relapse-free survival (RFS) rate. The secondary endpoints are RFS rate, the overall rate of response to MPA therapy, the conception rate after treatment, the outcome of pregnancy, toxicity evaluation and changes in insulin resistance and body mass index. A total of 120 patients will be enrolled from 15 Japanese institutions within a 2.5-year period and followed up for at least 3 years.Ethics and disseminationThe protocol was approved by the institutional review board at Chiba University Hospital and boards at 14 other institutions. The trial will be conducted according to the principles of the World Medical Association’s Declaration of Helsinki and in accordance with Good Clinical Practice (GCP) standards. The trial findings will be published in a peer-reviewed journal.Trial registration numberJapan Registry of Clinical Trials (jRCT2031190065).
Purpose
We analyzed the annual trends in and initial choice of pharmacotherapy for children with nocturnal enuresis (NE) using a large-scale medical claims database in Japan.
Methods
A retrospective ...descriptive study performed using data from the Japan Medical Data Center between January 2005 and March 2019 involving 23,814 registrants under 16 years of age. In the first cohort of children with NE, we analyzed the comorbidities and associated annual pharmacotherapy prescribing trends. In the second cohort of only newly diagnosed cases, we analyzed the first prescribed age and initial choice of pharmacotherapy.
Results
A total of 3494 children with NE were identified (mean age, 5.1 ± 3.6 years; male, 66.0%). An incremental increase in the proportion of children administered NE medications was observed. The proportion of children treated with desmopressin significantly increased, whereas the prescription of tricyclic antidepressants significantly decreased and that of anticholinergics did not significantly change. Among the newly diagnosed children, 1897 were treated with approximately 90% of the prescribed monotherapy. Sublingual desmopressin monotherapy accounts for more than half of the initial pharmacotherapy from 2016 onward. Regardless of the drug class, pharmacological therapy was commonly initiated at the age of 8.3 ± 2.1 years.
Conclusions
In Japan, the proportion of children treated with pharmacotherapy has been increasing. Furthermore, since the introduction of desmopressin sublingual formulations in 2012, a paradigm shift has occurred and this form of medication is now the most commonly prescribed, both from the annual perspective and as an initial choice among the newly diagnosed.
Constipation is common in children and can significantly affect quality of life. Prebiotics are reportedly helpful for constipation in adults, but few studies have examined their use in young ...children. In this study, the effect of 1-kestose (kestose), which has excellent bifidobacterial growth properties, on constipation in kindergarten children (
= 11) was compared with that of maltose (
= 12) in a randomized, double-blind study. Three grams of kestose per day for 8 weeks did not affect stool properties, but significantly increased the number of defecations per week (Median; 3 → 4 times/week,
= 0.017, effect size = 0.53). A significant decrease in
, a trend toward increased bifidobacteria, and a trend toward decreased
were observed after kestose ingestion, while concentrations of short-chain fatty acids in stools were unchanged.
Acute kidney injury (AKI) frequently occurs after cardiac surgery. Recently, transcatheter aortic valve implantation (TAVI), a less invasive option for aortic stenosis (AS), has been increasingly ...performed, particularly in elderly patients. We retrospectively investigated and compared the incidence and risk factors of postoperative AKI in patients who underwent surgical aortic valve replacement (SAVR) and TAVI. This was a retrospective single-center study. Seven days postoperatively, data were obtained from medical records. Patients were classified into SAVR and TAVI groups based on age, according to the policy of the Japanese Circulation Society. A total of 155 patients underwent surgery for AS between January 2020 and December 2021. Variables included age, sex, risk score, preoperative left ventricular ejection fraction, hypertension, and renal dysfunction. AKI was defined in accordance with the Kidney Disease: Improving Global Outcomes criteria. A total of 33 SAVR and 79 TAVI procedures were included in this study. The incidences of AKI in the SAVR and TAVI groups were 45.5% and 43.0%, respectively. No significant differences existed between the two groups. Weight (
p
= 0.0392) and pre-renal dysfunction (
p
= 0.0308) affected the incidence of AKI in the SAVR group, whereas no such variables were identified in the TAVI group. Within the current age-based treatment selection criteria for AS, no significant difference in the incidence of AKI was observed between the two procedures.Although preoperative renal function may be associated with postoperative AKI, further studies are required to select the optimal surgical procedure for patients with renal dysfunction.
PDF
