Maximizing the Value of Real-World Data and Real-World Evidence to Accelerate Healthcare Transformation in China: Summary of External Advisory Committee Meetings.

Use of real-world data (RWD) is gaining wide attention. To bridge the gap between diverse healthcare stakeholders and to leverage the impact of Chinese real-world evidence (RWE) globally, a multi-stakeholder External Advisory Committee (EAC) and EAC meetings were initiated, aiming to elucidate the current and evolving RWD landscape in China, articulate the values of RWE in ensuring Chinese patients' equitable access to affordable medicines and solutions, and identify strategic opportunities and partnerships for expansion of RWE generation in China. Chinese and international experts who are clinicians and academic researchers were selected as EAC members based on their professional background and familiarity with RWD/RWE. Three EAC meetings were held quarterly in 2023. Various topics were presented and discussed for insights and suggestions. Nine experts from China, one from South Korea, and two from Europe were selected as EAC members and attended these meetings. Experts' presentations were summarized by theme, including the RWD landscape and RWE enablement in China, as well as global development of a patient-centric ecosystem. Experts' insights and suggestions on maximizing the RWD/RWE value to accelerate healthcare transformation in China were collected. We concluded that though data access, sharing, and quality are still challenging, RWD is developing to support evidence generation in the medicinal product lifecycle, inform clinical practice, and empower patient management in China. RWD/RWE creates value, accelerates healthcare transformation, and improves patient outcomes. Fostering a patient-centric ecosystem across healthcare stakeholders and maintaining global partnerships and collaboration are essential for unlocking the power of RWD/RWE.

Establishment of RWS guidance reflecting contributions of China to regulatory science.

China's accession to the ICH has accelerated the advancement of its regulatory science. To foster innovation and improve the efficiency of pharmaceutical research and development, the China National Medical Products Administration (NMPA) encourages the use of real-world evidence (RWE) to support drug regulatory decision-making and has constructed a series of real-world study (RWS) related guidance, reflecting the contribution of the NMPA to the field of RWS in drug clinical development. Based on the four guidelines on RWE, real-world data (RWD), RWS design and protocol development, and communication with regulatory authorities, the guidance has been extended to more specific clinical applications, such as oncology, rare diseases, pediatric drugs, and traditional Chinese medicine. This paper reviews the core content and features of the series of RWS guidelines, presents their role in promoting drug development, and discusses challenges of using RWE in support of drug regulatory decision-making in China.

Effects of an early intensive blood pressure-lowering strategy using remifentanil and dexmedetomidine in patients with spontaneous intracerebral hemorrhage: a multicenter, prospective, superiority, randomized controlled trial.

BACKGROUND: Although it has been established that elevated blood pressure and its variability worsen outcomes in spontaneous intracerebral hemorrhage, antihypertensives use during the acute phase still lacks robust evidence. A blood pressure-lowering regimen using remifentanil and dexmedetomidine might be a reasonable therapeutic option given their analgesic and anti-sympathetic effects. The objective of this superiority trial was to validate the efficacy and safety of this blood pressure-lowering strategy that uses remifentanil and dexmedetomidine in patients with acute intracerebral hemorrhage. METHODS: In this multicenter, prospective, single-blinded, superiority randomized controlled trial, patients with intracerebral hemorrhage and systolic blood pressure (SBP) ≥150 mmHg were randomly allocated to the intervention group (a preset protocol with a standard guideline management using remifentanil and dexmedetomidine) or the control group (standard guideline-based management) to receive blood pressure-lowering treatment. The primary outcome was the SBP control rate (<140 mmHg) at 1 h posttreatment initiation. Secondary outcomes included blood pressure variability, neurologic function and clinical outcomes. RESULTS: A total of 338 patients were allocated to the intervention (n = 167) or control group (n = 171). The SBP control rate at 1 h posttreatment initiation in the intervention group was higher than that in controls (101/161, 62.7% vs. 66/166, 39.8%, difference 23.2%, 95% CI, 12.4 to 34.1%, P < 0.001). Analysis of secondary outcomes indicated that patients in the intervention group could effectively reduce agitation while achieving lighter sedation, but no improvement in clinical outcomes was observed. Regarding safety, the incidence of bradycardia and respiratory depression was higher in the intervention group. CONCLUSIONS: Among intracerebral hemorrhage patients with a SBP ≥ 150 mmHg, a preset protocol using a remifentanil and dexmedetomidine-based standard guideline management significantly increased the SBP control rate at 1 h posttreatment compared with the standard guideline-based management. (ClinicalTrials.gov number: NCT03207100, Registration date: June 30, 2017).

Inactivated COVID-19 vaccines in peri-pregnancy period: Evaluation of safety for both pregnant women and neonates.

BACKGROUND: Pregnant women have been excluded from vaccination of COVID-19 due to the lack of strong clinical evidence, which may place pregnant women at greater risk of contracting COVID-19. We conducted this study in China to investigate the maternal and neonatal safety of inactivated COVID-19 vaccination administered during the peri-pregnancy period. METHODS: This prospective observational cohort study enrolled pregnant women who received pregnancy care between January 1, 2021, and December 31, 2021. Pregnant women were categorized into vaccine group (n = 60) and control group (n = 60) based on whether they had received an inactivated COVID-19 vaccine within peri-pregnancy period. The primary outcomes were the incidence of maternal premature rupture of membranes (PROM) and neonatal adverse events, including induced labor/death, premature birth, low birth weight, and neonatal intensive care unit (NICU) admission and several secondary outcomes related to pregnant women and neonates. Inverse probability treatment weighting (IPTW) was employed to adjust for baseline covariates. Linear and logistic regression models were established after IPTW for continuous and binary outcomes, respectively. In sensitivity analysis, E-values were calculated and propensity score matching analysis and multivariate regression analysis used to demonstrate the robustness of IPTW results. Moreover, vaccination time subgroup analysis and medication subgroup analysis were conducted. RESULTS: Out of 120 neonates delivered, there was no significant difference in PROM (25.42 % vs. 19.67 %, p = 0.438) or neonatal adverse events (11.86 % vs. 4.92 %, p = 0.148) between the vaccine and control groups. Moreover, among the secondary outcomes only serum alanine transaminase (ALT) at first trimester had a statistically significant difference between the groups, ALT levels were significantly higher in the vaccine group during the first trimester (20.67 ± 20.34 vs. 13.05 ± 9.43; RR: 5.38; p = 0.04). In sensitivity analysis, the E-values calculated for the primary outcomes PROM and neonatal adverse events are 2.04 and 5.00 respectively. PSM analysis and multivariate regression analysis reached the same conclusion. The results of primary outcomes are both consistent across the vaccination time subgroup and medication subgroup. CONCLUSION: The sensitivity analysis illustrates the robustness of our results, so we can conclude that the vaccination of inactivated COVID-19 vaccine during the peri-pregnancy period is safe for both the pregnant woman and neonates no matter what time of vaccination and the use of medication. In addition, it is recommended to monitor ALT levels throughout the first trimester of pregnancy.

Safety and efficacy of glibenclamide combined with rtPA in acute cerebral ischemia with occlusion/stenosis of anterior circulation (SE-GRACE): a randomized, double-blind, placebo-controlled trial.

Background: Glibenclamide alleviates brain edema and improves neurological outcomes in experimental models of stroke. We aimed to assess whether glibenclamide improves functional outcomes in patients with acute ischemic stroke treated with recombinant tissue plasminogen activator (rtPA). Methods: In this randomized, double-blind, placebo-controlled trial, patients with acute ischemic stroke were recruited to eight academic hospitals in China. Patients were eligible if they were aged 18-74 years, presented with a symptomatic anterior circulation occlusion with a deficit on the NIHSS of 4-25, and had been treated with rtPA within 4.5 h of symptom onset. We used web-based randomization (1:1) to allocate eligible participants to the glibenclamide or placebo group, stratified according to endovascular treatment and baseline stroke severity. Glibenclamide or placebo was taken orally or via tube feeding at a loading dose of 1.25 mg within 10 h after symptom onset, followed by 0.625 mg every 8 h for 5 days. The primary outcome was the proportion of patients with good outcomes (modified Rankin Scale of 0-2) at 90 days, assessed in all randomly assigned patients who had been correctly diagnosed and had begun study medication. The study is registered with ClinicalTrials.gov, NCT03284463, and is closed to new participants. Findings: Between January 1, 2018, and May 28, 2022, 305 patients were randomly assigned, of whom 272 (142 received glibenclamide and 130 received placebo) were included in the primary efficacy analysis. 103 (73%) patients in the glibenclamide group and 94 (72%) in the placebo group had a good outcome (adjusted risk difference 0.002, 95% CI -0.098 to 0.103; p = 0.96). 12 (8%) patients allocated to glibenclamide and seven (5%) patients allocated to placebo died from any cause at 90 days (p = 0.35). The number and type of adverse events were similar between the two groups. There were no drug-related adverse events and no drug-related deaths. Interpretation: The addition of glibenclamide to thrombolytic therapy did not increase the proportion of patients who achieved good outcomes after stroke compared with placebo, but it did not lead to any safety concerns. Funding: Southern Medical University and Nanfang Hospital.

On variance estimation of target population created by inverse probability weighting.

Inverse probability weighting (IPW) is frequently used to reduce or minimize the observed confounding in observational studies. IPW creates a pseudo-sample by weighting each individual by the inverse of the conditional probability of receiving the treatment level that he/she has actually received. In the pseudo-sample there is no variation among the multiple individuals generated by weighting the same individual in the original sample. This would reduce the variability of the data and therefore bias the variance estimate in the target population. Conventional variance estimation methods for IPW estimators generally ignore this underestimation and tend to produce biased estimates of variance. We here propose a more reasonable method that incorporates this source of variability by using parametric bootstrapping based on intra-stratum variability estimates. This approach firstly uses propensity score stratification and intra-stratum standard deviation to approximate the variability among multiple individuals generated based on a single individual whose propensity score falls within the corresponding stratum. The parametric bootstrapping is then used to incorporate the target variability by re-generating outcomes after adding a random error term to the original data. The performance of the proposed method is compared with three existing methods including the naïve model-based variance estimator, the nonparametric bootstrap variance estimator, and the robust variance estimator in the simulation section. An example of patients with sarcopenia is used to illustrate the implementation of the proposed approach. According to the results, the proposed approach has desirable statistical properties and can be easily implemented using the provided R code.

Simplified Rapid Hydration Prevents Contrast-Associated Acute Kidney Injury Among CKD Patients Undergoing Coronary Angiography.

BACKGROUND: Patients with chronic kidney disease (CKD) undergoing coronary angiography (CAG) are at high risk of contrast-associated acute kidney injury (CA-AKI) and mortality. Therefore, there is a clinical need to explore safe, convenient, and effective strategies for preventing CA-AKI. OBJECTIVES: This study sought to assess whether simplified rapid hydration is noninferior to standard hydration for CA-AKI prevention in patients with CKD. METHODS: This multicenter, open-label, randomized controlled study was conducted across 21 teaching hospitals and included 1,002 patients with CKD. Patients were randomized to either simplified hydration (SH) (SH group, with normal saline from 1 hour before to 4 hours after CAG at a rate of 3 mL/kg/h) or standard hydration (control group, with normal saline 12 hours before and 12 hours after CAG at a rate of 1 mL/kg/h). The primary endpoint of CA-AKI was a ≥25% or 0.5-mg/dL rise in serum creatinine from baseline within 48 to 72 hours. RESULTS: CA-AKI occurred in 29 of 466 (6.2%) patients in the SH group and in 38 of 455 (8.4%) patients in the control group (relative risk: 0.8; 95% CI: 0.5-1.2; P = 0.216). In addition, the risk of acute heart failure and 1-year major adverse cardiovascular events did not differ significantly between the groups. However, the median hydration duration was significantly shorter in the SH group than in the control group (6 vs 25 hours; P < 0.001). CONCLUSIONS: In CKD patients undergoing CAG, SH is noninferior to standard hydration in preventing CA-AKI with a shorter hydration duration.

Polymyxin B therapy based on therapeutic drug monitoring in carbapenem-resistant organisms sepsis: the PMB-CROS randomized clinical trial.

BACKGROUND: The appropriate administration regimen of polymyxin B is yet controversial. The present study aimed to explore the optimal dose of polymyxin B under therapeutic drug monitoring (TDM) guidance. METHODS: In China's Henan province, 26 hospitals participated in a randomized controlled trial. We included patients with sepsis caused by carbapenem-resistant Gram-negative bacteria (CR-GNB) susceptible to polymyxin B. The patients were randomly divided into a high-dose (HD) group or a low-dose (LD) group and received 150 mg loading dose, 75 mg every 12 h and 100 mg loading dose, 50 mg every 12 h, respectively. TDM was employed to determine if the dose of polymyxin B needs adjustment based on the area under the concentration-time curve across 24 h at a steady state (ssAUC0-24) of 50-100 mg h/L. The primary outcome was the 14-day clinical response, and the secondary outcomes included 28- and 14-day mortality. RESULTS: This trial included 311 patients, with 152 assigned to the HD group and 159 assigned to the LD group. Intention-to-treat analysis showed that the 14-day clinical response was non-significant (p = 0.527): 95/152 (62.5%) in the HD group and 95/159 (59.7%) in the LD group. Kaplan-Meier's 180-day survival curve showed survival advantage in the HD group than in the LD group (p = 0.037). More patients achieved the target ssAUC0-24 in the HD than in the LD group (63.8% vs. 38.9%; p = 0.005) and in the septic shock subgroup compared to all subjects (HD group: 71.4% vs. 63.8%, p = 0.037; LD group: 58.3% vs. 38.9%, p = 0.0005). Also, the target AUC compliance was not correlated with clinical outcomes but with acute kidney injury (AKI) (p = 0.019). Adverse events did not differ between the HD and LD groups. CONCLUSION: A fixed polymyxin B loading dose of 150 mg and a maintenance dose of 75 mg every 12 h was safe for patients with sepsis caused by CR-GNB and improves long-term survival. The increased AUC was associated with increased incidence of AKI, and TDM results were valued to prevent AKI. Trial registration Trial registration ClinicalTrials.gov: ChiCTR2100043208, Registration date: January 26, 2021.

Real-world surgical treatment patterns and clinical outcomes in patients with stages IA-IIIA non-small cell lung cancer: a retrospective multicentric observational study involving 11,958 patients.

PURPOSE: Surgical resection is cornerstone treatment for early-stage non-small cell lung cancer (NSCLC) and offers a chance for cure. This study was conducted to determine current surgical treatment patterns and outcomes of Chinese patients with NSCLC. METHODS: Data of patients with histologically confirmed NSCLC of stages IA-IIIA and who underwent surgery between July 2014 and July 2020 were retrospectively collected from 9 tertiary hospitals in China. Cox model was used for multivariate analyses. RESULTS: This study included 11,958 patients, among whom 59.1%, 19.2%, and 21.7% were in stages I, II, and IIIA, respectively. Lobectomy was the most common operation method (78.4%), followed by wedge resection (8.2%), segmentectomy (5.4%), pneumonectomy (5.2%), and bronchial sleeve lobectomy (2.8%). Among patients who underwent wedge resection and segmentectomy, majority had stage I NSCLC (87.2% and 93.3%, respectively), and sublobectomy accounted for 20.7% of stage I operations. With a median follow-up time of 30.2 months, disease-free survival (DFS) and overall survival (OS) rates of entire population were 88.9% and 96.1% at 1 year, 75.2% and 85.1% at 3 years, and 65.3% and 77.0% at 5 years, respectively. The 5-year OS rates for stages IA, IB, IIA, IIB, and IIIA disease were 93.2%, 82.7%, 70.3%, 67.0%, and 52.1%, respectively. CONCLUSION: This is the largest real-world cohort study of patients with NSCLC who underwent surgery in China, where we described characteristics of surgical treatment and survival outcomes. The results of our study provide insights into real-world surgical treatment status for surgeons and clinicians.

A Double-Blind Randomized Placebo-Controlled Phase 3 Trial of Tobramycin Inhalation Solution in Adults With Bronchiectasis With Pseudomonas aeruginosa Infection.

BACKGROUND: Few large-scale studies have demonstrated the efficacy of tobramycin nebulization in bronchiectasis. We evaluated the efficacy and safety of nebulized tobramycin inhalation solution (TIS) in adults with bronchiectasis with Pseudomonas aeruginosa infection. RESEARCH QUESTION: Can TIS effectively reduce sputum P aeruginosa density and improve the bronchiectasis-specific quality of life in patients with bronchiectasis with P aeruginosa infection? STUDY DESIGN AND METHODS: This was a phase 3, 16-week, multicenter, randomized, double-blind, placebo-controlled trial. Eligible adults with bronchiectasis were recruited from October 2018 to July 2021. On the basis of usual care, patients nebulized TIS (300 mg/5 mL twice daily) or normal saline (5 mL twice daily) via vibrating-mesh nebulizer. Treatment consisted of two cycles, each consisting of 28 days on-treatment and 28 days off-treatment. The coprimary end points included changes from baseline in P aeruginosa density and Quality-of-Life Bronchiectasis Respiratory Symptoms score on day 29. RESULTS: The modified intention-to-treat population consisted of 167 patients in the tobramycin group and 172 patients in the placebo group. Compared with placebo, TIS resulted in a significantly greater reduction in P aeruginosa density (adjusted mean difference, 1.74 log10 colony-forming units/g; 95% CI, 1.12-2.35; P < .001) and greater improvement in Quality-of-Life Bronchiectasis Respiratory Symptoms score (adjusted mean difference, 7.91; 95% CI, 5.72-10.11; P < .001) on day 29. Similar findings were observed on day 85. TIS resulted in a significant reduction in 24-h sputum volume and sputum purulence score on days 29, 57, and 85. More patients became culture negative for P aeruginosa in the tobramycin group than in the placebo group on day 29 (29.3% vs 10.6%). The incidence of adverse events and serious adverse events were comparable between the two groups. INTERPRETATION: TIS is an effective treatment option and has an acceptable safety profile in patients with bronchiectasis with P aeruginosa infection. TRIAL REGISTRATION: ClinicalTrials.gov; No. NCT03715322; URL: www. CLINICALTRIALS: gov.

Evaluation of the effect of perioperative administration of S(+)-ketamine hydrochloride injection for postoperative acute pain in children: study protocol for a prospective, multicenter, randomized, open-label, parallel-group, pragmatic clinical trial.

BACKGROUND: Inadequate postoperative pain management increases the risk of adverse events after the surgery and aggressive perioperative pain prevention has both short-term and long-term benefits. S(+)-ketamine is an N-methyl-D-aspartic acid (NMDA) receptor antagonist with a strong analgesic effect and can significantly relieve postoperative acute pain and reduce opioid consumption. However, for children, it still needs to be confirmed by large sample clinical studies. METHODS: This is a pragmatic, randomized controlled trial which will evaluate the effect of perioperative administration of S(+)-ketamine hydrochloride injection for postoperative acute pain in children in a pragmatic clinical setting. A total of 3000 children (≤17 years old) undergoing surgery will be included in this protocol. Subjects will be randomized 2:1 to either receive S(+)-ketamine hydrochloride injection or conventional therapy without S(+)-ketamine during the entire perioperative period. The primary endpoints are the area under the receiver operating characteristic (ROC) curve of Face Legs Activity Cry and Consolability (FLACC, 0-7 years old) scale score or Numerical Rating Scale (NRS, 8-17 years old) score within 48 h after surgery, and the consumption of opioids within 48 h after surgery. The secondary endpoints include the time of first use of rescue analgesics after surgery, rescue analgesia rate within 48 h after surgery, anesthesia recovery time, incidence of emergency delirium (for 0-7 years old), changes of anxiety and depression scale scores at 48 h after surgery (for 8-17 years old), incidence of intraoperative adverse events (AEs), and incidence of postoperative AEs and pharmacoeconomic indicators. AEs and serious AEs were recorded to evaluate safety. DISCUSSION: This trial will be the first pragmatic clinical trial to prospectively assess the effect of perioperative administration of S(+)-ketamine hydrochloride injection for postoperative acute pain in children, which is of great significance to the continuous optimization of clinical anesthesia and analgesia programs for children. TRIAL REGISTRATION: This trial was registered in the U.S. National Institutes of Health ClinicalTrials.gov database ( http://clinicaltrials.gov ; Registration number: NCT04834427). Registered on 8 April 2021.

The Nadir Oxygen-Specific Heart Rate Response in Sleep Apnea Links With the Occurrence of Acute Myocardial Infarction.

Background: Little is known regarding the quantification of sleep apnea- and hypoxemia-elicited heart rate (HR) response and its prognostic significance of the cardiovascular risk. We sought to explore the impact of HR response and variability specific to obstructive sleep apnea (OSA) on the occurrence of a common cardiovascular event - acute myocardial infarction (AMI). Methods: Consecutive patients with suspected OSA were enrolled and underwent nocturnal respiratory study and electrocardiography monitoring. The minimal oxygen saturation (minSpO2) was determined from the oxygen saturation curve under a subject-specific search window. Primary HR metrics such as maximal HR in response to minSpO2 and respiratory event-specific HR variability were computed from the synchronized recordings. Multivariate regression analyses were conducted to analyze the associations between individualized HR metrics and the occurrence of AMI. Results: Of 2,748 patients recruited, 39% (n = 1,071) had moderate-to-severe OSA (respiratory event index, REI ≥ 15), and 11.4% (n = 313) patients had AMI. Patients with AMI experienced severe OSA, severe minSpO2, and greater HR reactions. Patients with minSpO2 <90% had an adjusted odds ratio (OR) of 1.48 [95% confidence interval (CI): 1.09-2.00, p = 0.012) for AMI. Notably, minSpO2-induced elevated mean HR response (HRmean > 73 bpm) was significantly associated with AMI (OR 1.72, 95% CI: 1.32-2.23, p < 0.001). Patients with both severe minSpO2 (<90%) and elevated HRmean carried an additive OR of 2.65 (95% CI: 1.74-4.05, p < 0.001) for the risk of AMI after adjustment for potential confounders. A large total power spectrum specific to respiratory events was correlated with an adjusted OR of 0.61 for AMI risk. Conclusion: Patients with substantial HR reactions to OSA-induced oxygen nadir and restricted cardiac cycle shifting to respiratory events were likely at increased risk of developing AMI. Detection of nocturnal HR response to hypoxemia may help improve cardiovascular risk stratification.

Efficacy and Safety of Apatinib for Radiation-induced Brain Injury Among Patients With Head and Neck Cancer: An Open-Label, Single-Arm, Phase 2 Study.

PURPOSE: The treatment of radiation-induced brain injury (RI) caused by radiation therapy for head and neck cancer is challenging. Antiangiogenic therapy is a promising treatment. Apatinib is an oral tyrosine kinase inhibitor that selectively inhibits vascular endothelial growth factor receptor 2. We aimed to assess the efficacy and safety of apatinib in patients with RI. METHODS AND MATERIALS: In this phase 2, open-label, single-arm, prospective study, we recruited patients aged 35 to 80 years with prior radiation therapy history for head and neck cancer who had newly diagnosed RI at the Sun Yat-sen Memorial Hospital, China. Apatinib was administered at a dosage of 250 mg once daily orally for 4 weeks. A Simon minimax 2-stage design was performed. The primary outcome was the proportion of patients with overall clinical efficacy, defined as a radiographic response of ≥25% reduction in baseline brain edema volume on magnetic resonance fluid attenuated inversion recovery images at week 4. Secondary end points were the overall improvement rate of brain necrosis, neurologic function, and safety. RESULTS: We screened 37 patients, 36 of whom were enrolled between October 17, 2019, and August 3, 2020. At the cutoff date, 36 patients were assessed for efficacy and safety (19 were enrolled in stage 1 and 17 in stage 2). Of the 36 patients evaluated for overall clinical efficacy, 22 patients (61.1%; 95% CI, 43.5%-76.9%) achieved the primary end point at week 4. Among the 31 patients with brain necrosis lesions, 19 patients (61.3%; 95% CI, 42.2%-78.2%) showed improvement of brain necrosis. The most common grade 1 to 2 adverse events were hand-foot syndrome, fatigue, and hypertension There were no treatment-related grade 4 to 5 toxic effects. CONCLUSIONS: Oral apatinib shows promising efficacy and is well-tolerated in patients with RI. Further randomized controlled studies are warranted.

Bayesian two-stage design for phase II oncology trials with binary endpoint.

In phase II oncology trials, two-stage design allowing early stopping for futility and/or efficacy is frequently used. However, this design based on frequentist statistical approaches could not guarantee a high posterior probability of attending the pre-specified clinically interesting rate from a Bayesian perspective. Here, we proposed a new Bayesian design enabling early terminating for efficacy as well as futility. In addition to the clinically uninteresting and interesting response rate, a prior distribution of response rate, the minimum posterior threshold probabilities and the lengths of the highest posterior density intervals were specified in the design. Finally, we defined the feasible design with the highest total effective predictive probability. We studied the properties of the proposed design and applied it to an oncology trial as an example. The proposed design ensured that the observed response rate fell within prespecified levels of posterior probability. The proposed design provides an alternative design to single-arm two-stage trials.

Laparoscopic vs Open Distal Gastrectomy for Locally Advanced Gastric Cancer: Five-Year Outcomes From the CLASS-01 Randomized Clinical Trial.

Importance: It is not clear whether laparoscopic and open distal gastrectomy produce similar outcomes among patients with locally advanced gastric cancer. Data from a multicenter, randomized clinical trial (Chinese Laparoscopic Gastrointestinal Surgical Study [CLASS]-01) showed that laparoscopic distal gastrectomy did not result in inferior disease-free survival at 3 years compared with open distal gastrectomy. Objective: To report 5-year overall survival data from the CLASS-01 trial of laparoscopic vs open distal gastrectomy among patients with locally advanced gastric cancer. Design, Setting, and Patients: This was a noninferiority, open-label, randomized clinical trial conducted at 14 centers in China. A total of 1056 eligible patients with clinical stage T2, T3, or T4a gastric cancer without bulky nodes or distant metastases were enrolled from September 12, 2012, to December 3, 2014. Final follow-up was on December 31, 2019. Interventions: Participants were randomized in a 1:1 ratio after stratification by site, age, cancer stage, and histologic features to undergo either laparoscopic distal gastrectomy (n = 528) or open distal gastrectomy (n = 528) with D2 lymphadenectomy. Main Outcomes and Measures: The 5-year overall survival rates were updated to compare laparoscopic distal gastrectomy with open distal gastrectomy. All analyses were performed on an intention-to-treat basis. In addition, per-protocol and as-treated analyses were performed for overall survival. Results: Data from 1039 patients (726 men [69.9%]; mean [SD] age, 56.2 [10.7] years) who received curative therapy were analyzed. At 5 years, the overall survival rates were 72.6% in the laparoscopic distal gastrectomy group and 76.3% in the open distal gastrectomy group (log-rank P = .19; hazard ratio, 1.17; 95% CI, 0.93-1.48; P = .19). After comparison for competing risk events, gastric cancer-related deaths (hazard ratio, 1.14; 95% CI, 0.87-1.49; P = .34) and deaths from other causes (hazard ratio, 1.23; 95% CI, 0.74-2.05; P = .42) did not differ significantly between groups. Overall rates of survival did not differ significantly between groups with each tumor stage. Conclusions and Relevance: This study found that laparoscopic distal gastrectomy with D2 lymphadenectomy performed by experienced surgeons in high-volume specialized institutions resulted in similar 5-year overall survival compared with open distal gastrectomy among patients with locally advanced gastric cancer. Trial Registration: ClinicalTrials.gov Identifier: NCT01609309.

Hydration for prevention of kidney injury after primary coronary intervention for acute myocardial infarction: a randomised clinical trial.

OBJECTIVE: To evaluate the efficacy of aggressive hydration compared with general hydration for contrast-induced acute kidney injury (CI-AKI) prevention among patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (pPCI). METHODS: The Aggressive hydraTion in patients with STEMI undergoing pPCI to prevenT Contrast-Induced Acute Kidney Injury study is an open-label, randomised controlled study at 15 teaching hospitals in China. A total of 560 adult patients were randomly assigned (1:1) to receive aggressive hydration or general hydration treatment. Aggressive hydration group received preprocedural loading dose of 125/250 mL normal saline within 30 min, followed by postprocedural hydration performed for 4 hours under left ventricular end-diastolic pressure guidance and additional hydration until 24 hours after pPCI. General hydration group received ≤500 mL 0.9% saline at 1 mL/kg/hour for 6 hours after randomisation. The primary end point is CI-AKI, defined as a >25% or 0.5 mg/dL increased in serum creatinine from baseline during the first 48-72 hours after primary angioplasty. The safety end point is acute heart failure. RESULTS: From July 2014 to May 2018, 469 patients were enrolled in the final analysis. CI-AKI occurred less frequently in aggressive hydration group than in general hydration group (21.8% vs 31.1%; risk ratio (RR) 0.70, 95% CI 0.52 to 0.96). Acute heart failure did not significantly differ between the aggressive hydration group and the general hydration group (8.1% vs 6.4%, RR 1.13, 95% CI 0.66 to 2.44). Several subgroup analysis showed the better effect of aggressive hydration in CI-AKI prevention in male, renal insufficient and non-anterior myocardial infarction participants. CONCLUSIONS: Comparing with general hydration, the peri-operative aggressive hydration seems to be safe and effective in preventing CI-AKI among patients with STEMI undergoing pPCI.

Perioperative intravenous S(+)-ketamine for acute postoperative pain in adults: study protocol for a multicentre, randomised, open-label, positive-controlled, pragmatic clinical trial (SAFE-SK-A trial).

INTRODUCTION: Postoperative pain remains incompletely controlled for decades. Recently, multimodal analgesia is emerging as a potential approach in the management of postoperative pain. Therein, S(+)-ketamine is appealing as an adjuvant drug in multimodal analgesia due to its unique pharmacological advantages. This pragmatic clinical trial (SAFE-SK-A trial) is designed to investigate the analgesic effect and safety of S(+)-ketamine for acute postoperative pain in adults and explore the optimal strategy of perioperative intravenous S(+)-ketamine in a real-world setting. METHODS AND ANALYSIS: This multicentre, randomised, open-label, positive-controlled, pragmatic clinical trial (SAFE-SK-A study) is planned to conduct in 80 centres from China and recruit a total of 12 000 adult participants undergoing a surgical procedure under general anaesthesia. Patient recruitment started in June 2021 and will end in June 2022. Participants will be randomised in a ratio of 2:1 to either receive perioperative intravenous S(+)-ketamine plus conventional anaesthesia or conventional anaesthesia only. Given the pragmatic nature of the study, no specific restriction as to the administration dosage, route, time, synergistic regimen or basic analgesics. Primary endpoints are the area under the broken line of Numerical Rating Scale (NRS) scores for pain intensity and the total opioid consumption within 48 hours postoperative. Secondary endpoints are postoperative NRS scores, the anaesthesia recovery time, time of first rescue analgesia, the incidence of rescue analgesia, the incidence of postoperative delirium, patient questionnaire for effect, changes from baseline in cognitive function and anxiety and depression, as well as the adverse events and pharmacoeconomic outcomes. The general linear model will be used for the primary endpoint, and appropriate methods will be used for the secondary endpoints. ETHICS AND DISSEMINATION: This trial has been approved by the local Institutional Review Board (S2021-026-02) and conducted following the Declaration of Helsinki. Results of this trial will be publicly disclosed and published in scientific journals. TRIAL REGISTRATION NUMBER: NCT04837170; Pre-results.

Associations between nocturnal continuous blood pressure fluctuations and the characteristics of oxygen desaturation in patients with obstructive sleep apnea: a pilot study.

BACKGROUND: Patients with obstructive sleep apnea (OSA) frequently experience apnea-related oxygen desaturation events (ODE) accompanied by striking blood pressure (BP) fluctuations during sleep. We aimed to investigate the effects of characteristics of ODE on nocturnal BP fluctuations in OSA patients. METHODS AND RESULTS: A total of 6199 ODE were obtained from 30 patients with who underwent overnight portable monitoring and beat-to-beat BP monitoring simultaneously. The associations between nocturnal BP parameters and the characteristics of ODE were studied. The mean value of systolic BP (SBP) monitored during ODE was higher than the non-hypoxia SBP value (122.0 ± 15.9 vs. 120.4 ± 15.1 mmHg, P = 0.001) and nighttime SBP value (122.0 ± 15.9 vs. 120.8 ± 15.0 mmHg, P = 0.002). SBP variability (SBPV) during ODE was higher than the values not during ODE (14.0 ± 2.8 vs. 13.2 ± 2.6 mmHg, P = 0.043) and nighttime SBPV (14.0 ± 2.8 vs. 12.9 ± 2.3 mmHg, P < 0.001). Hypoxia SBP index, defined as the percentage of SBP surge (△SBP) ≥10 mmHg to all △SBP during ODE, increased with greater respiratory event index (P = 0.01). Both the coefficient of variation for SBP values of an ODE (SBPV') and event-related SBP elevation (△SBP') increased with raised amplitude of ODE (P < 0.001 for SBPV' and P < 0.001 for △SBP'). Similar results were observed when the duration of events was analyzed (P < 0.001 for SBPV' and P < 0.001 for △SBP'). CONCLUSION: BP related to ODE may be the main component of increased BP during sleep in OSA patients. In addition to the frequency of respiratory events, the amplitude and duration of ODE may have a role in nocturnal BP fluctuations in OSA patients.

Ethnic disparities in stillbirth risk in Yunnan, China: a prospective cohort study, 2010-2018.

BACKGROUND: Racial and ethnic disparities in stillbirth risk had been documented in most western countries, but it remains unknown in China. This study was to determine whether exist ethnic disparities in stillbirth risk in mainland China. METHODS: Pregnancy outcomes and ethnicity data were obtained from the National Free Preconception Health Examination Project (NEPHEP), a nationwide prospective population-based cohort study conducted in Yunnan China from 2010-2018. The Han majority and other four main minorities including Yi, Dai, Miao, Hani were investigated in the analysis. The stillbirth hazards were estimated by life-table analysis. The excess stillbirth risk (ESR) was computed for Chinese minorities using multivariable logistic regression. RESULTS: Compared with other four minorities, women in Han majority were more likely to more educated, less multiparous, and less occupied in agriculture. The pattern of stillbirth hazard of Dai women across different gestation intervals were found to be different from other ethnic groups, especially in 20-23 weeks with 3.2 times higher than Han women. The ESR of the Dai, Hani, Miao, and Yi were 45.05, 18.70, -4.17 and 12.28%, respectively. Adjusted for maternal age, education, birth order and other general risk factors, the ethnic disparity still persisted between Dai women and Han women. Adjusted for preterm birth further (gestation age <37 weeks) can reduce 16.91% ESR of Dai women and made the disparity insignificant. Maternal diseases and congenital anomalies explained little for ethnic disparities. CONCLUSIONS: We identified the ethnic disparity in stillbirth risk between Dai women and Han women. General risk factors including sociodemographic factors and maternal diseases explained little. Considerable ethnic disparities can be attributed to preterm birth.

A risk biomarker for obstructive sleep apnea in patients with coronary artery disease: monocyte to high-density lipoprotein ratio.

PURPOSE: The monocyte to high-density lipoprotein ratio (MHR) has been postulated to be a novel indicator associated with adverse cardiovascular outcomes in patients with coronary artery disease (CAD). These patients often have obstructive sleep apnea (OSA) and whether or not MHR may provide prognostic value for this comorbidity remains unclear. Therefore, we sought to explore the clinical value of MHR in evaluating OSA in patients with CAD. METHODS: Consecutive patients with CAD were prospectively recruited and were assigned into four groups based on the quartiles of MHR. Portable monitoring for detecting nocturnal respiratory events was utilized to provide the diagnosis of OSA. Patients were defined as having OSA when respiratory event index ≥ 15 events/h. Univariate and multivariate regression analyses were used to explore the independent association between the levels of MHR and OSA. RESULTS: A total of 1243 patients with CAD was included with a prevalence of OSA reaching 40% (n = 497). Patients with higher levels of MHR experienced increasing severity of OSA. In univariate analysis, MHR was a risk factor for OSA (odds ratio [OR] 1.90, 95% confidence interval [CI] 1.33-2.71, p < 0.001). Multivariate analysis showed that MHR was independently associated with the presence of OSA (OR 1.63, 95% CI 1.06-2.52, p = 0.027) after adjusting for possible confounding factors. CONCLUSIONS: Elevated levels of MHR were independently associated with a higher likelihood of OSA in patients with CAD. MHR could be a screening tool and a risk biomarker of OSA in such patients.