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Phase I, Randomized, Placebo-Controlled, Dose-Escalation Study of GB223, a Fully-Humanized Monoclonal Antibody to RANKL, in Healthy Chinese Adults.
Li, C, Liu, H, Liao, Y, Zhu, Y, Tian, J, Wang, X, Hu, Z, Zhan, Y, Li, X, Liang, X, et al
BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy. 2023;(5):721-735
Abstract
BACKGROUND GB223 is a novel, fully-humanized monoclonal antibody against the receptor activator of nuclear factor-kappa B ligand (RANKL). In this phase I study, the safety, tolerability, pharmacokinetics, pharmacodynamics, and immunogenicity of GB223 were investigated. PATIENTS AND METHODS This was a randomized, double-blinded, placebo-controlled, single-dose escalation study conducted in 44 healthy Chinese adults. Participants were randomly assigned to receive a single subcutaneous injection dose of 7, 21, 63, 119, or 140 mg of GB223 (n = 34) or placebo (n = 10) and were followed up for 140-252 days. RESULTS The results of noncompartmental analysis showed that GB223 was slowly absorbed after dosing, with a time to reach maximum concentration (Tmax) ranging from 5 to 11 days. Serum GB223 concentrations decreased slowly, with a long half-life ranging from 7.91 to 19.60 days. A two-compartment Michaelis-Menten model was found to best describe the pharmacokinetics of GB223, and the absorption rate of GB223 differed between males (0.0146 h-1) and females (0.0081 h-1). Serum C-terminal telopeptide of type I collagen decreased significantly postdose, and the inhibition lasted 42-168 days. No deaths or drug-related serious adverse events occurred. The most frequent adverse events were blood parathyroid hormone increased (94.1%), blood phosphorus decreased (67.6%) and blood calcium decreased (58.8%). In the GB223 group, 44.1% (15/34) of subjects were antidrug antibody positive after dosing. CONCLUSION In this study, we demonstrated for the first time that a single subcutaneous injection of GB223, from 7 to 140 mg, is safe and well tolerated in healthy Chinese subjects. GB223 has a nonlinear pharmacokinetic profile, and sex was a potential covariate that may affect the absorption rate of GB223. CLINICAL TRIAL REGISTRATION NCT04178044 and ChiCTR1800020338.
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The Effect of Internet-Based Cognitive Behavioral Therapy on Major Depressive Disorder: Randomized Controlled Trial.
Lin, Z, Cheng, L, Han, X, Wang, H, Liao, Y, Guo, L, Shi, J, Fan, B, Teopiz, KM, Jawad, MY, et al
Journal of medical Internet research. 2023;:e42786
Abstract
BACKGROUND Many people living with major depressive disorder (MDD) in China do not receive treatment owing to a lack of mental health services, along with significant stigma toward mental illness. Internet-based cognitive behavioral therapy (ICBT) has been proposed to increase access to mental health care for people with MDD. OBJECTIVE The aims of this study were to (1) evaluate the efficacy of ICBT for depressive symptoms in patients with MDD; (2) evaluate the effect of ICBT on anxiety symptoms, nonspecific psychological distress, general self-efficacy, depression stigma, social function, and health-related quality of life (HRQoL); and (3) explore the acceptability of and satisfaction with the ICBT program among participants. METHODS Patients with MDD were enrolled and randomized to the ICBT group or the waiting-list control (WLC) group. The ICBT group received ICBT delivered through a WeChat mini-program with general support by nonspecialists. Participants in the 2 groups were self-evaluated online at baseline and posttreatment for changes in the primary outcome (ie, depressive symptoms) and secondary outcomes (ie, anxiety symptoms, nonspecific psychological distress, general self-efficacy, depression stigma, social functional impairment, and HRQoL). Changes in outcomes were measured by changes in overall scores on respective scales, and response and remission rates were calculated based on depressive symptoms. The acceptability of and satisfaction with the ICBT program were measured by treatment adherence and participants' feelings (ie, modules seriously completed, perceived benefit, and satisfaction). RESULTS We included 40 patients who were randomly assigned to the ICBT group and 44 who were assigned to the WLC group. Compared with the WLC group, the ICBT group had fewer depressive symptoms, fewer anxiety symptoms, less nonspecific psychological distress, and greater general self-efficacy. Moreover, the ICBT group had higher response (18/31, 58%) and remission rates (17/31, 55%). The adherence rate in the ICBT group was 78% (31/40), and the majority of participants who completed all ICBT modules were satisfied with the ICBT program. CONCLUSIONS ICBT demonstrated greater improvements in depressive symptoms, anxiety symptoms, nonspecific psychological distress, and general self-efficacy among selected patients with MDD in comparison with the findings in waiting-list controls. The ICBT program in this study had good acceptability and satisfaction among participants. TRIAL REGISTRATION Chinese Clinical Trial Registry (ChiCTR2100046425); https://tinyurl.com/bdcrj4zv.
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Effects of vaginal microbiota transfer on the neurodevelopment and microbiome of cesarean-born infants: A blinded randomized controlled trial.
Zhou, L, Qiu, W, Wang, J, Zhao, A, Zhou, C, Sun, T, Xiong, Z, Cao, P, Shen, W, Chen, J, et al
Cell host & microbe. 2023;(7):1232-1247.e5
Abstract
The microbiomes of cesarean-born infants differ from vaginally delivered infants and are associated with increased disease risks. Vaginal microbiota transfer (VMT) to newborns may reverse C-section-related microbiome disturbances. Here, we evaluated the effect of VMT by exposing newborns to maternal vaginal fluids and assessing neurodevelopment, as well as the fecal microbiota and metabolome. Sixty-eight cesarean-delivered infants were randomly assigned a VMT or saline gauze intervention immediately after delivery in a triple-blind manner (ChiCTR2000031326). Adverse events were not significantly different between the two groups. Infant neurodevelopment, as measured by the Ages and Stages Questionnaire (ASQ-3) score at 6 months, was significantly higher with VMT than saline. VMT significantly accelerated gut microbiota maturation and regulated levels of certain fecal metabolites and metabolic functions, including carbohydrate, energy, and amino acid metabolisms, within 42 days after birth. Overall, VMT is likely safe and may partially normalize neurodevelopment and the fecal microbiome in cesarean-delivered infants.
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Exenatide Twice Daily Plus Glargine Versus Aspart 70/30 Twice Daily in Patients With Type 2 Diabetes With Inadequate Glycemic Control on Premixed Human Insulin and Metformin.
Chen, X, Xu, Y, Zhang, J, Shao, S, Duan, Y, Liu, P, Shen, L, Zhang, J, Zeng, J, Lin, M, et al
Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists. 2021;(8):790-797
Abstract
OBJECTIVE Many patients with type 2 diabetes treated with premixed insulin gradually have inadequate glycemic control and switch to a basal-bolus regimen, which raises some concerns for weight gain and increased hypoglycemic risk. Switching to combination use of glp-1 agonist and basal insulin may be an alternative option. METHODS After a 12-week premixed human insulin 70/30 dosage optimization period, 200 patients with HbA1c of 7.0% to 10.0% were randomized into 24-week treatment groups with exenatide twice a day plus glargine or with aspart 70/30 twice a day. RESULTS After 24 weeks, the patients receiving exenatide plus glargine (n = 90) had improved HbA1c control compared with those receiving aspart 70/30 (n = 90) (least squares mean change: ‒0.59 vs ‒0.13%; difference [95% CI]: ‒0.45 [‒0.74 to ‒0.17]) in the full analysis set population. Weight decreased 3.5 kg with exenatide and decreased 0.4 kg with aspart 70/30 (P < .001). The insulin dose was reduced 10.7 units/day (95% CI, ‒12.2 to ‒9.2 units; P < .001) with exenatide, and increased 9.7 units/day (95% CI, 8.2 to 11.2 units; P < .001) with aspart 70/30. The most common adverse events were gastrointestinal adverse effects in the exenatide group (nausea [21%], vomiting [16%], diarrhea [13%]). The incidence of hypoglycemia was similar in 2 groups (27% for exenatide and 38% for aspart 70/30; P = .1). CONCLUSION In premixed human insulin‒treated patients with type 2 diabetes with inadequate glycemic control, switching to exenatide twice a day plus glargine was superior to aspart 70/30 twice a day for glycemic and weight control.
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A Low-Glucose Eating Pattern Improves Biomarkers of Postmenopausal Breast Cancer Risk: An Exploratory Secondary Analysis of a Randomized Feasibility Trial.
Schembre, SM, Jospe, MR, Giles, ED, Sears, DD, Liao, Y, Basen-Engquist, KM, Thomson, CA
Nutrients. 2021;(12)
Abstract
Postmenopausal breast cancer is the most common obesity-related cancer death among women in the U.S. Insulin resistance, which worsens in the setting of obesity, is associated with higher breast cancer incidence and mortality. Maladaptive eating patterns driving insulin resistance represent a key modifiable risk factor for breast cancer. Emerging evidence suggests that time-restricted feeding paradigms (TRF) improve cancer-related metabolic risk factors; however, more flexible approaches could be more feasible and effective. In this exploratory, secondary analysis, we identified participants following a low-glucose eating pattern (LGEP), defined as consuming energy when glucose levels are at or below average fasting levels, as an alternative to TRF. Results show that following an LGEP regimen for at least 40% of reported eating events improves insulin resistance (HOMA-IR) and other cancer-related serum biomarkers. The magnitude of serum biomarkers changes observed here has previously been shown to favorably modulate benign breast tissue in women with overweight and obesity who are at risk for postmenopausal breast cancer. By comparison, the observed effects of LGEP were similar to results from previously published TRF studies in similar populations. These preliminary findings support further testing of LGEP as an alternative to TRF and a postmenopausal breast cancer prevention strategy. However, results should be interpreted with caution, given the exploratory nature of analyses.
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BIS-guided deep anesthesia decreases short-term postoperative cognitive dysfunction and peripheral inflammation in elderly patients undergoing abdominal surgery.
Quan, C, Chen, J, Luo, Y, Zhou, L, He, X, Liao, Y, Chou, J, Guo, Q, Chen, AF, Wen, O
Brain and behavior. 2019;(4):e01238
Abstract
OBJECTIVES Postoperative cognitive dysfunction (POCD) is a common clinical complication, with an underlying pathophysiology linked to heightened levels of neuroinflammation. However, it requires clarification as to whether the depth of anesthesia modulates postoperative cognitive dysfunction. This study investigated the association between depth of anesthesia and POCD in elderly patients undergoing abdominal surgery. METHODS A total of 120 patients aged 60 years or older who were planned for abdominal surgery under total intravenous anesthesia were included in this study. The depth of anesthesia was guided by monitoring Bispectral Index (BIS) data. All study participants completed a battery of nine neuropsychological tests before surgery and at 7 days and 3 months after surgery. POCD was calculated by using the reliable change index. Plasma concentration of C-reactive protein (CRP), interleukin (IL)-1β, IL-10, S-100β, and norepinephrine (NE) were measured. RESULTS The incidence of POCD at 7 days after surgery in the deep anesthesia group was 19.2% (10/52), which was significantly lower (p = 0.032) than the light anesthesia group 39.6% (21/53). The depth of anesthesia had no effect on POCD at 3 months after surgery (10.3% vs 14.6%, respectively, p = 0.558). Similarly, plasma levels of CRP and IL-1β in deep anesthesia group were lower than that in light anesthesia group at 7 days after surgery (p < 0.05), but not at 3 months after surgery (p > 0.05). There were no significant differences in the plasma concentration of IL-10, S-100β, and NE between the groups (p > 0.05). CONCLUSIONS Deep anesthesia under total intravenous anesthesia could decrease the occurrence of short-term POCD and inhibit postoperative peripheral inflammation in elderly patients undergoing abdominal surgery, compared with light anesthesia.
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Roxadustat for Anemia in Patients with Kidney Disease Not Receiving Dialysis.
Chen, N, Hao, C, Peng, X, Lin, H, Yin, A, Hao, L, Tao, Y, Liang, X, Liu, Z, Xing, C, et al
The New England journal of medicine. 2019;(11):1001-1010
Abstract
BACKGROUND Roxadustat (FG-4592) is an oral inhibitor of hypoxia-inducible factor (HIF) prolyl hydroxylase that stimulates erythropoiesis and regulates iron metabolism. In phase 2 studies involving patients with chronic kidney disease, roxadustat increased levels of endogenous erythropoietin to within or near the physiologic range, along with increasing hemoglobin levels and improving iron homeostasis. Additional data are needed regarding the efficacy and safety of roxadustat for the treatment of anemia in patients with chronic kidney disease who are not undergoing dialysis. METHODS In this phase 3 trial conducted at 29 sites in China, we randomly assigned 154 patients with chronic kidney disease in a 2:1 ratio to receive roxadustat or placebo three times a week for 8 weeks in a double-blind manner. All the patients had a hemoglobin level of 7.0 to 10.0 g per deciliter at baseline. The randomized phase of the trial was followed by an 18-week open-label period in which all the patients received roxadustat; parenteral iron was withheld. The primary end point was the mean change from baseline in the hemoglobin level, averaged over weeks 7 through 9. RESULTS During the primary-analysis period, the mean (±SD) change from baseline in the hemoglobin level was an increase of 1.9±1.2 g per deciliter in the roxadustat group and a decrease of 0.4±0.8 g per deciliter in the placebo group (P<0.001). The mean reduction from baseline in the hepcidin level (associated with greater iron availability) was 56.14±63.40 ng per milliliter in the roxadustat group and 15.10±48.06 ng per milliliter in the placebo group. The reduction from baseline in the total cholesterol level was 40.6 mg per deciliter in the roxadustat group and 7.7 mg per deciliter in the placebo group. Hyperkalemia and metabolic acidosis occurred more frequently in the roxadustat group than in the placebo group. The efficacy of roxadustat in hemoglobin correction and maintenance was maintained during the 18-week open-label period. CONCLUSIONS In Chinese patients with chronic kidney disease who were not undergoing dialysis, those in the roxadustat group had a higher mean hemoglobin level than those in the placebo group after 8 weeks. During the 18-week open-label phase of the trial, roxadustat was associated with continued efficacy. (Funded by FibroGen and FibroGen [China] Medical Technology Development; ClinicalTrials.gov number, NCT02652819.).
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Efficacy and safety of the addition of ertugliflozin in patients with type 2 diabetes mellitus inadequately controlled with metformin and sitagliptin: The VERTIS SITA2 placebo-controlled randomized study.
Dagogo-Jack, S, Liu, J, Eldor, R, Amorin, G, Johnson, J, Hille, D, Liao, Y, Huyck, S, Golm, G, Terra, SG, et al
Diabetes, obesity & metabolism. 2018;(3):530-540
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Abstract
AIMS: To assess ertugliflozin in patients with type 2 diabetes who are inadequately controlled by metformin and sitagliptin. MATERIALS AND METHODS In this double-blind randomized study (Clinicaltrials.gov NCT02036515), patients (glycated haemoglobin [HbA1c] 7.0% to 10.5% [53-91 mmol/mol] receiving metformin ≥1500 mg/d and sitagliptin 100 mg/d; estimated glomerular filtration rate [eGFR] ≥60 mL/min/1.73 m2 ) were randomized to ertugliflozin 5 mg once-daily, 15 mg once-daily or placebo. The primary efficacy endpoint was change from baseline in HbA1c at Week 26; treatment was continued until Week 52. RESULTS A total of 464 patients were randomized (mean baseline HbA1c, 8.0% [64.3 mmol/mol]; eGFR, 87.9 mL/min/1.73 m2 ). After 26 weeks, placebo-adjusted least squares (LS) mean changes in HbA1c from baseline were -0.7% (-7.5 mmol/mol) and -0.8% (-8.3 mmol/mol) for ertugliflozin 5 and 15 mg, respectively (both P < .001); 17.0%, 32.1% and 39.9% of patients receiving placebo, ertugliflozin 5 mg or ertugliflozin 15 mg, respectively, had HbA1c <7.0% (53 mmol/mol). Significant reductions in fasting plasma glucose, body weight (BW) and systolic blood pressure (SBP) were observed with ertugliflozin relative to placebo. The positive effects of ertugliflozin on glycaemic control, BW and SBP were maintained through Week 52. A higher incidence of genital mycotic infections was observed in male and female patients receiving ertugliflozin (3.7%-14.1%) vs placebo (0%-1.9%) through Week 52. The incidence of urinary tract infections, symptomatic hypoglycaemia and hypovolaemia adverse events were not meaningfully different across groups. CONCLUSIONS Ertugliflozin added to metformin and sitagliptin was well-tolerated, and provided clinically meaningful, durable glycaemic control, BW and SBP reductions vs placebo over 52 weeks.
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Compliance of nursing home residents with a nutrient- and energy-dense oral nutritional supplement determines effects on nutritional status.
Jobse, I, Liao, Y, Bartram, M, Delantonio, K, Uter, W, Stehle, P, Sieber, CC, Volkert, D
The journal of nutrition, health & aging. 2015;(3):356-64
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Abstract
OBJECTIVES Administration of oral nutritional supplements (ONS) is an effective strategy to treat and avoid malnutrition, a persisting issue in nursing homes. However, little is known about compliance in the NH population. This study aimed to analyse the effects of compliance of NH residents with a low-volume, nutrient- and energy-dense ONS on nutritional status and to identify residents' characteristics associated with compliance. DESIGN AND SETTING Randomized, controlled trial in nursing homes. PARTICIPANTS AND INTERVENTION 87 nursing home residents (87 ± 6y, 91% female) with malnutrition or at risk of malnutrition were randomly allocated to an intervention group (IG) receiving 2 x 125 ml ONS (2.4 kcal/ml)/d for 12 weeks, or the control group (CG) with usual care. MEASUREMENTS ONS intake was recorded daily and compliance calculated. Low and high compliance were defined as ≤ 30% and ≥ 80% of provided ONS actually consumed, respectively. Body weight (BW), BMI, upper-arm (UAC) and calf-circumference (CC) and MNA-SF were assessed at baseline and after 12 weeks. Associations between compliance and changes of nutritional parameters and residents' characteristics were analysed. RESULTS Compliance was high in 35.7% and low in 28.6% of the IG (n=42). BW change was significantly higher in subjects with high compliance (median +3.0 (interquartile range +2.1;+3.8) kg, n=15) than in those with low compliance (-0.2 (-2.2;+1.6) kg, n=12) and CG (-0.1 (-1.2; +0.6) kg, n=35; p<0.001), and significantly correlated with compliance in IG (r=0.691; p<0.001). Significant differences and correlations were also identified for BMI, UAC and MNA-SF. High compliance was more often observed in residents with malnutrition (66.7 vs. 27.3%) and chewing difficulties (77.8 vs. 24.2%) than in those without these conditions. Low compliance was more prevalent in residents who were immobile (45.0 vs. 13.6%), depressed (33.3 vs. 6.7%) or had gastrointestinal complaints (50.0 vs. 17.9%) (all p<0.05). CONCLUSIONS A high compliance of nursing home residents with a low volume, nutrient- and energy dense ONS was related to a significantly improved nutritional status in comparison to low compliance and therefore enhanced the effectiveness of ONS. A higher compliance may be achieved by consideration of different residents' characteristics.
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Effects of Xuezhikang in patients with dyslipidemia: a multicenter, randomized, placebo-controlled study.
Moriarty, PM, Roth, EM, Karns, A, Ye, P, Zhao, SP, Liao, Y, Capuzzi, DM, Bays, HE, Zhang, F, Liu, S, et al
Journal of clinical lipidology. 2014;(6):568-575
Abstract
BACKGROUND Xuezhikang (XZK) is an extract of fermented red yeast rice that has lipid-lowering properties. OBJECTIVE To evaluate the effects of XZK on lipids in subjects with dyslipidemia but no coronary heart disease. METHODS A total of 116 adults with baseline non-high-density lipoprotein cholesterol (non-HDL-C) levels of approximately 208 mg/dL and low-density lipoprotein cholesterol (LDL-C) levels of approximately 175 mg/dL were randomized to either placebo or XZK 1200 or 2400 mg daily and treated for 12 weeks. RESULTS A majority of the patients were white (53.4%) or Asian (37.1%). Daily XZK 1200 mg and 2400 mg for 4 to 12 weeks resulted in statistically significant (P < .001) and clinically meaningful decreases in non-HDL-C (∼24% reduction) and LDL-C (∼27% reduction) compared with placebo. XZK treatment at either dose enabled approximately 50% of subjects to reduce their LDL-C levels by ≥ 30%. Doubling the XZK daily dose from 1200 to 2400 mg at treatment week 8 caused an additional 4.6% reduction in LDL-C. Significant benefits were also observed across secondary efficacy variables, including total cholesterol (TC), apolipoprotein B (Apo B), triglycerides, HDL-C, the TC/HDL-C ratio, and the Apo B/Apo A-I ratio, at treatment week 8 or 12. XZK was safe and well tolerated. Safety and tolerability profiles were similar across treatment groups. Most adverse events were gastrointestinal. No subject experienced myopathy or markedly elevated liver transaminases or creatine kinase. CONCLUSION Xuezhikang significantly reduced non-HDL-C and LDL-C, and was well tolerated. Further, longer-term studies in more diverse patient populations are needed to corroborate these findings.