Hetrombopag for the management of chemotherapy-induced thrombocytopenia in patients with advanced solid tumors: a multicenter, randomized, double-blind, placebo-controlled, phase II study.

Background: Chemotherapy-induced thrombocytopenia (CIT) increases the risk of bleeding, necessitates chemotherapy dose reductions and delays, and negatively impacts prognosis. Objectives: This study aimed to evaluate the efficacy and safety of hetrombopag for the management of CIT in patients with advanced solid tumors. Design: A multicenter, randomized, double-blind, placebo-controlled, phase II study. Methods: Patients with advanced solid tumors who experienced a chemotherapy delay of ⩾7 days due to thrombocytopenia (platelet count <75 × 109/L) were randomly assigned (1:1) to receive oral hetrombopag at an initial dose of 7.5 mg once daily or a matching placebo. The primary endpoint was the proportion of treatment responders, defined as patients resuming chemotherapy within 14 days (platelet count ⩾100 × 109/L) and not requiring a chemotherapy dose reduction of ⩾15% or a delay of ⩾4 days or rescue therapy for two consecutive cycles. Results: Between 9 October 2021 and 5 May 2022, 60 patients were randomized, with 59 receiving ⩾1 dose of assigned treatment (hetrombopag/placebo arm, n = 28/31). The proportion of treatment responders was significantly higher in the hetrombopag arm than in the placebo arm [60.7% (17/28) versus 12.9% (4/31); difference of proportion: 47.6% (95% confidence interval (CI): 26.0-69.3); odds ratio = 10.44 (95% CI: 2.82-38.65); p value (nominal) based on the Cochran-Mantel-Haenszel: <0.001)]. During the double-blind treatment period, grade 3 or higher adverse events (AEs) occurred in 35.7% (10/28) of patients with hetrombopag and 38.7% (12/31) of patients on placebo. The most common grade 3 or higher AEs were decreased neutrophil count [35.7% (10/28) versus 35.5% (11/31)] and decreased white blood cell count [17.9% (5/28) versus 19.4% (6/31)]. Serious AEs were reported in 3.6% (1/28) of patients with hetrombopag and 9.7% (3/31) of patients with placebo. Conclusion: Hetrombopag is an effective and well-tolerated alternative for managing CIT in patients with solid tumors. Trial registration: ClinicalTrials.gov identifier: NCT03976882.

Investigation of damping coefficients for elastic collision particles utilizing the acoustic frequency sampling method.

The damping coefficient serves to quantify the energy dissipation in particle collisions and constitutes a crucial parameter in discrete element simulations. Nevertheless, the factors influencing the damping coefficient remain unclear, and the damping coefficients of the majority of materials have not been precisely determined. In this investigation, the damping coefficients of eight representative particles were studied using the acoustic frequency sampling method, and the correlations between these coefficients and collision velocity, material density, and elastic modulus were analyzed. The findings indicate that damping coefficients exhibit insensitivity to velocity in strongly elastic and moderately elastic material particles. Conversely, for weakly elastic material particles, damping coefficients demonstrate an increase with rising velocity. The damping coefficient of metallic particles exhibits a linear relationship with material density and elastic modulus.

Dioxygen Reactivity of Copper(I)/Manganese(II)-Porphyrin Assemblies: Mechanistic Studies and Cooperative Activation of O2.

The oxidation of transition metals such as manganese and copper by dioxygen (O2) is of great interest to chemists and biochemists for fundamental and practical reasons. In this report, the O2 reactivities of 1:1 and 1:2 mixtures of [(TPP)MnII] (1; TPP: Tetraphenylporphyrin) and [(tmpa)CuI(MeCN)]+ (2; TMPA: Tris(2-pyridylmethyl)amine) in 2-methyltetrahydrofuran (MeTHF) are described. Variable-temperature (-110 °C to room temperature) absorption spectroscopic measurements support that, at low temperature, oxygenation of the (TPP)Mn/Cu mixtures leads to rapid formation of a cupric superoxo intermediate, [(tmpa)CuII(O2•-)]+ (3), independent of the presence of the manganese porphyrin complex (1). Complex 3 subsequently reacts with 1 to form a heterobinuclear µ-peroxo species, [(tmpa)CuII-(O22-)-MnIII(TPP)]+ (4; λmax = 443 nm), which thermally converts to a µ-oxo complex, [(tmpa)CuII-O-MnIII(TPP)]+ (5; λmax = 434 and 466 nm), confirmed by electrospray ionization mass spectrometry and nuclear magnetic resonance spectroscopy. In the 1:2 (TPP)Mn/Cu mixture, 4 is subsequently attacked by a second equivalent of 3, giving a bis-µ-peroxo species, i.e., [(tmpa)CuII-(O22-)-MnIV(TPP)-(O22-)-CuII(tmpa)]2+ (7; λmax = 420 nm and δpyrrolic = -44.90 ppm). The final decomposition product of the (TPP)Mn/Cu/O2 chemistry in MeTHF is [(TPP)MnIII(MeTHF)2]+ (6), whose X-ray structure is also presented and compared to literature analogs.

Safety and efficacy of SHR4640 combined with febuxostat for primary hyperuricemia: a multicenter, randomized, double-blind, phase II study.

BACKGROUND: To evaluate the safety, tolerability, and efficacy of SHR4640, a highly selective urate transporter-1 inhibitor, in combination with febuxostat, in patients with primary hyperuricemia. METHODS: In this randomized, double-blind, parallel-controlled phase II study, patients whose fasting serum uric acid (sUA) levels were ⩾ 480 µmol/L at screening with gout or sUA levels were ⩾ 420 µmol/L lasting for at least 3 months without gout, either with sUA levels ⩾ 540 µmol/L at screening or sUA levels ⩾ 480 µmol/L with comorbidities at screening, were enrolled. Patients were randomized (1:1:1) to receive SHR4640 10 mg plus febuxostat 80 mg, SHR4640 10 mg plus febuxostat 40 mg, and SHR4640 5 mg plus febuxostat 20 mg orally once daily. The primary end point was the incidence of treatment-emergent adverse events (TEAEs). RESULTS: A total of 93 patients were randomized and received treatment. TEAEs occurred in 55.9% of patients. The incidence of TEAEs was comparable among all the groups. Serious TEAEs occurred in one patient (1.1%), with no deaths observed. The proportion of patients who achieved the target sUA levels by week 4 was 79.3%, 96.6%, and 75.0% in the SHR4640 10 mg plus febuxostat 80 mg, SHR4640 10 mg plus febuxostat 40 mg, and SHR4640 5 mg plus febuxostat 20 mg groups, respectively. The mean percent reduction of sUA was 59.7%, 63.7%, and 41.8%, respectively. CONCLUSION: SHR4640 plus febuxostat exhibited a tolerable safety profile and substantial sUA lowering activity in patients with primary hyperuricemia. REGISTRATION: www.chinadrugtrials.org.cn; CTR 20192429.

Dose tapering to withdrawal stage and long-term efficacy and safety of hetrombopag for the treatment of immune thrombocytopenia: Results from an open-label extension study.

BACKGROUND: The efficacy of hetrombopag in Chinese patients with immune thrombocytopenia (ITP) has been demonstrated in a randomized, double-blind, placebo-controlled, multicenter, phase III trial (NCT03222843). OBJECTIVE: This study aimed to report comprehensive data on a ≤6-week dose tapering to withdrawal (Stage 3) and an additional 24-week long-term extension period (Stage 4) in this phase III trial. PATIENTS/METHODS: Patients who fulfilled the screening criteria were eligible to enter Stage 3 or 4. During Stage 3, hetrombopag was gradually tapered to withdrawal. During Stage 4, hetrombopag treatment was initiated at 2.5, 3.75, 5, or 7.5 mg once daily. The efficacy endpoints during Stage 3 or 4 and the safety profile during the entire treatment period were reported. RESULTS: Among 194 patients who entered Stage 3, 171 (88.1%) relapsed. The median time to the first relapse since the start of Stage 3 was 15.0 days (95% CI, 14.0-16.0). In Stage 4, 144 (42.5%) patients responded at ≥75% of their assessments and 254 (74.9%) patients achieved platelet count ≥30 × 109 /L at least once, which was at least twice their baseline platelet count in the hetrombopag group (n = 339). The most common adverse events were upper respiratory tract infection (53.1%), thrombocytopenia (27.1%), and urinary tract infection (21.2%) in the hetrombopag group. CONCLUSION: The majority of patients who experienced dose tapering to withdrawal experienced a relapse. Long-term treatment with hetrombopag was effective in increasing and maintaining platelet count within the desired range in Chinese adults with ITP. Hetrombopag was well tolerated.

A multicenter, randomized phase III trial of hetrombopag: a novel thrombopoietin receptor agonist for the treatment of immune thrombocytopenia.

BACKGROUND: Hetrombopag, a novel thrombopoietin receptor agonist, has been found in phase I studies to increase platelet counts and reduce bleeding risks in adults with immune thrombocytopenia (ITP). This phase III study aimed to evaluate the efficacy and safety of hetrombopag in ITP patients. METHODS: Patients who had not responded to or had relapsed after previous treatment were treated with an initial dosage of once-daily 2.5 or 5 mg hetrombopag (defined as the HETROM-2.5 or HETROM-5 group) or with matching placebo in a randomized, double-blind, 10-week treatment period. Patients who received placebo and completed 10 weeks of treatment switched to receive eltrombopag, and patients treated with hetrombopag in the double-blind period continued hetrombopag during the following open-label 14-week treatment. The primary endpoint was the proportion of responders (defined as those achieving a platelet count of ≥ 50 × 109/L) after 8 weeks of treatment. RESULTS: The primary endpoint was achieved by significantly more patients in the HETROM-2.5 (58.9%; odds ratio [OR] 25.97, 95% confidence interval [CI] 9.83-68.63; p < 0.0001) and HETROM-5 (64.3%; OR 32.81, 95% CI 12.39-86.87; p < 0.0001) group than in the Placebo group (5.9%). Hetrombopag was also superior to placebo in achieving a platelet response and in reducing the bleeding risk and use of rescue therapy throughout 8 weeks of treatment. The durable platelet response to hetrombopag was maintained throughout 24 weeks. The most common adverse events were upper respiratory tract infection (42.2%), urinary tract infection (17.1%), immune thrombocytopenic purpura (17.1%) and hematuria (15%) with 24-week hetrombopag treatment. CONCLUSIONS: In ITP patients, hetrombopag is efficacious and well tolerated with a manageable safety profile. Trial registration Clinical trials.gov NCT03222843 , registered July 19, 2017, retrospectively registered.

Using a distributed lag non-linear model to identify impact of temperature variables on haemorrhagic fever with renal syndrome in Shandong Province.

Haemorrhagic fever with renal syndrome (HFRS) is transmitted to humans mainly by rodents and this transmission could be easily influenced by meteorological factors. Given the long-term changes in climate associated with global climate change, it is important to better identify the effects of meteorological factors of HFRS in epidemic areas. Shandong province is one of the most seriously suffered provinces of HFRS in China. Daily HFRS data and meteorological data from 2007 to 2012 in Shandong province were applied. Quasi-Poisson regression with the distributed lag non-linear model was used to estimate the influences of mean temperature and Diurnal temperature range (DTR) on HFRS by sex, adjusting for the effects of relative humidity, precipitation, day-of-the-week, long-term trends and seasonality. A total of 6707 HFRS cases were reported in our study. The two peaks of HFRS were from March to June and from October to December, particularly, the latter peak in 2012. The estimated effects of mean temperature and DTR on HFRS were non-linear. The immediate and strong effect of low temperature and high DTR on HFRS was found. The lowest temperature -8.86°C at lag 0 days indicated the largest related relative risk (RRs) with the reference (14.85 °C), respectively, 1.46 (95% CI 1.11-1.90) for total cases, 1.33 (95% CI 1.00-1.78) for the males and 1.76 (95% CI 1.12-2.79) for the females. Highest DTR was associated with a higher risk on HFRS, the largest RRs (95% CI) were obtained when DTR = 15.97 °C with a reference at 8.62 °C, with 1.26 (0.96-1.64) for total cases and 1.52 (0.97-2.38) for the female at lag 0 days, 1.22 (1.05-1.41) for the male at lag 5 days. Non-linear lag effects of mean temperature and DTR on HFRS were identified and there were slight differences for different sexes.

Forecasting the Incidence of Mumps in Zibo City Based on a SARIMA Model.

This study aimed to predict the incidence of mumps using a seasonal autoregressive integrated moving average (SARIMA) model, and provide theoretical evidence for early warning prevention and control in Zibo City, Shandong Province, China. Monthly mumps data from Zibo City gathered between 2005 and 2013 were used as a training set to construct a SARIMA model, and the monthly mumps in 2014 were defined as a test set for the model. From 2005 to 2014, a total of 8722 cases of mumps were reported in Zibo City; the male-to-female ratio of cases was 1.85:1, the age group of 1-20 years old accounted for 94.05% of all reported cases, and students made up the largest proportion (65.89%). The main serious endemic areas of mumps were located in Huantai County, Linzi District, and Boshan District of Zibo City. There were two epidemic peaks from April to July and from October to January in next year. The fitted model SARIMA (0, 1, 1) (0, 1, 1)12 was established (AIC = 157.528), which has high validity and reasonability. The SARIMA model fitted dynamic changes of mumps in Zibo City well. It can be used for short-term forecasting and early warning of mumps.

Epidemiological Characteristics and Spatial-Temporal Clusters of Mumps in Shandong Province, China, 2005-2014.

Mumps presents a serious threat to public health in China. We conducted a descriptive analysis to identify the epidemiological characteristics of mumps in Shandong Province. Spatial autocorrelation and space-time scan analyses were utilized to detect spatial-temporal clusters. From 2005 to 2014, 115745 mumps cases were reported in Shandong, with an average male-to-female ratio of 1.94. Mumps occurred mostly in spring (32.17% of all reported cases) and in children aged 5 to 9 (40.79% of all reported cases). The Moran's I test was significant and local indicators of spatial autocorrelation (LISA) analysis revealed significant spatial clusters with high incidence. The results showed that the mid-west of Shandong Province and some coastal regions (Qingdao City and Weihai City) were high-risk areas, particularly in the center of the Jining City and the junction of Dongying City, Binzhou City and Zibo City. The results could assist local and national public health agencies in formulating better public health strategic planning and resource allocation.

The short-term association between meteorological factors and mumps in Jining, China.

BACKGROUND: An increasing trend of the incidence of mumps has been observed in a few developing countries in recent years, presenting a major threat to children's health. A few studies have examined the relationship between meteorological factors and mumps with inconsistent findings. METHODS: The daily data of meteorological variables and mumps from 2009 to 2013 were obtained from Jining, a temperate inland city of China. A generalized additive model was used to quantify the association between meteorological factors and mumps based on the exposure-response relationship. RESULTS: A total of 8520 mumps cases were included in this study. We found a nonlinear relationship of daily mean temperature, sunshine duration and relative humidity with mumps, with an approximately linear association for mean temperature above 4°C (excess risk (ER) for 1°C increase was 2.72%, 95% confidence interval (CI): 2.38%, 3.05% on the current day), for relative humidity above 54%, the ER for 1% increase was -1.86% (95% CI: -2.06%, -1.65%) at lag day 14; and for sunshine duration higher than 5h/d, the ER for per 1h/d increase was12.91% (95% CI: 11.38%, 14.47%) at lag day 1. While we found linear effects for daily wind speed (ER: 2.98%, 95% CI: 2.71%, 3.26% at lag day 13). CONCLUSIONS: This study suggests that meteorological factors might be important predictors of incidence of mumps, and should be considered in its control and prevention.

Adverse Events in Treating Smear-Positive Tuberculosis Patients in China.

This study aimed to estimate the adverse events (AE) rate during anti-tuberculosis treatment and to explore AE-related risk factors. New and previously treated smear-positive tuberculosis (TB) cases were enrolled from eight regions in China between April 2009 and October 2010. The AE rate was estimated, and AE risk factors during anti-TB treatment were assessed using Cox proportional models. Among 2091 Chinese subjects with anti-TB treatment, 462 (22.1%, 95% confidence interval (CI), 20.3-23.9) patients developed AE, with liver injury and gastrointestinal reactions constituting the most common AE. Specifically, 9.8% (95% CI, 8.5-11.1) and 6.3% (95% CI, 5.3-7.4) developed liver injuries and gastrointestinal reactions, respectively. We found that AE rate differed by regions, TB knowledge score, symptoms score and smoking status. Liver injuries were associated with age, sex and smoking status; gastrointestinal reactions were associated with education level and symptom score. Improving patients' knowledge on TB could reduce AE rate.