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1.
Sovleplenib (HMPL-523), a novel Syk inhibitor, for patients with primary immune thrombocytopenia in China: a randomised, double-blind, placebo-controlled, phase 1b/2 study
Liu X, Zhou H, Hu Y, Yin J, Li J, Chen W, Huang R, Gong Y, Luo C, Mei H, et al
The Lancet. Haematology. 2023
Abstract
BACKGROUND Spleen tyrosine kinase (Syk) inhibitor is a treatment option for primary immune thrombocytopenia. We aimed to evaluate the safety, tolerability, pharmacokinetics, preliminary activity, and recommended phase 2 dose of sovleplenib in patients with primary immune thrombocytopenia. METHODS This randomised, double-blind, placebo-controlled, phase 1b/2 study was conducted at nine hospitals in China. Eligible patients were aged 18-75 years, had an ECOG performance score of 0-1, had primary immune thrombocytopenia for more than 6 months, and did not respond or relapsed after previous first-line treatment or had poor response or postoperative relapse after a splenectomy. Dose-escalation (100 mg, 200 mg, or 300 mg given orally once a day) and dose-expansion phases (recommended phase 2 dose) each consisted of an 8-week, double-blind, placebo-controlled period in which patients were randomly assigned (3:1) to receive sovleplenib or placebo with an interactive web response system followed by a 16-week, open-label period with sovleplenib. Patients, investigators, and the sponsor were masked to treatment allocation during the first 8 weeks. The main efficacy endpoint was the proportion of patients whose platelet count reached 30 × 10(9) platelets per L or higher and was double of the baseline at two consecutive visits during 0-8 weeks without rescue therapy. Efficacy was evaluated by intention-to-treat. This study is registered with ClinicalTrials.gov, NCT03951623. FINDINGS Between May 30, 2019, and April 22, 2021, 62 patients were assessed for eligibility and 45 (73%) were randomly assigned. Patients received at least one dose of the study drug during the 8-week double-blind period (placebo [n=11] and sovleplenib 100 mg [n=6], 200 mg [n=6], 300 mg [n=16], and 400 mg [n=6]; this group was added following the observation of no protocol-specified safety events at the previous doses). All participants were Asian; 18 (40%) of 45 were male and 27 (60%) were female. The median age was 40·0 years (IQR 33·0-50·0). Ten (29%) of 34 patients in sovleplenib groups versus five (45%) of 11 in the placebo group received concomitant anti-primary immune thrombocytopenia therapy. The recommended phase 2 dose was determined as 300 mg once a day. The proportion of patients who met the main efficacy endpoint were three (50%; 95% CI 12-88) in the 100 mg group, three (50%; 12-88) in the 200 mg group, ten (63%; 35-85) in the 300 mg group, and two (33%; 4-78) in the 400 mg group compared with one (9%; 0-41) in the placebo group. The overall response rate in the 300 mg group was 80% (16 of 20 who received continuous sovleplenib plus those who crossed over from placebo) and the durable response rate was 31% (11-59; five of 16) in the continuous sovleplenib 300 mg and 75% (19-99; three of four) crossed from placebo to sovleplenib during 0-24 weeks. During the 28-day safety evaluation period, two grade 2 or worse treatment-related treatment-emergent adverse events occurred in the sovleplenib groups (hypertriglyceridaemia and anaemia). During 0-8 weeks, the most frequent treatment-emergent adverse events were an increase in blood lactate dehydrogenase, haematuria, and urinary tract infection (seven [21%] of 34 in sovleplenib groups vs one [9%] of 11 in the placebo group); and occult blood-positive and hyperuricaemia (four [12%] vs three [27%] for each). No fatal treatment-emergent adverse events were recorded. INTERPRETATION Sovleplenib was well tolerated, and the recommended phase 2 dose showed a promising durable response in patients with primary immune thrombocytopenia, which provides evidence for future investigations. A phase 3 trial is ongoing (NCT05029635) to confirm the efficacy and safety of sovleplenib in patients with primary immune thrombocytopenia. FUNDING HUTCHMED.
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2.
An innovated elastic compression hemostasis technique for extremity excision in patients with extensive burns: A prospective clinical randomized controlled trial
Shen C, Liu X, Zhang B, Cai J, Sun T, Li D, Deng H, Yuan H
Surgery. 2023
Abstract
OBJECTIVE To introduce an innovative elastic compression hemostasis technique for extremity excision in extensively burnt patients and investigate its effectiveness. METHODS Ten patients were included and divided into 2 groups: the control group (4 patients, 12 extremities) receiving the conventional hemostasis technique and the experimental group (6 patients, 14 extremities) receiving the innovative technique. General data of the patients were collected, excision size measured, hemostasis time recorded, average blood loss per 1% total body surface area of the excised wound calculated, incidence of subcutaneous hematoma and take rate determined. RESULTS The 2 groups had no statistical difference in the baseline data. Average blood loss per 1% total body surface area of the excised wound in the upper and the lower extremities was (62.1 ± 11.5) mL and (35.6 ± 11.0) mL in the experimental group, significantly less than (94.3 ± 6.9) mL and (82.3 ± 6.2) mL in the control group; a reduction of 34.1% and 56.8% respectively. Hemostasis time in the upper and the lower extremities were (5.0 ± 0.7) min/1% total body surface area and (2.6 ± 0.3) min/1% total body surface area, respectively, in the experimental group, significantly less than (7.4 ± 0.6) min/1% total body surface area and (4.0 ± 0.9) min/1% total body surface area in the control group; a reduction of 31.8% and 34.9% respectively. The incidences of subcutaneous hematoma were 7.1% and 8.3%, and the take rate (85.9 ± 6.0)% and (86.5 ± 4.8)% in the experimental and the control group, respectively, with no statistically significant differences. CONCLUSION The innovative elastic compression hemostasis technique is a reliable new method that significantly reduces blood loss during extremity excision in patients with extensive burns and is worth wider understanding and application.
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3.
A multicenter, prospective, randomized clinical study to evaluate the efficacy and safety of fibrin sealant as an adjunct to sutured dural repair
Yu R, Zhu W, Kocharian R, Ilie B, Wang Z, Kang D, Zhao G, Yang H, Shu K, Liu X, et al
Chinese medical journal. 2022;135(20):2506-2508
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4.
A multicenter, randomized phase III trial of hetrombopag: a novel thrombopoietin receptor agonist for the treatment of immune thrombocytopenia
Mei H, Liu X, Li Y, Zhou H, Feng Y, Gao G, Cheng P, Huang R, Yang L, Hu J, et al
Journal of hematology & oncology. 2021;14(1):37
Abstract
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 × 10(9)/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.
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5.
Early intravenous tranexamic acid intervention reduces post-traumatic hidden blood loss in elderly patients with intertrochanteric fracture: a randomized controlled trial
Ma H, Wang H, Long X, Xu Z, Chen X, Li M, He T, Wang W, Liu L, Liu X
Journal of orthopaedic surgery and research. 2021;16(1):106
Abstract
PURPOSE Elderly patients with intertrochanteric fractures exhibit post-traumatic hidden blood loss (HBL). This study aimed to evaluate the efficacy and safety of reducing post-traumatic HBL via early intravenous (IV) tranexamic acid (TXA) intervention in elderly patients with intertrochanteric fracture. METHODS A prospective randomized controlled study was conducted with 125 patients (age ≥ 65 years, injury time ≤ 6 h) who presented with intertrochanteric fracture from September 2018 and September 2019. Patients in the TXA group (n = 63) received 1 g of IV TXA at admission, whereas those in the normal saline (NS) group (n = 62) received an equal volume of saline. Hemoglobin (Hgb) and hematocrit (Hct) were recorded at post-traumatic admission (PTA) and on post-traumatic days (PTDs) 1-3. HBL was calculated using the Gross formula. Lower extremity venous ultrasound was performed to detect venous thrombosis. RESULTS Hgb on PTDs 2 and 3 was statistically higher in the TXA group than in the NS group. Hct and HBL on PTDs 1-3 were significantly less in the TXA group compared to the NS group. Preoperative transfusion rate was significantly lower in the TXA group compared with the NS group. There was no difference between the two groups with regard to the rates of complications. CONCLUSION Early IV TXA intervention could reduce post-traumatic HBL and pre-operative transfusion rate in elderly patients with intertrochanteric fractures without increasing the risk of venous thrombosis.
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6.
Efficacy and safety of eltrombopag in Chinese patients with chronic immune thrombocytopenia: stage 2 results from a multicenter phase III study
Liu X, Hou M, Li J, Jin J, Huang M, Yu Z, Xu X, Zhang X, Yang R
Platelets. 2020;:1-7
Abstract
This phase III, randomized, placebo-controlled study conducted in three stages (6-week, randomized, placebo-controlled stage 1; 24-week, open-label stage 2; and continuous extension stage 3) assessed the long-term efficacy and safety of eltrombopag use in Chinese patients with chronic immune thrombocytopenia (ITP). This article presents the results from stage 2. Overall, 150 patients (placebo-eltrombopag [P-E], 50; eltrombopag-eltrombopag [E-E], 100) received open-label eltrombopag. The median platelet count was maintained between 41 × 10(9)/L and 80 × 10(9)/L. Most patients in both groups (P-E, 90.0%; E-E, 81.8%) achieved platelet counts ≥30 × 10(9)/L and ≥2 times the baseline platelet count at least once with eltrombopag treatment. Overall, 32% of patients achieved platelet counts ≥50 × 10(9)/L in ≥75% of platelet count assessments. Both groups showed a decreased tendency to infrequent bleeding and clinically significant bleeding events during stage 2 compared with baseline. Among patients who received ≥1 ITP medication at baseline, 70.4% in the P-E group and 40.8% in the E-E group reduced or permanently stopped ≥1 of their ITP medications. The stage 2 results further demonstrated a sustainable long-term efficacy and good tolerability of eltrombopag with a favorable benefit-risk ratio in Chinese chronic ITP patients. Trial registration: Clinicaltrials.gov NCT01762761. Registered 8 January 2013, https://clinicaltrials.gov/ct2/show/NCT01762761.
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7.
Internal Iliac Artery Balloon Occlusion for Placenta Previa and Suspected Placenta Accreta: A Randomized Controlled Trial
Chen M, Liu X, You Y, Wang X, Li T, Luo H, Qu H, Xu L
Obstet Gynecol. 2020
Abstract
OBJECTIVE To investigate the effect of intraoperative balloon occlusion of the internal iliac arteries in women with placenta previa and antenatally diagnosed placenta accreta. METHODS In this single-center, randomized controlled trial, women with placenta previa and antenatally suspected placenta accreta were randomly assigned to either the balloon occlusion group or to the control group. The perioperative management approach was similar for both groups, other than preoperative balloon catheter placement and intraoperative occlusion of bilateral internal iliac arteries. The primary outcome was the number of packed red blood cell (RBC) units transfused. With a two-sided alpha of 0.05 and a power of 0.8, a sample size of 48 women per group was calculated to detect a mean reduction of 2 units packed RBCs transfused with an expected SD of 3.5. RESULTS From August 2017 to July 2018, we randomized 50 eligible women to the balloon group and 50 to the control group. Demographic, obstetric, and placental imaging characteristics were similar between groups. The number of packed RBC units transfused was not significantly different between groups (5.3+/-5.3 in the occlusion group vs 4.7+/-5.4 in the control group, P=.54). Hospitalization costs and incidence of postoperative fever were significantly higher in the balloon group. No significant differences were found in other outcomes. CONCLUSION Intraoperative balloon occlusion of the internal iliac arteries did not reduce the number of packed RBC units transfused in women with placenta previa and antenatally suspected placenta accreta. CLINICAL TRIAL REGISTRATION Chinese Clinical Trial Registry, ChiCTR-IOR-17012244.
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A new nomogram for individualized prediction of the probability of hemorrhagic transformation after intravenous thrombolysis for ischemic stroke patients
Wu Y, Chen H, Liu X, Cai X, Kong Y, Wang H, Zhou Y, Zhu J, Zhang L, Fang Q, et al
BMC neurology. 2020;20(1):426
Abstract
BACKGROUND A reliable scoring tool to detect the risk of intracerebral hemorrhage (ICH) after intravenous thrombolysis for ischemic stroke is warranted. The present study was designed to develop and validate a new nomogram for individualized prediction of the probability of hemorrhagic transformation (HT) in patients treated with intravenous (IV) recombinant tissue plasminogen activator (rt-PA). METHODS We enrolled patients who suffered from acute ischemic stroke (AIS) with IV rt-PA treatment in our emergency green channel between August 2016 and July 2018. The main outcome was defined as any type of intracerebral hemorrhage according to the European Cooperative Acute Stroke Study II (ECASS II). All patients were randomly divided into two cohorts: the primary cohort and the validation cohort. On the basis of multivariate logistic model, the predictive nomogram was generated. The performance of the nomogram was evaluated by Harrell's concordance index (C-index) and calibration plot. RESULTS A total of 194 patients with complete data were enrolled, of whom 131 comprised the primary cohort and 63 comprised the validation cohort, with HT rate 12.2, 9.5% respectively. The score of chronic disease scale (CDS), the global burden of cerebral small vascular disease (CSVD), National Institutes of Health Stroke Scale (NIHSS) score ≥ 13, and onset-to-treatment time (OTT) ≥ 180 were detected important determinants of ICH and included to construct the nomogram. The nomogram derived from the primary cohort for HT had C- Statistics of 0.9562 and the calibration plot revealed generally fit in predicting the risk of HT. Furthermore, we made a comparison between our new nomogram and several other risk-assessed scales for HT with receiver operating characteristic (ROC) curve analysis, and the results showed the nomogram model gave an area under curve of 0.9562 (95%CI, 0.9221-0.9904, P < 0.01) greater than HAT (Hemorrhage After Thrombolysis), SEDAN (blood Sugar, Early infarct and hyper Dense cerebral artery sign on non-contrast computed tomography, Age, and NIHSS) and SPAN-100 (Stroke Prognostication using Age and NIHSS) scores. CONCLUSIONS This proposed nomogram based on the score of CDS, the global burden of CSVD, NIHSS score ≥ 13, and OTT ≥ 180 gives rise to a more accurate and more comprehensive prediction for HT in patients with ischemic stroke receiving IV rt-PA treatment.
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9.
Safety and efficacy of herbal medicine for acute intracerebral hemorrhage (CRRICH): a multicentre randomised controlled trial
Zeng L, Tang G, Wang J, Zhong J, Xia Z, Li J, Chen G, Zhang Y, Luo S, Huang G, et al
BMJ open. 2019;9(5):e024932
Abstract
OBJECTIVE To evaluate the safety and efficacy of removing blood stasis (RBS) herbal medicine for the treatment of acute intracerebral haemorrhage (AICH) within a 6-hour time window. STUDY DESIGN A randomised, multicentre, double-blind, placebo-controlled study performed in 14 hospitals in China. PARTICIPANTS AND INTERVENTIONS Patients with AICH were randomly assigned to receive a placebo, the ICH-1 (Intracerebral Haemorrhage) formula (eight herbs, including the RBS herbs hirudo and tabanus) or the ICH-2 formula (six herbs without the RBS herbs hirudo and tabanus) within 6 hours of ICH onset. OUTCOMES The primary safety outcome was the incidence of haematoma enlargement at 24 hours and at 10 days after treatment. The secondary outcome was the incidence of poor prognosis (mortality or modified Rankin Scale score ≥5) assessed at 90 days after symptom onset. RESULTS A total of 324 subjects were randomised between October 2013 and May 2016: 105 patients received placebo; 108 patients received the ICH-1 formula; and 111 patients received the ICH-2 formula. The incidence of haematoma enlargement at 24 hours was 7.8% in the placebo group, 12.3% in the ICH-1 group and 7.5% in the ICH-2 group; the incidence of haematoma enlargement on day 10 was 1.1% in the placebo group, 1.1% in the ICH-1 group, and 3.1% in the ICH-2 group, with no significant differences among the groups (P>0.05). The mortality rates were 3.8% in the placebo group, 2.8% in the ICH-1 group, and 0.9% in the ICH-2 group; the incidences of poor prognosis were 7.1% in the placebo group, 6.0% in the ICH-1 group and 4.8% in the ICH-2 group at 3 months, with no significant differences among the groups (p>0.05). However, the overall frequency of treatment-emergent adverse events in the ICH-1 group (12.1%) was higher among the three groups (5.8% and 2.8%, respectively, p<0.05). All three cases of serious adverse events were in the ICH-1 group. CONCLUSIONS Ultra-early administration of ICH-1 formula for AICH patients did not exert significant beneficial effects on clinical outcomes but increased the risk of bleeding, which probably resulted from the inclusion of RBS herbal medicines in ICH-1. TRIALREGISTRATION NUMBER NCT01918722.
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10.
Intra-articular injections of platelet-rich plasma, hyaluronic acid or corticosteroids for knee osteoarthritis : A prospective randomized controlled study
Huang Y, Liu X, Xu X, Liu J
Der Orthopade. 2019
Abstract
BACKGROUND Knee osteoarthritis (KOA) is a degenerative joint disease leading to pain and disability for which no curative treatment exists. Intra-articular (IA) therapies are part of this multimodal approach and are approved by the Food and Drug Administration (FDA) and European Medicines Agency (EMA). Platelet-rich plasma (PRP), hyaluronic acid (HA), and corticosteroids (CS) have been increasingly used in recent years to treat KOA. PURPOSE To determine whether IA-PRP was superior to IA-HA or IA-CS administration routes in these patients. MATERIAL AND METHODS In this trial the patients were randomized to IA-HA (2ml/week, for 3 weeks), IA-CS (1ml) or IA-PRP (3 times, 4ml, every 3 weeks) groups. The outcome was assessed using the Western Ontario and McMaster Universities (WOMAC) score prior to the first injection and then at 3, 6, 9 and 12 months. Pain was evaluated by a visual analogue scale (VAS) prior to treatment and after 12 months. RESULTS In this study 120 patients were randomized into 3 groups. There was a significant improvement in all scores (WOMAC, VAS) in each group compared to the pretreatment values (P< 0.05). The mean WOMAC scores for the IA-HA group from pretreatment to 3, 6, 9, and 12 months were 47.23+/- 5.37, 25.02+/- 4.98, 26.38+/- 5.20, 27.86+/- 4.34, and 30.64+/- 8.36, respectively. Similar improvements were noted in the IA-CS and IA-PRP groups. There were no significant differences in the WOMAC scores between the 3 groups 3 months after treatment (P> 0.05) but IA-PRP showed significantly lower scores 6, 9 and 12 months after treatment (P< 0.05). CONCLUSION Intra-articular PRP injections into the knee for symptomatic early stages of KOA are a valid treatment option. The clinical efficacy of IA-PRP is comparable to that of the IA-HA and IA-CS forms after 3 months and the long-term efficacy of IA PRP is superior to IA-HA and IA-CS.