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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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Prevention of delayed post-polypectomy bleeding by prophylactic clipping after endoscopic colorectal polypectomy: a meta-analysis
Yu Z, Albéniz E, Hu J, Li P, Li Q, Hu Y, Chen J, Wang J
International journal of colorectal disease. 2022
Abstract
PURPOSE This meta-analysis aims to investigate the role of prophylactic clipping after endoscopic colorectal polypectomy or endoscopic mucosal resection (EMR) in prevention of delayed bleeding (DB) following polypectomy. METHODS We searched the PubMed, Embase, and Cochrane Library databases for randomized controlled trials comparing the effect of prophylactic clipping versus no clipping on DB since inception to 22nd April 2022. We then performed a meta-analysis using a random-effects model. RESULTS We included 8 studies with 5648 patients and 10,436 lesions. Prophylactic clipping did not reduce the overall risk of DB compared with no clipping (1.54% vs 2.05%; Log RR, -0.29; 95% confidence interval [CI], -0.59, 0.01; P = 0.06). In subgroup analyses, clipping significantly reduced DB rate in polyps ≥ 2 cm (Log RR, -0.63; 95% CI, -1.08, -0.18; P = 0.01), in non-pedunculated polyps (Log RR, -0.63; 95% CI, -1.01, -0.24; P = 0.00), and in large (≥ 2 cm) proximal polyps (Log RR, -0.81; 95% CI, -1.56, 0.05; P = 0.04), but not in polyps < 2 cm (Log RR, 0.01; 95% CI, -.40, 0.42; P = 0.95). CONCLUSION Prophylactic clipping does not prevent post-polypectomy bleeding after all EMR and should not be performed as a routine practice. Although prophylactic clipping may reduce DB rate following resection of large proximal polyps and non-pedunculated polyps, more high-quality studies are needed to determine the effects of factors such as polyp location, polyp morphology, antithrombotic drug use and complete or partial closure on the effectiveness of prophylactic clipping.
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Comparative efficacy of platelet-rich plasma applied in myringoplasty: A systematic review and meta-analysis
Huang J, Shi Y, Wu L, Lv C, Hu Y, Shen Y
PloS one. 2021;16(1):e0245968
Abstract
BACKGROUND Tympanic membrane (TM) perforation is quite common in the clinical setting. Chronic TM perforations require surgical treatments such as myringoplasty. Currently, platelet-rich plasma (PRP) is a novel, effective substance that is increasingly utilized for TM perforation repair. This study aims to evaluate the effectiveness of PRP in the application of TM perforation repair. METHODS A systematic search was conducted to screen the Medline, Embase, Cochrane, Scopus and Web of Science databases up to July 2020. Studies were identified in accordance with the selection criteria by two coauthors independently. Data regarding the healing and hearing outcomes were pooled and analyzed via Review Manager version 5.3 and STATA version 12.0 software. Odds ratio (OR) was utilized to compare the closure rate. Furthermore, the results of hearing improvements and incidence of complications were also compared to evaluate the effectiveness of PRP. RESULTS A total of eight studies with 455 participants were eligible according to the selection criteria. Compared to conventional surgery, the OR of closure was 2.70 (95% CI: 1.27 to 5.76, P = 0.01, I2 = 0%) in randomized controlled trial (RCT) subgroup and 6.18 (95% CI: 2.22 to 17.25, P = 0.0005, I2 = 0) in non-RCT subgroup. The overall OR of closure was 3.69 (95% CI: 2.02 to 6.74, P<0.0001, I2 = 0%), suggesting a significant effect on the healing of TM perforation. Between preoperative and postoperative hearing results, there is no statistical difference between the PRP and the control groups. Additionally, the use of PRP resulted in a lower incidence of complication than the use of conventional approaches. CONCLUSION The application of PRP during the TM surgeries can enhance the closure rate, provide similar hearing improvements and decrease the incidence of postoperative complications. Given these advantages, PRP can be considered an effective treatment for TM regeneration.
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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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Effect of Convalescent Plasma Therapy on Time to Clinical Improvement in Patients With Severe and Life-threatening COVID-19: A Randomized Clinical Trial
Li L, Zhang W, Hu Y, Tong X, Zheng S, Yang J, Kong Y, Ren L, Wei Q, Mei H, et al
Jama. 2020
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Abstract
Importance: Convalescent plasma is a potential therapeutic option for patients with coronavirus disease 2019 (COVID-19), but further data from randomized clinical trials are needed. Objective: To evaluate the efficacy and adverse effects of convalescent plasma therapy for patients with COVID-19. Design, Setting, and Participants: Open-label, multicenter, randomized clinical trial performed in 7 medical centers in Wuhan, China, from February 14, 2020, to April 1, 2020, with final follow-up April 28, 2020. The trial included 103 participants with laboratory-confirmed COVID-19 that was severe (respiratory distress and/or hypoxemia) or life-threatening (shock, organ failure, or requiring mechanical ventilation). The trial was terminated early after 103 of a planned 200 patients were enrolled. Intervention: Convalescent plasma in addition to standard treatment (n = 52) vs standard treatment alone (control) (n = 51), stratified by disease severity. Main Outcomes and Measures: Primary outcome was time to clinical improvement within 28 days, defined as patient discharged alive or reduction of 2 points on a 6-point disease severity scale (ranging from 1 [discharge] to 6 [death]). Secondary outcomes included 28-day mortality, time to discharge, and the rate of viral polymerase chain reaction (PCR) results turned from positive at baseline to negative at up to 72 hours. Results: Of 103 patients who were randomized (median age, 70 years; 60 [58.3%] male), 101 (98.1%) completed the trial. Clinical improvement occurred within 28 days in 51.9% (27/52) of the convalescent plasma group vs 43.1% (22/51) in the control group (difference, 8.8% [95% CI, -10.4% to 28.0%]; hazard ratio [HR], 1.40 [95% CI, 0.79-2.49]; P = .26). Among those with severe disease, the primary outcome occurred in 91.3% (21/23) of the convalescent plasma group vs 68.2% (15/22) of the control group (HR, 2.15 [95% CI, 1.07-4.32]; P = .03); among those with life-threatening disease the primary outcome occurred in 20.7% (6/29) of the convalescent plasma group vs 24.1% (7/29) of the control group (HR, 0.88 [95% CI, 0.30-2.63]; P = .83) (P for interaction = .17). There was no significant difference in 28-day mortality (15.7% vs 24.0%; OR, 0.65 [95% CI, 0.29-1.46]; P = .30) or time from randomization to discharge (51.0% vs 36.0% discharged by day 28; HR, 1.61 [95% CI, 0.88-2.93]; P = .12). Convalescent plasma treatment was associated with a negative conversion rate of viral PCR at 72 hours in 87.2% of the convalescent plasma group vs 37.5% of the control group (OR, 11.39 [95% CI, 3.91-33.18]; P < .001). Two patients in the convalescent plasma group experienced adverse events within hours after transfusion that improved with supportive care. Conclusion and Relevance: Among patients with severe or life-threatening COVID-19, convalescent plasma therapy added to standard treatment, compared with standard treatment alone, did not result in a statistically significant improvement in time to clinical improvement within 28 days. Interpretation is limited by early termination of the trial, which may have been underpowered to detect a clinically important difference. Trial Registration: Chinese Clinical Trial Registry: ChiCTR2000029757.
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Early coagulation tests predict risk stratification and prognosis of COVID-19
Luo L, Xu M, Du M, Kou H, Liao D, Cheng Z, Mei H, Hu Y
Aging. 2020;12
Abstract
The ongoing outbreak of Coronavirus Disease 2019 (COVID-19) is hitting the world hard, but the relationship between coagulation disorders and COVID-19 is still not clear. This study aimed to explore whether early coagulation tests can predict risk stratification and prognosis. PubMed, Web of Science, Cochrane Library, and Scopus were searched electronically for relevant research studies published up to March 24, 2020, producing 24 articles for the final inclusion. The pooled standard mean difference (SMD) of coagulation parameters at admission were calculated to determine severe and composite endpoint conditions (ICU or death) in COVID-19 patients. Meta-analyses revealed that platelet count was not statistically related to disease severity and composite endpoint; elevated D-dimer correlated positively with disease severity (SMD 0.787 (0.277-1.298), P= 0.003, I(2)= 96.7%) but had no significant statistical relationship with composite endpoints. Similarly, patients with prolonged prothrombin time (PT) had an increased risk of ICU and increased risk of death (SMD 1.338 (0.551-2.125), P = 0.001, I(2) = 92.7%). Besides, increased fibrin degradation products (FDP) and decreased antithrombin might also mean the disease is worsening. Therefore, early coagulation tests followed by dynamic monitoring is useful for recognizing coagulation disorders accompanied by COVID-19 and guiding timely therapy to improve prognosis.
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Efficacy and safety of tranexamic acid in total hip replacement: A PRISMA-compliant meta-analysis of 25 randomized controlled trials
Zhu J, Zhu Y, Lei P, Zeng M., Su W, Hu Y
Medicine. 2017;96((52)):e9552.
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Abstract
BACKGROUND Hip osteoarthritis is one of the most prevalent musculoskeletal degenerative diseases in elderly. Total hip arthroplasty (THA) is the most effective surgical treatment for end stage hip osteoarthritis. Tranexamic acid (TA) is a potent drug to reduce surgical blood loss in surgery, therefore, as a potential drug for application in THA. OBJECTIVES To identify the combined efficacy of TA administration in THA. A meta-analysis including 25 randomized controlled trials was conducted for generating synthesized effects. METHODS This meta-analysis followed the Preferred Reporting Items for Systematic reviews and Meta-Analysis (PRISMA) guidelines for reporting systematic reviews and meta-analysis. A total of 25 Randomized controlled trials (RCTs) were included for meta-analysis. RESULTS The pooled results illustrated that total blood loss, intraoperative blood loss, postoperative blood loss, hemoglobin drop, transfusion rate, and average hospital stay were significantly lower than controls (standardized mean difference or odds ratio (OR) (95%CI): -0.87, (-1.13,-0.61), -0.68, (-0.96,-0.39), -1.41, (-2.24,-0.59), -1.11, (-1.63,-0.58), 0.28, (0.20,-0.38), -0.17, (-0.49,0.14), P < .05, respectively). Moreover, TA acts efficiently without increasing risk of thromboembolic events with OR = 1.14, 95%CI = 0.50-2.62, P = .75. Subgroup analysis indicated no statistically significant differences between a higher dose of topical TA (≥2 g or 15 mg/kg) or a lower dose (<2 g or 15 mg/kg). CONCLUSION The findings indicated that TA is clinically effective and safe in patients receiving total hip arthroplasty.
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Intravenous immunoglobulin treatment for repeated IVF/ICSI failure and unexplained infertility: a systematic review and a meta-analysis
Li J, Chen Y, Liu C, Hu Y, Li L
American Journal of Reproductive Immunology. 2013;70((6):):434-47.
Abstract
Intravenous immunoglobulin (IVIG) has been introduced empirically into IVF/ICSI programs with the hopes of improving in vitro fertilization (IVF) success. However, the effects of IVIG have been inconsistent. We investigated the effects of IVIG on hard outcomes, including implantation rate, clinical pregnancy rate, live birth rate, miscarriage rate, and live birth rate per embryo transferred. The PubMed, EMBASE, and CNKI databases were searched up to June of 2013 and 10 studies were included. Case-controlled studies comparing IVIG with placebo in IVF/ICSI women and/or unexplained infertility were included. Using fixed and random effects models, the pooled risk ratios (RR) with 95% confidence intervals (CIs) were calculated. The use of IVIG was significantly associated with a higher implantation rate and RR was 2.708 (95%CI: 1.302-5.629) compared with the placebo. The clinical pregnancy rate and the live birth rate were significantly increased in patients randomized to IVIG; RR was 1.475 (95%CI: 1.191-1.825) for the clinical pregnancy rate and RR was 1.616 (95%CI: 1.243-2.101) for the live birth rate. Moreover, the miscarriage rate was significantly less in patients randomized to IVIG (0.352, 95%CI: 0.168-0.738), but the live birthrate per embryo transferred was not (2.893; 95%CI: 0.810-10.331) less. Our results strongly support that IVIG is a useful treatment option for women undergoing repeated IVF failure. 2013 John Wiley & Sons Ltd.