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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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The therapeutic value of arthroscopic microfracture technique in combination with platelet-rich plasma injection for knee cartilage injury
Yang Z, Wu Y, Yin K, Xiang J, Liu C, Chen W, Dai Z
American journal of translational research. 2021;13(4):2694-2701
Abstract
OBJECTIVE The purpose of this study was to analyze the efficacy of platelet-rich plasma (PRP) injection combined with arthroscopic microfracture technique for knee cartilage injury. METHODS Seventy-nine patients with knee cartilage injury were randomly divided into a control group (CG, n=39) and an observation group (OBG, n=40). Both of the groups were treated with the arthroscopic microfracture technique, and the OBG was additionally treated with PRP injection. RESULTS The VAS scores for pain in the affected area of the OBG were lower than those of the CG at 1, 3, 5, and 7 days after surgery (P < 0.05). Knee flexion, hyperextension, and rotation angles in the OBG were greater than those in the CG at 1 month after surgery (P < 0.05). IKDC scores in the OBG were lower than those in the CG at 1, 2, and 3 weeks after surgery (P < 0.05). The Tegner and Lysholm scores in the OBG were higher than those in the CG at 1, 2, and 3 months after surgery (P < 0.05). The complication rate in the OBG was 10.00%, which was lower than that of 28.21% in the CG (P < 0.05). CONCLUSION The efficacy of microfracture technique combined with PRP injection in the treatment of knee joint cartilage injury is significantly improved compared with that of microfracture technique alone, which can reduce postoperative complications and improve the range of motion and function of the knee joint.
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Low-dose PPI to prevent bleeding after ESD: A multicenter randomized controlled study
Yang L, Qi J, Chen W, Guo Q, Xie R, Zhao Z, Qin S, Liu A, Den M, Fan C, et al
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie. 2021;136:111251
Abstract
BACKGROUND Although proton pump inhibitors (PPIs) are widely used in the prevention of gastric bleeding caused by endoscopic submucosal dissection (ESD), there is no consensus on the optimal regimen for these patients. Therefore, we aim to investigate whether intermittent use of low-dose PPI is sufficient to prevent post-ESD bleeding. METHODS This multicenter, non-inferiority, randomized controlled trial was conducted at 9 hospitals in China. Consecutive eligible patients with a diagnosis of gastric mucosal lesions after ESD treatment were randomly assigned (1:1) to receive either intermittent low-dose or continuous high-dose PPIs treatment. After three days, all patients administered orally esomeprazole 40 mg once a day for 8 weeks. The primary endpoint was post-ESD bleeding within 7 days. Analysis was done according to the intention-to-treat principle with the non-inferiority margin (Δ) of 5%. RESULTS 526 consecutive patients were assessed for eligibility from 30 September 2017 to 30 July 2019, of whom 414 were randomly assigned to low-dose (n = 209) or high-dose (n = 205) esomeprazole treatment group without dropouts within7 days. The total post-ESD bleeding is occurred in 13 (6.2 %, 95 % CI 3.3-9.6) of 209 within 7 days in the intermittent low-dose group, and 12 (5.9 %, 95 % CI 2.9-9.3) of 205 in the continuous high-dose group. The absolute risk reduction (ARR) was 0.4 % (-4.2, 4.9). One month after ESD, There are 44 patients (21.1 %, 95 % CI 15.8, 26.8) and 39 patients (19.0 % 95 % CI 13.7, 24.4) in scar stage respectively in low-dose group and high-dose group (P = 0.875).The hospital costs in the low-dose PPI group was lower than high -dose group (P = 0.005). CONCLUSION The intermittent use of low-dose PPIs is sufficient to prevent post-ESD bleeding. It might be applied in clinical practice to prevent post-ESD bleeding and reduce the costs related to PPIs.
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The effect of adjunctive intravitreal conbercept at the end of diabetic vitrectomy for the prevention of post-vitrectomy hemorrhage in patients with severe proliferative diabetic retinopathy: a prospective, randomized pilot study
Jiang T, Gu J, Zhang P, Chen W, Chang Q
BMC ophthalmology. 2020;20(1):43
Abstract
BACKGROUND To investigate the effect of intravitreal conbercept (IVC) injections on the incidence of postoperative vitreous hemorrhage (VH) in eyes undergoing surgery for severe proliferative diabetic retinopathy. METHODS This was a pilot prospective, comparative, and randomized study. Thirty patients, who underwent vitrectomy for severe proliferative diabetic retinopathy, were assigned randomly to either group 1 (intravitreal conbercept [IVC] injection at the end of pars plana vitrectomy) or group 2 (no IVC injection). Postoperative follow-up was performed on the first day, first week, first month, third month, sixth month and first year after surgery. The primary outcome was the incidence of postoperative VH. Secondary outcomes were the initial time of vitreous clearing (ITVC), best-corrected visual acuity (BCVA) and central retinal thickness (CRT) after surgery. RESULTS A total of 30 eyes, from 30 patients, were included. Fifteen eyes were enrolled in the IVC group and fifteen in the control group. The incidence of early and late postoperative VH was not significantly different between the control and IVC groups. ITVC was shorter in the IVC group than that in the control group, but this was not significant (7.38 +/- 10.66 vs 13.23 +/- 17.35, P = 0.31). Final BCVA, 1 year after surgery, showed significant improvement compared to baseline in both groups. However, analysis of the BCVA at any postoperative visit after surgery showed no significant differences between the two groups. There were two cases of recurrent VH identified at 3 and 6 months after surgery in each group, requiring a second round of surgery. Foveal thickness was significantly different between the two groups at the 3-month, 6-month and 1-year follow-up visits. CONCLUSIONS In this pilot study, the effect of IVC injection in reducing the incidence of postoperative VH after diabetic vitrectomy at the end of vitrectomy was not shown. TRIAL REGISTRATION The study was registered with the Chinese Clinical Trial Registry. (Reference Number: ChiCTR1800015751).
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A randomised controlled trial of fibrinogen concentrate during scoliosis surgery
Chen W, Shen J, Zhang Y, Hu A, Liang J, Ma L, Yu X, Huang Y
Anaesthesia. 2020
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Abstract
Bleeding and blood transfusion are common after scoliosis surgery. Fibrinogen is essential for blood clot formation and depletes quickly during haemorrhage. We randomly allocated 102 children 12-18 years old having surgery for idiopathic scoliosis, 51 to intra-operative fibrinogen concentrate 30 mg.kg(-1) (maximum 2 g) and 51 to saline placebo. Fibrinogen reduced peri-operative blood loss by a median (95%CI) volume of 155 (5-320) ml, from a median (IQR [range]) of 1035 (818-1420 [400-3030]) ml to 885 (755-1155 [270-2645]) ml, p = 0.04. Seven and four children received allogeneic red blood cell transfusion after fibrinogen and placebo, respectively, p = 0.34. There were no side-effects.
PICO Summary
Population
Patients between 12 to 18 years old having surgery for idiopathic scoliosis (n= 102).
Intervention
Intraoperative fibrinogen concentrate (30 mg.kg−1, maximum 2 g), (n= 51).
Comparison
Saline placebo (n= 51).
Outcome
Fibrinogen concentrate infusion reduced median perioperative bleeding by about 155ml compared with placebo. Fibrinogen did not reduce postoperative blood transfusion or increase postoperative haemoglobin concentration.
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[Acupuncture artificial menstrual cycle method for abnormal uterine bleeding-ovulatory dysfunction (spleen deficiency syndrome)]
Zhang L, Li J, Pan S, Zhang X, Li Y, Hu S, Chen W
Zhongguo zhen jiu = Chinese acupuncture & moxibustion. 2019;39(5):489-94
Abstract
OBJECTIVE To compare the clinical efficacy between acupuncture artificial menstrual cycle method and medication artificial menstrual cycle method for abnormal uterine bleeding-ovulatory (AUB-O) dysfunction (spleen deficiency syndrome). METHODS Sixty patients were randomly assigned into an observation group and a control group, 30 cases in each one. 3 cases dropped out in the observation group and 27 cases were included into analysis; 2 cases dropped out in the control group and 28 cases were included into analysis. The patients in the observation group were treated with acupuncture artificial menstrual cycle method. The acupoints were selected according to different stages of menstrual cycle. The acupuncture was given for 30 min per treatment, once every other day; no treatment was given during menstrual period. Xuehai (SP 10), Sanyinjiao (SP 6), Taixi (KI 3), Guanyuan (CV 4), Qihai (CV 6), Zusanli (ST 36) and Zhangmen (LR 13) were selected after menstrual period. Taichong (LR 3), Hegu (LI 4), Yaoyangguan (GV 3), Geshu (BL 17), Ganshu (BL 18), Sanyinjiao (SP 6), Pishu (BL 20) were selected in ovulaton periods. Baihui (GV 20), Shenshu (BL 23), Yaoyangguan (GV 3), Geshu (BL 17), Sanyinjiao (SP 6), Zusanli (ST 36), Gongsun (SP 4) were selected before menstrual period. The patients in the control group were treated with medication artificial menstrual cycle method. Femoston (estradiol tablets/estradiol dydrogesterone tablets) was taken orally. The white tablets were estradiol (1 mg), while the gray tablets were estradiol (1 mg) and dydrogesterone (10 mg). The Femoston was taken once a day, white tablets for the first 14 days, then gray tablets for the last 14 days. The 28-day treatment was taken as one session, and one cycle menstrual was taken as one treatment course, and totally 3 courses were given in the two groups. The clinical symptom score was observed before and after treatment as well as in follow-up visit (3 months after treatment). The clinical efficacy was evaluated based on the total effective rate, the marked effective rate of main symptoms (including menstrual cycle, menstrual period, menstrual volume) and basal body temperature (BBT). RESULTS 1 in circle Compared before treatment, the clinical symptom score in the two groups was decreased after treatment and in the follow-up visit (P<0.05). Compared with the control group, the clinical symptom score after treatment as well as the difference of that before and after treatment had no significant difference in the observation group (P>0.05). Compared with the control group, the clinical symptom score in the follow-up visit as well as the difference of that between pre-treatment and follow-up visit had significant difference in the observation group (P<0.05, P<0.01). 2 in circle The total effective rate was 81.5% (22/27) in the observation group and 85.7% (24/28) in the control group, without significant difference between the two groups (P>0.05). 3 in circle After treatment, the marked effective rate of menstrual cycle, menstrual period, menstrual volume had no significant difference between the two groups (P>0.05); during the follow-up visit, the marked effective rate of menstrual cycle in the observation group was superior to that in the control group (P<0.05), but that of menstrual period and menstrual volume had no significant difference between the two groups (P>0.05). 4 in circle After treatment, the diphasic curve rate of BBT had no significant difference between the two groups (P>0.05); during the follow-up visit, the diphasic curve rate of BBT in the observation group was higher than that in the control group (P<0.05). CONCLUSION Acupuncture artificial menstrual cycle method has superior efficacy for AUB-O dysfunction (spleen deficiency syndrome), which has similar efficacy with medication artificial menstrual cycle method. Moreover, acupuncture has advantages in regulating menstrual cycle and improving ovulation, and has a longer curative effect.