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Eptacog beta efficacy and safety in the treatment and control of bleeding in paediatric subjects (<12 years) with haemophilia A or B with inhibitors
Pipe SW, Hermans C, Chitlur M, Carcao M, Castaman G, Davis JA, Ducore J, Dunn AL, Escobar M, Journeycake J, et al
Haemophilia : the official journal of the World Federation of Hemophilia. 2022
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Abstract
INTRODUCTION Eptacog beta is a new recombinant activated human factor VII bypassing agent approved in the United States for the treatment and control of bleeding in patients with haemophilia A or B with inhibitors 12 years of age or older. AIM: To prospectively assess in a phase 3 clinical trial (PERSEPT 2) eptacog beta efficacy and safety for treatment of bleeding in children <12 years of age with haemophilia A or B with inhibitors. METHODS Using a randomised crossover design, subjects received initial doses of 75 or 225 μg/kg eptacog beta followed by 75 μg/kg dosing at predefined intervals (as determined by clinical response) to treat bleeding episodes (BEs). Treatment success criteria included a haemostasis evaluation of 'excellent' or 'good' without use of additional eptacog beta, alternative haemostatic agent or blood product, and no increase in pain following the first 'excellent' or 'good' assessment. RESULTS Treatment success proportions in 25 subjects (1-11 years) who experienced 546 mild or moderate BEs were 65% in the 75 μg/kg initial dose regimen (IDR) and 60% in the 225 μg/kg IDR 12 h following initial eptacog beta infusion. By 24 h, the treatment success proportions were 97% for the 75 μg/kg IDR and 98% for the 225 μg/kg IDR. No thrombotic events, allergic reactions, neutralising antibodies or treatment-related adverse events were reported. CONCLUSION Both 75 and 225 μg/kg eptacog beta IDRs provided safe and effective treatment and control of bleeding in children <12 years of age.
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Can intraoperative suturing reduce the incidence of posttonsillectomy hemorrhage? A systematic review and meta-analysis
Li B, Wang M, Wang Y, Zhou L
Laryngoscope investigative otolaryngology. 2022;7(4):1206-1216
Abstract
OBJECTIVE This study was to compare tonsillectomy with intraoperative suturing (TIS) and tonsillectomy without intraoperative suturing (TsIS) in preventing postoperative tonsillectomy hemorrhage (PTH). METHODS The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines was followed. Articles compare TIS and TsIS in preventing PTH were included. The quality of eligible studies was assessed with the Newcastle-Ottawa Scale (NOS) by two independent investigators. Random effect models were used to determine odds ratio (OR) with 95% CIs. RESULTS A total of 15 studies were analyzed. The pooled results showed the PTH rate was lower in the TIS group (OR = 0.64; 95% CI, 0.47-0.88). The TIS group had a lower primary and secondary PTH rate than the TsIS group with OR values of 0.44 (95% CI, 0.30-0.64) and 0.70 (95% CI, 0.54-0.90), respectively. However, suturing did not show an advantage in reducing the risk of returning to the operation room for hemostasis (OR = 0.57; 95% CI, 0.13-2.47). Adults might benefit from the intraoperative suturing procedure (OR = 0.31; 95% CI, 0.16-0.60). Patients with more than three stitches on each side had a lower PTH rate (OR: 0.44; 95% CI, 0.32-0.60). Suturing the tonsillar fossa and pillars simultaneously could reduce the PTH rate (OR = 0.47; 95% CI, 0.34-0.64). CONCLUSIONS Intraoperative suturing is a good strategy for preventing PTH. More multicenter randomized controlled studies should be conducted to demonstrate the efficacy of this procedure. LEVEL OF EVIDENCE 5.
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Efficacy and safety of darbepoetin alfa injection replacing epoetin alfa injection for the treatment of renal anemia in Chinese hemodialysis patients: A randomized, open-label, parallel-group, noninferiority phase III trial
Liu B, Chen N, Zhao J, Yin A, Wu X, Xing C, Jiang G, Fu J, Wang M, Wang R, et al
Chronic diseases and translational medicine. 2022;8(2):134-144
Abstract
BACKGROUND This study was to explore the clinical efficacy and safety of darbepoetin alfa injection replacing epoetin alfa injection (recombinant human erythropoietin injection, rHuEPO) for the treatment of anemia associated with chronic kidney failure in Chinese patients undergoing hemodialysis. METHOD This study was a multicenter, randomized, open-label, intergroup parallel control phase III noninferiority trial from April 19, 2013 to September 9, 2014 at 25 sites. In this study, the members of the darbepoetin alfa group underwent intravenous administration once per week or once every two weeks. The members of the control drug epoetin alfa group underwent intravenous administration two or three times per week. All subjects underwent epoetin alfa administration during the 8-week baseline period. After that, subjects were randomly assigned to the darbepoetin alfa group or epoetin alfa group. The noninferiority in the changes of the average Hb concentrations from the baseline to the end of the evaluation period (noninferiority threshold: -1.0 g/dl) was tested between the two treatments. The time-dependent hemoglobin (Hb) concentration and the maintenance rate of the target Hb concentration (the proportion of subjects with Hb concentrations between 10.0 and 12.0 g/dl) were also evaluated. Iron metabolism, including changes in the serum iron, total iron-binding capacity, ferritin, transferrin saturation, and comparisons of the dose adjustments between the two groups during the treatment period were analyzed further. Adverse events (AEs) were also observed and compared, and the safety was analyzed between the two treatment groups. The conversion rate switching from epoetin alfa to darbepoetin alfa was also discussed. SAS® software version 9.2 was used to perform all statistical analyses. Descriptive statistics were used for all efficacy, safety, and demographic variable analyses, including for the primary efficacy indicators. RESULTS Four hundred and sixty-six patients were enrolled in this study, and ultimately 384 cases were analyzed for safety, including 267 cases in the darbepoetin alfa group and 117 cases in the epoetin alfa group. There were 211 cases in the per-protocol set, including 152 cases in the darbepoetin alfa group and 59 cases in the epoetin alfa group. The changes in the average Hb concentrations from the baseline to the end of the evaluation period were -0.07 and -0.15 g/dl in the darbepoetin alfa group and epoetin alfa group respectively. The difference between the two groups was 0.08 g/dl (95% confidence interval [CI]: -0.22 to 0.39), and the lower limit of the 95% CI was -0.22 > -1.0 g/dl. The average Hb concentrations of the two groups were 10.88-11.43 g/dl (darbepoetin alfa) and 10.91-11.38 g/dl (epoetin alfa) during the study period of Weeks 0-28, with the maintenance rates of the target Hb concentration ranging within 71%-87% and 78%-95% in the darbepoetin alfa group and epoetin alfa group respectively. During the period of comparison between the two groups, the incidence of AEs in the darbepoetin alfa group was 61.42%, while in the epoetin alfa group it was 56.41%. All of the adverse events and reactions in the study were those commonly associated with hemodialysis. CONCLUSION The overall efficacy and safety of darbepoetin alfa for the treatment of Chinese renal anemia patients undergoing hemodialysis are consistent with those of epoetin alfa.
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Darbepoetin alfa injection versus epoetin alfa injection for treating anemia of Chinese hemodialysis patients with chronic kidney failure: A randomized, open-label, parallel-group, non-inferiority Phase III trail
Chen N, Xing C, Niu J, Liu B, Fu J, Zhao J, Ni Z, Wang M, Liu W, Zhao J, et al
Chronic diseases and translational medicine. 2022;8(1):59-70
Abstract
BACKGROUND Erythropoietin is a glycoprotein that mainly regulates erythropoiesis. In patients with chronic renal failure with anemia, darbepoetin alfa can stimulate erythropoiesis, correct anemia, and maintain hemoglobin levels. This study was designed to demonstrate the efficacy and safety of darbepoetin alfa injections as being not inferior to epoetin alfa injections (Recombinant Human Erythropoietin injection, rHuEPO) when maintaining hemoglobin (Hb) levels within the target range (10.0-12.0 g/dL) for the treatment of renal anemia. METHODS Ninety-five patients were enrolled in this study from April 15, 2013 to April 10, 2014 at 25 sites. In this study, patients (n = 95) aged 18-70 years were randomized into a once per week intravenous darbepoetin alfa group (n = 56) and a twice or three times per week intravenous epoetin alfa group (n = 39) for 28 weeks, who had anemia with hemoglobin levels between 6 g/dL and 10 g/dL due to chronic kidney disease (CKD) and were undergoing hemodialysis or hemofiltration with ESA-naive (erythropoiesis stimulating agent-naive). The primary efficacy profile was the mean Hb level (the non-inferiority margin was -1.0 g/dL, week 21-28); the secondary efficacy profiles were the Hb increase rate (week 0-4), the target Hb achievement cumulative rate and time, the change trends of the Hb levels, and the target Hb maintenance ratio. Adverse events (AEs) were observed and compared, and the efficacy and safety were analyzed between the two treatment groups. Additionally, the frequencies of dose adjustments between the darbepoetin alfa and epoetin alfa groups were compared during the treatment period. SAS® software version 9.2 was used to perform all statistical analyses. Descriptive statistics were used for all efficacy, safety, and demographic variable analyses, including for the primary efficacy indicators. RESULTS The mean Hb level was 11.3 g/dL in the darbepoetin alfa group and 10.7 g/dL in the epoetin alfa group, respectively; the difference of the lower limits of the 95% confidence intervals (CI) between the two groups was 0.1 g/dL (>-1.0 g/dL), and non-inferiority was proven; the Hb levels started to increase in the first four weeks at a similar increase rate; no obvious differences were observed between the groups in the target Hb achievement cumulative rates, and the Hb levels as well as the target Hb level maintenance rate changed over time. The incidence of AEs was 62.5% in the darbepoetin alfa group and 76.9% in the epoetin alfa group. All the adverse events observed in the study were those commonly associated with hemodialysis. CONCLUSION Darbepoetin alfa intravenously once per week can effectively increase Hb levels and maintain the target Hb levels well, which makes it not inferior to epoetin alfa intravenously twice or three times per week. Darbepoetin alfa shows an efficacy and safety comparable to epoetin alfa for the treatment of renal anemia.
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Effects of stored autotransfusion on electrolytes and postoperative complications in patients undergoing elective orthopedic surgery
Han Z, Wang M, Yu S
American journal of translational research. 2021;13(6):7200-7206
Abstract
OBJECTIVE To ivestigate the effect of stored autotransfusion on the electrolytes and postoperative complications in patients undergoing elective orthopedic surgery. METHODS A total of 76 cases of patients undergoing elective orthopedic surgery were randomly divided into an observation group (38 cases, taking stored autotransfusion) and a control group (38 cases, taking allogeneic blood transfusion) according to a random number table method. The intraoperative-related indexes (intraoperative blood loss, autologous or allogeneic blood transfusion volume, urine volume, and length of hospital stay), electrolyte levels before and 48 hours after the operation, routine blood and coagulation function were compared between the two groups, and the postoperative complications related to blood transfusion were recorded. RESULTS The length of hospital stay of the observation group was significantly lower than that of the control group (P<0.05). The concentrations of K(+) and Na(+) in the control group 48 h after the operation were higher than those before the operation and than those in the observation group, while the concentration of Ca(2+) was lower than that before the operation and that in the observation group (all P<0.05). The levels of Hb, RBC, and HCT in the control group 48 h after the operation were lower than those before the operation and those in the observation group (all P<0.05). The levels of WBC in the two groups 48 h after the operation were significantly higher, but those in the observation group were lower than those in the control group (all P<0.05). There were no significant changes in Pt, APTT, D-D, and FIB levels between the two groups. There were no significant changes in Pt, APTT, D-D, and FIB levels 48 hours after the operation compared with those before the operation (P>0.05). The incidence of postoperative complications caused by blood transfusion in the observation group was lower than that in the control group (P<0.05). CONCLUSION Storage autotransfusion can effectively balance the electrolyte level and reduce the incidence of complications in patients undergoing elective orthopedic surgery. This is worthy of clinical application.
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The safety of activated eptacog beta in the management of bleeding episodes and perioperative haemostasis in adult and paediatric haemophilia patients with inhibitors
Escobar M, Castaman G, Boix SB, Callaghan M, de Moerloose P, Ducore J, Hermans C, Journeycake J, Leissinger C, Luck J, et al
Haemophilia : the official journal of the World Federation of Hemophilia. 2021
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Abstract
INTRODUCTION Haemophilia patients with inhibitors often require a bypassing agent (BPA) for bleeding episode management. Eptacog beta (EB) is a new FDA-approved recombinant activated human factor VII BPA for the treatment and control of bleeding in haemophilia A or B patients with inhibitors (≥12 years of age). We describe here the EB safety profile from the three prospective Phase 3 clinical trials performed to date. AIM: To assess EB safety, immunogenicity and thrombotic potential in children and adults who received EB for treatment of bleeding and perioperative care. METHODS Using a randomized crossover design, 27 subjects in PERSEPT 1 (12-54 years) and 25 subjects in PERSEPT 2 (1-11 years) treated bleeding episodes with 75 or 225 μg/kg EB initially followed by 75 μg/kg dosing at predefined intervals as determined by clinical response. Twelve PERSEPT 3 subjects (2-56 years) received an initial preoperative infusion of 75 μg/kg (minor procedures) or 200 μg/kg EB (major surgeries) with subsequent 75 μg/kg doses administered intraoperatively and post-operatively as indicated. Descriptive statistics were used for data analyses. RESULTS Sixty subjects who received 3388 EB doses in three trials were evaluated. EB was well tolerated, with no allergic, hypersensitivity, anaphylactic or thrombotic events reported and no neutralizing anti-EB antibodies detected. A death occurred during PERSEPT 3 and was determined to be unlikely related to EB treatment by the data monitoring committee. CONCLUSION Results from all three Phase 3 trials establish an excellent safety profile of EB in haemophilia A or B patients with inhibitors for treatment of bleeding and perioperative use.
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High-dose dexamethasone plus recombinant human thrombopoietin versus high-dose dexamethasone alone as frontline treatment for newly diagnosed adult primary immune thrombocytopenia:a prospective, multicenter, randomized trial
Yu Y, Wang M, Hou Y, Qin P, Zeng Q, Yu W, Guo X, Wang J, Wang X, Liu G, et al
American journal of hematology. 2020
Abstract
We conducted a prospective, multicenter, randomized, controlled clinical trial to compare the efficacy and safety of high-dose dexamethasone (HD-DXM) plus recombinant human thrombopoietin (rhTPO) versus HD-DXM alone in newly diagnosed adult immune thrombocytopenia (ITP) patients. Enrolled patients were randomly assigned to receive DXM plus rhTPO or DXM monotherapy. Another 4-day course of DXM was repeated if response was not achieved by day 10 in both arms. One hundred patients in the HD-DXM plus rhTPO arm and 96 patients in the HD-DXM monotherapy arm were included in the full analysis set. HD-DXM plus rhTPO resulted in a higher incidence of initial response (89.0% vs. 66.7%, P < 0.001) and complete response (CR, 75.0% vs. 42.7%, P < 0.001) compared with HD-DXM monotherapy. Response rate at 6 months was also higher in the HD-DXM plus rhTPO arm than that in the HD-DXM monotherapy arm (51.0% vs. 36.5%, P = 0.02; sustained CR: 46.0% vs. 32.3%, P = 0.043). Throughout the follow-up period, the overall duration of response was greater in the HD-DXM plus rhTPO arm compared to the HD-DXM monotherapy arm (P = 0.04), as estimated by the Kaplan-Meier analysis. The study drugs were generally well tolerated. In conclusion, the combination of HD-DXM with rhTPO significantly improved the initial response and yielded favorable SR in newly diagnosed ITP patients, thus could be further validated as a frontline treatment for ITP. This study is registered as clinicaltrials.gov identifier: NCT01734044. This article is protected by copyright. All rights reserved.
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The efficacy and safety of anti-fibrinolytic agents in blood management following peri-acetabular osteotomy: A meta-analysis
Wang M, Tan H, Wu Z, Liang Y
Medicine. 2018;97((34)):e11967.
Abstract
BACKGROUND Blood management after peri-acetabular osteotomy (PAO) has become a serious problem. We performed a meta-analysis to evaluate the efficacy and safety of antifibrinolytics for blood management after PAO. METHODS PubMed, OVID, Embase, ScienceDirect, and Web of Science were searched up to January, 2018 without restrictions on publication date and language. We also searched the relevant publication sources. The research was reported according to the Preferred Reporting Items for Systematic Reviews and Meta-analysis guidelines. Randomized controlled trials (RCTs) and non-RCTs were included in our study. Weighted mean differences, risk difference, and 95% confidence intervals were calculated. We assessed statistical heterogeneity for each outcome with the use of a standard chi-square test and I statistic. The data were extracted by 2 of the co-authors independently and were analyzed by RevMan5.3. Primary outcomes were total blood loss, postoperative hemoglobin decline, and transfusion rates. Secondary outcomes were length of a hospital stay and postoperative complications. RESULTS Four studies including 1 RCT and 3 non-RCTs were included in our study. The present meta-analysis indicated that antifibrinolytics was associated with a significant reduction of the total blood loss, postoperative hemoglobin decline, transfusion rates, and length of a hospital stay compared with control groups. No significant differences were identified in terms of the incidence of postoperative complications. CONCLUSION Intravenous antifibrinolytics was efficacious in reduction of total blood loss, postoperative hemoglobin decline, and length of a hospital stay after PAO without increasing the risk of thromboembolic complications. More high-quality RCTs with long follow-up period were necessary for proper comparisons of the efficacy and safety of antifibrinolytics with placebo.
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Oral all-trans retinoic acid plus danazol versus danazol as second-line treatment in adults with primary immune thrombocytopenia: a multicentre, randomised, open-label, phase 2 trial
Feng FE, Feng R, Wang M, Zhang JM, Jiang H, Jiang Q, Lu J, Liu H, Peng J, Hou M, et al
The Lancet. Haematology. 2017;4((10):):e487-e496. e487
Abstract
BACKGROUND Primary immune thrombocytopenia is a severe bleeding disorder. About 50-85% of patients achieve initial remission from first-line therapies, but optimal second-line treatment remains a challenge. All-trans retinoic acid (ATRA) has an immunomodulatory effect on haemopoiesis, making it a possible treatment option. We aimed to evaluate the efficacy and safety of ATRA plus danazol versus danazol in non-splenectomised patients with corticosteroid-resistant or relapsed primary immune thrombocytopenia. METHODS We did a multicentre, randomised, open-label, phase 2 study of adult patients (≥18 years) with primary immune thrombocytopenia from five different tertiary medical centres in China. Those eligible were non-splenectomised, resistant to corticosteroid treatment or relapsed, and had a platelet count less than 30 x 109 per L. Masked statisticians used simple randomisation to assign patients (1:1) to receive oral ATRA (10 mg twice daily) plus oral danazol (200 mg twice daily) or oral danazol monotherapy (200 mg twice daily) for 16 weeks. Neither clinicians nor patients were masked to group assignments. All patients were assessed every week during the first 8 weeks of treatment, and at 2-week intervals thereafter. The primary endpoint was 12-month sustained response defined as platelet count of 30 x 109 per L or more and at least a doubling of baseline platelet count (partial response), or a platelet count of 100 x 109 per L or more (complete response) and the absence of bleeding without rescue medication at the 12-month follow-up. All randomly allocated patients, except for those who withdrew consent, were included in the modified intention-to-treat population and efficacy assessment, and all patients who received at least one dose of the study agents were included in the safety analysis. Study enrolment was stopped early because the trial results crossed the interim analysis efficacy boundary for sustained response. This trial is registered with ClinicalTrials.gov, number NCT01667263. FINDINGS From June 1, 2012, to July 1, 2016, we screened 130 patients for eligibility; 34 were excluded and 96 were randomly assigned. 93 patients were included in the modified intention-to-treat analysis: 45 in the ATRA plus danazol group and 48 in the danazol group. At the 12-month follow-up, sustained response was achieved more frequently in patients receiving ATRA plus danazol than in those receiving danazol monotherapy (28 [62%] of 45 vs 12 [25%] of 48; odds ratio 4.94, 95% CI 2.03-12.02, p=0.00037). Only two grade 3 adverse events were reported: one (2%) patient receiving ATRA plus danazol with dry skin, and one (2%) patient receiving danazol monotherapy with liver injury. There was no grade 4 or worse adverse event or treatment-related death in either group. INTERPRETATION Patients with primary immune thrombocytopenia given ATRA plus danazol had a rapid and sustained response compared with danazol monotherapy. This finding suggests that ATRA represents a promising candidate for patients with corticosteroid-resistant or relapsed primary immune thrombocytopenia. FUNDING National Natural Science Foundation of China, Beijing Natural Science Foundation, Beijing Municipal Science and Technology Commission, and the National Key Research and Development Program of China.
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PERSEPT 1: a phase 3 trial of activated eptacog beta for on-demand treatment of haemophilia inhibitor-related bleeding
Wang M, Lawrence JB, Quon DV, Ducore J, Simpson ML, Boggio LN, Mitchell IS, Yuan G, Alexander WA, Schved JF
Haemophilia : the Official Journal of the World Federation of Hemophilia. 2017;23((6):):832-843
Abstract
INTRODUCTION Haemophilia A or B patients with inhibitors have been treated with FVIIa-containing bypassing agents for over 20 years. However, due to uncertainty regarding dose response and thrombotic risk, the use of a gradual, titrated, minimal dosing strategy remains prevalent, potentially hampering early haemostasis. AIM: Evaluate the dose-dependent efficacy, safety and immunogenicity of activated eptacog beta (rhFVIIa), a new recombinant inhibitor bypassing agent for the treatment of bleeding episodes (BEs). METHODS A Phase 3, randomized, cross-over study of initial dose regimens (IDRs) in 27 bleeding congenital haemophilia A or B subjects with inhibitors was conducted to evaluate on-demand treatment of mild/moderate BEs. Intravenous 75 mug/kg or 225 mug/kg initial doses with 75 mug/kg subsequent doses by schedule were administered until clinical response. RESULTS The primary endpoint was sustained clinical response within 12 hours, determined by a composite of objective and pain measures. In the 75 mug/kg IDR, 84.9% (95% CI; 74.0%, 95.7%) of mild/moderate BEs at 12 hours were successfully treated compared to 93.2% (95% CI; 88.1%, 98.3%) treated in the 225 mug/kg IDR. Efficacy between the IDRs was statistically different (P<.020) in mild/moderate bleeding episodes. Both IDRs were well tolerated with no detectable immunogenic or thrombotic responses to rhFVIIa or host cell proteins. CONCLUSION The dose-dependent efficacy seen in this study supports individualizing the initial dose of eptacog beta to optimize clinical response. By reducing uncertainty, the PERSEPT 1 results should increase the adoption of early haemostasis as a treatment goal for clinicians who treat haemorrhage in the inhibitor population.