Abstract

BACKGROUND Fitusiran, a subcutaneous investigational small interfering RNA therapeutic, targets antithrombin to rebalance haemostasis in people with haemophilia A or haemophilia B, irrespective of inhibitor status. We evaluated the efficacy and safety of fitusiran prophylaxis in people with haemophilia A or haemophilia B with inhibitors. METHODS This multicentre, randomised, open-label phase 3 study was done at 26 sites (primarily secondary or tertiary centres) in 12 countries. Men, boys, and young adults aged 12 years or older with severe haemophilia A or haemophilia B with inhibitors previously treated with on-demand bypassing agents were randomly assigned (2:1) to receive once-a-month 80 mg subcutaneous fitusiran prophylaxis (fitusiran prophylaxis group) or to continue with bypassing agents on-demand (bypassing agents on-demand group) for 9 months. The primary endpoint was mean annualised bleeding rate during the efficacy period in the intention-to-treat population estimated by negative binomial model. Safety was assessed as a secondary endpoint in the safety population. This trial is complete and is registered with ClinicalTrials.gov, NCT03417102. FINDINGS Between Feb 14, 2018, and June 23, 2021, 85 participants were screened for inclusion, of whom 57 (67%; 57 [100%] men; median age 27·0 years [IQR 19·5-33·5]) were randomly assigned: 19 (33%) participants to the bypassing agent on-demand group and 38 (67%) participants to the fitusiran prophylaxis. Negative binomial model-based mean annualised bleeding rate was significantly lower in the fitusiran prophylaxis group (1·7 [95% CI 1·0-2·7]) than in the bypassing agents on-demand group (18·1 [10·6-30·8]), corresponding to a 90·8% (95% CI 80·8-95·6) reduction in annualised bleeding rate in favour of fitusiran prophylaxis (p<0·0001). 25 (66%) participants had zero treated bleeds in the fitusiran prophylaxis group versus one (5%) in the bypassing agents on-demand group. The most frequent treatment-emergent adverse event in the fitusiran prophylaxis group was increased alanine aminotransferase in 13 (32%) of 41 participants in the safety population; there were no increased alanine aminotransferase treatment-emergent adverse events in the bypassing agents on-demand group. Suspected or confirmed thromboembolic events were reported in two (5%) participants in the fitusiran prophylaxis group. No deaths were reported. INTERPRETATION Subcutaneous fitusiran prophylaxis resulted in statistically significant reductions in annualised bleeding rate in participants with haemophilia A or haemophilia B with inhibitors, with two-thirds of participants having zero bleeds. Fitusiran prophylaxis might show haemostatic efficacy in participants with haemophilia A or haemophilia B with inhibitors; therefore, the therapeutic might have the potential to improve the management of people with haemophilia. FUNDING Sanofi.

Abstract

Immune thrombocytopenia (ITP) is one of the most common acquired immune-mediated bleeding disorders found in children. Prednisone is usually considered a first-line therapeutic agent for ITP in children. Yet, prolonged exposure to prednisone has been associated with certain side effects. This prospective randomized study comparatively assessed the efficacy and safety of short-course high-dose dexamethasone (HDD) and standard prednisone (PDN) as a first-line treatment for children with previously untreated primary ITP. Two hundred eleven children were randomized into the HDD (n = 110) and PDN (n = 101) groups. There was no difference in baseline characteristics between the two groups (p > 0.05). Early response rates were 92.7% and 93% (p = 0.923); initial response rates were 93.6% and 95% (p = 0.658) and durable response rates were 90% and 91% (p = 0.787) in the HDD and PDN groups, respectively. More remission patients in the HDD group compared with the PDN group (86.3% vs. 80.1%) at 12th month after treatment, yet no statistical difference was observed (p = 0.703). Bleeding events were 10.9% and 14.8% (p = 0.105), and bleeding score improvement rates were 78.2% and 76.2% (p = 0.284) in the HDD and PDN groups, respectively. Cushing's disease, weight gain and infection rates were higher in the PDN group compared to the HDD group (80% vs. 10%, p = 0.001; 74.2% vs. 13.6%, p = 0.001; and 26% vs. 11.8%, p = 0.012) 1 month after treatment. HDD showed non-inferior efficacy and fewer glucocorticoid-related adverse effects compared with PDN. These findings indicated that HDD could be considered as a first-line treatment in children with previously untreated primary ITP, thus replacing standard PDN.

Abstract

Previous studies showed that tumor necrosis factor (TNF) inhibitors might decrease the rate of coronary artery abnormalities in pediatrics with intravenous immunoglobulin (IVIG)-resistant Kawasaki disease (KD). Therefore, we aimed to evaluate the effect and safety of TNF inhibitors in IVIG-resistant KD. We undertook a meta-analysis of clinical trials identified in systematic searches of PubMed, EMBASE, Cochrane Database, and Google scholar through May 2016. Five studies were included. Overall, rate of coronary artery aneurysm was comparable between groups (relative risk (RR), 1.05; 95 % confidence interval (95 % CI), 0.60 to 1.81; P = 0.87). No significant differences were recorded between groups in coronary artery Z scores (standardized mean difference (SMD), 0.27; 95 % CI, -0.30 to 0.85; P = 0.35). Meanwhile, TNF inhibitors were not associated with a significant decreased risk of treatment resistance compared with IVIG treatment (RR, 0.65; 95 % CI, 0.37 to 0.15; P = 0.14). However, days of fever was significantly reduced in the TNF inhibitor group (SMD, -0.66; 95 % CI, -0.90 to -0.41; P < 0.001). Additionally, risk of serious adverse events was similar between groups. Therefore, TNF inhibitors could shorten the duration of fever in IVIG-resistant KD. However, TNF inhibitors appear to have no cardioprotective effect in patients with IVIG-resistant KD.

Abstract

PURPOSE Current evidence suggests that preconditioning with erythropoietin (EPO) can protect against ischemia reperfusion injury in rodents. However, randomized controlled trials (RCTs) assessing the efficacy and safety of high-dose EPO in kidney transplantation have yielded inconclusive results. Herein, we performed a meta-analysis of RCTs to assess whether the administration of high-dose EPO can improve graft function and the potential adverse events. METHODS Relevant RCT studies that investigated high-dose EPO on graft function after kidney transplantation were comprehensively searched in Pubmed, Embase, and Cochrane Library until July 10, 2014. All statistical analyses were performed using Review Manager 5.0 and STATA 12.0. RESULTS A total of 4 RCTs involving 356 patients were identified. Comprehensively, a trend of reduction in the incidence of delayed graft function could be observed in the EPO group (EPO vs. placebo groups: RR=0.88); however, the result did not reach the significance level (95% CI, 0.72-1.08; P=0.21). Furthermore, no significant difference in the incidences of adverse events was observed between the two groups. CONCLUSIONS The current meta-analysis indicates that the administration of high-dose EPO is, to some extent, prone to protect kidney function without increasing the susceptibility to adverse events.Copyright © 2014 Elsevier Masson SAS. All rights reserved.