Fitusiran prophylaxis in people with severe haemophilia A or haemophilia B without inhibitors (ATLAS-A/B): a multicentre, open-label, randomised, phase 3 trial.

BACKGROUND: Fitusiran, a subcutaneous investigational siRNA therapeutic, targets antithrombin with the goal of rebalancing haemostasis in people with haemophilia A or haemophilia B, regardless of inhibitor status. We aimed to evaluate the efficacy and safety of fitusiran prophylaxis in people with severe haemophilia without inhibitors. METHODS: This multicentre, open-label, randomised phase 3 study was conducted at 45 sites in 17 countries. Male participants aged at least 12 years with severe haemophilia A or B without inhibitors, who had previously been treated on-demand with clotting factor concentrates, were randomly assigned in a 2:1 ratio to receive 80 mg subcutaneous fitusiran prophylaxis once per month or to continue on-demand clotting factor concentrates for a total of 9 months. Randomisation was stratified by the number of bleeding events in the 6 months before screening (≤10 bleeds and >10 bleeds) and by haemophilia type (haemophilia A or B). The primary endpoint was annualised bleeding rate, analysed in the intention-to-treat analysis set. Safety and tolerability were assessed in the safety analysis set. This trial is registered with ClinicalTrials.gov, NCT03417245, and is complete. FINDINGS: Between March 1, 2018, and July 14, 2021, 177 male participants were screened for eligibility and 120 were randomly assigned to receive fitusiran prophylaxis (n=80) or on-demand clotting factor concentrates (n=40). Median follow-up was 7·8 months (IQR 7·8-7·8) in the fitusiran group and 7·8 months (7·8-7·8) in the on-demand clotting factor concentrates group. The median annualised bleeding rate was 0·0 (0·0-3·4) in the fitusiran group and 21·8 (8·4-41·0) in the on-demand clotting factor concentrates group. The estimated mean annualised bleeding rate was significantly lower in the fitusiran prophylaxis group (3·1 [95% CI 2·3-4·3]) than in the on-demand clotting factor concentrates group (31·0 [21·1-45·5]; rate ratio 0·101 [95% CI 0·064-0·159]; p<0·0001). In the fitusiran group, 40 (51%) of 79 treated participants had no treated bleeds compared with two (5%) of 40 participants in the on-demand clotting factor concentrates group. Increased alanine aminotransferase concentration (18 [23%] of 79 participants in the safety analysis set) was the most common treatment-emergent adverse event in the fitusiran group and hypertension (four (10%) of 40 participants) was the most common in the on-demand clotting factor concentrates group. Treatment-emergent serious adverse events were reported in five (6%) participants in the fitusiran group (cholelithiasis [n=2, 3%], cholecystitis [n=1, 1%], lower respiratory tract infection [n=1, 1%], and asthma [n=1, 1%]) and five (13%) participants in the on-demand clotting factor concentrates group (gastroenteritis, pneumonia, suicidal ideation, diplopia, osteoarthritis, epidural haemorrhage, humerus fracture, subdural haemorrhage, and tibia fracture [all n=1, 3%]). No treatment-related thrombosis or deaths were reported. INTERPRETATION: In participants with haemophilia A or B without inhibitors, fitusiran prophylaxis resulted in significant reductions in annualised bleeding rate compared with on-demand clotting factor concentrates and no bleeding events in approximately half of participants. Fitusiran prophylaxis shows haemostatic efficacy in both haemophilia A and haemophilia B, and therefore has the potential to be transformative in the management of all people with haemophilia. FUNDING: Sanofi.

Efficacy and safety of fitusiran prophylaxis in people with haemophilia A or haemophilia B with inhibitors (ATLAS-INH): a multicentre, open-label, randomised phase 3 trial.

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.

Measurements of abdominal wall defect and hernia sac volume for the treatment of incisional hernia: Application of the ultrasonic volume auto-scan in 50 cases.

PURPOSE: Abdominal incisional hernia is one of the most common complications after surgery. The preoperative evaluation of the area of abdominal wall defect and the hernia sac volume(HCV) is very important for the selection of patch size and incisional herniorrhaphy. Meanwhile the overlap range of reinforcement repair is controversial. This study aimed to explore the value of ultrasonic volume auto-scan(UVAS) in the diagnosis, classification and treatment of incisional hernia. METHODS: Both the width and the area of abdominal wall defect and HCV were measured by UVAS in 50 cases with incisional hernias. In 32 of these cases, the measurements of HCV were compared with those of CT. Classification of incisional hernia based on ultrasonic images were compared with operative diagnosis. RESULTS: The measurements of HCV by UVAS and CT 3D reconstruction had good consistency, of which the mean ratio was 1.0084. According to the location and width of abdominal wall defect, UVAS, which showed good accuracy rate (90%, 96%), reached a good agreement in the classification of incisional hernias with operative diagnoses (Kappa = 0.85, Confidence Interval [0.718,0.996]; Kappa = 0.95, Confidence Interval [0.887,0.999]). The patch area should be at least two times as large as the defect area. CONCLUSIONS: UVAS is an accurate alternative to measure the abdominal wall defect and HCV and classify the incisional hernia, with additional benefits of no radiation exposure and instant bedside interpretation. The use of UVAS is conducive to preoperative assessment of the risk of hernia recurrence and abdominal compartment syndrome.

Molecular Epidemiology of New Delhi Metallo-ß-Lactamase-Producing Escherichia coli in Food-Producing Animals in China.

We conducted a molecular surveillance study for carbapenem-resistant Enterobacteriaceae (CRE) colonization in food-producing animals in China that included primarily swine and poultry for three consecutive years. A total of 2,771 samples from food-producing animals and their surrounding environments were collected from different regions in China from 2015 to 2017. Enrichment cultures supplemented with meropenem were used to isolate carbapenem non-susceptible isolates and these were subsequently identified by MALDI-TOF MS. Resistance phenotypes and genotypes were confirmed using antimicrobial susceptibility testing and molecular biological techniques. Genomic characteristics of the carbapenemase-producing isolates were investigated using whole genome sequencing (WGS) and bioinformatic analysis. In total, 88 NDM-positive Enterobacteriaceae were identified from 2,771 samples and 96.6% were Escherichia coli. The New Delhi metallo-ß-lactamase (NDM)-positive E. coli displayed a diversity of sequence types (ST), and ST48 and ST165 were the most prevalent. Three variants of bla NDM (bla NDM-1, bla NDM-4, and bla NDM-5) were detected and WGS indicated that bla NDM-5 predominated and was carried primarily on IncX3 plasmids. All these isolates were also multiply-drug resistant. These results revealed that food-producing animals in China are an important reservoir for NDM-positive E. coli and pose a potential threat to public health.

A comparative study of contrast-enhanced ultrasound and contrast-enhanced CT for the detection and characterization of renal masses.

This study aims to compare the value of contrast-enhanced ultrasound (CEUS) and contrast-enhanced CT (CECT) in the differential diagnosis of benign and malignant renal masses. Included in this retrospective study were 143 renal masses in 141 patients using histopathological findings as the gold standard. A comparison was made of the two modalities in image characteristics for their accuracy in the differential diagnosis of renal masses. CEUS and CECT were both used for 39 masses in 37 patients, with 31 (79.5%) being malignant and 8 (20.5%) benign. The differences between the benign and malignant groups in perfusion intensity, perfusion uniformity and entry and exit of the contrast agent were not statistically significant (P > 0.05). However, CEUS could better display the circular perfusion of renal cell carcinoma than CECT (P < 0.05). CECT alone detected 109 masses in 107 patients, with 93 (85.3%) being malignant and 16 (14.7%) benign. CEUS detected 73 masses in 71 patients, with 56 (76.7%) being malignant and 17 (23.3%) benign. No statistically significant differences were observed between CEUS and CECT in the diagnosis of renal cell carcinoma (92.8% vs. 90.3%), with a specificity of 52.9% vs. 31.2%, an accuracy of 83.5% vs. 81.6%, and a positive predictive value of 86.7% vs. 88.4% or a negative predictive value of 69.2% vs. 35.7% (P > 0.05 for all). These results suggested both CEUS and CECT are highly valuable in the differential diagnosis of renal masses, and CEUS can be used as an important supplement for CECT in diagnosis of renal cancer.

Electrospun P(LLA-CL) Nanoscale Fibrinogen Patch vs Porcine Small Intestine Submucosa Graft Repair of Inguinal Hernia in Adults: A Randomized, Single-Blind, Controlled, Multicenter, Noninferiority Trial.

BACKGROUND: The aim of this study was to compare primary efficacy indicators of a low-cost, electrospun, nanoscale P(LLA-CL)/fibrinogen patch with a porcine small intestine submucosa patch for hernia repair. STUDY DESIGN: A randomized, single-blind, controlled multicenter trial was performed in 3 hospitals in Shanghai. Eligible patients (20 to 75 years old) with primary unilateral, reducible groin hernias were randomly assigned (1:1) to electrospun nanoscale P(LLA-CL)/fibrinogen patch (experimental group) or porcine small intestine submucosa (control group) patch groups. Patients were treated with the Lichtenstein technique, and the primary endpoint was hernia recurrence at 33 months after surgery. The secondary endpoints were postoperative complications including groin pain and operative site infections. RESULTS: Between July 2014 and February 2016, 172 patients were assigned to experimental (n = 86) and control (n = 86) groups. At 6-month follow-up, postoperative complications occurred in 5 patients (5 of 86, 5.81%) and 2 (2 of 86, 2.35%) patients in the control and experimental groups, respectively (p < 0.05). At 33-month follow-up, recurrence was observed in 2 patients (2 of 79, 2.53%) in the control group vs none in the experimental group (0 of 78) (the 95% CI difference between the experimental and control groups was -0.93% to 6.00% and within the preset noninferior margin of Δ10%). No significant differences were found in the degree of chronic pain and complications 33 months after surgery between the 2 groups. CONCLUSIONS: Because the recurrence rates and postoperative complications after 33 months were not inferior in the experimental group, we believe that the P(LLA-CL)/fibrinogen patch, as a low cost alternative, has prospects for widespread clinical use.

Considerations for pediatric trial designs and analyses.

There are challenges in designing pediatric trials arising from special ethical issues and the relatively small accessible patient population. The application of conventional phase 3 trial designs to pediatrics is not realistic in some therapeutic areas. To address this issue, we propose various approaches for designing pediatric trials that incorporate data available from adult studies using James-Stein shrinkage estimation, empirical shrinkage estimation, and Bayesian methods. We also apply the concept of consistency used in multi-regional trials to pediatric trials. The performance of these methods is assessed through representative scenarios and an example using actual Type 2 diabetes mellitus (T2DM) trials.

On generalized fixed sequence procedures for controlling the FWER.

Testing a sequence of pre-ordered hypotheses to decide which of these can be rejected or accepted while controlling the familywise error rate (FWER) is of importance in many scientific studies such as clinical trials. In this paper, we first introduce a generalized fixed sequence procedure whose critical values are defined by using a function of the numbers of rejections and acceptances, and which allows follow-up hypotheses to be tested even if some earlier hypotheses are not rejected. We then construct the least favorable configuration for this generalized fixed sequence procedure and present a sufficient condition for the FWER control under arbitrary dependence. Based on the condition, we develop three new generalized fixed sequence procedures controlling the FWER under arbitrary dependence. We also prove that each generalized fixed sequence procedure can be described as a specific closed testing procedure. Through simulation studies and a clinical trial example, we compare the power performance of these proposed procedures with those of the existing FWER controlling procedures. Finally, when the pairwise joint distributions of the true null p-values are known, we further improve these procedures by incorporating pairwise correlation information while maintaining the control of the FWER. Copyright © 2015 John Wiley & Sons, Ltd.

Identification of implanted mesh after incisional hernia repair using an automated breast volume scanner.

OBJECTIVES: This study aimed to evaluate the utility of an automated breast volume scanner (ABVS) versus handheld ultrasound (US) for identifying implanted mesh after incisional hernia repair. METHODS: In vitro, the appearances of 3 samples of different flat mesh and a mesh plug on both ABVS and handheld US examinations were evaluated. In vivo, 97 patients received both ABVS and handheld US examinations in the incisional region. The frequency used for handheld US was 11 MHz. The presence of the previously implanted mesh in the incisional region was evaluated and compared between the US modalities. The identified results were confirmed by surgical findings. RESULTS: In the in vitro study, the ABVS had more visualized and efficient imaging results for implanted mesh than handheld US. In the in vivo study, among 97 cases, 39 and 32 were identified as regions with mesh by the ABVS and handheld US, respectively. The ABVS had better identification performance than handheld US in terms of accuracy (94.8% versus 83.5%), sensitivity (90.5% versus 69.0%), and specificity (98.2% versus 94.5%). The κ values showed that handheld US had substantial agreement with surgical findings (κ = 0.78; 95% confidence interval, 0.66-0.90), whereas the ABVS had almost perfect agreement with surgical findings (κ = 0.93; 95% confidence interval, 0.86-1.00). More importantly, the ABVS could display the texture of lightweight mesh in the coronal plane. The specificity and sensitivity for mesh texture were 100.0% (55 of 55) and 94.4% (17 of 18), respectively. CONCLUSIONS: The use of an ABVS may help identify the presence of implanted mesh after incisional hernia repair in some cases in which the implant is difficult to appreciate on handheld US imaging with an 11-MHz transducer.

Diagnostic value of automated 3D ultrasound for incisional hernia.

The automated volume scanning system (AVSS) has been applied in breast diseases, but its use in incisional hernias has not been reported. In this study, conventional handheld B-mode ultrasound (HHUS) and AVSS examined a total of 122 hernia defects in 78 patients. The results from two modalities were then compared with surgical findings for the purpose of assessing the diagnostic value of AVSS. Statistics showed that surgeries identified 38 small, 23 medium and 17 large incisional hernias. The results of AVSS completely agreed with surgical findings; however, HHUS misidentified nine large hernias as medium and seven medium hernias as large. AVSS proved to be more accurate than HHUS in measuring the length and width of the hernia. It also outperformed HHUS in both detecting the incisional hernias (91.8% vs. 78.7%, p = 0.00) and determining hernia contents (89.3% vs. 68.0%, p = 0.00). Moreover, the coronal images AVSS obtained clearly displayed the shapes of the hernias, with 46 being regular and 32 irregular. Overall, AVSS can be used as a promising diagnostic modality for incisional hernias.

Diagnostic value of an automated breast volume scanner for abdominal hernias.

OBJECTIVES: This study explored the diagnostic values of an automated breast volume scanner (ABVS) for abdominal external hernias. METHODS: Conventional sonograms and ABVS images from 128 abdominal external hernias in 104 patients (98 male and 6 female; age range, 41-79 years; mean age ± SD, 68.0 ± 14.6 years) were analyzed. The results were identified by surgical outcomes. The hernia type, hernial ring position, hernial sac size, hernia content, and hernia structure were evaluated by both sonographic modalities. RESULTS: The sensitivity and accuracy differences between the ABVS and conventional sonography for diagnosis of abdominal hernias and hernia size measurements were compared. The hernia types, as confirmed by surgery, included 45 indirect inguinal hernias (30 reducible and 15 irreducible), 12 reducible direct inguinal hernias, 5 femoral hernias, 62 incisional hernias (42 isolated and 20 multiple), and 4 umbilical hernias. The sensitivity of the ABVS was higher than that of conventional sonography for incisional hernias (P < .01), whereas there were no statistical differences in sensitivity for other types of hernias. The ABVS hernial sac number detection rate for both isolated and multiple incisional hernias was significantly higher compared with that of conventional sonography (both P < .01). The ABVS measurements correlated well with surgical results (length, P = .47; width, P = .31). CONCLUSIONS: Automated breast volume scanner images have the outstanding advantage of displaying the entire scope of the internal structure and the relationship with adjacent tissues of abdominal hernias. Therefore, an ABVS has good application prospects for diagnosis of abdominal external hernias and merits further research.