Lower injection-site reactions and long-term safety, immunogenicity, and efficacy of etanercept biosimilar YLB113: Results from a post-hoc analysis of a double-blind, randomized, phase III comparative study and its open-label extension in patients with rheumatoid arthritis.

AIM: YLB113 biosimilar was evaluated in an open-label extension single-arm study to assess long-term safety, efficacy, and immunogenicity in patients with rheumatoid arthritis (RA). We also report post-hoc results on the incidence of injection-site reactions (ISRs) and injection-site erythema (ISE) from a phase III study. METHOD: Participants from the phase III, double-blind, randomized, 96 week equivalence study who completed the final visit received 50 mg YLB113 subcutaneously every 2 weeks. Key safety end points were assessed through adverse events (AEs), ISRs, ISE, and anti-drug antibody (ADA) incidence. The efficacy end point was change from baseline in Disease Activity Score 28-joint count (DAS28) over time. RESULTS: Of 201 participants, 184 (91.5%) completed the study. Treatment-emergent AEs were experienced by 93.5% and severe AEs by 10.0% of participants. The discontinuation rate due to AEs was 2.0%. Overall, 20.0% of participants reported an incidence of ISRs throughout the open-label extension study. Two participants developed ADAs, and none developed neutralizing ADAs at any time after study drug administration. The overall DAS28 (mean ± SD) change was 2.22 ± 0.95 at the study transition, 2.10 ± 0.91 at week 72, and 2.06 ± 0.89 at the end of the study. In the post-hoc analysis, YLB113 showed a statistically significant lower incidence of ISRs (10 [3.8%], P < 0.0001) and ISE (5 [1.9%], P < 0.0001) compared with the reference product Enbrel®. CONCLUSION: YLB113 demonstrated long-term safety and sustained efficacy for up to 96 weeks. Patients on YLB113 experienced significantly lower ISRs and ISE in a post-hoc analysis of the phase III study when compared with reference product.

Comparison of two biosimilarity studies of FKB327 with the adalimumab reference product: randomized phase 1 studies of single-blind, single-dose subcutaneous injection in healthy Japanese male participants.

BACKGROUND: FKB327 has been developed as a biosimilar of the adalimumab reference product (RP). We compared the pharmacokinetics (PK), safety, and immunogenicity of FKB327 with those of the adalimumab RP after a single dose by subcutaneous (SC) injection in Japanese male participants. METHODS: Two randomized, single-blind, single-dose studies were conducted in healthy Japanese male participants to compare PK characteristics between FKB327 and the RP. Study 1 included 130 participants who were randomized in a 1:1 ratio to receive a subcutaneous injection of 40 mg of either FKB327 or the RP into the abdomen. In Study 2, another 130 subjects were randomized in a 1:1 ratio to receive either drug as in Study 1, but the drug administration site was changed to the thigh. The primary PK endpoints of both studies were area under the concentration-time curve from time zero to the last measurable concentration (AUC0-t) and maximum serum concentration; area under the concentration-time curve from time zero to 360 h was also evaluated as one of the primary endpoints in Study 1. Biosimilarity in terms of pharmacokinetics was determined if the 90% confidence interval of the mean difference in geometric mean ratio of all primary PK parameters was within the prespecified equivalence criteria (0.80-1.25). Immunogenicity and safety were also evaluated as secondary endpoints. RESULTS: The serum concentration-time profiles were comparable between the FKB327 and the RP treatment groups in both studies. Primary PK parameters were within the prespecified bioequivalence range in Study 2, although AUC0-t was slightly outside the upper side of the range in Study 1. No differences in safety profile were observed in these studies. The incidence of anti-drug antibodies (ADAs) and impact of ADAs on PK profile were similar among the treatment groups in both studies. CONCLUSION: Biosimilarity between FKB327 and the RP after a single 40-mg SC injection was confirmed in healthy Japanese male participants by modifying the study design. TRIAL REGISTRATION: jRCT2071200058 (https://jrct.niph.go.jp/en-latest-detail/jRCT2071200058, https://rctportal.niph.go.jp/en/detail?trial_id=jRCT2071200058) and jRCT2071200057 (https://jrct.niph.go.jp/en-latest-detail/jRCT2071200057, https://rctportal.niph.go.jp/en/detail?trial_id=jRCT2071200057). Retrospectively registered 25/11/2020.

Roux-En-Y gastric bypass following failed fundoplication.

INTRODUCTION: Roux-En-Y gastric bypass (RYGB) is an alternative to reoperative fundoplication. The aim of this study was to expand long-term outcomes of patients undergoing RYGB after failed fundoplication and assess symptom resolution. METHODS: A single institution prospective study was performed of patients undergoing fundoplication takedown and RYGB between March 2007 and September 2016. Demographics, body mass index (BMI), preoperative symptoms, operative duration and findings, and postoperative outcomes were recorded. Data were assessed using standard statistical methods. RESULTS: 87 patients with failed antireflux surgery underwent RYGB. Median age 58 years (range 25-79 years). Median preoperative BMI 32.4 kg/m2 (range 21.6-50.6 kg/m2). Comorbidities included hypertension (48.3%) and diabetes (11.5%). Sixty-six patients had undergone 1 prior fundoplication, 18 had 2 prior fundoplications, and 3 had 3 prior fundoplications. At least one previous open antireflux procedure had been performed in 16.1% of patients. The most common recurrent symptoms were reflux (85.1%), dysphagia (36.7%), pain (35.6%), and regurgitation (29.9%). Median symptom-free interval from last antireflux surgery was 3 years (range 0-25 years). RYGB was performed laparoscopically in 47.1% of cases, robotically in 44.8% of cases, and open in 5.9%. Operative duration was longer in the robotic group (p = 0.04). During RYGB, 85.1% patients were found to have an associated hiatal hernia, 34.5% had intrathoracic migration of the fundoplication, 32.2% a slipped fundoplication onto proximal stomach, and 13.8% had wrap disruption. Median length of stay (LOS) was 4 days (range 1-33 days). Median follow-up was 35.8 months, 11 patients (12.6%) had recurrent reflux symptoms. Excess body weight loss (%EWL) was 80.4%. There was no mortality but 8 patients required reoperation during follow-up. CONCLUSIONS: Fundoplication takedown with RYGB was successful for long-term reflux resolution. Most can be performed via a minimally invasive approach with acceptable perioperative morbidity, symptom resolution, and the additional benefit of %EWL.

Seasonal influenza vaccination in patients with COPD: a systematic literature review.

BACKGROUND: Influenza is a frequent cause of exacerbations of chronic obstructive pulmonary disease (COPD). Exacerbations are associated with worsening of the airflow obstruction, hospitalisation, reduced quality of life, disease progression, death, and ultimately, substantial healthcare-related costs. Despite longstanding recommendations to vaccinate vulnerable high-risk groups against seasonal influenza, including patients with COPD, vaccination rates remain sub-optimal in this population. METHODS: We conducted a systematic review to summarise current evidence from randomised controlled trials (RCTs) and observational studies on the immunogenicity, safety, efficacy, and effectiveness of seasonal influenza vaccination in patients with COPD. The selection of relevant articles was based on a three-step selection procedure according to predefined inclusion and exclusion criteria. The search yielded 650 unique hits of which 48 eligible articles were screened in full-text. RESULTS: Seventeen articles describing 13 different studies were found to be pertinent to this review. Results of four RCTs and one observational study demonstrate that seasonal influenza vaccination is immunogenic in patients with COPD. Two studies assessed the occurrence of COPD exacerbations 14 days after influenza vaccination and found no evidence of an increased risk of exacerbation. Three RCTs showed no significant difference in the occurrence of systemic effects between groups receiving influenza vaccine or placebo. Six out of seven studies on vaccine efficacy or effectiveness indicated long-term benefits of seasonal influenza vaccination, such as reduced number of exacerbations, reduced hospitalisations and outpatient visits, and decreased all-cause and respiratory mortality. CONCLUSIONS: Additional large and well-designed observational studies would contribute to understanding the impact of disease severity and patient characteristics on the response to influenza vaccination. Overall, the evidence supports a positive benefit-risk ratio for seasonal influenza vaccination in patients with COPD, and supports current vaccination recommendations in this population.

The American College of Surgeons/Association of Program Directors in Surgery National Skills Curriculum: adoption rate, challenges and strategies for effective implementation into surgical residency programs.

BACKGROUND: The American College of Surgeons/Association of Program Directors in Surgery (ACS/APDS) National Skills Curriculum is a 3-phase program targeting technical and nontechnical skills development. Few data exist regarding the adoption of this curriculum by surgical residencies. This study attempted to determine the rate of uptake and identify implementation enablers/barriers. METHODS: A web-based survey was developed by an international expert panel of surgical educators (5 surgeons and 1 psychologist). After piloting, the survey was sent to all general surgery program directors via email link. Descriptive statistics were used to determine the residency program characteristics and perceptions of the curriculum. Implementation rates for each phase and module were calculated. Adoption barriers were identified quantitatively and qualitatively using free text responses. Standardized qualitative methodology of emergent theme analysis was used to identify strategies for success and details of support required for implementation. RESULTS: Of the 238 program directors approached, 117 (49%) responded to the survey. Twenty-one percent (25/117) were unaware of the ACS/APDS curriculum. Implementation rates for were 36% for phase I, 19% for phase II, and 16% for phase III. The most common modules adopted were the suturing, knot-tying, and chest tube modules of phase I. Over 50% of respondents identified lack of faculty protected time, limited personnel, significant costs, and resident work-hour restrictions as major obstacles to implementation. Strategies for effective uptake included faculty incentives, adequate funding, administrative support, and dedicated time and resources. CONCLUSION: Despite the availability of a comprehensive curriculum, its diffusion into general surgery residency programs remains low. Obstacles related to successful implementation include personnel, learner, and administrative issues. Addressing these issues may improve the adoption rate of the curriculum.

Laparoscopic skills laboratories: current assessment and a call for resident training standards.

BACKGROUND: Numerous protocols for laparoscopic skills training using simulator-based laboratories have proven effective. However, little is known about the availability and uniformity of such facilities. The purpose of this study was to evaluate the prevalence, utilization, and costs of skills laboratories currently in use. METHODS: A survey was mailed to 253 general surgery program directors to determine the perceived value, prevalence, equipment, types of training, supervision, and costs of the labs. RESULTS: One hundred sixty-two (64%) programs completed the survey. Eighty-eight percent of responders consider skills labs effective in improving operating room performance; however, only 55% have skills labs. Of 89 programs with skills labs, 99% have videotrainer equipment (mean 3.8 trainers per lab, range 1 to 15); 46% have virtual reality trainer equipment (mean 1.7 trainers per lab, range 1 to 7). Eighty-two percent of programs teach basic skills using a variety of tasks (Rosser/Southwestern stations, MIST-VR, MISTELS, department-created); 96% teach suturing (intracorporeal, extracorporeal, suture devices). On average, residents train 0.8 hours per week (range 0 to 6). Training is mandatory in 55% and supervised in 73% of the programs. The mean development cost was 133,000 dollars (range 300 dollars to 1,000,000 dollars). CONCLUSIONS: While a large majority of program directors consider skills labs important, 45% of programs have no such facilities. Moreover, significant variability of equipment and training practices exist in currently available labs. Strategies are needed for more widespread implementation of skills labs, and standards should be developed to facilitate uniform adoption of validated curricula that reliably maximize training efficiency and educational benefit.

Simulator training for laparoscopic suturing using performance goals translates to the operating room.

BACKGROUND: The purpose of this study was to develop a performance-based laparoscopic suturing curriculum using simulators and to test the effectiveness (transferability) of the curriculum. STUDY DESIGN: Surgical residents (PGY1 to PGY5, n = 17) proficient in basic skills, but with minimal laparoscopic suturing experience, were enrolled in an IRB-approved, randomized controlled protocol. Subjects viewed an instructional video and were pretested on a live porcine laparoscopic Nissen fundoplication model by placing three gastrogastric sutures tied in an intracorporeal fashion. A blinded rater objectively scored each knot based on a previously published formula (600 minus completion time [sec] minus penalties for accuracy and knot integrity errors). Subjects were stratified according to pretest scores and randomized. The trained group practiced on a videotrainer suturing model until an expert-derived proficiency score (512) was achieved on 12 attempts. The control group received no training. Both the trained and control groups were posttested on the porcine Nissen model. RESULTS: For the training group, mean time to demonstrate simulator proficiency was 151 minutes (range 107 to 224 minutes) and mean number of attempts was 37 (range 24 to 51 attempts). Both the trained and control groups demonstrated significant improvement in overall score from baseline. But the trained group performed significantly better than the control group at posttesting (389 +/- 70 versus 217 +/- 140, p < 0.001), confirming curriculum effectiveness. CONCLUSIONS: These data suggest that training to a predetermined expert level on a videotrainer suture model provides trainees with skills that translate into improved operative performance. Such curricula should be further developed and implemented as a means of ensuring proficiency.