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Rationale: Tocilizumab, an anti–interleukin-6 receptor antibody, had no statistically significant effect on skin sclerosis but preserved lung function over 48 weeks in patients with early systemic ...

Objectives: To evaluate the long-term efficacy and safety/tolerability of oral blonanserin in adolescents with schizophrenia (Study registration number: JapicCTI-111725). Methods: This 52-week, mul...

Objectives To assess the safety and effectiveness of mycophenolate mofetil (MMF) in Japanese adults with lupus nephritis (LN) in real-world clinical practice. Methods This multicentre, prospective, post-marketing surveillance study investigated the effectiveness and safety of MMF, as induction or maintenance therapy, in LN patients. Primary endpoints were adverse drug reactions (ADRs), changes in renal function from baseline, and relapse rate (RR) after 6 months in the maintenance group, estimated using the Kaplan–Meier method. Complete remission (CR) and partial remission (PR) were estimated by renal measurements. Results Overall, 112 patients were enrolled in the induction group and 340 in the maintenance group. Of these 452 patients, 418 were evaluable for safety and 396 for effectiveness. Eighty-three patients (19.85%) experienced ADRs, most commonly herpes zoster (3.34%) and diarrhoea (3.11%). Serious ADRs occurring in more than three patients were cytomegalovirus infections (1.43%), acute pyelonephritis (0.71%), and herpes zoster (0.71%). One patient died from herpes zoster disseminated. CR and PR were 19.54% and 44.82%, respectively, in the induction group, and 40.62% and 66.16%, respectively, in the maintenance group. RR in the maintenance group was 0.70%. Conclusions The tolerability of MMF is in line with that reported in other studies. Since the average dose of MMF was

ObjectiveThis work aims to evaluate the long-term safety of rituximab (RTX) in primary Sjögren syndrome (pSS) and to determine the safety and the efficacy of long-term treatment with B cell depleting therapy in pSS patients with active systemic disease.MethodsA historical cohort study, enrolling 35 patients with pSS treated with RTX between 2008 and 2019 in a single rheumatologic unit, was performed. When patients experienced adverse events, the treatment was suspended and patients’ data were recorded.ResultsThe included patients were mainly female (91%), with a mean age of 54 years. During the time of observation, 13 patients (37.1%) suspended RTX treatment (10 cases per 100 patient-years, 95% CI 0.06–0.17). Baseline demographics, disease characteristics, European Alliance of Associations for Rheumatology (EULAR) Sjögren’s Syndrome Disease Activity Index (ESSDAI) values, and treatment were comparable across RTX-suspended and nonsuspended groups. Patients exposed to RTX had been followed for 35.82 ± 32.56 months, and the time of observation varied from 6 to 96 months. All the patients except one experienced a significant and persisting meaningful improvement of their ESSDAI (≥ 3 points) during the long-term follow-up. For the duration of the follow-up, 13 (37%) patients discontinued RTX treatment. Four out of 13 (30.8%) discontinued the treatment after the first administration due to infusion-related reactions. During subsequent RTX courses, the main cause of withdrawal was hypogammaglobulinemia onset (7 patients). In 2 patients, hypogammaglobulinemia was associated with severe infections.ConclusionLong-term RTX administration was shown to be a safe, well tolerated, and effective treatment in patients with active systemic disease, significantly reducing ESSDAI and controlling disease activity.

Conflicting results can be found in the literature on the frequency of hepatitis B virus (HBV) reactivation (HBVr) on rituximab (RTX) in rheumatic patients with previously resolved HBV (prHBV) infection. Here, we report the frequency of HBVr in a large historical cohort of caucasian rheumatic patients with prHBV receiving RTX. Registry data of rheumatic patients treated with RTX were retrospectively analysed. Demographic and clinical characteristics including evaluation of anti-HCV and HBV markers, annual HBV-DNA determination and aminotransferase levels assessed every three months, were recorded. Kaplan-Meier estimate was used to compare the risk of being still under therapy at different time points in patients with or without prHBV infection. Cox regression analysis was used to determine the association between recorded variables and treatment discontinuation. A total of 311 patients treated with RTX, 44 (14.1%) with and 267 (85.9%) without prHBV were analysed. No significant difference between the two groups regarding demographic and clinical characteristics was observed. During RTX treatment, detectable HBV-DNA and reappearance of HBsAg in patients with prHBV (seroreversion) were never observed. Kaplan-Meier functions were similar in patients with or without prHBV infection which was not associated with RTX discontinuation neither at univariate nor at multivariate analysis. These data are in favor of the concept that patients with rheumatologic diseases have a very low risk of reactivation of the HBV infection under RTX treatment. However, future prospective studies, including a larger number of patients, are still necessary to draw definitive conclusions.

Background: Dimethyl fumarate (DMF) demonstrated favorable benefit–risk in relapsing-remitting multiple sclerosis (RRMS) patients in phase-III DEFINE and CONFIRM trials, and ENDORSE extension. Objective: The main aim of this study is assessing DMF safety/efficacy up to 13 years in ENDORSE. Methods: Randomized patients received DMF 240 mg twice daily or placebo (PBO; Years 0–2), then DMF (Years 3–10; continuous DMF/DMF or PBO/DMF); maximum follow-up (combined studies), 13 years. Results: By January 2020, 1736 patients enrolled/dosed in ENDORSE (median follow-up 8.76 years (ENDORSE range: 0.04–10.98) in DEFINE/CONFIRM and ENDORSE); 52% treated in ENDORSE for ⩾6 years. Overall, 551 (32%) patients experienced serious adverse events (mostly multiple sclerosis (MS) relapse or fall; one progressive multifocal leukoencephalopathy); 243 (14%) discontinued treatment due to adverse events (4% gastrointestinal (GI) disorders). Rare opportunistic infections, malignancies, and serious herpes zoster occurred, irrespective of lymphocyte count. For DMF/DMF ( n = 501), overall annualized relapse rate (ARR) remained low (0.143 (95% confidence interval (CI), 0.120–0.169)), while for PBO/DMF ( n = 249), ARR decreased after initiating DMF and remained low throughout (ARR 0–2 years, 0.330 (95% CI, 0.266–0.408); overall ARR (ENDORSE, 0.151 (95% CI, 0.118–0.194)). Over 10 years, 72% DMF/DMF and 73% PBO/DMF had no 24-week confirmed disability worsening. Conclusion: Sustained DMF safety/efficacy was observed in patients followed up to 13 years, supporting DMF’s positive benefit/risk profile for long-term RRMS treatment.

PURPOSE To study the safety of extended monthly intravitreal infliximab injections in patients with active posterior uveitis in Behcet's disease. METHODS This is a prospective, interventional, noncomparative, open-label, pilot study of 9 monthly intravitreal infliximab injections (1 mg/0.05 mL) for 22 eyes of 16 patients with active posterior uveitis in Behcet's disease. Control of inflammation and visual outcomes were assessed, and ocular complications were monitored during the study period. RESULTS Successful treatment was achieved in 7 eyes (35%), and failure was encountered in 13 eyes (65%). Only seven eyes of six patients (35%) had completed the study and achieved complete resolution of inflammation with improved best-corrected visual acuity and no complications. Failure was either because of inability to control the inflammation in nine eyes (45%) or development of exacerbation of inflammation in four eyes (20%). Four eyes developed severe immunological reaction from the drug after first (n = 1), second (n = 2), and third (n = 1) injections and had to discontinue the injections. Kaplan-Meier survival analysis showed that the mean estimated time to failure was 3.3 ± 0.2 months, and all failed eyes required revision of their systemic immunotherapy to control the ocular inflammation. CONCLUSION Intravitreal infliximab for active posterior uveitis in Behcet's disease was associated with a high complication rate and failure to control inflammation in most eyes. It should not be considered a substitute to systemic therapy.

Long-term service status of a large-scale arch dam is affected by variations of loads and material properties with randomness and fuzziness. This study aims to resolve the problems of a variety of uncertain variables that coexist in the reliability assessment of arch dams. Firstly, a time-varying non-probabilistic reliability (N-PR) solution method of the arch dams is proposed based on the convex set model. Subsequently, non-probabilistic target reliability indexes are put forward according to the defined probabilistic reliability indexes during long-term operation of the arch dams. Afterwards, a fuzzy prediction index is formulated based on the mixed statistical model and the Info-gap model under the most unfavorable reservoir water depth, so as to timely find defects and avoid the potential failure of the arch dams. Numerical simulation on the Jinping I arch dam is conducted to validate the proposed methods. The possible failure modes and the long-term N-PR of the world’s highest arch dam is appraised, and the fuzzy prediction indexes are concluded. Research results can provide a feasible way for large-scale arch dam reliability and safety assessment.

Rituximab appears to be effective for treating pemphigus, although there are limited long-term data.This retrospective single-center study evaluated patients with conventional treatment-resistant pemphigus who received rituximab during September 2010-December 2019. The first rituximab cycle was based on the rheumatoid arthritis protocol in all patients except one patient, and additional single doses (500 mg or 1000 mg) were administered after clinical and/or serological relapse. The consensus definitions were used for complete remission off therapy, complete remission on minimal therapy, and clinical relapse. Serological relapse was defined as a progressive ≥2-fold increase in anti-desmoglein titers (vs. previous the measurement).The study included 52 patients with pemphigus vulgaris and 1 patient with pemphigus foliaceus. The mean number of infusions was 5 and the average follow-up after the first infusion was 56 months. The average time to clinical and/or serological relapse was 12 months. Complete remission was achieved in 84.9% of patients, including after the first rituximab cycle in 25 patients (47.1%). Two patients died during the follow-up period.Additional rituximab cycles may help achieve and prolong remission in patients with moderate-to-severe pemphigus resistant to conventional therapies. However, prospective trials are needed to identify the optimal dosing protocol.

Resumen Introduccion El angiomiolipoma renal (AMLr) es una manifestacion frecuente del complejo de esclerosis tuberosa (CET), estableciendose, recientemente, el tratamiento con everolimus, como opcion terapeutica novedosa, alternativa y no invasiva; sin embargo, existen datos limitados en la vida real y a largo plazo, por ello, el analisis de nuestra experiencia, en materia de seguridad y eficacia, aporta un valor anadido. Material y metodos Se realiza un analisis descriptivo de nuestra experiencia en pacientes con AMLr bilaterales gigantes, en el contexto de CET, tratados con 10 mg por via oral de everolimus diario, durante una mediana de 71,5 meses. Evaluamos los parametros como: tasa y duracion de la respuesta; reduccion del volumen renal y las lesiones; prevencion de complicaciones, toxicidad presentada y causa. Resultados Confirmamos la efectividad del tratamiento en cuatro pacientes jovenes, con AMLr renales bilaterales, multiples, de 12 (5 a 19) cm de diametro maximo como mediana, desde junio del 2013 hasta la actualidad, con una reduccion continua del tamano de las lesiones, descenso del 30% del volumen, en el 75% al sexto mes y del 50% en la mitad de los sujetos despues dos anos, permaneciendo aun en respuesta. No se presentaron complicaciones como sangrado o deterioro del filtrado glomerular a largo plazo, con un perfil de seguridad favorable, sin interrupciones y con efectos adversos no acumulativos leves a moderados, en su mayoria durante el primer ano de tratamiento. Conclusion Everolimus es una opcion terapeutica segura y eficaz para el AMLr y para diversas manifestaciones del CET, que se reproduce en la vida real, con seis anos de seguimiento.

Background and ObjectiveMyotonic dystrophy types 1 and 2 are progressive multisystem genetic disorders whose core clinical feature is myotonia. Mexiletine, an antagonist of voltage-gated sodium channels, is a recommended antimyotonic agent in the nondystrophic myotonias, but its use in myotonic dystrophy is limited because of lack of data regarding its long-term efficacy and safety profile.MethodsTo address this issue, this study retrospectively evaluated patients with myotonic dystrophy receiving mexiletine over a mean time period of 32.9 months (range 0.1–216 months).ResultsThis study demonstrated that 96% of patients reported some improvement in myotonia symptoms with mexiletine treatment. No clinically relevant cardiac adverse events were associated with the long-term use of mexiletine.ConclusionsThese findings support that mexiletine is both safe and effective when used long-term in myotonic dystrophy.Classification of EvidenceThis study provides Class IV evidence that mexiletine is a well-tolerated and effective treatment for myotonic dystrophy types 1 and 2.

On freeways with high traffic demand, hard shoulder running (HSR) can be an effective traffic management measure to increase the capacity by providing an additional travel lane during peak hours. While the positive effects of HSR on traffic flow quality were documented in several studies, the implications of HSR on road safety are more ambiguous. This paper presents results of a study in which accident data for seven freeway sections with HSR on freeways in Germany were analyzed over a long period of 13 years. All investigated sections are equipped with variable speed limits. The evaluation of crash frequencies on the investigated freeway sections revealed a high safety level. By combining crash data and traffic data it is shown that crash occurrence depends on the prevailing traffic conditions, with congestion being the most critical traffic state in relation to safety. Therefore, safety improvements upstream of HSR segments can be related to the improved traffic flow and the reduction of congestion. In conclusion, the results of the investigation provide evidence that the implementation of HSR can improve road safety if state-of-the-art traffic control technology is applied and congestion can be relieved.

Introduction BAY 94‐9027 (damoctocog alfa pegol; an extended half‐life PEGylated recombinant factor VIII [FVIII]) demonstrated efficacy and safety in previously treated paediatric patients (PTPs) aged

We examined long-term risks and predictors of mesh erosion and reoperation following mid urethral sling procedure for stress urinary incontinence.Women aged 18 years or older who received a mid urethral sling for stress urinary incontinence between 2008 and 2016 in outpatient surgical settings in New York State were included in our study. Those who underwent concomitant mesh pelvic organ prolapse repair were excluded. Primary outcomes were post-implantation time to erosion and reoperations. Kaplan-Meier analysis and Cox proportional hazard models were used to assess the risks of erosion diagnosis and reoperation.Our cohort included 36,195 women with a mean±SD age of 53.7±12.4 years. Estimated risks of erosions and reoperations at 7 years after sling procedures were 3.7% and 6.7%, respectively. Older age (≥65 vs65: HR 0.83, 95% CI 0.70-0.99) and high volume facilities (high vs low: HR 0.79, 95% CI 0.68-0.92) were associated with a lower risk of erosion. History of hysterectomy was associated with a higher risk of erosion (HR 1.62, 95% CI 1.36-1.92). Predictors of reoperation included concurrent abdominal or native tissue transvaginal prolapse repair, previous hysterectomy and depression.One in 27 women had sling erosions and 1 in 15 had invasive reoperations at 7 years after sling procedures. The highest erosion cases were observed among younger White women treated at low volume facilities. Continued and vigilant surveillance of mesh in stress urinary incontinence repairs, the nature and burden of stress urinary incontinence recurrence, different types of re-treatment, patient reported outcomes and information about treating surgeons are crucial.

Background To evaluate the long-term safety and efficacy of rilpivirine (RPV), a non-nucleoside reverse transcriptase inhibitor (NNRTI), in combination with nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) in human immunodeficiency virus (HIV)–infected patients. Methods RPV-treated HIV-infected patients from phase 2b or 3 studies rolled-over into this phase 3, open-label study and received RPV 25 mg once daily (QD) with choice of two NRTIs. Adverse events (AEs), plasma viral load, CD4+ cell count, and antiviral resistance were evaluated. Results Of the 482 patients treated, 437 (>90%) patients discontinued study treatment; 371 (77%) had switched to commercially available RPV, 14 (2.9%) discontinued due to AEs, and 6 (1.2%) had virologic failure. In this rollover study, patients were followed up to week 336, although data was limited beyond 288 weeks. Forty-five (9.3%) patients were still undergoing treatment at the time of data cut-off for the current analysis (8 February 2018). The most frequently reported AEs were pregnancy in 7 (1.5%) patients and syphilis in 5 (1.0%) patients. Grade 3–4 AEs were reported in 17 (3.5%) patients, and AEs possibly related to RPV in 23 (4.8%) patients. Over 288 weeks of treatment, 80.1% (95% CI: 74.9%; 84.3%) of patients maintained virologic suppression (HIV-1 RNA + cell count increased over time until week 192 and remained constant thereafter. Conclusions RPV 25 mg QD in combination with an investigator-selected background regimen of two NRTIs demonstrated sustained long-term virologic suppression. The treatment was well-tolerated with no new safety findings.

Background Long-term transmural double-pigtail stent (DPS) placement is recommended for patients with disconnected pancreatic duct syndrome (DPDS) and peripancreatic fluid collections (peri-PFCs). The long-term safety and efficacy of indwelling DPSs were evaluated. Methods Medical files of patients treated with DPS for DPDS-associated peri-PFC and with a follow-up ≥ 48 months were reviewed. Early ( Results From 2002 to 2014 we identified 116 patients, with mean (SD) follow-up of 80.6 (34.4) months. Among early complications (n = 20), 6 occurred peri-interventionally. Late complications (n = 17) were mainly pain due to DPS-induced ulcer or erosion (n = 10) and 14 of these were treated conservatively or by stent removal; 2 gastro-pancreatico-colo-cutaneous fistulas and 1 persisting bleed required surgical intervention. No DPS-related deaths were recorded. The incidence rate (95 %CI) of late complications was 2.18 (1.27–3.49) per 100 patient-years of follow-up. Short- and long-term success rates (with 95 %CI) of endoscopic treatment were 97.4 % (94.5 %–100 %) and 94 % (89.6 %–98.3 %), respectively. The peri-PFC recurrence rate was 28 % (20.1 %–35.9 %), and 92.3 % of these occurred within the first 2 years. Stent migration, chronic pancreatitis, and length of stent (> 6 cm) were independently associated with higher rates of peri-PFC recurrence. Conclusions Long-term transmural drainage with DPS is a safe and effective treatment for DPDS-associated peri-PFCs. However, about one quarter of peri-PFCs will recur.

고준위방사성폐기물의 심층처분 개념에서 처분장은 처분 후 수만 년에서 수십만 년 동안 방사성 핵종을 고립시키거나 그 이동을 지연시켜야 하기 때문에 장기 안전성 평가가 필수적이다. 이 연구에서는, 고준위방사성폐기물 지하 처분장의 장기 안전성과 관련한 지구조 및 지질환경 진화에 관한 연구들을 검토하였다. 핀란드, 스웨덴, 그리고 일본 등 원자력 선도국들의 연구를 살펴보면, 각 국은 자국의 지리 및 지질환경 특성에 따라 다양한 방식으로 지질환경 진화 연구를 수행하였다. 향후 심층처분을 위하여 진행될 국내 장기 지질환경 진화 연구 역시, 안전성 확보가 중점적으로 필요한 분야를 선정하고 관련 기술을 개발하는 데에 있어 한반도의 지리 및 지질환경 특성을 고려함으로써 한반도 지질환경에 적합한 효율적인 기술개발이 가능할 것으로 생각된다. 이에 따라 처분 관련 지질환경 진화를 연구하기 위해 고려하여야 할 한반도의 지리 및 지질환경 특성을 토의하였다.

SGLT-2 inhibitors have recently emerged as an important class of oral drugs for treatment of type 2 diabetes mellitus, especially in patients with cardiovascular or renal impairment, recommended in all recent treatment guidelines. They have additional advantages of weight and blood pressure reduction but also pose problems like genitourinary infections. These drugs generally have a high cost making affordability a major consideration in their prescription in developing countries like India. A new molecule remogliflozin has been approved in India in 2019 after a phase 3 trial proved its efficacy and safety in comparison to dapagliflozin. This drug has been priced substantially lower than other SGLT-2 inhibitors, and despite the disadvantage of twice daily administration, it potentially reduces treatment cost to less than half compared to other molecules of this class. With a good tolerability profile on the basis of available safety data till date, remogliflozin could be a useful alternative for providing SGLT-2 inhibitor therapy in a country like India where out of pocket expenses for drug acquisition matter significantly for the general population. However, long term safety and efficacy data especially on cardiovascular and renal outcomes are currently lacking for the drug.

Background and Objectives Topiroxostat, a selective xanthine oxidoreductase inhibitor, is used for the management of hyperuricemic patients with or without gout in Japan. Accumulating evidence has demonstrated the efficacy of topiroxostat for the treatment of hyperuricemia with or without gout. However, the safety and efficacy of topiroxostat in the clinical setting remain unclear, and there is little large-scale clinical evidence. We conducted a post-marketing observational study over 54 weeks. Patients and Methods Patients were centrally enrolled, and case report forms of 4491 patients were collected between April 2014 and March 2019 from 825 medical sites. Results Overall, 4329 patients were assessed for safety and 4253 patients for effectiveness. The overall incidence of adverse drug reactions was 6.95%, and the incidence rates of adverse drug reactions of gouty arthritis, hepatic dysfunction, and skin disorders, which are of special interest in this study, were 0.79%, 1.73%, and 0.95%, respectively. No case of serious gouty arthritis was observed. Serum urate levels decreased stably over time and showed a significant reduction rate at 54 weeks (21.19% ± 22.07%) and on the final visit (19.91% ± 23.35%) compared to the baseline. The rates for subjects who achieved serum uric acid levels ≤ 6.0 mg/dL at 18 and 54 weeks after administration were 43.80% and 48.28%, respectively. Conclusions This study suggests that there is no particular concern about adverse drug reactions or the efficacy of topiroxostat for hyperuricemic patients with or without gout in a post-marketing setting in Japan. Electronic supplementary material The online version of this article (10.1007/s40261-020-00941-3) contains supplementary material, which is available to authorized users.

BACKGROUND This study is the first to evaluate the short-term efficacy and long-term safety of AZD0585, a mixture of omega-3 free fatty acids, in Japanese patients with dyslipidemia.Methods and Results:In this randomized double-blind placebo-controlled Phase III study, 383 patients were randomized to 2 g AZD0585, 4 g AZD0585, or placebo once daily for 52 weeks. Eligible patients had low-density lipoprotein cholesterol (LDL-C) levels controlled regardless of statin use, and triglyceride levels between 150 and 499 mg/dL. The least-squares (LS) mean percentage changes in triglyceride concentrations from baseline to the 12-week endpoint (mean of measurements at Weeks 10 and 12) in the 2 and 4 g AZD0585 and placebo groups were -15.57%, -21.75%, and 11.15% respectively (P

Long-term safety and efficacy data of extended half-life factor IX (FIX) prophylaxis in children with hemophilia B (HB) are sparse. paradigm 5 is a multinational, open-label, single-arm, phase III trial assessing once-weekly (40 IU/kg) prophylactic nonacog beta pegol (N9-GP) in previously treated patients (PTPs) aged ≤ 12 years with HB (FIX activity ≤ 2%). Primary endpoint: incidence of anti-FIX inhibitory antibodies (≥ 0.6 Bethesda Units). We present a 5-year analysis (N = 25, including remaining patients with ≥ 5 years' follow-up) and compare with a 1-year analysis (≥ 52 weeks' exposure). The main phase enrolled 25 children; 22 entered the extension phase; 17 remained in trial at data cutoff. Median treatment period: 5.6 years/patient; median total number of N9-GP exposure days: 290.0/patient. No patients developed anti-FIX inhibitory antibodies. No other safety concerns, including thromboembolic events, were reported. Neurological examinations have not revealed any new abnormal findings. Sixteen (64.0%) patients remained free from spontaneous bleeds; all bleeds were mild/moderate in severity; 93.0% were controlled with 1 to 2 N9-GP injections. No intracranial hemorrhages were reported. Annualized bleeding rates (ABRs) were very low at 5 years (median/Poisson-estimated mean overall ABR: 0.66/0.99), having decreased from the 1-year analysis (1.00/1.44). Median/Poisson-estimated mean spontaneous ABRs for the 1- and 5-year analyses: 0.00/0.45 and 0.00/0.33. Mean FIX trough activity at 5 years: 17.9%. Mean polyethylene glycol plasma concentration reached steady state at 6 months, increasing slightly over time, in line with increased FIX trough activity. N9-GP administered for ≥ 5 years shows favorable long-term safety and efficacy in PTPs with HB (FIX activity ≤ 2%).

Background An international, multicenter extension study evaluated recombinant fusion protein linking recombinant coagulation factor IX (FIX) with recombinant human albumin (rIX‐FP) in hemophilia B (FIX ≤ 2%) patients previously enrolled in a phase III study or who initiated rIX‐FP prophylaxis following surgery. Objectives To investigate the long‐term safety and efficacy of rIX‐FP prophylaxis in adult previously treated patients (PTPs) with hemophilia B. Methods Male PTPs were treated with a 7‐ (35‐50 IU/kg), 10‐ or 14‐day regimen (50‐75 IU/kg). Patients ≥18 years who were well‐controlled on a 14‐day regimen for ≥6 months could switch to a 21‐day regimen (100 IU/kg). Results A total of 59 patients (aged 13‐63 years) participated in the study. Following a single dose of 100 IU/kg rIX‐FP, in patients eligible for the 21‐day regimen, the mean terminal half‐life was 143.2 hours. Mean steady‐state FIX trough activity levels ranged from 22% with the 7‐day regimen to 7.6% with the 21‐day regimen. Median (Q1, Q3) annualized spontaneous bleeding rates were 0.00 (0.00, 1.67), 0.28 (0.00, 1.10), 0.37 (0.00, 1.68), and 0.00 (0.00, 0.45) for the 7‐, 10‐, 14‐, and 21‐day regimens, respectively. Comparable efficacy was demonstrated for both the 14‐ and 21‐day regimens compared to the 7‐day regimen. Overall, 96.5% of bleeding episodes were treated successfully with 1 to 2 rIX‐FP infusions. No patients developed an inhibitor and treatment was well tolerated. Conclusions rIX‐FP extended interval prophylaxis provides dosing flexibility and, in selected patients, a 21‐day regimen may provide an alternative option to minimize treatment burden and individualize treatment.

Objective: To evaluate the long-term safety and effectiveness of biosimilar insulin glargine (GLY) in real-world clinical practice.Methods: This prospective, non-interventional, multicenter, observ...

This study aimed to characterize the safety and effectiveness of GH treatments, in usual clinical practice, in children with short stature born small for gestational age (SGA). This was a multicenter, open-label, non-interventional study (NCT01110928) conducted at 150 sites in Japan (2009–2018). The primary objective was to assess the type and frequency of serious adverse drug reactions (SADRs) associated with long-term GH use. Overall, 452 naïve and 46 non-naïve (previously treated) children were enrolled. GH treatment was well‑tolerated, with SADRs occurring in 1.3% (6/452) and 0% (0/46) of naïve and non-naïve children, respectively. No new safety concerns or notable changes in glucose metabolism were identified during long-term treatment. Altogether, 57 children (32 naïve and 25 non-naïve) reached near adult height (NAH). In naïve and non-naïve children, mean ± standard deviation (SD) height standard deviation score (SDS) at NAH were –2.03 ± 0.77 and –1.53 ± 0.81, respectively, representing a change of +0.85 ± 0.72 and +1.24 ± 0.66 from baseline height SDS, respectively. Mean treatment duration to NAH was 4.29 (naïve) and 7.26 (non-naïve) yr. Thus, long-term GH treatment for short stature in children born SGA was confirmed to have a good safety profile and was effective for improving adult height.

The laparoscopic sacrocolpopexy (LSC) is performed to support DeLancey’s level I in patients with pelvic organ prolapse (POP). Although several studies have been conducted on the safety, objective and subjective outcomes of LSC, the specific effect of retroperitonealisation of mesh is unknown. This study is aimed at analysing the safety, objective and subjective outcomes of the LSC without peritoneal closure of mesh. The patients included have undergone an LSC for POP between 2004 and 2014. Retrospectively, a cohort of n = 178 was identified and asked to participate in a follow-up study. Chart research was performed. When informed consent was obtained, questionnaires were sent and the patients underwent a physical examination, including a POP-Q assessment. Each complication was scored by four reviewers for possibly being related to the non-peritonealisation of mesh. The data on the outcome cohorts were complete for safety n = 178, objective n = 124, and subjective n = 61. The Patient Global Impression of Improvement (PGI-I) score is provided in 106 questionnaires. In this study, 77 complications were observed in 49 different patients. The total success rate (no reoperation, no descent beyond the hymen and no bulging symptoms) is 59.0% with a median follow-up (IQR) of 35 months (18–51). Seventy-six patients (71.7%) described their condition as being (much) improved after LSC. Three serious complications observed during the 178 LSCs were, by full consensus, thought to be possibly related to the non-peritonealisation of mesh. More than 70% of the patients found their condition to be (much) improved after the procedure.

This post-marketing surveillance is to investigate the long-term safety and effectiveness of the growth hormone receptor antagonist pegvisomant, which is used in patients with acromegaly in routine clinical practice. This surveillance included all cases treated with pegvisomant during the study period from the start of marketing (June 5, 2007) to December 2015. Data for 251 patients with acromegaly treated with pegvisomant were collected from 119 institutions nationwide in Japan. Eighty-five patients received pegvisomant monotherapy throughout their treatment, while 165 patients were treated with somatostatin analogue or dopamine agonist in combination with pegvisomant. Mean dose of pegvisomant was 10.6 ± 6.1 mg/day in the entire treatment period (except for initial loading dose). The incidence of adverse drug reactions was 35.6% (89/250). No new safety concerns related to long-term treatment were observed. The major investigation items of incidence of abnormal liver function and tumor enlargement were 16.0% (40/250), and 5.2% (13/250) respectively. Efficacy at the final evaluation point was 96.4% (217/225) based on the overall clinical judgement of attending physicians, and efficacy in each observation period was over 94%. Improvement in IGF-I levels and clinical symptoms scores were also observed by comparing the data at baseline with each observation point during treatment. IGF-I normalization rate was 68.2% at 5 years. Pegvisomant monotherapy showed similar improvement here as well. These results suggest that long-term treatment with pegvisomant is effective in clinical practice.

Introduction Diquafosol is a P2Y2 receptor agonist that has been shown to be effective in the treatment of dry eye disease (DED) in short-term studies; however, its long-term safety and effectiveness have not been evaluated in a real-world setting. Methods This prospective, multicentre, open-label observational study was conducted in patients with DED over 12 months. Safety endpoints included the incidence of adverse drug reactions (ADRs) and serious ADRs. Effectiveness endpoints included change from baseline in keratoconjunctival staining score, tear film break-up time (BUT) and Dry Eye-related Quality of Life Score (DEQS). Results A total of 580 patients were included, most of whom were female (82.9%). The proportion of patients who completed 12 months of observation was 55.0%, the most common reason for discontinuation was patient decision (54.6%). The incidence of ADRs was 10.7% and was highest during the first month of treatment (5.5%); no serious ADRs were reported. Compared with baseline, significant improvements in all effectiveness outcomes, including keratoconjunctival fluorescein staining score, BUT and DEQS summary score, were observed at each evaluation during the treatment period (p

In principle, mandatory vaccination in employment could be justified in certain circumstances. These include: (1) the availability of safe and effective vaccination; (2) if alternative, less coercive strategies did not work; and, (3) the costs to the individual were proportionate. However, in COVID-19, the long term safety of vaccines is yet to be established. Vaccines should be made available by employers, and voluntary vaccination encouraged.

Backgound/Introduction In phase I KAT301 trial, adenovirus-mediated intramyocardial vascular endothelial growth factor-DΔNΔC (VEGF-D) gene therapy (GT) resulted in a significant improvement in myocardial perfusion reserve and relieved angina at 1-year follow-up without major safety concerns. Purpose Our objective was to investigate the long-term safety and efficacy of AdVEGF-D GT. A total of 30 patients (24 VEGF-D and 6 randomized and blinded controls) participated in KAT301 trial. Methods The mean follow-up time was 8.2 years (range 6.3–10.4 years). Patients were interviewed for the current severity of symptoms (Canadian Cardiovascular Society class, CCS) and perceived benefit from GT. Medical records were reviewed to assess the incidence of major cardiovascular adverse events (MACEs) and other predefined endpoints including cancer. Results MACE occurred in 15 patients in VEGF-D group and in five patients in control group (21.5 vs. 24.9 per 100 patient-years; hazard ratio 0.90; 95% confidence interval 0.09–9.32; P=0.95). Mortality and comorbidity were similar between the groups. Angina symptoms (CCS) were less severe compared to baseline in VEGF-D group (1.9 vs. 2.9; P=0.006) but not in control group (2.2 vs. 2.6; P=0.414). Conclusion(s) Our study indicates that intramyocardial AdVEGF-D GT is safe in the long-term. In addition, the relief of symptoms remained significant during the follow-up. Funding Acknowledgement Type of funding sources: Public hospital(s). Main funding source(s): Kuopio University Hospital Heart Center Figure 1. The incidence of MACEFigure 2. CCS class

Introduction Adeno-associated virus (AAV)-based gene therapy for haemophilia presents a challenge to the existing structure of haemophilia centres and requires a rethink of current collaboration and information exchange with the aim of ensuring a system that is fit-for-purpose for advanced therapies to maximise benefits and minimise risks. In Europe, a certification process based on the number of patients and facilities is offered to the haemophilia centres by European Haemophilia Network (EUHANET). Aim and methods This joint European Association for Haemophilia and Allied Disorders (EAHAD) and European Haemophilia Consortium (EHC) publication describes criteria for centres participating in gene therapy care that require a reassessment of the infrastructure of comprehensive care and provides an outlook on how these criteria can be implemented in the future work of haemophilia centres. Results The core definition of a haemophilia treatment centre remains, but additional roles could be implemented. A modifiable ‘hub-and-spoke’ model addresses all aspects associated with gene therapy, including preparation and administration of the gene therapy product, determination of coagulation and immunological parameters, joint score and function, and liver health. This will also include the strategy on how to follow-up patients for a long-term safety and efficacy surveillance. Conclusion We propose a modifiable, networked ‘hub and spoke’ model with a long term safety and efficacy surveillance system. This approach will be progressively developed with the goal of making haemophilia centres better qualified to deliver gene therapy and to make gene therapy accessible to all persons with haemophilia, irrespective of their country or centre of origin.

Cladribine is currently registered as a 10-milligram tablet formulation with a fixed cumulative dosage of 3.5 mg/kg over 2 years. It is important to investigate if an increased dosage may lead to further clinical stability with preserved safety. This study used an off-label subcutaneous (s.c.) formulation of cladribine and compared outcomes (Expanded Disability Status Scale (EDSS) scores and disease progression) between 52 relapsing multiple sclerosis (RMS) patients receiving different s.c. dosing regimens with up to 20 years of follow-up. The study group received induction therapy with s.c. cladribine (1.8 mg/kg cumulative dose, consistent with 3.5 mg/kg of cladribine tablets). Patients were subsequently offered maintenance therapy (repeated courses of 0.3 mg/kg s.c. cladribine during 5–20-year follow-up). Forty-one patients received an increased cumulative dose (higher than the induction dose of 1.8 mg/kg), 11 received the standard induction dose. Risk of progression on the EDSS correlated with lower cumulative dose (p &lt, 0.05) and more advanced disability at treatment initiation (p &lt, 0.05) as assessed by EDSS change between year 1 and years 5 and 10 as the last follow-up. Maintenance treatment was safe and well-tolerated, based on limited source data. Subcutaneous cladribine with increased cumulative maintenance dosage was associated with disease stability and favorable safety over a prolonged period of follow-up (up to 20 years) in RMS patients.

Purpose The purpose of this study was to systematically search for long-term complications, including Nephrogenic Systemic Fibrosis (NSF), in patients who were previously administered the gadolinium-based contrast agent Gadofosveset at our institute. Materials and methods All patients who were administered Gadofosveset at our institute between 2006 and 2009 were identified in our Radiological Information System (RIS). Clinical data such as cause of death during follow-up, and dermatological or nephrological diseases were systematically searched for in electronic patient records (EPR). Results During 2006–2009, Gadofosveset was administered a total of 67 times to 62 patients. One patient was unavailable for follow-up. The remaining 61 patients were followed up for up to 14 (median 12) years based on RIS and EPR data. There were 13 deaths among the 61 patients, all assessed as unrelated to Gadofosveset administration. No dermatological or renal disease suggestive of NSF, or potentially related to Gadofosveset administration, was found. At the time of examination, six patients were diagnosed with various stages of renal insufficiency, three of whom were on hemodialysis. Another three patients were diagnosed with renal insufficiency during the follow-up period, but none of these diagnoses were suspected to be related to the administration of Gadofosveset. Conclusions Based on the results of this retrospective safety analysis of up to 14 years following 1–2 exposures, we conclude that Gadofosveset in clinical practice is safe in the long-term.

Purpose: To examine patterns of standard (trabeculectomy or glaucoma drainage devices, GDDs) vs novel (minimally invasive glaucoma surgery, MIGS) surgical techniques in the US.Methods: We used the American Academy of Ophthalmology (AAO) IRIS® Registry (Intelligent Research in Sight) queried between 2013 and 2018 (inclusive) to calculate the cumulative proportion of stand-alone, concurrent (same day) or sequential (subsequent day) glaucoma surgical techniques performed in each glaucoma diagnosis type. Secondary analyses of adjusted proportions of concurrent and sequential surgeries stratified by glaucoma diagnosis were also performed.Results: Of 203,146 eyes receiving glaucoma surgeries, open angle glaucoma (OAG) was most likely to undergo all types of intervention. The iStent was the most commonly performed MIGS, primarily for those with normal tension glaucoma (NTG) or OAG (p < .001). Conversely, GDD was the most commonly performed procedure in secondary glaucoma or other (specified) glaucoma (p < .001). ECP and iStent were the most common concurrent procedures performed; most often for OAG and NTG (p < .001). After an initial standard surgery, most eyes underwent recurrent standard interventions (90.3%). ECP was the most common MIGS performed after an initial standard surgery; particularly in primary angle-closure (PACG) and secondary glaucoma eyes (p < .001).Conclusion: Glaucoma type may influence the choice of glaucoma procedures and the decision to perform concurrent as well sequential surgical procedures. Given the poorly understood long term safety and effectiveness of MIGS, and with substantially increasing use of MIGS procedures in recent years, future studies comparing their safety and effectiveness vs standard interventions, for a variety of glaucoma types, is needed.

The primary objective of this trial (SP1042; NCT02582866) was to assess long‐term safety and tolerability of lacosamide monotherapy (200‐600 mg/day) in adults with focal (partial‐onset) seizures or generalized tonic‐clonic seizures (without clear focal origin). This Phase III, long‐term, open‐label, multicenter, follow‐up trial enrolled patients with epilepsy who were taking lacosamide in, and completed, the previous double‐blind trial (SP0994; NCT01465997). Primary safety outcomes were treatment‐emergent adverse events (TEAEs), discontinuations due to TEAEs, and serious TEAEs. One hundred and six patients were enrolled and received lacosamide: 84 (79.2%) completed the trial and 22 (20.8%) discontinued. The median duration of exposure was 854.0 days, with a median modal dose of 200 mg/day. Ninety‐six (90.6%), 64 (60.4%), and 44 (41.5%) patients had ≥12, ≥24, and ≥36 months of lacosamide exposure, respectively. At least one TEAE was reported by 61 (57.5%) patients. The most common (≥4%) TEAEs were headache (10 [9.4%]), nasopharyngitis (eight [7.5%]), and back pain (five [4.7%]). One (0.9%) patient discontinued due to a TEAE (sudden unexpected death in epilepsy; not considered drug‐related), 14 (13.2%) patients reported serious TEAEs, and seven (6.6%) patients reported TEAEs that were considered drug‐related. Overall, long‐term lacosamide monotherapy was generally well tolerated up to 600 mg/day, with no new safety signals identified.