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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

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.

Introduction: Hypofractionated stereotactic radiotherapy (hSRT) has emerged as an alternative to single-fraction stereotactic radiosurgery (SRS) and conventionally fractionated radiotherapy for the treatment of intracranial meningiomas (ICMs). However, there is a need for data showing long-term efficacy and complication rates, particularly for larger tumors in sensitive locations. Methods: A retrospective review was conducted on adult patients with ICMs seen at a tertiary care center. Eligible patients were treated with the CyberKnife platform and had a planned treatment course of 3–5 fractions from 2011–2020. The local control was assessed based on radiographic stability and the late toxicity/radionecrosis rates were recorded. Radiographic progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan–Meier method. Results: In total, 62 patients (age 26–87) with 67 treated tumors were included in this study with a median follow-up of 64.7 months. RT was delivered as the primary treatment in 62.7% of cases and for recurrence in 37.3%. The most common tumor locations were the convexity of the brain and the base of the skull. The tumor sizes ranged from 0.1–51.8 cc and the median planning target volume was 4.9 cc. The most common treatment schedule was 18 Gy in 3 fractions. The five-year PFS and OS were 85.2% and 91.0%, respectively. The late grade III/IV toxicity rate was 3.2% and the radionecrosis rate was 4.8%. Conclusions: Based on our data, hSRT remains an effective modality to treat low-grade ICMs with acceptable long-term toxicity and radionecrosis rates. hSRT should be offered to patients who are not ideal candidates for SRS while preserving the benefits of hypofractionation.

Background: Azithromycin maintenance therapy is widely used in cystic fibrosis (CF), but little is known about its long-term safety. We investigated whether chronic azithromycin use is safe regarding renal function, hepatic cell toxicity and QTc-interval prolongation. Methods: Adult CF patients (72 patients using azithromycin for a cumulative period of 364.8 years and 19 controls, 108.8 years) from two CF-centers in the Netherlands with azithromycin (non)-use for at least three uninterrupted years were studied retrospectively. Results: There was no difference in mean decline of estimated glomerular filtration rate (eGFR), nor in occurrence of eGFR-events. No drug-induced liver injury could be attributed to azithromycin. Of the 39 azithromycin users of whom an ECG was available, 4/39 (10.3%) had borderline and 4/39 (10.3%) prolonged QTc-intervals, with 7/8 patients using other QTc-prolonging medication. Of the control patients 1/6 (16.7%) had a borderline QTc-interval, without using other QTc-prolonging medication. No cardiac arrhythmias were observed. Conclusion: We observed no renal or hepatic toxicity, nor cardiac arrythmias during azithromycin use in CF patients for a mean study duration of more than 5 years. One should be aware of possible QTc-interval prolongation, in particular in patients using other QTc-interval prolonging medication.

Understanding the long-term benefits and risks of treatments, devices, and vaccines is critically important for individual- and population-level healthcare decision-making. Extension studies, or ‘roll-over studies,’ are studies that allow for patients participating in a parent clinical trial to ‘roll-over’ into a subsequent related study to continue to observe and measure long-term safety, tolerability, and/or effectiveness. These designs are not new and are often used as an approach to satisfy regulatory post-approval safety requirements. However, designs using traditional clinical trial infrastructure can be expensive and burdensome to conduct, particularly, when following patients for many years post trial completion. Given the increasing availability and access of real-world data (RWD) sources, direct-to-patient technologies, and novel real-world study designs, there are more cost-efficient approaches to conducting extension studies while assessing important long-term outcomes. Here, we describe various fit-for-purpose design options for extension studies, discuss related methodological considerations, and provide scientific and operational guidance on practices when planning to conduct an extension study using RWD. This manuscript is endorsed by the International Society for Pharmacoepidemiology (ISPE).

Patients in the GEMINI 1 or 2 study ({"type":"clinical-trial","attrs":{"text":"NCT00790933","term_id":"NCT00790933"}}NCT00790933; Eudra CT2008‐002784‐14) with ulcerative colitis or Crohn disease had low immunogenicity rates after vedolizumab treatment for up to 52 weeks. We report immunogenicity rates from the GEMINI long‐term safety (LTS) study using a new drug‐tolerant electrochemiluminescence assay, including analyses in patients who received continuous vedolizumab induction and maintenance in GEMINI 1 or 2 and long term safety, or vedolizumab induction and placebo maintenance in GEMINI 1 or 2 followed by re‐treatment in long term safety (treatment interruption). Patients were enrolled in GEMINI long term safety from GEMINI 1, 2, or 3, or as de novo vedolizumab‐treated patients; all received vedolizumab 300 mg intravenously every 4 weeks. Vedolizumab antidrug antibody (ADA) status was determined by electrochemiluminescence assay; ADA‐positive samples were characterized by neutralizing activity. Vedolizumab ADA data were available for 1753 patients: 1513 continuously treated with vedolizumab before/during GEMINI long term safety, 240 re‐treated after treatment interruption. Among continuously treated patients, 36 (2.4%) were ADA positive (15 persistently, 20 neutralizing ADA positive). Among re‐treated patients, 53 (22.1%) were ADA positive (42 persistently, 40 neutralizing ADA positive). Longitudinal immunogenicity rates increased during placebo maintenance (19.4% at week 52), then decreased in GEMINI long term safety to rates (0 at the final visit) similar to continuously treated patients. ADA positivity was 1.1% vs 2.5% (continuous treatment) and 23.1% vs 22.0% (re‐treatment) among patients with and without infusion‐related reactions, respectively. Long‐term vedolizumab treatment was associated with generally low immunogenicity rates; vedolizumab–re‐treated patients had higher rates during placebo maintenance, which decreased during re‐treatment. No relationship was observed between immunogenicity and infusion‐related reactions.

Context Growth hormone (GH) treatment has a generally good safety profile; however, concerns about increased mortality risk in adulthood have been raised. Objective This work aims to assess the long-term safety of GH treatment in clinical practice. Methods Data were collected from 676 clinics participating in 2 multicenter longitudinal observational studies: the NordiNet International Outcome Study (2006-2016, Europe) and ANSWER Program (2002-2016, USA). Pediatric patients treated with GH were classified into 3 risk groups based on diagnosis. Intervention consisted of daily GH treatment, and main outcome measures included incidence rates (events/1000 patient-years) of adverse drug reactions (ADRs), serious adverse events (SAEs), and serious ADRs, and their relationship to GH dose. Results The combined studies comprised 37 702 patients (68.4% in low-risk, 27.5% in intermediate-risk, and 4.1% in high-risk groups) and 130 476 patient-years of exposure. The low-risk group included children born small for gestational age (SGA; 20.7%) and non-SGA children (eg, with GH deficiency; 79.3%). Average GH dose up to the first adverse event (AE) decreased with increasing risk category. Patients without AEs received higher average GH doses than patients with more than one AE across all groups. A significant inverse relationship with GH dose was shown for ADR and SAE incidence rates in the low-risk group (P = .003 and P = .001, respectively) and the non-SGA subgroup (both P = .002), and for SAEs in the intermediate- and high-risk groups (P = .002 and P = .05, respectively). Conclusions We observed no indication of increased mortality risk nor AE incidence related to GH dose in any risk group. A short visual summary of our work is available (1).

Introduction: The phase 2/3 PROTECT VIII main study demonstrated efficacy and safety of BAY 94–9027 (damoctocog alfa pegol; Jivi®), a B-domain-deleted recombinant factor VIII (FVIII), site-specifically PEGylated to extend its half-life. Aim: To report the final efficacy and safety data for BAY 94–9027 from the PROTECT VIII extension. Methods: Previously treated males aged 12–65 years with severe haemophilia A (FVIII

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.

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

John Sheppard,1 Mark Bergmann,2 Barry A Schechter,3 Jodi Luchs,4 Abayomi Ogundele,5 Paul Karpecki6 1Virginia Eye Consultants, Norfolk, VA, USA; 2Apex Eye, Cincinnati, OH, USA; 3Florida Eye Microsurgical Institute, Boynton Beach, FL, USA; 4Florida Vision Institute, West Palm Beach, FL, USA; 5Medical Affairs, Sun Pharmaceutical Industries, Inc, Princeton, NJ, USA; 6Kentucky Eye Institute, Lexington, KY, USACorrespondence: John SheppardVirginia Eye Consultants, Suite #210, 241 Corporate Blvd, Norfolk, VA 23502, USATel +1 757 226-8021Email jsheppard@cvphealth.comBackground: OTX-101 is approved for treatment of keratoconjunctivitis sicca (KCS). We present results of a phase 3 worse-eye efficacy analysis and 1-year safety extension.Methods: During the double-masked treatment phase, patients with bilateral KCS were randomized 1:1 to 12 weeks OTX-101 or vehicle 1 drop per eye twice daily. Efficacy assessments included Schirmer’s test and corneal and conjunctival staining. All patients who completed the treatment phase were eligible for enrollment in the open-label extension and received 1 drop OTX-101 twice daily for up to 52 weeks. Safety endpoints included adverse event (AE) monitoring, Snellen visual acuity (VA), intraocular pressure (IOP), slit-lamp examination (SLE), and dilated fundoscopy.Results: Overall, 745 and 258 patients enrolled in the treatment and safety extension phases, respectively. At 12 weeks, number (%) of patients with Schirmer’s score increase of ≥ 10 mm from baseline was 76 (20.5%) vs. 42 (11.3%) for OTX-101 vs. vehicle (P=0.0005). OTX-101 significantly improved total conjunctival staining vs. vehicle at week 12 (least squares mean change from baseline − 1.65 [0.12] vs. − 1.12 [0.12], P=0.0013), and number (%) of patients with clear central corneas vs. vehicle at week 12 (222 [64.0%] vs. 199 [55.3%], P=0.0179). In the 1-year safety extension, AEs were mostly mild; instillation site pain was most common in 59 (22.9%) patients (17 [13.2%] vs. 42 [32.6%] patients receiving prior OTX-101 and vehicle). No safety concerns were raised by VA, IOP, SLE, and fundoscopy.Conclusion: OTX-101 efficacy was confirmed in the eye with lower baseline Schirmer’s score. OTX-101 was well tolerated long term.Clinical Trial: Registered at ClinicalTrials.gov on July 27, 2016. NCT02845674 https://clinicaltrials.gov/ct2/show/NCT02845674?term=OTX-101&draw=2&rank=1.Keywords: cyclosporine A, dry-eye disease, keratoconjunctivitis sicca; KCS, OTX-101

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.

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 Hyperkalemia is associated with many chronic diseases and renin-angiotensin-aldosterone system inhibitor therapy. Sodium zirconium cyclosilicate (SZC), an oral, highly selective cation-exchanger, is approved for the treatment of hyperkalemia. Methods This phase 3, multicenter, open-label, single-arm, flexible-dose study assessed the safety and efficacy of SZC in Japanese patients with hyperkalemia during a correction phase of up to 3 days and long-term (1 year) maintenance phase (NCT03172702). Results Overall, 150 patients received treatment during both study phases; the study population was generally representative of hyperkalemic Japanese patients in clinical practice. Most patients (78.7%) had three doses of SZC during the correction phase. All but one patient received SZC for ≤ 48 h before transitioning to the maintenance phase. In the maintenance phase, mean (standard deviation; SD) exposure to the study drug was 319.4 (98.1) days and mean (SD) dose was 7.38 (2.85) g/day. Adverse events (AEs) were reported in 131 patients (87.3%); most were mild. The most common treatment-related AEs as evaluated by investigators were constipation (6.7%), peripheral edema (4.0%), and hypertension (2.7%). In the correction phase, 78.7% of patients were normokalemic at 24 h and 98.7% within 48 h; ≥ 65.5% maintained normokalemia throughout the maintenance phase. Conclusion After a year of exposure, SZC treatment was well tolerated by Japanese patients and potassium levels were well controlled.

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...

The objective of this study was to evaluate the safety and efficacy of JR‐131, a biosimilar of darbepoetin alfa, for long‐term treatment of renal anemia patients undergoing hemodialysis. In this multicenter, single‐arm, phase 3 study, 159 patients with renal anemia who had been receiving darbepoetin alfa or recombinant human erythropoietins were treated with intravenous JR‐131 for 52 weeks. In patients receiving darbepoetin alfa, JR‐131 was administered at the same dose, while in patients receiving recombinant human erythropoietin the dose was determined based on the 1:200 conversion ratio following the Japanese darbepoetin alfa package insert. No notable adverse drug reactions were reported, and no anti‐JR‐131 antibodies were detected. The hemoglobin levels were maintained in the range of 10.0–12.0 g/dL throughout the study. JR‐131 proved to be a useful and lower‐cost alternative to darbepoetin alfa in the management of renal anemia in patients undergoing hemodialysis.

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

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.

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.

INI has emerged as a potential treatment for T2DM-related functional decline and is safe in adults without T2DM. However, INI safety in T2DM-IDDM is unknown. We aimed to demonstrate safety of long-term INI use in T2DM-IDDM MemAID participants. We screened 86 participants with T2DM-IDDM, 14 were randomized (9 INI/5 Placebo), 9 started treatment (5 INI [60±14 years, 2 Female]; 4 Placebo [68±2 years, 1 Female]). Of those, 2-INI and 3-Placebo participants completed 24 weeks of treatment and 24 weeks of follow-up. Participants underwent one week of continuous glucose monitoring (CGM)(Medtronic IPro2) at baseline and after INI (Novolin® R ) or placebo initiation. HbA1c, fasting plasma and capillary glucose, and insulin were measured throughout the study. Insulin levels were unchanged across the study. In 2 INI-treated participants, HbA1c, fasting plasma and capillary glucose declined from baseline, but the average values were similar during treatment and follow up, and comparable to 3 placebo-treated participants. Both INI-treated participants had adjustments of IDDM regimens. Capillary glucose did not decline 2 hours after INI administration, and there were no interactions between INI and subcutaneous insulin. There were no INI-related serious adverse events. Of 13 hypoglycemia (HG) episodes across the study, 2 asymptomatic level-1 HG (15.4%) occurred in INI group and 7 (53.8%) in placebo group. There were 2 asymptomatic level-2 HG (15.4%) in both INI and placebo groups. INI therapy was not associated with serious adverse events or HG in older participants with T2DM-IDDM. This study may pave the way towards future larger studies evaluating the safety of concomitant administration of INI and subcutaneous insulin (NCT02415556). Disclosure L. Aponte becerra: None. B. Galindo mendez: None. F. Khan: None. C. Mantzoros: Advisory Panel; Self; Amgen Inc., GENFIT, Intercept Pharmaceuticals, Inc., Novo Nordisk, Regeneron Pharmaceuticals Inc. P. Novak: Other Relationship; Self; Dysimmune Foundation, Endonovo Therapeutics, Oxford Press. V. Lioutas: Consultant; Self; QMetis. L. H. Ngo: Consultant; Self; Five Islands Consulting, Other Relationship; Self; Radiological Society of America. Memaid investigators (j. trevino): n/a. V. Novak: Advisory Panel; Spouse/Partner; Endonovo Therapeutics, Inc., Consultant; Spouse/Partner; Dysimmune Foundtation, Other Relationship; Spouse/Partner; Oxford University Press. Funding National Institute of Diabetes and Digestive and Kidney Diseases (1R01DK103902); U.S. Food and Drug Administration (IND107690); Novo Nordisk (ISS-001063), Medtronic (NERP15-0310); World Health Organization (UTN-U111-1175-1588)

Objective A large‐scale, double‐blind trial (SP0993; NCT01243177) demonstrated that lacosamide was noninferior to controlled‐release carbamazepine (carbamazepine‐CR) in terms of efficacy, and well tolerated as first‐line monotherapy in patients (≥16 years of age) with newly diagnosed epilepsy. We report primary safety outcomes from the double‐blind extension of the noninferiority trial (SP0994; NCT01465997) and post hoc analyses of pooled long‐term safety and efficacy data from both trials. Methods Patients were randomized 1:1 to lacosamide or carbamazepine‐CR. Doses were escalated (lacosamide: 200/400/600 mg/d; carbamazepine‐CR: 400/800/1200 mg/d) based on seizure control. Eligible patients continued randomized treatment in the extension. Primary outcomes of the extension were treatment‐emergent adverse events (TEAEs), serious TEAEs, and discontinuations due to TEAEs. Post hoc analyses of data from combined trials included 12‐ and 24‐month seizure freedom and TEAEs by number of comorbid conditions. Results A total of 886 patients were treated in the initial trial and 548 in the extension; 211 of 279 patients (75.6%) on lacosamide and 180/269 (66.9%) on carbamazepine‐CR completed the extension. In the extension, 181 patients (64.9%) on lacosamide and 182 (67.7%) on carbamazepine‐CR reported TEAEs; in both groups, nasopharyngitis, headache, and dizziness were most common. Serious TEAEs were reported by 32 patients (11.5%) on lacosamide and 22 (8.2%) on carbamazepine‐CR; 12 (4.3%) and 21 (7.8%) discontinued due to TEAEs. In the combined trials (median exposure: lacosamide 630 days; carbamazepine‐CR 589 days), Kaplan‐Meier estimated proportions of patients with 12‐ and 24‐month seizure freedom from first dose were 50.8% (95% confidence interval 46.2%‐55.4%) and 47.0% (42.2%‐51.7%) on lacosamide, and 54.9% (50.3%‐59.6%) and 50.9% (46.0%‐55.7%) on carbamazepine‐CR. Incidences of drug‐related TEAEs and discontinuations due to TEAEs increased by number of comorbid conditions and were lower in patients on lacosamide. Significance Long‐term (median ~2 years) lacosamide monotherapy was efficacious and generally well tolerated in adults with newly diagnosed epilepsy. Seizure freedom rates were similar with lacosamide and carbamazepine‐CR.

Background Alirocumab reduces low-density lipoprotein cholesterol (LDL-C) levels by up to 61%. The ODYSSEY Open-Label Extension study investigated the effect of alirocumab in patients with heterozygous familial hypercholesterolaemia (HeFH) over 144 weeks. Methods Eligible patients with HeFH had completed an earlier double-blind, randomised, placebo-controlled parent study. Patients were initiated on 75 mg alirocumab Q2W subcutaneous (SC) unless baseline LDL-C was > 8.9 mmol/l, in which case they received 150 mg alirocumab Q2W. Dose titration to 150 mg Q2W was at the investigator's discretion. Results The study enrolled 167 patients and the parent study mean (± SD) baseline LDL-C level was 3.65 ± 1.9 mmol/l. Mean LDL-C level was reduced by 48.7% at week 144; mean on-treatment LDL-C was 2.30 ± 1.24 mmol/l. Eight patients reported injection-site reactions, with one treatment discontinuation. Treatment emergent anti-drug antibodies were identified in five patients but these did not affect the efficacy. Conclusions Alirocumab effectively and safely reduced LDL-C in these patients.

Background and Objectives: Ethanol retention therapy (ERT) under EUS guidance or a percutaneous approach is a safe treatment for large symptomatic hepatic cysts. However, reports on the long-term outcomes after ERT are very rare. Therefore, we aimed to evaluate the long-term outcomes of ERT in symptomatic large hepatic cysts. Materials and Methods: A total of 47 consecutive patients with large symptomatic hepatic cysts treated at the Asan Medical Center from April 2009 to October 2017 were analyzed. Thirty patients with right hepatic cysts were treated with ERT through a percutaneous approach, and 14 patients with left hepatic cysts were treated with ERT under EUS guidance. Three patients were treated with ERT using both methods. Results: Of the 47 patients, 43 (91%) showed complete regression and four (9%) showed partial regression on abdominal computed tomography. Recurrence of the cysts was not observed during the follow-up surveillance of a median of 66 months. Conclusions: Percutaneous catheter drainage-guided ERT and EUS-guided ERT, based on their favorable long-term outcomes, may be considered as first-line treatments in patients with large symptomatic hepatic cysts.

Rationale & Objective Epoetin alfa-epbx is a biosimilar to the reference product, epoetin alfa. We compare the safety of epoetin alfa-epbx versus epoetin alfa based on a pooled analysis of findings from 2 randomized, double-blind, comparative clinical studies, and report new data for the long-term safety of epoetin alfa-epbx. Study Design Pooled analyses of previously conducted studies. Setting & Participants Hemodialysis patients with anemia. Interventions Data from patients who received 1 or more subcutaneous or intravenous doses of study drug were integrated across route of administration in combined randomized groups (epoetin alfa-epbx, n = 423; epoetin alfa, n = 426). Data from patients who received 1 or more doses of epoetin alfa-epbx in either open-label extension trial were integrated across route of administration in a combined long-term safety studies group (n = 576). Outcomes Adverse events (AEs), immunogenicity, and other outcomes were assessed. Results Incidences of treatment-emergent AEs, serious AEs, and discontinuation of study drug treatment because of treatment-emergent AEs were similar between combined randomized epoetin alfa-epbx and epoetin alfa, which had mean treatment durations of 18.1 and 17.7 weeks, respectively. Incidences of treatment-emergent AEs, serious AEs, and discontinuation of study drug treatment because of treatment-emergent AEs were 86.5%, 39.4%, and 6.6%, respectively, for the combined long-term safety studies group, which had a mean treatment duration of 40.0 weeks. In total, 12 patients across the combined randomized groups (epoetin alfa-epbx, n = 5; epoetin alfa, n = 7) and 9 patients in the combined long-term safety studies group tested anti-recombinant human erythropoietin antibody positive in 1 or more visits during study conduct. No patient in any group developed neutralizing antibodies or pure red blood cell aplasia. Limitations Epoetin alfa comparator not included in the long-term safety studies, greater cumulative exposure to study drug for epoetin alfa-epbx, shorter follow-up in the randomized studies, and potential for selection bias among patients in the open-label long-term safety studies. Conclusions This analysis reinforces previous conclusions of similar safety profiles between epoetin alfa-epbx and epoetin alfa. Furthermore, epoetin alfa-epbx had no unexpected safety signals during long-term treatment. Funding This study was funded by Hospira Inc, which was acquired by Pfizer Inc in September 2015. Trial Registration ClinicalTrials.gov EPOE-10-13 (NCT01473420); EPOE-10-01 (NCT01473407); EPOE-11-04 (NCT01628120); EPOE-11-03 (NCT01628107)., Graphical abstract

Purpose Clinical trials have demonstrated the favorable efficacy/safety profile of pasireotide in patients with Cushing’s disease (CD). We report interim long-term results of an ongoing real-world evidence study of subcutaneous pasireotide in patients with CD. Methods Adults with CD receiving pasireotide, initiated before (prior-use) or at study entry (new-use), were monitored for ≤ 3 years during a multicenter observational study (http://clinicaltrials.gov identifier NCT02310269). Primary objective was to assess long-term safety of pasireotide alone or with other CD therapies. Results At the time of this interim analysis, 127 patients had received pasireotide (new-use, n = 31; prior-use, n = 96). Eight patients had completed the 3-year observation period, 53 were ongoing, and 66 had discontinued. Among 31 new-use and 92 prior-use patients with ≥ 1 safety assessment, respectively: 24 (77%) and 37 (40%) had drug-related adverse events (AEs); 7 (23%) and 10 (11%) had serious drug-related AEs. Most common drug-related AEs were nausea (14%), hyperglycemia (11%) and diarrhea (11%); these were more frequently reported in new users and mostly of mild-to-moderate severity. 14 (45%) new-use and 15 (16%) prior-use patients experienced hyperglycemia-related AEs. Mean urinary free cortisol (mUFC) was within normal range at baseline and months 1, 12 and 24, respectively, in: 1/16 (6%), 9/18 (50%), 1/3 (33%) and 0/0 new users; 28/43 (65%), 15/27 (56%), 27/33 (82%) and 12/19 (63%) prior users. Conclusions Pasireotide is well tolerated and provides sustained reductions in mUFC during real-world treatment of CD. The lower rate of hyperglycemia-related AEs in prior users suggests that hyperglycemia tends not to deteriorate if effectively managed soon after onset. Clinical Trial Registration Number: NCT02310269.

Objectives To address the need for long-term lasmiditan data, the GLADIATOR study evaluated the safety (primary) and efficacy (secondary) of lasmiditan for the intermittent, acute treatment of migraine attacks for up to 1 year. Methods In this prospective, randomized, open-label, Phase 3 study, patients who had completed either of two single-attack studies were offered the opportunity to be randomized 1:1 to lasmiditan 100 mg or 200 mg. Patients were asked to use lasmiditan as the first treatment for each new migraine attack of at least moderate severity. Assessments occurred at baseline and at prespecified time increments up to 48 hours after each dose of study drug using an electronic diary, and safety was assessed throughout the study. Migraine Disability Assessment (MIDAS) was assessed at each visit. Results As of the cut-off date for this interim analysis (6 March 2018), 1978 patients had received ≥ 1 lasmiditan dose and treated 19,058 migraine attacks. Overall, treatment-emergent adverse events (TEAEs) were similar to those in the single-attack studies and included dizziness (18.6%), somnolence (8.5%), and paresthesia (6.8%). The frequency of TEAEs generally decreased with subsequent attacks. No treatment-related serious adverse events and no cardiovascular TEAEs potentially due to vasoconstriction were observed. For both lasmiditan doses, efficacy measures were generally consistent over study quarters and treated attacks. Overall, across all treated attacks at 2 hours post-dose, pain freedom was observed in 26.9% of the attacks treated with lasmiditan 100 mg and 32.4% of the attacks treated with lasmiditan 200 mg. MIDAS total scores decreased over time. Conclusions The interim results of this long-term study showed intermittent lasmiditan (100 mg and 200 mg) to be generally well tolerated and efficacious for the acute treatment of migraine over a 1-year period. Trial registration number: NCT02565186; https://clinicaltrials.gov/ct2/show/NCT02565186

The selection criteria, safety, and efficacy of bariatric surgery are well established in adults but are less well defined for severely obese adolescents. The number of severely obese adolescents who could benefit from weight loss surgery is increasing, although referral rates have plateaued. Surgical options for these adolescents are controversial and raise several questions. Recent studies, including the prospective Teen-Longitudinal Assessment of Bariatric Surgery Study and the Adolescent Morbid Obesity Surgery Study, help answer these questions. Early bariatric surgical intervention improves body mass index but, more importantly, improves cardiovascular and metabolic co-morbidities of severe obesity. A review of the medical, psychosocial, and economic risks and benefits of bariatric surgery in severely obese adolescents is a step toward improving the management of a challenging and increasing population. We describe the current knowledge of eligibility criteria, preoperative evaluation, surgical options, outcomes, and referral barriers of adolescents for bariatric surgery.

STUDY QUESTION Which clinical and ethical aspects of preimplantation genetic testing for monogenic disorders or structural rearrangements (PGT-M, PGT-SR) should be considered when accepting requests and counselling couples for PGT when applied for more than one condition (combination-PGT; cPGT-M/SR)? SUMMARY ANSWER cPGT is a feasible extension of the practice of PGT-M/SR that may require adapting the criteria many countries have in place with regard to indications-setting for PGT-M/SR, while leading to complex choices that require timely counselling and information. WHAT IS KNOWN ALREADY Although PGT-M/SR is usually performed to prevent transmission of one disorder, requests for PGT-M/SR for more than one condition (cPGT-M/SR) are becoming less exceptional. However, knowledge about implications for a responsible application of such treatments is lacking. STUDY DESIGN, SIZE, DURATION Retrospective review of all (40) PGT-M/SR applications concerning more than one genetic condition over the period 1995-2018 in the files of the Dutch national PGT centre. This comprises all relevant national data since the start of PGT in the Netherlands. PARTICIPANTS/MATERIALS, SETTING AND METHODS Data regarding cPGT-M/SR cases were collected by means of reviewing medical files of couples applying for cPGT-M/SR. Ethical challenges arising with cPGT-M/SR were explored against the background of PGT-M/SR regulations in several European countries, as well as of relevant ESHRE-guidance regarding both indications-setting and transfer-decisions. MAIN RESULTS AND THE ROLE OF CHANCE We report 40 couples applying for cPGT-M/SR of which 16 couples started their IVF treatment. Together they underwent 39 IVF cycles leading to the birth of five healthy children. Of the couples applying for cPGT, 45% differentiated between a primary and secondary condition in terms of perceived severity. In the light of an altered balance of benefits and drawbacks, we argue the 'high risk of a serious condition' standard that many countries uphold as governing indications-setting, should be lowered for secondary conditions in couples who already have an indication for PGT-M/SR. As a consequence of cPGT, professionals will more often be confronted with requests for transferring embryos known to be affected with a condition that they were tested for. In line with ESHRE guidance, such transfers may well be acceptable, on the condition of avoiding a high risk of a child with a seriously diminished quality of life. LIMITATIONS, REASONS FOR CAUTION We are the first to give an overview of cPGT-M/SR treatments. Retrospective analysis was performed using national data, possibly not reflecting current trends worldwide. WIDER IMPLICATIONS OF THE FINDINGS Our observations have led to recommendations for cPGT-M/SR that may add to centre policy making and to the formulation of professional guidelines. Given that the introduction of generic methods for genomic analysis in PGT will regularly yield incidental findings leading to transfer requests with these same challenges, the importance of our discussion exceeds the present discussion of cPGT. STUDY FUNDING/COMPETING INTEREST(S) The research for this publication was funded by the Dutch Organization for Health Research and Development (ZonMw), project number: 141111002 (Long term safety, quality and ethics of Preimplantation Genetic Diagnosis). None of the authors has any competing interests to declare.