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Objective To investigate the long-term safety and tolerability of a once-daily, dual-release hydrocortisone (DR-HC) tablet as oral glucocorticoid replacement therapy in patients with primary adrenal insufficiency (AI). Design Prospective, open-label, multicenter, 5-year extension study of DR-HC conducted at five university clinics in Sweden. Methods Seventy-one adult patients diagnosed with primary AI who were receiving stable glucocorticoid replacement therapy were recruited. Safety and tolerability outcomes included adverse events (AEs), intercurrent illness episodes, laboratory parameters and vital signs. Quality of life (QoL) was evaluated using generic questionnaires. Results Total DR-HC exposure was 328 patient-treatment years. Seventy patients reported 1060 AEs (323 per 100 patient-years); 85% were considered unrelated to DR-HC by the investigator. The most common AEs were nasopharyngitis (70%), fatigue (52%) and gastroenteritis (48%). Of 65 serious AEs reported by 32 patients (20 per 100 patient-years), four were considered to be possibly related to DR-HC: acute AI (n = 2), gastritis (n = 1) and syncope (n = 1). Two deaths were reported (fall from height and subarachnoid hemorrhage), both considered to be unrelated to DR-HC. From baseline to 5 years, intercurrent illness episodes remained relatively stable (mean 2.6–5.4 episodes per patient per year), fasting plasma glucose (0.7 mmol/L; P P P = 0.008). Conclusions In the first prospective study evaluating the long-term safety of glucocorticoid replacement therapy in patients with primary AI, DR-HC was well tolerated with no safety concerns observed during 5-year treatment.

BACKGROUND Nonacog alfa, the recombinant Factor IX (F IX) used for the treatment of hemophilia B, was approved in Europe in 1998. A reformulated version was approved for European use in 2007. STUDY DESIGN AND METHODS This postmarketing study, as recommended by the risk management plan, was conducted to confirm the safety of reformulated nonacog alfa in a usual care setting in France. This open-label, noninterventional, prospective, longitudinal postmarketing study comprised 19 French hemophilia centers. Patients with hemophilia B receiving reformulated nonacog alfa for prophylaxis or on-demand treatment were followed up on usual care schedule. RESULTS A total of 58 subjects were enrolled, of whom 29 (50%) were less than 18 years of age. Hemophilia was severe (baseline F IX activity

The Icatibant Outcome Survey (IOS) is an observational study monitoring safety and effectiveness of icatibant in the real‐world setting. We analyzed safety data from 3025 icatibant‐treated attacks in 557 patients (enrolled between July 2009 and February 2015). Icatibant was generally well tolerated. Excluding off‐label use and pregnancy, 438 patients (78.6%) did not report adverse events (AEs). The remaining 119 (21.4%) patients reported 341 AEs, primarily gastrointestinal disorders (19.6%). Of these, 43 AEs in 17 patients (3.1%) were related to icatibant. Serious AEs (SAEs) occurred infrequently. A total of 143 SAEs occurred in 59 (10.6%) patients; only three events (drug inefficacy, gastritis, and reflux esophagitis) in two patients were considered related to icatibant. Notably, no SAEs related to icatibant occurred in patients with cardiovascular disease, nor in those using icatibant at a frequency above label guidelines. Additionally, no major differences were noted in AEs occurring in on‐label vs off‐label icatibant users.

Psoriasis is a chronic immunomediated and inflammatory disease involving mainly skin and joints, often associated with several metabolic and non-metabolic comorbidities. TNF-alpha inhibitors have shown long-term efficacy and safety/tolerability in psoriasis, and preliminary data support the use of certolizumab pegol (CZP) as well. Areas covered: The authors review the pharmacological properties of CZP, as well as its safety data and efficacy profile. They also review the quality of life outcomes related to CZP in psoriasis. The authors also provide their expert opinion on the subject. Expert opinion: CZP is a promising treatment for psoriasis owing to its rapid reduction of disease activity, long-term therapeutic efficacy - both in bio-naive and non-bio-naive patients, long term safety and low rate of site injection reactions. CZP seems to be a promising therapeutic option for psoriasis patients, although further evidence supporting the continuing clinical program for development of CZP in psoriasis is needed.

Background: Omalizumab is effective and well-tolerated in children with moderate to severe allergic asthma. However, the effects of long-term treatment with omalizumab in this population haven't been well investigated. The objective of this study is to evaluate the long-term safety, efficacy, pharmacokinetics and pharmacodynamics of omalizumab in children with uncontrolled severe asthma. Methods: Thirty-eight Japanese children (aged 7–16 years) who completed the 24-week treatment core study were included in an uncontrolled extension study, in which treatment with omalizumab continued until the pediatric indication was approved in Japan (ClinicalTrials.gov number: NCT01328886). Results: Thirty-five patients (92.1%) completed the extension study. The median exposure throughout the core and extension studies was 116.6 weeks (range, 46.9–151.1 weeks). The most common adverse events were nasopharyngitis, influenza, upper respiratory tract infection, and asthma. Serious adverse events developed in 10 patients (26.3%), but resolved completely with additional treatments. Incidence of adverse events didn't increase with extended exposure with omalizumab. Twenty-nine patients (76.3%) achieved completely- or well-controlled asthma compared with 9 patients (23.7%) at the start of the extension study. QOL scores, the rates (per year) of hospitalizations and ER visits were significantly improved compared with the baseline of the core study [39.0 vs 48.0 (median), p

The safety and biological effects of a long-term dose of D-allulose were evaluated in healthy dogs. For 12 weeks, the dogs were administered D-allulose (0.2 g/kg) or placebo daily. Plasma total cholesterol concentrations in the D-allulose group were significantly lower than those in the control group at and after week 2 (P

SummaryThe safety, efficacy, and prolonged half-life of recombinant factor IX Fc fusion protein (rFIXFc) were demonstrated in the Phase 3 B-LONG (adults/adolescents ≥12 years) and Kids B-LONG (children Supplementary Material to this article is available online at www.thrombosis-online.com.

Nachweise der Tragfähigkeit, Gebrauchstauglichkeit und Dauerhaftigkeit durch eine Berechnung, unter anderem mit den Methoden der Baustatik oder Geotechnik, sind unverzichtbarer Bestandteil der Entwurfsarbeit von Bauwerken. Standsicherheitsnachweise als Ergebnis der Tragwerksplanung umfassen die vorgesehene Nutzungs- und Lebensdauer des geplanten Bauwerkes unter Einbeziehung der für den Standort angenommenen und zulässigen Belastungen. Diese Beanspruchungen unterliegen zum Teil großen Streuungen und sind bedingt durch Kraft- und Verformungswirkungen, sowie durch chemische und physikalische Einflüsse. Aus der Gegenüberstellung mit vorhandenen Widerständen resultieren Sicherheitsabstände, die projektbezogen erreicht werden müssen. Dieses Vorgehen aus den traditionellen Ingenieurdisziplinen hat in der Deponietechnik noch nicht umfassend Einzug gehalten. In der Planungsphase werden Aspekte der Betriebstauglichkeit und Wartbarkeit im Hinblick auf die Standsicherheit von technischen Systemen im Betrieb berücksichtigt. Es wird jedoch als Bestandteil der Planung zur langfristigen Umweltverträglichkeit kein Nachweis der Emissionssicherheit der Deponiekonstruktion für die gesamte Lebensdauer gefordert. Der empfohlene Weg ist die auf langfristigen Boden- und Grundwasserschutz bemessene Deponiesicherung unter systematischer Berücksichtigung der Standort- und Milieubedingungen. Folgt man dem grundsätzlichen Vorgehen aus dem Ingenieurbau, kann zuverlässig eine Sicherheitsbetrachtung als Gesamtschau aller Beanspruchungen und Widerstände im Planungsstadium einer Deponiekonstruktion, also nach dem Prinzip Vorsorge, im Einklang mit den Forderungen nach Wirtschaftlichkeit durchgeführt werden.

Summary Background Children aged ≥ 6 to < 12 years with severe atopic dermatitis (AD) have limited treatment options. In a 16‐week, randomized, placebo‐controlled, phase III trial in children, dupilumab, a monoclonal antibody inhibiting interleukin (IL)‐4/IL‐13 signalling, significantly improved signs and symptoms with acceptable safety; longer‐term safety and efficacy data are lacking. Objectives To report the pharmacokinetic profile and long‐term safety and efficacy of dupilumab in children (aged ≥ 6 to < 12 years) with severe AD. Methods Children (aged ≥ 6 to < 12 years) with severe AD were enrolled in a global, multicentre, phase IIa, open‐label, ascending‐dose, sequential cohort study and subsequent open‐label extension (OLE) study. Patients received single‐dose dupilumab 2 or 4 mg kg−1 followed by 8‐week pharmacokinetic sampling, then 2 or 4 mg kg−1 weekly for 4 weeks (phase IIa), followed by the same weekly regimen (OLE). Primary endpoints were dupilumab concentration–time profile and treatment‐emergent adverse events (TEAEs); secondary assessments included Eczema Area and Severity Index (EASI) and Peak Pruritus Numeric Rating Scale (PP‐NRS) score. Results Of 38 children enrolled, 37 completed phase IIa and 33 continued to the OLE. Nonlinear, target‐mediated pharmacokinetics characterized dupilumab concentrations (week 24–48 mean serum concentrations: 2 mg kg−1, 61–77 mg L−1; 4 mg kg−1, 143–181 mg L−1). TEAEs were mostly mild to moderate and transient; none led to treatment discontinuation. The most commonly reported TEAEs were nasopharyngitis (2 mg kg−1, 47%; 4 mg kg−1, 56%) and AD exacerbation (29% and 13%, respectively). Single‐dose dupilumab rapidly improved AD with further improvements through week 52. Mean EASI and PP‐NRS improved by −37%/−33% and −17%/−20% at week 2 (phase IIa) and −92%/−84% and −70%/−58% at week 52 (OLE), respectively. Conclusions These safety and efficacy results support the use of dupilumab as a continuous long‐term treatment for children aged ≥ 6 to < 12 years with severe AD., What is already known about this topic? Severe atopic dermatitis (AD) has a marked negative impact on patient quality of life and can cause financial burden owing to a lack of effective treatments.Dupilumab significantly improved signs and symptoms of AD with an acceptable safety profile in a 16‐week randomized, double‐blind, placebo‐controlled phase III study in children aged ≥ 6 to < 12 years with severe AD. What does this study add? This study extends information on the safety, efficacy and pharmacokinetic profile of dupilumab treatment for up to 52 weeks in children aged ≥ 6 to < 12 years with severe AD.The results support the use of dupilumab as a continuous long‐term treatment for children aged ≥ 6 to < 12 years with severe AD. Linked Comment: Sibbald. Br J Dermatol 2021; 184:792–793.

Introduction Immune thrombocytopenia (ITP) is an autoimmune disorder characterized by platelet (plt) destruction and/or impaired production. Some patients with ITP are refractory or have inadequate responses to existing therapy. In vitro data have demonstrated that the sera of ~50% of patients with ITP can activate the classical complement pathway (CP) and/or fix complement on plt surfaces. We hypothesized that a primary mechanism of thrombocytopenia in a subset of patients with ITP is CP-dependent, and that CP inhibition with sutimlimab (formerly BIVV009), a humanized monoclonal antibody that selectively inhibits activation of the CP by binding to C1s, should improve thrombocytopenia. Interim results on sutimlimab use in patients with chronic ITP were previously reported. Here we present long-term data from a larger group of patients. Methods Adults with chronic (duration >1 year) severe ITP (plt count ≤30×109/L at screening) with an inadequate response to ≥2 prior therapies were enrolled in an open-label Phase 1 trial. Concomitant ITP medications were allowed if the patient was receiving a stable dose for the last month and unable to sustain plts ≥30×109/L without bleeds. In Part A, patients received sutimlimab on Days 0 and 7, then biweekly for up to 21 weeks, followed by a scheduled 9-week washout to evaluate relapse and eligibility to be re-treated in a long-term extension phase (Part B). Eligibility for Part B included a clinically meaningful response to sutimlimab and no rescue ITP therapy after Dose 2. Results Interim results are as of April 9, 2020. Twelve patients (mean [range] age, 45 [27-66] years; 75% [n=9] female) received ≥1 dose of sutimlimab. Median (range) disease duration at screening was 5 (2-36) years and 4 patients had prior splenectomy. Median (range) prior ITP medications was 4 (2-10). Eight patients had insufficient response to rituximab and 9 had insufficient response to thrombopoietin receptor agonists. Seven patients completed Part A including protocol washout (mean [range] washout time, 3 [0-7] weeks) and 4 were removed early due to the need for rescue therapy or unresponsiveness. Six patients enrolled in Part B (mean [range] duration, 55 [8-83] weeks). In Part A, mean (standard deviation [SD]) plt count increased from 25×109/L (16.9) at baseline to 54×109/L (60.2) 24 hours after sutimlimab initiation and to 139×109/L (157.3) at Day 7 (Figure 1). Mean plt count was maintained at >50×109/L in Part A and 5 (42%) patients achieved overall response (plt count ≥50×109/L and >2-fold increase from baseline on 2 consecutive occasions >7 days apart). Median time to first plt count ≥50×109/L was 2 days. Four (33%) patients achieved complete response (plt count ≥100×109/L on 2 consecutive occasions >7 days apart). Five (42%) patients achieved durable response (plt count ≥50×109/L in ≥50% of visits from Week 5 to 21 and did not use rescue ITP therapy after the second dose until Week 21). Plt responses correlated with changes in CP activity (Figure 1), consistent with CP inhibition. Seven patients fulfilled criteria for Part B. In Part B, mean (SD) baseline plt count before re-treatment was 22×109/L (19.2) and increased to 65×109/L (56.6) at Day 4 and to 126×109/L (155.5) at Day 7 (Figure 1). As of April 9, 2020, in Part A, 9 patients experienced a total of 62 treatment-emergent adverse events (TEAE) and 2 patients experienced a total of 3 treatment-emergent serious adverse events (TESAE), of which 1 TESAE (migraine) was assessed as possibly related to sutimlimab by the investigator. In Part B, 6 patients experienced a total of 51 TEAEs and 1 patient with a history of diverticulitis experienced 1 TESAE of diverticulitis assessed as not related to sutimlimab by the investigator. There were no deaths or thromboembolic events during the study, and no discontinuation of study drug due to an AE. Conclusions Sutimlimab therapy results in a rapid and durable response in plt count in a subset of patients with chronic ITP who had inadequate responses to multiple prior therapies. The response is sustained after more than 1 year of therapy with an acceptable safety profile. This is continued clinical evidence that the complement pathway plays a role in thrombocytopenia in a subset of patients with ITP. These sustained responses suggest ≥1 additional pathophysiologic explanation for the clinical heterogeneity of ITP and provide a strong platform for continued evaluation of CP inhibition in ITP treatment. Disclosures Broome: Alexion Pharmaceuticals, Inc: Honoraria, Research Funding; Bioverativ: Honoraria, Research Funding; Cellphire: Honoraria, Research Funding; Incyte: Honoraria, Research Funding; Rigel: Honoraria, Research Funding; Sanofi Genzyme: Honoraria, Research Funding. Röth:Sanofi: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; Biocryst: Consultancy, Honoraria; Apellis: Consultancy, Honoraria; Alexion Pharmaceuticals Inc.: Consultancy, Honoraria, Research Funding. Kuter:Up-To-Date: Consultancy, Honoraria, Patents & Royalties; Shionogi: Consultancy, Honoraria; Momenta: Consultancy, Honoraria; Merck Sharp Dohme: Consultancy, Honoraria; Kyowa-Kirin: Consultancy, Honoraria; Kezar Life Sciences, Inc: Other, Research Funding; CRICO: Consultancy, Honoraria; Caremark: Consultancy, Honoraria; Immunovant: Other: Travel Expenses, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Other: Travel Expenses, Research Funding; Argenx: Consultancy, Honoraria, Other: Travel Expenses, Research Funding; Sanofi (Genzyme): Consultancy, Honoraria; Zafgen: Consultancy, Honoraria; Protalex: Consultancy, Honoraria, Research Funding; Shionogi: Consultancy; Protalix Biotherapeutics: Consultancy; Shire: Consultancy, Honoraria; Principia: Consultancy, Research Funding; Dova: Consultancy, Honoraria; Takeda (Bioverativ): Consultancy, Honoraria, Other, Research Funding; Rigel: Consultancy, Honoraria, Other, Research Funding; Protalex: Consultancy, Honoraria, Other, Research Funding; Principia Biopharma: Consultancy, Honoraria, Other, Research Funding; Incyte: Consultancy, Honoraria; Immunovant: Consultancy, Honoraria; Genzyme: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Other: Travel Expenses, Research Funding; Alnylam: Consultancy, Honoraria, Other: Travel Expenses, Research Funding; Agios: Consultancy, Honoraria, Other: Travel Expenses, Research Funding; Daiichi Sankyo: Consultancy, Honoraria; Actelion (Syntimmune): Consultancy, Honoraria, Other: Travel Expenses, Research Funding; UCB: Consultancy, Honoraria; Platelet Disorder Support Association: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Scully:Takeda: Consultancy, Speakers Bureau; Takeda: Speakers Bureau; Novartis: Other: Advisory Board, Speakers Bureau; Alexion: Consultancy, Speakers Bureau; Shire/Takeda: Other: Advisory Board, Research Funding, Speakers Bureau; Ablynx/Sanofi: Consultancy, Other: Advisory Board, Speakers Bureau; Sanofi: Consultancy, Speakers Bureau. Smith:Bioverativ: Honoraria; Alnylam: Honoraria. Wang:Sanofi: Current Employment. Jiang:Sanofi: Current Employment. Reuter:Pediatric Infectious Disease Society: Other: Member of the vaccine advocacy and social media committees; Sanofi: Current Employment. Daak:Sanofi: Current Employment, Current equity holder in publicly-traded company. Hobbs:Sanofi: Ended employment in the past 24 months.

In some countries the time for undertaking a long-term safety assessment for a repository for high-level radioactive waste is set down in law.

Introduction/Background Niraparib is a poly(ADP-ribose) polymerase inhibitor (PARPi) approved in the United States and Europe for maintenance treatment of patients with recurrent ovarian, fallopian tube, or primary peritoneal cancer (ROC) following complete or partial response to platinum-based chemotherapy. Here, we present long-term safety data of niraparib, reporting the incidence of treatment-emergent adverse events (TEAEs) among patients in the ENGOT-OV16/NOVA trial. Methodology ENGOT-OV16/NOVA enrolled 553 patients with ROC who received 2–3 prior lines of platinum-based chemotherapy. Patients were randomised 2:1 to receive niraparib (300 mg once daily) or placebo in independent germline BRCA-mutated (gBRCAmut) or non-gBRCAmut cohorts. We report TEAE incidence monthly for the first 6 months and for months 7–12 combined. After month 12, we report TEAEs to the safety data cutoff of September 2017. Results Overall, 367 patients received niraparib 300 mg once daily. Dose reductions due to TEAEs were highest in month 1 (34%). In month 5, only 7% of patients required dose reductions. The incidence of any-grade and grade ≥3 haematologic and symptomatic TEAEs decreased each month in the first 6 months and remained low thereafter. Incidence of grade ≥3 thrombocytopenia was highest in month 1 (28%) and decreased to 10% and 5% at months 2 and 3, respectively. Treatment discontinuations due to TEAEs were Conclusion The incidence of haematologic and symptomatic TEAEs decreased quickly over the first 3 months and continued to decrease over the duration of the trial. Dose reductions and grade ≥3 thrombocytopenia events were highest in month 1 and decreased rapidly thereafter. Treatment discontinuations due to TEAEs were Disclosure AD, IMBB, DB-R, JH, EK, JB, PD, IB, SL: Nothing to disclose WG, SH, FdJ: Employee of Tesaro MRM: Consulting for Clovis, AstraZeneca, Tesaro BB: Honoraria from AstraZeneca, Insys, Funding from Tesaro SM: Grant and Personal Fees from Tesaro, AstraZeneca, Medac, MSD, PharmaMar, Roche, Teva. Personal Fees from Clovis, Sensor Kinesis PB: Site payment for clinical trial conduct from Tesaro JL: Ad Boards and PI for trials with AstraZeneca, Clovis, Pfizer. Ad Boards for Roche. Clinical Trials with MSD/Merck. BJR: Consulting with AstraZeneca, Tesaro, Genentech/Roche. Honoraria from Genentech UC: Honoraria and fees for consulting and Ad boards from Roche, AstraZeneca IPV: Travel and Accomodations from PharmaMar, Roche. Expert Testimony for AstraZeneca. Research Funding from Novartis, Tesaro DL: Ad Board for Tesaro, Clovis, AstraZeneca. Research Support from Clovis. Study Conduction support from Tesaro and PharmaMar UAM: Consulting for Merck KGaA, Clovis, Geneos, Eli Lilly, 2x Oncology

We describe the results of the (to our knowledge) longest long-term noninterventional study so far performed to obtain real-life data on the treatment of hemophilia A patients with a single plasma-derived FVIII concentrate containing von Willebrand factor (pdFVIII; Haemoctin/Faktor VIII SDH Intersero). A total of 198 patients (146 in Germany and 52 in Hungary), of whom 160 had severe and 38 nonsevere hemophilia A, representing all age groups (0-88 years; mean ∼25 years at inclusion) were analyzed during prophylactic or on-demand treatment over 18 years (overall 1,418 patient-years; mean7 years). pdFVIII was very effective and well tolerated. The mean annual bleeding rate, including spontaneous and traumatic bleeds, was considerably lower for patients treated prophylactically (mean 5.4; median 3.1) than for patients treated on demand (mean 26.1; median 21.9). Inhibitors were found in 13% (3/23) and high-titer inhibitors in 4% (1/23) of previously untreated patients with severe hemophilia A. Four previously treated patients with severe hemophilia A developed inhibitors, thereof three high-titer inhibitors (3.3 and 2.5 high-titer inhibitors in 1,000 patient-years). No unexpected adverse effect on the health of the patients, no pdFVIII-related thrombosis, thromboembolic event, or hypersensitivity reaction, and no suspected viral transmission related to pdFVIII were documented.Wir berichten über die Ergebnisse der unseres Wissens längsten nicht-interventionellen Langzeitstudie mit einem von-Willebrand-Faktor-haltigem humanen FVIII-Konzentrat (pdFVIII, Haemoctin®/Faktor VIII SDH Intersero®) zur Erfassung praxisnaher Daten aus der alltäglichen Therapie von Patienten mit einer Hämophilie A. 198 Patienten (146 in Deutschland und 52 in Ungarn) aller Altersgruppen (0–88 Jahre; durchschnittlich ∼25 Jahre alt beim Einschluss), 160 davon mit schwerer und 38 mit nicht schwerer Hämophilie A, wurden im Rahmen ihrer prophylaktischen oder Bedarfstherapie über 18 Jahre analysiert (insgesamt 1418 Patientenjahre; durchschnittlich7 Jahre). Der pdFVIII erwies sich als sehr wirksam und verträglich. Die durchschnittliche jährliche Blutungsrate (spontane und traumatische Blutungen) war deutlich geringer in Patienten, die prophylaktisch (Mittelwert 5,4; Median 3,1) anstatt bei Bedarf (Mittelwert 26,1; Median 21,9) mit pdFVIII behandelt wurden. Inhibitoren wurden in 13% (3/23) und hochtitrige in 4% (1/23) der zuvor unbehandelten Patienten mit schwerer Hämophilie A dokumentiert. Vier der vorbehandelten Patienten mit schwerer Hämophilie A entwickelten Inhibitoren, 3 davon hochtitrige (3.3 Inhibitoren und 2.5 hochtitrige pro 1000 Patientenjahren). Während der Langzeittherapie mit pdFVIII wurde kein unerwünschter Einfluss auf den allgemeinen Gesundheitszustand der Patienten festgestellt. Es trat keine thromboembolische Reaktion, keine Überempfindlichkeitsreaktion, und keine Virusübertragung im kausalen Zusammenhang mit pdFVIII auf.

Background: Prostacyclins (PCs) are used as targeted treatment for pulmonary arterial hypertension (PAH). Data regarding safety and long-term outcomes of s.c. and/or i.v. treprostinil (T) administered via s.c. Corno and the implantable LENUS Pro pump in patients with PAH are lacking. Methods: Thirty-seven PAH patients (20 females, 51±15 y.o., mean pulmonary arterial pressure 62.3±14.4 mmHg, cardiac index 2.4±0.7 L/min/m2, 6 WHO functional class II, 26 III, 5 IV) on triple targeted PAH medication (ERA, PDE5 inhibitors and treprostinil s.c.) were clinically assessed every 3 months. Survival rate was analysed using Kaplan Mayer estimation. Results: Patients showed a significant improvement of 6-minute walking distance after 3 (p=0.021), 6 (p=0.033) and 12 months (p=0.042) of s.c. treprostinil treatment. Furthermore, tricuspid annular plane systolic excursion, right atrial and right ventricular area improved after 3 and 6 months s.c. treatment (all p Conclusion: Subcutaneous T as add-on to double combination treatment significantly improved right heart size and function in this patient cohort. In most patients T could be continued i.v. by implanted Lenus Pro pump with a good overall-survival.

Objective: To evaluate long-term safety, efficacy, and immunogenicity of BI 695501 in patients with moderately-to-severely active rheumatoid arthritis (RA) who have completed VOLTAIRE-RA. Methods: Eligible patients for this phase 3b open-label extension study (VOLTAIRE-RAext), who had completed 48 weeks’ treatment with BI 695501 (Group A), 24 weeks each of adalimumab RP then BI 695501 (Group B), or 48 weeks of adalimumab RP (Group C) in VOLTAIRE-RA, were enrolled. Results: Altogether, 430 patients received BI 695501 fortnightly for 48 weeks: Group A, n = 225; Group B, n = 103; Group C, n = 102. The proportion of patients with drug-related adverse events (AEs; overall 20.2%) was similar across Groups A, B, and C: 21.3%, 20.4%, and 17.6%, respectively. The majority of treatment-emergent AEs were non-serious and of mild/moderate intensity. Consistent with adalimumab RP’s safety profile, most drug-related AEs were in the system organ class infections and infestations. BI 695501 and adalimumab RP responses at the end of VOLTAIRE-RA were sustained during VOLTAIRE-RAext and all efficacy and immunogenicity endpoints were similar across groups. Conclusion: Over 2 years, BI 695501 showed similar safety, efficacy, and immunogenicity to adalimumab RP, independent of initial treatment in VOLTAIRE-RA. No previously unknown adalimumab side effects were identified. Clinical trial registration: NCT02640612.

AimsTo assess the long‐term safety of subcutaneous buprenorphine (CAM2038) weekly and monthly depots.DesignPhase 3, open‐label, observational, multi‐centre 48‐week trial (ClinicalTrials.gov NCT02672111).SettingTwenty‐six out‐patient sites (United States, United Kingdom, Hungary, Denmark, Sweden, Germany, Australia) between 14 December 2015 and 12 April 2017.ParticipantsTwo hundred and twenty‐eight adults with opioid use disorder; 227 received CAM2038 (37 initiated onto CAM2038 and 190 converted from sublingual buprenorphine).InterventionsCAM2038 weekly (8, 16, 24 or 32 mg) or monthly (64, 96, 128 or 160 mg) with flexible dosing and individualized titration utilizing multiple CAM2038 weekly and monthly doses.MeasurementsSafety variables, urine toxicology samples and self‐reported illicit opioid use were collected at each visit. Participants were administered a patient satisfaction survey at months 6 and 12, completed by 162 of 227 (71.4%) participants.FindingsThe study treatment period was completed by 167 of 227 (73.6%) participants. At least one treatment‐emergent adverse event (TEAE) was reported by 143 of 227 (63.0%) participants, of whom 60 of 227 (26.4%) reported as being drug‐related. Most of the TEAEs, reported by 128 of 227 (56.4%) of participants, were mild or moderate in intensity. Injection‐site reactions were reported by 46 of 227 (20.3%) participants, with most [45 of 46 (97.8%)] reported as mild to moderate. Five participants (2.2%) discontinued the study drug due to a TEAE, two cases (0.9%) of which were injection‐site‐related. No serious adverse events were attributed to the study drug. At the end of the study, the percentage of opioid‐negative urine tests combined with self‐reports was 63.0% (17 of 37) in new‐to‐treatment participants and 82.8% (111 of 190) for participants converted from sublingual buprenorphine. Participants reported high levels of satisfaction with CAM2038.ConclusionsSubcutaneous buprenorphine delivered weekly or monthly (CAM2038) was well tolerated, with a systemic safety profile consistent with the known profile of sublingual buprenorphine. CAM2038 weekly and monthly was associated with high retention rates and low levels of illicit opioid use throughout this study.

Permanent therapeutically placed implants often used in situations when regeneration or transplantation are not practical or possible. They include metallic grafts for osteosynthesis, bulk metallic glasses, ceramics, and non-resorbable polymers providing mechanical support. Repair of the tissues on micro scale can also benefit from the biocompatible permanent implants. Vascular graft engineering and repairs of the spinal cord and peripheral nerves are among the most demanding application. Carbon fibers (CF) have superior mechanical and chemical properties, however, their long-time safety was never systematically estimated. The biggest concern comes from residual polymers used for pyrolysis and epoxy laminating resins. Here we attempted to investigate survival of the cells cultured on carbon fibers and to evaluate the tissue responses towards the long-term implanted material. Immortalized rat Schwann cells displayed efficient sporadic attachment to the carbon fibers with survival rate over 90%. Carbon fiber implants in adipose and on connective tissues were tolerable by animals during about 40% of their lifespan with no signs of inflammation on physiological, morphological or gene expression level.

Background The efficacy and safety of ixekizumab (IXE) in patients with radiographic axial spondyloarthritis (r-axSpA) were investigated in the COAST trial program. Objectives To report the long-term safety of IXE in r-axSpA patients using integrated safety data from the COAST trials program. Methods Safety data for r-axSpA patients treated with IXE were integrated from COAST-V (biologic-naive; NCT02696785) and COAST-W (Inadequate responders or intolerant to 1 or 2 TNF inhibitors; NCT02696798) studies. Patients fulfilled ASAS criteria for r-axSpA and mNY criteria for ankylosing spondylitis. Trial eligibility criteria were previously reported.1,2 In these studies, participants were randomized to placebo (n=191), adalimumab (n=90, active reference arm, COAST-V only), or ixekizumab (n=376). Study participants initially randomized to IXE in both trials were treated with a starting dose (80-mg or 160-mg) and then 80-mg IXE every 2 weeks (IXEQ2W) or 4 weeks (IXEQ4W). Patients initially treated with placebo or adalimumab were re-randomized at Week 16 to receive either IXEQ2W or IXEQ4W following a 160-mg starting dose. The analysis population included all ixekizumab-exposed patients in both trials. Incidence rates (IR) per 100 person years with 95% confidence intervals (CI) and the number of patients are reported. Adverse Event (AE) codes were derived from MedDRA (v21.0). Integrated safety data presented here include all data collected between May 6. 2016 and Sept. 20, 2018. Results The integrated population consisted of 641 patients with 749.6 total patient-years of exposure to IXE. Mean follow up time was 427 days. Mean baseline age was 43.8±12.3 years. Mean and median baseline disease symptom duration (since onset) were 17.2±10.8 years and 15.5 years (Min: 1.1, Max: 56.2), respectively. Safety data are presented in Table 1. Among these patients, 489 (76.3%) reported ≥1 treatment emergent AEs with an IR of 65.2. Serious AEs (≥1) were reported for 51 (8.0%) patients with an IR of 6.8. Discontinuations due to AEs were reported for 38 (5.9%) patients with an IR of 5.1. One death was reported, a suicide, in a patient with a documented prior history of depression and judged by the blinded principal investigator to be unrelated to the investigational product. The overall infection IR was 39.4, with both serious and opportunistic infections reported with an IR of 1.7. Among opportunistic infections, no Tuberculosis infections or reactivations were reported and the Candida infection IR was 1.2. No infections were associated with grade 3 or 4 neutropenia. The confirmed major adverse cardiovascular events IR was 0.1. The malignancy IR was 0.4 with acute promyelocytic leukemia, bladder cancer, and ovarian cancer reported. The depression IR was 0.8. The adjudicated inflammatory bowel disease (IBD) IR was 1.5 with 4 of 11 patients having prior history of IBD. The Anterior uveitis (AU) IR was 3.9 with 24 of 29 patients having prior history of AU. The injection site reaction IR was 11.3. Conclusion The reported safety profile for IXE in r-axSpA is consistent with the profile reported for other indications. During the extension period, the overall safety profile of ixekizumab remained consistent with that observed during the double-blind period of COAST-V and COAST-W.1,2 References [1 ] [Van der Heijde et al Lancet 2018 2Deodhar et al Arthritis Rheumatol 2018] Disclosure of Interests Helena Marzo-Ortega Grant/research support from: Janssen, Novartis and Pfizer, Consultant for: AbbVie, Celgene, Janssen, Eli-Lilly, Novartis and UCB, Speakers bureau: AbbVie, Celgene, Janssen, Eli-Lilly, Novartis and UCB, Eduardo Mysler Grant/research support from: AbbVie, Bristol-Myers Squibb, Eli Lilly, Pfizer, Novartis, Janssen, Grant/research support from: AbbVie, Bristol-Myers Squibb, Eli Lily, Janssen, Medimmune, Pfizer Inc, and Roche, Consultant for: AbbVie, Bristol-Myers Squibb, Eli Lily, Janssen, Medimmune, Pfizer Inc, and Roche, Speakers bureau: AbbVie, Bristol-Myers Squibb, Eli Lilly, Pfizer, Novartis, Janssen, Speakers bureau: AbbVie, Bristol-Myers Squibb, Eli Lily, Janssen, Medimmune, Pfizer Inc, and Roche, Tetsuya Tomita Consultant for: AbbVie, Astellas, Bristol-Myers Squibb, Eisai, Eli Lilly and Company, Janssen, Mitsubishi Tanabe, Novartis, Takeda, and Pfizer, Speakers bureau: AbbVie, Astellas, Bristol-Myers Squibb, Eisai, Eli Lilly and Company, Janssen, Mitsubishi Tanabe, Novartis, Takeda, and Pfizer, Jeffrey Lisse Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Silvia Santisteban Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Sandra Garces Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Wen Xu Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Martin Rudwaleit Consultant for: AbbVie, BMS, Celgene, Janssen, Eli Lilly, MSD, Novartis, Pfizer, Roche, UCB Pharma, Consultant for: AbbVie, BMS, Celgene, Janssen, Eli Lilly, MSD, Novartis, Pfizer, Roche, UCB Pharma, Carlo Salvarani Grant/research support from: Roche, Consultant for: Eli Lilly and Company, Roche, Abbvie, Sergio Schwartzman Shareholder of: Amgen, Boston Scientific, Gilead, Medtronic, and Pfizer, Consultant for: AbbVie, Crescendo, Dermtech, Janssen, Gilead, Lilly, Myriad, Novartis, Regeneron, Samsung, Sanofi, and Union Chimique Belge, Speakers bureau: Abbott/AbbVie, Genentech, Janssen, Lilly, Novartis, Pfizer, Regeneron, Sanofi, and Union Chimique Belge

Background Upadacitinib (UPA), an oral, JAK1-selective inhibitor showed efficacy over 12 weeks (wks) in patients (pts) with moderately to severely active rheumatoid arthritis (RA) and inadequate response to csDMARDs (SELECT-NEXT).1 Objectives We assessed safety and efficacy of UPA through Wk60 in an ongoing extension of the phase 3 SELECT-NEXT study. Methods Pts received once-daily (QD) UPA at 15 mg (UPA15), 30 mg (UPA30) or placebo (PBO) for 12 wks on stable background csDMARDs. From Wk12, the start of a long-term blinded extension, pts initially randomized to PBO at BL were switched to UPA15mg or 30mg per pre-specified assignment at BL. Pts randomized to UPA continued their assigned dose. No dose adjustments of UPA were allowed; however, starting at Wk24, adjustments to background RA medications were permitted. Sites/subjects remain blinded to UPA dose throughout the extension period. Efficacy data up to Wk60 are reported “As Observed”. Adverse events (AE) per 100 pt yrs (PY) are summarized based on a cut-off date of Mar 22 2018. Results 611/661 (92%) pts completed Wk12 and continued on to the extension. By the safety data cut-off date, 125/611 (20%) had discontinued study drug, 50 (8.2%) discontinued due to an AE, and 10 (1.6%) due to lack of efficacy. Cumulative exposure was 393.3 PYs and 372.4 PYs for UPA15 and UPA30 respectively. Based on As Observed analysis, for pts who continued on UPA15 (262/310 [85%]) and UPA30 (243/301 [81%]), clinical and functional outcomes continued to improve or were maintained through Wk60, with 59% and 56% of pts achieving DAS28-CRP Conclusion UPA15mg and 30mg on background csDMARD therapy demonstrated consistent efficacy and safety over 60 weeks in RA patients with inadequate response to csDMARDs. Both doses of UPA showed a similar efficacy profile at Wk 60, with numerically higher rates for certain safety events noted in the UPA30 group. An integrated safety analysis of upadacitinib across the phase 3 program is required to fully characterize the benefit:risk of UPA in RA. Reference [1] Burmester, et al. Lancet. 2018 Jun 23;391(10139):2503-2512 Acknowledgement AbbVie, Inc was the study sponsor, contributed to study design, data collection, analysis & interpretation, and to writing, reviewing, and approval of final version. Medical writing support was provided by Naina Barretto, of AbbVie, Inc. Disclosure of Interests Gerd Rudiger Burmester Consultant for: Roche, Sanofi-Genzyme, Speakers bureau: Roche, Sanofi-Genzyme, Filip van den Bosch Consultant for: AbbVie, BMS, Galapagos, Janssen, Lilly, Merck, Novartis, Pfizer and UCB, Speakers bureau: AbbVie, BMS, Janssen, Lilly, Merck, Novartis, Pfizer and UCB., Louis Bessette Grant/research support from: Amgen, BMS, Janssen, Roche, UCB, AbbVie, Pfizer, Merck, Celgene, Sanofi, Lilly, Novartis, Consultant for: Amgen, BMS, Janssen, Roche, UCB, AbbVie, Pfizer, Merck, Celgene, Sanofi, Lilly, Novartis, Speakers bureau: Amgen, BMS, Janssen, Roche, UCB, AbbVie, Pfizer, Merck, Celgene, Sanofi, Lilly, Novartis, Alan Kivitz Shareholder of: Novartis, Consultant for: Abbvie, Janssen, Pfizer, UCB, Genzyme, Sanofi, Regeneron, Boehringer Ingelheim, Sun Pharma Advanced Research, Flexion., Paid instructor for: Celgene, Horizon, Merck, Novartis, Pfizer, Genzyme, Sanofi, Regeneron, Speakers bureau: Celgene, Horizon, Merck and Genetech, Flexion, Yihan Li Shareholder of: AbbVie, Employee of: AbbVie, Alan Friedman Shareholder of: AbbVie, Employee of: AbbVie, Aileen Pangan Shareholder of: AbbVie, Employee of: AbbVie, Heidi Camp Shareholder of: AbbVie, Employee of: AbbVie, Joel Kremer Grant/research support from: AbbVie, Genentech, Lilly, Novartis, Pfizer, Consultant for: AbbVie, Amgen, BMS, Genentech, Lilly, Regeneron, Sanofi, Pfizer

Background: Eversense CGM is the first implantable long-term continuous glucose monitoring system. Prior studies evaluated the safety of the system using a study design of one insertion and removal cycle. The purpose of this prospective PMCF registry was to assess the long-term safety of the Eversense CGM System after repeated insertions. Methods: Eversense users from 15 European countries were followed prospectively until the first 100 participants completed their 4th insertion cycle. Visits were made every 90 to 180 days (dependent on sensor configuration) to replace sensors once sensor end life was reached. At each visit, Adverse Events (AEs) that occurred during the visit or during use since the previous visit were recorded. The primary endpoint was the rate of serious adverse events (SAEs) that were device-related, procedure-related, or drug (dexamethasone acetate) related through the sensor insertion/removal cycles. Results: 3066 participants were enrolled in the study with 43% on 2 or more sensor cycles. There were no device- or procedure-related SAEs reported. A total of 130 potentially-related AEs were reported, of which 106 were adjudicated as related or possibly/probably related to the device or insertion/removal procedure. Conclusion: Repeat insertions of the Eversense CGM confirmed the promising safety profile of prior studies and show it to be safe for long-term continuous use. Disclosure G. Carlson: Consultant; Self; Abbott Laboratories, Edwards Lifesciences Corporation, Senseonics, St. Jude Medical. K.S. Tweden: Employee; Self; Senseonics. C. Mdingi: Employee; Self; Senseonics. H. Haridas: Employee; Self; Senseonics.

Introduction Adults with moderate-to-severe Crohn’s disease (CD) who responded to risankizumab (RZB) in the phase 2 induction and maintenance study (Feagan, 2017) could enroll in an open-label extension (OLE) study. Interim efficacy and safety of RZB maintenance treatment from the OLE, up to 2 years, are reported. Methods Patients (pts) achieving clinical response (decrease from baseline [BL] in CD Activity Index [CDAI] ≥100) without remission (CDAI Results A total of 65 pts were enrolled (including 4 who were re-induced). Mean (standard deviation) exposure to RZB was 657.2 (190.73) days. At the data cut-off, 14 (21.5%) pts have discontinued the study. Up to wk 48, clinical remission rates were sustained and the proportion of pts with endoscopic remission increased from BL (table 1). Adverse events (AEs) were reported for 58 (89.2%) pts; 18(27.7%) pts had serious AEs. AEs occurring in >10% of pts were nasopharyngitis (26.2%), fatigue (16.9%), arthralgia and worsening CD (15.4% each). Four serious infections in 5 pts were perianal abscess (n=1), Campylobacter (n=1), viral gastroenteritis (n=2), and peritonitis (n=2). No events of tuberculosis, malignancies or deaths occurred. Conclusions In this interim analysis, clinical remission and endoscopic remission were sustained in CD pts receiving long-term RZB treatment. The safety profile of RZB was consistent with previously published data (Feagan, 2017). References Feagan BG, et al. Lancet 2017,29;389(10080):1699–1709. Feagan BG, et al. Gastroenterology 2017;152(5):S1310.

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Background Sarilumab, a human IL-6R blocker approved for the treatment of RA, has shown efficacy as monotherapy and in combination with csDMARDs in Phase 3 trials. Objectives We assessed long-term safety from the sarilumab clinical development program in adult patients with RA who received subcutaneous (SC) sarilumab in eight clinical trials and their open-label extensions: MOBILITY (NCT01061736), TARGET (NCT01709578), ASCERTAIN (NCT01768572), EASY (NCT02057250), COMPARE (NCT01764997), ACT11575 (NCT01217814), MONARCH (NCT02332590), ONE (NCT02121210), and the open-label extension EXTEND (NCT01146652). Methods Data (cut-off Jan 15, 2018) were pooled from patients on sarilumab+csDMARD (N=2887) or sarilumab monotherapy (N=471). Patients had received sarilumab 200 mg or 150 mg q2w SC, except for 151 patients from MOBILITY Part A who received 100 mg qw, 150 mg qw, or 100 mg q2w. Treatment-emergent (TE) adverse events (AEs), AEs of special interest (AESIs), and discontinuations were assessed. Results Demographics were similar between combination and monotherapy pools (mean age 52 years; 81–83% female), and 38.7% and 8.5% of patients had received prior bDMARDs. Cumulative drug exposure was 7,985.5 and 798.7 patient-years (PY), with maximum duration 7.3 and 3.5 years. Exposure-adjusted rates of TEAEs, serious AEs, and TEAEs leading to discontinuations were similar (Table). Infections were the most common AESI. Rates of serious infection were 3.7 and 1.0/100 PY for combination and monotherapy, respectively, and were not associated with decreased absolute neutrophil counts (ANCs). Incidences of ALT >3× upper limit of normal and ANC Conclusion The long-term safety profile of sarilumab, either as monotherapy (observed for >3.5 years) or with csDMARD (observed for >7 years), remains stable and consistent with the anticipated profile of an IL-6R blocker. Acknowledgement Study funding and editorial support (Helen Johns, Adelphi) were provided by Sanofi and Regeneron Pharmaceuticals, Inc. These data were previously presented at the 2018 American College of Rheumatology annual meeting. Disclosure of Interests Roy Fleischmann Grant/research support from: AbbVie, Amgen, AstraZeneca, Bristol-Myers Squibb, Celtrion, Genentech, GSK, Janssen, Lilly, Novartis, Pfizer Inc, Sanofi-Aventis, UCB, Consultant for: AbbVie, Amgen, AstraZeneca, Bristol-Myers Squibb, Celtrion, Genentech, GSK, Janssen, Lilly, Novartis, Pfizer Inc, Sanofi-Aventis, UCB, Yong Lin Shareholder of: Sanofi Genzyme, Employee of: Sanofi Genzyme, Gregory St John Shareholder of: Regeneron Pharmaceuticals Inc, Employee of: Regeneron Pharmaceuticals Inc, Desiree van der Heijde Consultant for: AbbVie, Amgen, Astellas, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Daiichi, Eli-Lilly, Galapagos, Gilead, GlaxoSmithKline, Janssen, Merck, Novartis, Pfizer, Regeneron, Roche, Sanofi, Takeda, Union Chimique Belge, Chunfu Qiu Shareholder of: Sanofi Genzyme, Employee of: Sanofi Genzyme, Juan Jose Gomez-Reino Grant/research support from: Biogen, Gilead, Eli Lilly, Merck Sharp & Dohme, Pfizer, Roche, Consultant for: Biogen, Gilead, Eli Lilly, Merck Sharp & Dohme, Pfizer, Roche, Jose Antonio Maldonado-Cocco Consultant for: Pfizer, Merck Sharp Dohme, Sanofi – Aventis, Novartis, Bristol Myers Squibb, Roche, Boehringer Ingelheim, Schering – Plough, Abbott, UCB, Eli Lilly, Gilead, Speakers bureau: Pfizer, Merck Sharp Dohme, Sanofi – Aventis, Novartis, Bristol Myers Squibb, Roche, Boehringer Ingelheim, Schering – Plough, Abbott, UCB, Eli Lilly., Marina Stanislav Consultant for: R-Pharm, Bruno Seriolo: None declared, Gerd Rudiger Burmester Consultant for: Roche, Sanofi-Genzyme, Speakers bureau: Roche, Sanofi-Genzyme

Background Previously published three-month placebo-controlled and one-year open-label clinical trial data have provided information on the efficacy and safety of erenumab. Methods Interim analysis was undertaken from an ongoing five-year open-label treatment phase after all patients completed three years in the open-label treatment phase or discontinued the study. Adult patients with episodic migraine enrolled in the open-label treatment phase initially received 70 mg erenumab monthly. A protocol amendment increased the dosage to 140 mg monthly to assess long-term safety of the higher dose. Safety and tolerability were assessed by monitoring adverse events, electrocardiograms, laboratory assessments, and vital signs. Results Of 383 patients enrolled in the open-label treatment phase, at data cutoff 235 (61.3%) remained in the study, all received 140 mg for ≥1 year. Median (Q1, Q3) exposure (70 or 140 mg) for all patients enrolled was 3.2 (1.3, 3.4) years. The most frequent adverse events (≥4.0/100 patient-years) were reported as viral upper respiratory tract infection, sinusitis, influenza, and back pain. Exposure-adjusted serious adverse event rates were 4.2/100 patient-years. There was no increase in cardiovascular events over time. Conclusions In this long-term study of a CGRP-receptor antibody, erenumab was found to be safe and well-tolerated with a spectrum and rate of adverse events consistent with shorter-term placebo-controlled studies. Trial registration ClinicalTrials.gov NCT01952574

Fabry disease is characterized by deficient activity of α-galactosidase A, which results in accumulation of glycolipids, such as globotriaosylceremide, in various tissue. Clinical symptoms are varied. In childhood, pain in extremities, hypohidrosis, and angiokeratoma are main symptoms, In adulthood, renal, cardiac and cerebrovascular symptoms are occurred In past, only symptomatic treatments were available. In early 2000th, enzyme replacement therapy was developed after positive results of clinical trials. Ten years after approval, the data of long term safety and efficacy of enzyme replacement.

Glycerol phenylbutyrate (GPB) is currently approved for use in the US and Europe for patients of all ages with urea cycle disorders (UCD) who cannot be managed with protein restriction and/or amino acid supplementation alone. Currently available data on GPB is limited to 12 months exposure. Here, we present long-term experience with GPB.This was an open-label, long-term safety study of GPB conducted in the US (17 sites) and Canada (1 site) monitoring the use of GPB in UCD patients who had previously completed 12 months of treatment in the previous safety extension studies. Ninety patients completed the previous studies with 88 of these continuing into the long-term evaluation. The duration of therapy was open ended until GPB was commercially available. The primary endpoint was the rate of adverse events (AEs). Secondary endpoints were venous ammonia levels, number and causes of hyperammonemic crises (HACs) and neuropsychological testing.A total of 45 pediatric patients between the ages of 1 to 17 years (median 7 years) and 43 adult patients between the ages of 19 and 61 years (median 30 years) were enrolled. The treatment emergent adverse events (TEAE) reported in ≥10% of adult or pediatric patients were consistent with the TEAEs reported in the previous safety extension studies with no increase in the overall incidence of TEAEs and no new TEAEs that indicated a new safety signal. Mean ammonia levels remained stable and below the adult upper limit of normal (35 µmol/L) through 24 months of treatment in both the pediatric and adult population. Over time, glutamine levels decreased in the overall population. The mean annualized rate of HACs (0.29) established in the previously reported 12-month follow-up study was maintained with continued GPB exposure.Following the completion of 12-month follow-up studies with GPB treatment, UCD patients were followed for an additional median of 1.85 (range 0 to 5.86) years in the present study with continued maintenance of ammonia control, similar rates of adverse events, and no new adverse events identified.

The therapeutic role of fecal microbiota transplantation in ulcerative colitis varies across different reports. This study aims to evaluate the long-term safety and efficacy of a strategy called step-up fecal microbiota transplantation for ulcerative colitis. Two clinical trials (NCT01790061, NCT02560727) for moderate-to-severe ulcerative colitis (Mayo score range 6–12) were performed from November 2012 to July 2017. Both studies were pooled for analysis on the safety and efficacy of fecal microbiota transplantation in patients with ulcerative colitis over a 1-year follow-up. The step-up fecal microbiota transplantation strategy included step 1: single fecal microbiota transplantation; step 2: two or more fecal microbiota transplantations; and step 3: fecal microbiota transplantations followed by immunosuppressants. Long-term clinical efficacy and adverse events were assessed, and multiple factors related to fecal microbiota transplantation were evaluated. Of 134 eligible patients in this real-word study, 81.3% (109/134) were included for analysis. The follow-up ranged from 1 to 5 years. Fecal microbiota transplantation-related adverse events were observed in 17.4% (43/247) of fecal microbiota transplantation procedures including one serious adverse event (myasthenia gravis) and 56 non-serious adverse events. Multivariable logistic regression analysis showed that both the method of preparation of microbiota from stool using the automatic system and the delivery method of colonic transendoscopic enteral tubing were associated with a lower rate of fecal microbiota transplantation-related adverse events (p = 0.023, p = 0.017, respectively). In total, 74.3% (81/109) and 51.4% (56/109) of patients achieved clinical response at 1 month and 3 months after step-up fecal microbiota transplantation, respectively. Fecal microbiota transplantation should be a safe and promising therapy for ulcerative colitis. The improved fecal microbiota preparation and colonic transendoscopic enteral tubing might reduce the rate of adverse events in ulcerative colitis. ClinicalTrials.gov NCT01790061, NCT02560727.

Testosterone (T) therapy has garnered widespread public enthusiasm and media attention due to its potential role in age-related T decline in men, commonly known as late-onset hypogonadism (LOH), andropause, or low T syndrome. The serum T concentration gradually declines across the lifespan and the symptoms between aging and hypogonadism overlap. These have led to the speculation that a causal relationship might exists between age-related reduction in serum T concentration and symptoms commonly seen in aging. However, it remains uncertain if T therapy could ameliorate symptoms associated with LOH, without significant risks. Despite the lack of clinical evidence and long term safety data, prescribing rates of T therapy have skyrocketed in many countries (1, 2), leading to efforts by regulatory authorities to limit such inappropriate prescribing practice (3). Importantly, the fundamental question of what constitutes clinically significant LOH was largely unaddressed until recently. Heterogeneity in definitions of LOH and the use of specificity-limited immunoassays for T measurements in many previous epidemiological and interventional studies have precluded robust comparisons across studies (4). Due to the expanding aging population, LOH is becoming an increasingly important topic. We reviewed the evidence from recent population-based studies and intervention trials to provide better understanding of the diagnosis, pathophysiology, and management for LOH.

INTRODUCTION AND OBJECTIVES:Macroplastique (MPQ) is a urethral bulking agent used in the treatment of stress urinary incontinence (SUI) in women with intrinsic sphincter deficiency (ISD). Ghoniem e...

Introduction: PATRO Children is a non-interventional, international, longitudinal study of the long-term safety of a recombinant human growth hormone (rhGH; Omnitrope®, Sandoz) in patients requiring this therapy. Here we compare data from participants in the US with the ROW. Methods: The study population includes infants, children and adolescents receiving Omnitrope® therapy according to local prescribing information. All adverse events (AEs) are monitored and recorded for evaluation of rhGH safety. Laboratory values (including glucose metabolism and anti-hGH antibodies) are requested at least once a year. Height standard deviation score (HSDS), height velocity (HV) and HVSDS are calculated using height measurements and country-specific reference tables to evaluate rhGH efficacy. Results: As of September 2018, 294 US patients (including 65.6% GHD, 21.1% ISS, 2.7% SGA) and 6500 ROW patients (including 57.9% GHD, 25.8% SGA, 3.0% ISS) had been enrolled in the study. Mean (± standard deviation [SD]) age at enrollment was 10.44 ± 3.64 years for US patients and 72.8% were male. For ROW, mean ± SD age at enrollment was 8.95 ± 3.90 years and 58.7% were male. Overall, 53.1% (US) and 86.3% (ROW) of patients were rhGH naïve. Mean ± SD Omnitrope® treatment duration was 40.24 ± 17.39 and 38.18 ± 26.89 months in US and ROW patients, respectively; 49.66% (US) and 42.35% (ROW) of patients had completed 3 years’ treatment. Mean ± SD doses at study baseline and after 3 years were 0.0473 ± 0.0144 and 0.0541 ± 0.0289 mg/kg/day in the US group, and 0.0321 (0.0094) and 0.0359 (0.0106) mg/kg/day in the ROW group. In total, 886 AEs were recorded in 194 (66.0%) US patients; 5 AEs in 5 patients were considered treatment-related, and 3 (1.3%) patients discontinued therapy due to an AE. For ROW, 11716 AEs were recorded in 2977 (48.0%) patients, 636 (452 patients) of which were considered treatment-related; 105 (1.7%) discontinued due to an AE. Serious AEs were noted in 14 (4.8%) US patients (19 events) and 738 (11.9%) ROW patients (1429 events). No clinically relevant positive anti-hGH antibody titers have been found after the start of rhGH therapy in patients tested so far. After 3 years, improvement from baseline in HSDS and HVSDS among prepubertal, treatment-naïve GHD patients was similar between the US (+1.34; +3.06) and ROW (+1.35; +3.55) groups. Conclusions: Based on this snapshot of data from the ongoing PATRO Children study, Omnitrope® treatment appears to be similarly well tolerated and effective in patients enrolled from the US and ROW. Some differences between the US and ROW patients are apparent, likely reflecting differences in referral patterns, rhGH treatment practices and approved indications across different regions.

BACKGROUND: Lumateperone (ITI-007) is an investigational drug for the treatment of schizophrenia, bipolar depression, agitation associated with dementia and other neuropsychiatric disorders. With a unique mechanism of action, lumateperone modulates serotonin, dopamine and glutamate neurotransmission. More specifically, lumateperone is a potent serotonin 5-HT2A receptor antagonist, a dopamine D2 receptor pre-synaptic partial agonist and post-synaptic antagonist, a dopamine D1 receptor-dependent modulator of glutamate (both NDMA and AMPA), and a serotonin reuptake inhibitor. In two previous placebo-controlled trials, lumateperone demonstrated statistically significant improvements over placebo on change from baseline on the PANSS total score in patients with acute schizophrenia. In this population, lumateperone was found to be well tolerated with a safety profile similar to placebo. Moreover, the first part of an open-label safety study demonstrated a favorable safety profile, with improvement in metabolic parameters, when patients with stable schizophrenia were switched from standard-of-care (SOC) to lumateperone for 6-weeks of treatment. These safety benefits were lost when patients were switched back to SOC. The purpose of the present study, the second part of the open-label safety study, was to evaluate the long-term safety and tolerability of lumateperone administered to patients with stable schizophrenia for up to 1-year treatment duration. METHODS: 603 patients with schizophrenia were treated for up to 1 year with lumateperone tosylate (ITI-007) 60 mg QPM, with no dose titration. To be eligible for inclusion in the study, patients must have had a clinical diagnosis of schizophrenia according to the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) and be stable with respect to their schizophrenia symptoms. The primary objective was to determine the safety of lumateperone, assessed by adverse events, body weight, 12-lead electrocardiograms, vital signs, clinical laboratory tests, motor assessments, and the Columbia-Suicide Severity Rating Scale. The secondary objectives were to determine the effectiveness of lumateperone to maintain or improve psychopathology as measured by the PANSS and the CGI-S. RESULTS: Lumateperone was well tolerated with a favorable safety profile. There were no clinically relevant changes in extrapyramidal side effect assessments. Mean body weight decreased from SOC antipsychotic baseline with long-term lumateperone treatment. Lumateperone also demonstrated a favorable cardiometabolic and endocrine safety profile. Symptoms of schizophrenia generally remained stable or improved as measured by PANSS and CGI-S. DISCUSSION: Lumateperone represents a novel approach to the treatment of schizophrenia with a favorable safety profile in clinical trials. The lack of metabolic, motor and cardiovascular safety issues presents a safety profile differentiated from SOC antipsychotic therapy. These data, taken together, are consistent with and extend data previously reported in placebo-controlled studies in patients with acute schizophrenia with lumateperone and short-term evaluation of lumateperone’s safety.

Shigella-infected bacillary dysentery or commonly known as Shigellosis is a leading cause of morbidity and mortality worldwide. The gradual emergence of multidrug resistantShigellaspp. has triggered the search for alternatives to conventional antibiotics. Phage therapy could be one such suitable alternative, given its proven long term safety profile as well as the rapid expansion of phage therapy research. To be successful, phage therapy will need an adequate regulatory framework, effective strategies, the proper selection of appropriate phages, early solutions to overcome phage therapy limitations, the implementation of safety protocols, and finally improved public awareness. To achieve all these criteria and successfully apply phage therapy against multidrug resistant shigellosis, a comprehensive study is required. In fact, a variety of phage-based approaches and products including single phages, phage cocktails, mutated phages, genetically engineered phages, and combinations of phages with antibiotics have already been carried out to test the applications of phage therapy against multidrug resistantShigella.This review provides a broad survey of phage treatments from past to present, focusing on the history, applications, limitations and effective solutions related to, as well as the prospects for, the use of phage therapy against multidrug resistantShigellaspp. and other multidrug resistant bacterial pathogens.

Rupatadine is a novel H1 antihistamine with platelet-activating factor antagonist activity. Its efficacy and safety on pruritic skin diseases have been demonstrated by 10mg/day rupatadine in a two weeks clinical trial.To investigate the long-term efficacy and safety of rupatadine in the management of pruritus, and the clinical effect of updosing to 20mg in Japanese adult and adolescent patients.In this 52-week, multicenter, open-label clinical trial (JapicCTI-152787), 206 patients (132, eczema or dermatitis; 58, pruritus; and 16, chronic spontaneous urticaria) received the study medication. The primary efficacy endpoint was change from baseline in the total pruritus score to Week 2 by treatment with rupatadine 10mg once daily. From Week 3 to Week 52, rupatadine updosing to 20mg was allowed.The mean [95% CI] change from baseline to Week 2 in the total pruritus score was -1.241 [-1.450, -1.033] (paired t test, P0.001). The therapeutic effect persisted up to Week 52 (paired t test, P0.001). Adverse drug reactions (ADRs) were reported at an overall incidence of 18.0% (45 events in 37 patients). No serious or clinically significant ADRs were reported. Somnolence was the most common ADR (14.1%).This clinical trial demonstrated the short- and long-term benefits of rupatadine in the management of patients with chronic spontaneous urticaria, dermatitis, and pruritus. Rupatadine 10 and 20mg doses are effective for the treatment of itch in adults and adolescents, and can be used safely on a long-term basis.

Objectives: To evaluate the safety, tolerability and efficacy of magnesium valproate and sodium valproate as monotherapies in patients with epilepsy in China. Methods: We recruited patients admitted with seizures over a two-year period. All patients underwent early neurological assessments, electroencephalogram testing, and neuroimaging. The treatments received at baseline and at one year of follow-up were compared. Results: In total, 175 patients were included. The retention rates of the magnesium valproate and sodium valproate treatments were 73.1% and 64.2%, respectively. The main cause of discontinuation was the development of intolerable adverse events. The retention rate and total effective rate in the magnesium valproate group were significantly higher than those in the sodium valproate group (73.1% and 70.2% versus 64.2% and 47.2%, respectively). The safety endpoints included 120 patients (magnesium valproate: n = 67; sodium valproate: n = 53). The incidence of adverse events in the magnesium valproate group was significantly lower than that in the sodium valproate group (30% versus 51%). Conclusions: Magnesium valproate treatment shows favorable safety and tolerability and is associated with markedly improved seizure control. Ideally, future large, prospective, randomized, and double-blind studies are needed to confirm these findings.