Type Of Serious Adverse Events Research Articles

A comprehensive analysis on the safety of two biologics dupilumab and omalizumab.

Dupilumab was approved for the treatment of several dermatologic immune-mediated inflammatory diseases, such as atopic dermatitis and bullous pemphigoid; whereas omalizumab is the first biological agent which was approved to treat chronic spontaneous urticaria. None of the published meta-analyses has provided the sufficient data regarding the safety of these two biologics, especially regarding their potential serious adverse events (SAEs). The aim of this study was, to comprehensively evaluate the safety of the two biologics dupilumab and omalizumab. In this study, we included 32 randomized trials, and performed meta-analyses on 113 types of SAEs regarding dupilumab and 61 types of SAEs regarding omalizumab. We identified that: (1) use of dupilumab was significantly associated with the lower incidence of atopic dermatitis, while use of omalizumab was significantly associated with the lower incidence of asthma; and (2) use of dupilumab was not significantly associated with the incidences of 112 other kinds of SAEs including various infectious diseases, while use of omalizumab was not significantly associated with the incidences of 60 other kinds of SAEs including various infectious diseases. This meta-analysis for the first time assessed the association between use of dupilumab or omalizumab and incidences of various SAEs, and identified that neither dupilumab use nor omalizumab use was associated with the increased risks of any SAEs including various infectious diseases. These findings further confirm the general safety of the two biologics dupilumab and omalizumab. This informs clinicians that there is no need to worry too much about the safety issues of these two biologics.

Long-Term Safety and Effectiveness of Delayed-release Dimethyl Fumarate in Multiple Sclerosis Patients Treated in Routine Medical Practice, an updated analysis of the ESTEEM Study (P7-3.009)

Long-Term Safety and Effectiveness of Delayed-release Dimethyl Fumarate in Multiple Sclerosis Patients Treated in Routine Medical Practice, an updated analysis of the ESTEEM Study (P7-3.009)

Exploring the genetic landscape of diphtheria, tetanus and pertussis vaccination-associated seizures or subsequent epilepsies

Diphtheria, Tetanus, and whole-cell Pertussis (DTwP) vaccination-associated seizures form the commonest type of serious adverse event following immunization in India and are an important reason for vaccine hesitancy. Our study explored the genetic explanation of DTwP vaccination-associated seizures or subsequent epilepsies. Between March 2017 and March 2019, we screened 67 children with DTwP vaccination-associated seizures or subsequent epilepsies, and of those, we studied 54 without prior seizures or neurodevelopmental deficits. Our study design was cross-sectional with a 1-year follow-up having both retrospective and prospective cases. We performed clinical exome sequencing focused on 157 epilepsy-associated genes and multiplex ligation-dependent probe amplification of the SCN1A gene at enrolment. We applied the Vineland Social Maturity Scale for neurodevelopmental assessment at follow-up. Of 54 children enrolled and underwent genetic testing (median age 37.5 months, interquartile range 7.7–67.2; diagnosis at enrolment: epilepsy 29, febrile seizure 21, and febrile seizure-plus 4), we found 33 pathogenic variants of 12 genes. Of 33 variants, 13 (39%) were novel. Most pathogenic variants were found in SCN1A gene (n = 21/33; 64%), SCN8A in 2 children, and 10 children had one variant in CDKL5 , DEPDC5 , GNAO1 , KCNA2 , KCNT1 , KCNQ2 , NPRL3 , PCDH19 , RHOBTB2 , and SLC2A1 . Five or more seizures (odds ratio [OR] = 5.3, confidence interval [CI]: 1.6–18.4, p = 0.006), drug-resistant epilepsy (OR = 9.8, 95% CI: 2.6–30.7, p = 0.001) and neurodevelopmental impairment (social quotient < 70) (OR = 5.6, 95% CI: 1.65–17.6, p = 0.006) were significant predictors of genetic diagnosis. Our study provides proof-of-concept for genetic aetiology in children with DTwP vaccination-associated seizures or subsequent epilepsies and has important implications for vaccination policies in developing countries. International Pediatric Association Foundation, Inc. (IPAF): İhsan Doğramaci research award 2016/2017; Indian Council of Medical Research (ICMR), New Delhi, India: No.3/1/3/JRF-2016/HRD/LS/71/10940.

Long-term safety and efficacy of lentiviral hematopoietic stem/progenitor cell gene therapy for Wiskott–Aldrich syndrome

Patients with Wiskott–Aldrich syndrome (WAS) lacking a human leukocyte antigen-matched donor may benefit from gene therapy through the provision of gene-corrected, autologous hematopoietic stem/progenitor cells. Here, we present comprehensive, long-term follow-up results (median follow-up, 7.6 years) (phase I/II trial no. NCT02333760) for eight patients with WAS having undergone phase I/II lentiviral vector-based gene therapy trials (nos. NCT01347346 and NCT01347242), with a focus on thrombocytopenia and autoimmunity. Primary outcomes of the long-term study were to establish clinical and biological safety, efficacy and tolerability by evaluating the incidence and type of serious adverse events and clinical status and biological parameters including lentiviral genomic integration sites in different cell subpopulations from 3 years to 15 years after gene therapy. Secondary outcomes included monitoring the need for additional treatment and T cell repertoire diversity. An interim analysis shows that the study meets the primary outcome criteria tested given that the gene-corrected cells engrafted stably, and no serious treatment-associated adverse events occurred. Overall, severe infections and eczema resolved. Autoimmune disorders and bleeding episodes were significantly less frequent, despite only partial correction of the platelet compartment. The results suggest that lentiviral gene therapy provides sustained clinical benefits for patients with WAS.

Treatment tapering and stopping in patients with rheumatoid arthritis in stable remission (RETRO): a multicentre, randomised, controlled, open-label, phase 3 trial.

Owing to increasing remission rates, the management of patients with rheumatoid arthritis in sustained remission is of growing interest. The Rheumatoid Arthritis in Ongoing Remission (RETRO) study investigated tapering and withdrawal of disease-modifying antirheumatic drugs (DMARDs) in patients with rheumatoid arthritis in stable remission to test whether remission could be retained without the need to take DMARD therapy despite an absence of symptoms. RETRO was an investigator-initiated, multicentre, prospective, randomised, controlled, open-label, parallel-group phase 3 trial in patients aged at least 18 years with rheumatoid arthritis for at least 12 months before randomisation who were in sustained Disease Activity Score using 28 joints with erythrocyte sedimentation rate (ESR) remission (score <2·6 units). Eligible patients were recruited consecutively from 14 German hospitals or rheumatology practices and randomly assigned (1:1:1) without stratification and regardless of baseline treatment, using a sequence that was computer-generated by the study statistician, to continue 100% dose DMARD (continue group), taper to 50% dose DMARD (taper group), or 50% dose DMARD for 6 months before stopping DMARDs (stop group). Neither patients nor investigators were masked to the treatment assignment. Patients were assessed every 3 months and screened for disease activity and relapse. The primary endpoint was the proportion of patients in sustained DAS28-ESR remission without relapse at 12 months, analysed using a log-rank test of trend and Cox regression. Analysis by a trained statistician of the primary outcome and safety was done in a modified intention-to-treat population that included participants with non-missing baseline data. This study is completed and closed to new participants and is registered with ClinicalTrials.gov (NCT02779114). Between May 26, 2010, and May 29, 2018, 303 patients were enrolled and allocated to continue (n=100), taper (n=102), or stop DMARDs (n=101). 282 (93%) of 303 patients were analysed (93 [93%] of 100 for continue, 93 [91%] of 102 for taper, and 96 [95%] of 101 for stop). Remission was maintained at 12 months by 81·2% (95% CI 73·3-90·0) in the continue group, 58·6% (49·2-70·0) in the taper group, and 43·3% (34·6-55·5) in the stop group (p=0·0005 with log-rank test for trend). Hazard ratios for relapse were 3·02 (1·69-5·40; p=0.0003) for the taper group and 4·34 (2·48-7·60; p<0.0001)) for the stop group, in comparison with the continue group. The majority of patients who relapsed regained remission after reintroduction of 100% dose DMARDs. Serious adverse events occurred in ten of 93 (11%) patients in the continue group, seven of 93 (8%) patients in taper group, and 13 of 96 (14%) patients in the stop group. None were considered to be related to the intervention. The most frequent type of serious adverse event was injuries or procedural complications (n=9). Reducing antirheumatic drugs in patients with rheumatoid arthritis in stable remission is feasible, with maintenance of remission occurring in about half of the patients. Because relapse rates were significantly higher in patients who tapered or stopped antirheumatic drugs than in patients who continued with a 100% dose, such approaches will require tight monitoring of disease activity. However, remission was regained after reintroduction of antirheumatic treatments in most of those who relapsed in this study. These results might help to prevent overtreatment in a substantial number of patients with rheumatoid arthritis. None.

Pallidal versus subthalamic deep-brain stimulation for meige syndrome: a retrospective study

Deep-brain stimulation (DBS) is an effective treatment for patients with Meige syndrome. The globus pallidus interna (GPi) and the subthalamic nucleus (STN) are accepted targets for this treatment. We compared 12-month outcomes for patients who had undergone bilateral stimulation of the GPi or STN. Forty-two Asian patients with primary Meige syndrome who underwent GPi or STN neurostimulation were recruited between September 2017 and September 2019 at the Department of Neurosurgery, Peking University People’s Hospital. The primary outcome was the change in motor function, including the Burke–Fahn–Marsden Dystonia Rating Scale movement (BFMDRS-M) and disability subscale (BFMDRS-D) at 3 days before DBS (baseline) surgery and 1, 3, 6, and 12 months after surgery. Secondary outcomes included health-related quality of life, sleep quality status, depression severity, and anxiety severity at 3 days before and 12 months after DBS surgery. Adverse events during the 12 months were also recorded. Changes in BFMDRS-M and BFMDRS-D scores at 1, 3, 6, and 12 months with DBS and without medication did not significantly differ based on the stimulation target. There were also no significant differences in the changes in health-related quality of life (36-Item Short-Form General Health Survey) and sleep quality status (Pittsburgh Sleep Quality Index) at 12 months. However, there were larger improvements in the STN than the GPi group in mean score changes on the 17-item Hamilton depression rating scale (− 3.38 vs. − 0.33 points; P = 0.014) and 14-item Hamilton anxiety rating scale (− 3.43 vs. − 0.19 points; P < 0.001). There were no significant between-group differences in the frequency or type of serious adverse events. Patients with Meige syndrome had similar improvements in motor function, quality of life and sleep after either pallidal or subthalamic stimulation. Depression and anxiety factors may reasonably be included during the selection of DBS targets for Meige syndrome.

Adverse Events in Intensive Care and Continuing Care Units During Bed-Bath Procedures: The Prospective Observational NURSIng during critical carE (NURSIE) Study.

Standard nursing interventions, especially bed-baths, in ICUs can lead to complications or adverse events defined as a physiologic change that can be life-threatening or that prolongs hospitalization. However, the frequency and type of these adverse events are rarely reported in the literature. The primary objective of our study was to describe the proportion of patients experiencing at least one serious adverse event during bed-bath. The secondary objectives were to determine the incidence of each type of serious adverse event and identify risk factors for these serious adverse events. Prospective multicenter observational study. Twenty-four ICUs in France, Belgium, and Luxembourg. The patients included in this study had been admitted to an ICU for less than 72 hours and required at least one of the following treatments: invasive ventilation, vasopressors, noninvasive ventilation, high-flow oxygen therapy. Serious adverse events were defined as cardiac arrest, accidental extubation, desaturation and/or mucus plugging/inhalation, hypotension and/or arrhythmia and/or agitation requiring therapeutic intervention, acute pain, accidental disconnection or dysfunction of equipment, and patient fall requiring additional assistance. None. The study included 253 patients from May 1, 2018, to July 31, 2018 in 24 ICUs, representing 1,529 nursing procedures. The mean Simplified Acute Physiology Score II was 54 ± 19. Nursing care was administered by an average of 2 ± 1 caregivers and lasted between 11 and 20 minutes. Of the 253 patients included, 142 (56%) experienced at least one serious adverse event. Of the 1,529 nursing procedures, 295 (19%) were complicated by at least one serious adverse event. In multivariate analysis, the factors associated with serious adverse event were as follows: presence of a specific protocol (p = 0.011); tracheostomy (p = 0.032); administration of opioids (p = 0.007); presence of a physician (p = 0.0004); duration of nursing care between 6 and 10 minutes (p = 0.003), duration of nursing care between 11 and 20 minutes (p = 0.005), duration of nursing care greater than 40 minutes (p = 0.04) with a reference duration of nursing care between 20 and 40 minutes. Serious adverse events were observed in one-half of patients and concerned one-fifth of nurses, confirming the need for caution. Further studies are needed to test systematic serious adverse event prevention strategies.

Serious adverse events in children with juvenile idiopathic arthritis and other rheumatic diseases on tocilizumab – a real-world experience

ObjectivesTo assess the incidence rate and type of serious adverse events (SAE) in children with rheumatic inflammatory diseases treated with the interleukin 6 blocker tocilizumab (TCZ). MethodsA retrospective review of all consecutive patients diagnosed with an inflammatory rheumatic disease and receiving at least one dose of TCZ was performed in two French tertiary pediatric rheumatology centers between 01/2007 and 06/2019. SAE were defined as a life-threatening event and/or an event requiring hospital admission, leading to permanent disability or treatment discontinuation. ResultsOne hundred four children (64 female) were included. Most children suffered from systemic (n = 43) or polyarticular-course juvenile idiopathic arthritis (n = 43). Median age at TCZ start was 8.9 years (IQR 4.7 – 12.1), most children had received prednisone (81%), and/or a biologic agent (84%) prior to TCZ. Median TCZ treatment duration was 1.6 years (IQR 0.5 – 2.7), total TCZ exposure 215 patient years. Thirty-three SAE were observed in 26 (25%) children (SAE 15.3/100 patient years), mostly infections and infusion reactions. Children with SAE were significantly younger at disease onset (p = 0.034) and TCZ initiation (p = 0.016). Children experiencing infusion reactions were more likely to have systemic JIA or another autoinflammatory disease (p = 0.021), they all had active disease. At last follow up, 61 (59%) children remained on TCZ. ConclusionIn this cohort, SAE and most commonly serious infections were observed in a quarter of children. Severe infusion reactions were associated with persistently active autoinflammatory disease. Ongoing careful monitoring of TCZ-treated patients, especially young children with marked systemic inflammation is required.

Effect of ready-to-use supplementary food on mortality in severely immunocompromised HIV-infected individuals in Africa initiating antiretroviral therapy (REALITY): an open-label, parallel-group, randomised controlled trial

SummaryBackgroundIn sub-Saharan Africa, severely immunocompromised HIV-infected individuals have a high risk of mortality during the first few months after starting antiretroviral therapy (ART). We hypothesise that universally providing ready-to-use supplementary food (RUSF) would increase early weight gain, thereby reducing early mortality compared with current guidelines recommending ready-to-use therapeutic food (RUTF) for severely malnourished individuals only.MethodsWe did a 2 × 2 × 2 factorial, open-label, parallel-group trial at inpatient and outpatient facilities in eight urban or periurban regional hospitals in Kenya, Malawi, Uganda, and Zimbabwe. Eligible participants were ART-naive adults and children aged at least 5 years with confirmed HIV infection and a CD4 cell count of fewer than 100 cells per μL, who were initiating ART at the facilities. We randomly assigned participants (1:1) to initiate ART either with (RUSF) or without (no-RUSF) 12 weeks' of peanut-based RUSF containing 1000 kcal per day and micronutrients, given as two 92 g packets per day for adults and one packet (500 kcal per day) for children aged 5–12 years, regardless of nutritional status. In both groups, individuals received supplementation with RUTF only when severely malnourished (ie, body-mass index [BMI] <16–18 kg/m2 or BMI-for-age Z scores <–3 for children). We did the randomisation with computer-generated, sequentially numbered tables with different block sizes incorporated within an online database. Randomisation was stratified by centre, age, and two other factorial randomisations, to 12 week adjunctive raltegravir and enhanced anti-infection prophylaxis (reported elsewhere). Clinic visits were scheduled at weeks 2, 4, 8, 12, 18, 24, 36, and 48, and included nurse assessment of vital status and symptoms and dispensing of all medication including ART and RUSF. The primary outcome was mortality at week 24, analysed by intention to treat. Secondary outcomes included absolute changes in weight, BMI, and mid-upper-arm circumference (MUAC). Safety was analysed in all randomly assigned participants. Follow-up was 48 weeks. This trial is registered with ClinicalTrials.gov (NCT01825031) and the ISRCTN registry (43622374).FindingsBetween June 18, 2013, and April 10, 2015, we randomly assigned 1805 participants to treatment: 897 to RUSF and 908 to no-RUSF. 56 (3%) were lost-to-follow-up. 96 (10·9%, 95% CI 9·0–13·1) participants allocated to RUSF and 92 (10·3%, 8·5–12·5) to no-RUSF died within 24 weeks (hazard ratio 1·05, 95% CI 0·79–1·40; log-rank p=0·75), with no evidence of interaction with the other randomisations (both p>0·7). Through 48 weeks, adults and adolescents aged 13 years and older in the RUSF group had significantly greater gains in weight, BMI, and MUAC than the no-RUSF group (p=0·004, 0·004, and 0·03, respectively). The most common type of serious adverse event was specific infections, occurring in 90 (10%) of 897 participants assigned RUSF and 87 (10%) of 908 assigned no-RUSF. By week 48, 205 participants had serious adverse events in both groups (p=0·81), and 181 had grade 4 adverse events in the RUSF group compared with 172 in the non-RUSF group (p=0·45).InterpretationIn severely immunocompromised HIV-infected individuals, providing RUSF universally at ART initiation, compared with providing RUTF to severely malnourished individuals only, improved short-term weight gain but not mortality. A change in policy to provide nutritional supplementation to all severely immunocompromised HIV-infected individuals starting ART is therefore not warranted at present.FundingJoint Global Health Trials Scheme (UK Medical Research Council, UK Department for International Development, and Wellcome Trust).

The risk associated with spinal manipulation: an overview of reviews

BackgroundSpinal manipulative therapy (SMT) is a widely used manual treatment, but many reviews exist with conflicting conclusions about the safety of SMT. We performed an overview of reviews to elucidate and quantify the risk of serious adverse events (SAEs) associated with SMT.MethodsWe searched five electronic databases from inception to December 8, 2015. We included reviews on any type of studies, patients, and SMT technique. Our primary outcome was SAEs. Quality of the included reviews was assessed using a measurement tool to assess systematic reviews (AMSTAR). Since there were insufficient data for calculating incidence rates of SAEs, we used an alternative approach; the conclusions regarding safety of SMT were extracted for each review, and the communicated opinion were judged by two reviewers independently as safe, harmful, or neutral/unclear. Risk ratios (RRs) of a review communicating that SMT is safe and meeting the requirements for each AMSTAR item, were calculated.ResultsWe identified 283 eligible reviews, but only 118 provided data for synthesis. The most frequently described adverse events (AEs) were stroke, headache, and vertebral artery dissection. Fifty-four reviews (46%) expressed that SMT is safe, 15 (13%) expressed that SMT is harmful, and 49 reviews (42%) were neutral or unclear. Thirteen reviews reported incidence estimates for SAEs, roughly ranging from 1 in 20,000 to 1 in 250,000,000 manipulations. Low methodological quality was present, with a median of 4 of 11 AMSTAR items met (interquartile range, 3 to 6). Reviews meeting the requirements for each of the AMSTAR items (i.e. good internal validity) had a higher chance of expressing that SMT is safe.ConclusionsIt is currently not possible to provide an overall conclusion about the safety of SMT; however, the types of SAEs reported can indeed be significant, sustaining that some risk is present. High quality research and consistent reporting of AEs and SAEs are needed.Systematic review registrationPROSPERO CRD42015030068.

Abstract TP70: Incidence of Serious Adverse Events Following Acute Stroke: Data From the Efficacy of Nitric Oxide in Stroke (ENOS) Trial

Background: Reporting of serious adverse events (SAEs) is an essential safety procedure in randomised controlled trials. Risk factors for SAEs post-stroke and the relationship of SAEs with outcome were studied in the ENOS trial. Methods: ENOS assessed glyceryl trinitrate (GTN, 5 mg) vs no GTN for 7 days in 4,011 patients with acute stroke and high blood pressure. Information on SAEs was collected up to day 90. SAEs were adjudicated centrally with blinding to treatment assignment. Results: SAEs were reported in 1022 (25.5%) patients, 43.8% of whom died. Patients who suffered SAEs were more likely to be older (mean age 74.2 vs. 69.0 years, p&lt;0.001) and have a history of atrial fibrillation (AF) (relative risk [RR] 1.80, p&lt;0.001). Patients with non-oral feeding at baseline were more vulnerable to SAEs (RR 2.14, p&lt;0.001) and fatal SAEs (RR 3.77, p&lt;0.001) as compared with those with oral feeding. Males were at less risk than females to suffer an SAE (RR 0.83, p&lt;0.001), as were smokers (RR 0.73, p&lt;0.001). Smokers also suffered fewer fatal SAEs (RR 0.55, p&lt;0.001). GTN did not increase the incidence of SAEs. The most common type of SAE was pneumonia (6% incidence) with a high risk of death (RR 9.29, p&lt;0.001). Conclusions: SAEs are associated with a range of risk factors that should be taken into account in clinical practice. AF and non-oral feeding status were associated with increased, and smoking with reduced, risk of of SAEs. Incidence of pneumonia was a common and life threatening issue amongst patients.

The Effect of Chronic Kidney Disease on a Physical Activity Intervention: Impact on Physical Function, Adherence, and Safety.

BackgroundBecause chronic kidney disease (CKD) is associated with muscle wasting, older adults with CKD are likely to have physical function deficits. Physical activity can improve these deficits, but whether CKD attenuates the benefits is unknown. Our objective was to determine if CKD modified the effect of a physical activity intervention in older adults.MethodsThis is an exploratory analysis of the LIFE-P study, which compared a 12-month physical activity program (PA) to a successful aging education program (SA) in older adults. CKD was defined as a baseline eGFR < 60 mL/min/1.73 m2. We examined the Short Physical Performance Battery (SPPB) at baseline, 6 and 12 months. Secondary outcomes included serious adverse events (SAE) and adherence to intervention frequency. Linear mixed models were adjusted for age, sex, diabetes, hypertension, CKD, intervention, site, visit, baseline SPPB, and interactions of intervention and visit and of intervention, visit, and baseline CKD.ResultsThe sample included 368 participants. CKD was present in 105 (28.5%) participants with a mean eGFR of 49.2 ± 8.1 mL/min/1.73 m2. Mean SPPB was 7.38 ± 1.41 in CKD participants; 7.59 ± 1.44 in those without CKD (p = 0.20). For CKD participants in PA, 12-month SPPBs increased to 8.90 (95% CI 8.32, 9.47), while PA participants without CKD increased to 8.40 (95% CI 8.01, 8.79, p = 0.43). For CKD participants in SA, 12-month SPPBs increased to 7.67 (95% CI 7.07, 8.27), while participants without CKD increased to 8.12 (95% CI 7.72, 8.52, p = 0.86). Interaction between CKD and intervention was non-significant (p = 0.88). Number and type of SAEs were not different between CKD and non-CKD participants (all p > 0.05). In PA, adherence for CKD participants was 65.5 ± 25.4%, while for those without CKD was 74.0 ± 22.2% (p = 0.12).ConclusionDespite lower adherence, older adults with CKD likely derive clinically meaningful benefits from physical activity with no apparent impact on safety, compared to those without CKD.

Efficacy and safety of boceprevir based triple therapy in Hungarian patients with hepatitis C genotype 1 infection, advanced stage fibrosis and prior treatment failure

During 2011 and 2013, 155 Hungarian hepatitis C genotype 1 infected patients, mostly with advanced liver fibrosis, who did not respond to prior peginterferon + ribavirin dual therapy, started boceprevir based triple therapy in an early access program. Efficacy and safety of the therapy was retrospectively assessed based on sustained virologic responses, as well as on frequency and type of serious adverse events and of those leading to therapy discontinuation. In an intent-to-treat analysis 39.4% patients (61/155) reached sustained virologic response. Amongst pervious relapsers, partial responders and null-responders 59.5%, 41.4 % and 22.9% (p<0.05 compared to the other two categories) reached sustained virologic response, respectively, while amongst non-cirrhotics and cirrhotics 52.5% and 31.3% (p<0.05 compared to the non-cirrhotics) achieved sutained virologic response, respectively. Six out of the 33 most difficult to cure patients (previous null responder and cirrhotic) have reached sustained virologic response (18.2%). Frequency of early discontinuations due to insufficient virologic response was 31.1%, while due to adverse event 10.3%. Reported frequency of serious adverse event was 9.8%. These events represented anemia, diarrhoea, depression, agranulocytosis, elevated aminotransferases, generalized dermatitis and severe gingivitis with loss of teeth, prolonged QT interval on ECG, generalized oedema and severe dyspnoea, uroinfection, exacerbation of Crohn's disease, Campylobacter pylori infection and unacceptable weakness and fatigue. Eight patients received transfusion, 4 patients erythropoietin and 1 granulocyte colony stimulating factor during therapy. No death has been reported. With boceprevir based triple therapy, one of the bests available in 2011-2013 in Hungary, a relevant proportion of hepatitis C infected patients with advanced liver fibrosis achieved sustained viral response. In this cohort, side-effects resembled those reported in registration studies, and resulted in therapy discontinuation with consequent treatment failure in a relevant number of patients. Efficacy and tolerability of boceprevir-based triple therapy are suboptimal, particularly in the most difficult to cure patient population. Orv. Hetil., 2016, 157(34), 1366-1374.

OP0114 Interim Safety and Efficacy Results of Patients with Cryopyrin-Associated Periodic Syndrome Participating in the β-Confident Registry

BackgroundCryopyrin-associated periodic syndrome (CAPS) is a continuum of rare hereditary disorders that includes three phenotypes, in the order of severity: familial cold auto-inflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and chronic...

Long-Term Safety and Efficacy and Association between Baseline Treatment History and Postbaseline Relapses in Multiple Sclerosis Patients Treated with Natalizumab in the TYSABRI(R) Observational Program (TOP) (P04.134)

Objective: Evaluate long-term safety, efficacy, and associations between baseline treatment history and postbaseline annualized relapse rate (ARR) in multiple sclerosis (MS) patients treated with natalizumab. Background The ongoing natalizumab (TYSABRI®) Observational Program (TOP) study is an open-label, multinational, observational study assessing long-term outcomes in relapsing-remitting MS patients in the postmarketing setting in Europe, Australia, and Canada. Design/Methods: As of June 2011, 3484 patients from 15 countries were enrolled. Incidence of serious adverse events (SAEs) was analyzed. ARR and Expanded Disability Status Scale (EDSS) scores were assessed. Associations between baseline therapy and postbaseline ARR were analyzed using negative binomial regression for 5 baseline groups: therapy naive (n=337), interferon (IFN) only (n=1626), glatiramer acetate (GA) only (n=288), switched between GA and IFN in either order (n=595), or immunosuppressant (IS) use (n=487). Results: - 53]) natalizumab infusions. Overall, 5.1% of patients experienced ≥1 SAE; infections (1.1%) and hypersensitivity reactions (0.7%) were most frequent. Seven cases of progressive multifocal leukoencephalopathy (PML) occurred after 35, 29, 28, 26, 24, 24, and 12 natalizumab infusions. Three of them were previously exposed to mitoxantrone. Overall, the mean EDSS score was 3.5 at baseline and 3.4 after 3 years. ARR was significantly decreased regardless of baseline treatment history; mean ARR decreased (n=3458) from baseline (1.98) to postbaseline (0.28; P Conclusions: The overall incidence and type of SAEs reported in TOP are consistent with natalizumab9s known safety profile. EDSS scores were stable and ARR was significantly reduced after 3 years of natalizumab therapy. ARRs were lowest in therapy-naive patients and highest in patients with prior IS. Supported by: Biogen Idec Inc. and Elan Pharmaceuticals, Inc. Disclosure: Dr. Kappos has received research support from Acorda Therapeutics, Actelion, Allozyne, BaroFold, Inc., Bayer Pharmaceuticals Corporation, Bayhill Therapeutics, Biogen Idec, Boehringer Ingelheim Pharmaceuticals, Inc, Elan Corporation, Genmab, GlaxoSmithKline, Inc., Glenmark Pharma, Merck Serono, MediciNova, Novartis, Sanofi-Aventis Pharmaceuticals, Santhera Pharmaceuticals, Shire, Roche Diagnostics, Teva Neuroscience, UCB Pharma, Pfizer Inc, Swiss MS Society, Swiss National Research Foundation, European Union, Gianni Rubatto Foundation, Novartis and Roche Research Foundations. Dr. Belachew has received personal compensation for activities with Bayer Pharmaceuticals Corporation, Biogen Idec and Merck Serono as a consultant. Dr. Belachew has received research support from Biogen Idec, Merck Serono, Novartis, Sanofi-Aventis Pharmaceuticals, and Teva Neuroscience. Dr. Butzkueven has received personal compensation for activities with Biogen Idec, Merck Serono, Novartis, Sanofi-Aventis Pharmaceuticals, Inc., National Health and Medical Research Council, and National MS Society. Dr. Butzkueven has received personal compensation in an editorial capacity for Multiple Sclerosis International Federation and Multiple Sclerosis. Dr Butzkueven has received research support from Biogen Idec, Merck Serono, and Novartis. Dr. Pellegrini has received personal compensation for activities with Biogen Idec as a consultant. Dr. Trojano has received personal compensation for activities with Bayer Pharmaceuticals Corporation, Biogen Idec and Sanofi-Aventis Pharmaceuticals, Inc. as a consultant and/or speaker. Dr. Trojano has received research support from Merck & Co., Inc. Dr. Wiendl has received personal compensation for activities with Bayer Pharmaceuticals Corporation, Biogen Idec, Merck Serono, Novo Nordisk, Sanofi-Aventis Pharmaceuticals, Inc., Schering AG and Teva Neuroscience. Dr. Wiendl has received research support from Bayer Pharmaceuticals Corporation, Biogen Idec, Medac, Merck-Serono, Novo Nordisk, Sanofi-Aventis Pharmaceuticals, Inc., Schering AG and Teva Neuroscience. Dr. Zhang has received personal compensation for activities with Biogen Idec as an employee. Dr. Hotermans has received personal compensation for activities with Biogen Idec as an employee.Dr. Hotermans holds stock and/or stock options in Biogen Idec which sponsored research in which Dr. Hotermans was involved as an investigator.

An Open-Label, Randomized, Parallel, Multi-Center Trial Comparing the Safety and Efficacy of rFVIIa When Administered as I.V. Bolus or I.V. Continuous Infusion to Hemophilia Patients with Inhibitors during and after Surgery.

Background and Purpose: Bolus infusion (BI) of recombinant FVIIa (rFVIIa) is effective for the treatment of bleeding and surgical prophylaxis in congenital hemophilia A or B patients with FVIII or IX inhibitors. In principle, continuous infusion (CI) of rFVIIa could maintain the hemostatic effect at a steady state while avoiding the peaks and troughs of repetitive BI. The purpose of this study was to compare the efficacy and safety of rFVIIa CI with rFVIIa BI in major surgery in hemophilia patients with inhibitors. Methods: A 10-day, open-label, randomized, multicenter trial was conducted in hemophilia A or B patients (age &gt; 5 yr) with inhibitors to FVIII or FIX who underwent elective major surgery. Patients received rFVIIa as an initial bolus dose of 90 μg/kg followed by intermittent i.v. bolus (90 μg/kg) or i.v. continuous (50 μg/kg/hr) infusion. BI was administered every 2 hours during surgery and through Day 5, then every 4 hours for Days 6 to 10. CI was administered at 50 μg/kg/hr through Day 5 and at 25 μg/kg/hr Days 6 to10. A third control group of 10 non-inhibitor hemophilia A or B patients who underwent similar surgery and were treated with FVIII or FIX (based on current standard of care and physician’s choice) was assessed to compare adverse event and coagulation profiles. Safety was assessed throughout the study periods. Efficacy was defined as having no treatment failures during the given time and was evaluated at 48 hours, 5 days, and 10 days postoperatively. Treatment was considered ineffective in patients who received more than 2 additional doses of rFVIIa beyond the protocol-defined doses during a 24 hour period. Patients who received alternative hemostatic therapy following the permitted two additional doses of rFVIIa were considered treatment failures. Results: Twenty-four patients (12 CI arm, 12 BI arm) underwent 9 major types of surgeries. Knee (n=11) and hip (n=3) replacements were the most common surgeries. Recombinant FVIIa efficacy in major surgeries was 92% (11 CI, 11 BI) at 48 hours; 83% (10 CI) and 92% (11 BI) at Day 5; 83% (10 CI) and 75% (9 BI) at Day 10. Sixty-six rescue doses (rFVIIa, 90 μg/kg) were administered in the CI group (54 in one patient), and 7 in 3 patients in the BI group. Adverse events occurred more frequently in the CI treatment group (239; 141 in one patient) compared to the BI group (89 AEs); 64 AEs occurred in the control group. Eight patients (3 CI, 4 BI, 1 control) experienced 10 serious adverse events (SAEs). SAEs occurred most frequently in the BI treatment group (3 CI, 6 BI, 1 control). The types of SAEs were equally distributed among the three groups. There were no serious thromboembolic events reported during the study. Conclusions: This summary of 24 major surgeries indicates that rFVIIa is effective as prophylactic therapy for major surgery in hemophilia A or B patients with inhibitors. The numbers of patients were too small to distinguish efficacy rates between the two groups. The safety profile for patients treated with rFVIIa (BI or CI) was similar to the profile for non-inhibitor patients treated with other factors. Presented on behalf of the NovoSeven in Surgery Study Investigators.

Serious adverse events following treatment with ivermectin for onchocerciasis control: a review of reported cases.

This paper presents a summary of reported cases of Serious Adverse Events (SAEs) following treatment with Mectizan® (ivermectin, Merck, Sharpe & Dohme) in onchocerciasis mass treatment programs from January 1, 1989 to December 31, 2001 through a passive surveillance system. A total of 207 SAE cases were reported out of approximately 165 million reported treatments delivered during the period under review, giving rise to a cumulative incidence of 1 reported SAE per 800,000 reported treatments. The mean age was 40 years and 70% of the cases were males. The mean time between ivermectin intake and onset of illness was 1 day. For 57% of the cases (n = 118), that was their first exposure to ivermectin. The majority of cases were reported from Cameroon (n = 176; 85%) with peaks in the incidence of SAE reporting in 1989–1991 and 1994–1995 when the program expanded to ivermectin-naïve populations. Fifty-five percent of the cases from Cameroon (i.e. 97 out of 176 cases) were encephalopathic and were reported from the central-southern region of the country; two-thirds of these cases were 'probable' or 'possible' cases of Loa loa encephalopathy temporally related to ivermectin treatment. Reporting bias may explain some but not all of the differences in SAE reporting between the 34 onchocerciasis-endemic countries that have, or have had, mass treatment programs. Further research is needed to understand the apparent clustering of encephalopathy cases in central-southern Cameroon since L. loa infection alone probably does not explain the increased incidence of this type of SAE from this region.

A multicenter trial on the efficacy of using tirilazad mesylate in cases of head injury

The authors prospectively studied the efficacy of tirilazad mesylate, a novel aminosteroid, in humans with head injuries. A cohort of 1120 head-injured patients received at least one dose of study medication (tirilazad or placebo). Eighty-five percent (957) of the patients had suffered a severe head injury (Glasgow Coma Scale [GCS] score 4-8) and 15% (163) had sustained a moderate head injury (GCS score 9-12). Six-month outcomes for the tirilazad- and placebo-treated groups for the Glasgow Outcome Scale categories of both good recovery and death showed no significant difference (good recovery in the tirilazad-treated group was 39% compared with the placebo group in which it was 42% [p=0.461]; death in the tirilazad-treated group occurred in 26% of patients compared with the placebo group, in which it occurred in 25% [p=0.750]). Subgroup analysis suggested that tirilazad mesylate may be effective in reducing mortality rates in males suffering from severe head injury with accompanying traumatic subarachnoid hemorrhage (death in the tirilazad-treated group occurred in 34% of patients; in the placebo group it occurred in 43% [p=0.026]). No significant differences in frequency or types of serious adverse events were shown between the treatment and placebo groups. Striking problems with imbalance concerning basic prognostic variables were observed in spite of the large population studied. These imbalances concerned pretreatment hypotension, pretreatment hypoxia, and the incidence of epidural hematomas. In future trials of pharmacological therapy for severe head injury, serious consideration must be given to alternative randomization strategies. Given the heterogeneous nature of head injury and the identification of populations that do relatively well with standard therapy, target populations with a higher risk for mortality and morbidity may be more suitable for clinical trials of such agents.