Non-serious Adverse Events Research Articles

Safety of esketamine nasal spray: Analysis of post-marketing reports submitted to the FDA adverse event reporting system in the first year on the market

IntroductionThe approval of the esketamine nasal spray for treatment-resistant depression in March 2019 by the Food and Drug Administration (FDA), and few months later by the European Medicine Agency, triggered a vivid debate and many concerns, mainly because of the lack of convincing evidence on its efficacy and safety, based on the development programs, approval trials and few post-marketing trials.ObjectivesWe aimed to detect and characterize safety signals for esketamine, by analyzing relevant adverse events (AEs) reports in the FDA Adverse Event Reporting System (FAERS) database (March 2019-March 2020).MethodsWe performed disproportionality analysis through the case/non-case approach: reporting odds ratios (ROR) and information components (IC) with 95% confidence intervals (95%CI) were estimated for esketamine-related AEs with at least four counts. We compared serious and non-serious AEs using non-parametrical tests.ResultsThe FAERS database registered 962 reports of esketamine-related AEs in one year. Signals (i.e., statistically significant disproportionality) were detected for several AEs, such as dissociation, sedation, feeling drunk, suicidal ideation and completed suicide. Signals for suicidal ideation, but not suicide attempt and completed suicide, remained significant when comparing esketamine to venlafaxine. The comparison of patients with serious vs. non-serious esketamine AEs revealed that females, patients receiving antidepressant polypharmacy, co-medication with antipsychotics, mood stabilizers, benzodiazepines or somatic medications were more likely to suffer from serious AEs.ConclusionsThis real-world pharmacovigilance analysis detected signals of serious unexpected esketamine-related AEs, thus reinforcing current worries regarding esketamine safety/acceptability. Further real-world studies are urgently needed to unravel the safety profile of esketamine.DisclosureNo significant relationships.

Effectiveness and Safety of the Clareon Monofocal Intraocular Lens: Outcomes from a 12-Month Single-Arm Clinical Study in a Large Sample.

PurposeThis study assessed effectiveness and safety of the novel Clareon intraocular lens (IOL; model SY60CL; Alcon Vision LLC).Patients and MethodsThis was a prospective, single-arm, unmasked clinical trial at 16 investigative clinical sites in the United States. Included were adults ≥22 years who required cataract extraction by phacoemulsification. Following phacoemulsification, 350 subjects received SY60CL IOL unilaterally; 342 completed the study. Monocular best corrected distance visual acuity (CDVA) and uncorrected distance visual acuity (UDVA) were evaluated. The primary effectiveness endpoint was the percentage of subjects with CDVA ≤0.3 logMAR at month 12. Safety was assessed by monitoring adverse events (AEs). Visual acuity and safety outcomes were compared with historical safety and performance endpoint (SPE) rates.ResultsAt 12 months post-implantation, 99.7% of subjects receiving the SY60CL IOL achieved monocular CDVA ≤0.3 logMAR (primary effectiveness endpoint; 1-sided 95% upper confidence limit >SPE rate); 99.7% and 86.8% of subjects achieved monocular CDVA of ≤0.34 (20/40 Snellen or better) and ≤0.04 logMAR (20/20 Snellen or better), respectively. At 12 months, >95% of subjects achieved mean monocular UDVA ≤0.3 logMAR; 97.1% and 57.6% of subjects achieved monocular CDVA of ≤0.34 and ≤0.04 logMAR, respectively. Mean monocular CDVA and UDVA were −0.05 and 0.04 logMAR, respectively. AEs were within SPE limits. The most common nonserious ocular AE was posterior capsule opacification (5.4%). Serious AEs were <1%, and no serious ocular AEs were assessed as related to the device. There were no observations for IOL glistenings at 12 months.ConclusionResults of this study supported effectiveness and safety of the SY60CL IOL. Visual acuity outcomes with the SY60CL IOL exceeded the SPE rates for monocular CDVA and AEs were within the limit of historic SPE rates. (Model number SY60WF is the Clareon lens approved by the FDA.)

Feasibility of scaling-up a community-based exercise program for young people with disability

Purpose To evaluate feasibility of scaling up a 12-week community-based exercise program (FitSkills) in which young people with disability exercise with a student mentor. Method Within a stepped wedge cluster randomised trial, seven domains of feasibility were assessed: demand, implementation, acceptability, practicality, adaptation, integration, and expansion. Results Of the 163 participants with disability (61 females; 20.8 ± 5 y) and 226 mentors who enrolled, 123 participants and mentors completed FitSkills. Population demand was estimated at 9% of members of participating organisations. Most participants (76%) completed the twice-weekly program within 12 weeks, attending 79% of sessions (mean 18.9 ± 4.7). Key program elements valued by participants were the mentor, tailored exercise, and regular program schedule. Majority (87%) of mentors were recruited from physiotherapy, occupational therapy, and exercise science courses. Positives for participants were perceived benefits and organisational support, and for mentors, understanding disability. Communication and scheduling were burdens. Three serious and 28 non-serious adverse events occurred. Adaptations (additional screening, risk analysis, extra mentor support, or in-person consultation) enabled 29 young people with complexity to participate. The number of trial sites was expanded to 11 to accommodate participants. Conclusions Scaling-up FitSkills is feasible, but with caveats related to communication, scheduling, and efficiency of recruitment. IMPLICATIONS FOR REHABILITATION Key elements valued by participants as part of the successful scale-up of a community-based exercise program (FitSkills) across a large metropolitan city included a peer-mentor, tailored exercise, and organisational support structure. FitSkills can be adapted to include young people with complex disability with additional supports including screening, risk analysis, and professional support for the peer-mentor. The benefits of FitSkills, including social connectedness for young people with a disability and normalisation of disability for mentors, outweigh the burdens of participation. Communication with program organisers and scheduling logistics between the young person, their family/carers and peer mentors are important factors to manage for the successful implementation of FitSkills.

Decentralised hepatitis C testing and treatment in rural Cambodia: evaluation of a simplified service model integrated in an existing public health system

Direct-acting antiviral treatment for hepatitis C virus (HCV) has provided the opportunity for simplified models of care delivered in decentralised settings by non-specialist clinical personnel. However, in low-income and middle-income countries, increasing overall access to HCV care remains an ongoing issue, particularly for populations outside of urban centres. We therefore aimed to implement a simplified model of HCV care via decentralised health services within a rural health operational district in Battambang province, Cambodia. The study cohort included adult residents (≥18 years) of the health operational district of Moung Russei who were voluntarily screened at 13 local health centres. Serology testing was done by a rapid diagnostic test using SD Bioline HCV (SD Bioline HCV, Standard Diagnostics, South Korea) with capillary blood. HCV viral load testing was done by GeneXpert (Cepheid, Sunnyvale, CA, USA). Viraemic patients (HCV viral load ≥10 IU/mL) received pretreatment assessment by a general physician and minimal treatment evaluation tests at the health operational district referral hospital. Viraemic patients who did not have additional complications received all HCV care follow-up at the local health centres, provided by nursing staff, and patients who had decompensated cirrhosis, previously treated with a direct-acting antiviral, HBV co-infection, or other comorbidities requiring observation continued receiving care at the referral hospital with a general physician. Patients deemed eligible for treatment were prescribed oral sofosbuvir (400 mg) and daclatasvir (60 mg) once a day for 12 weeks, or 24 weeks for patients with decompensated cirrhosis or those previously treated with a direct-acting antiviral. HCV cure was defined as sustained virological response at 12 weeks after treatment (HCV viral load <10 IU/mL). Patients were assessed for serious and non-serious adverse events at any time between treatment initiation and 12 weeks post-treatment testing. Between March 12, 2018, and Jan 18, 2019, 10 425 residents (ie, 7·6% of the estimated 136 571 adults in the health operational district of Moung Russei) were screened. Of those patients screened, the median age was 44 years (IQR 31-55) and 778 (7·5%) were HCV-antibody positive. 761 (97·8%) of 778 antibody-positive patients received HCV viral load testing, and 540 (71·0%) of those tested were HCV viraemic. Among these 540 patients, linkage to treatment and follow-up care was high, with 533 (98·7%) attending a baseline consultation at the HCV clinic, of whom 530 (99·4%) initiated treatment. 485 (91·5%) of 530 patients who initiated treatment received follow-up at a health centre and 45 (8·5%) were followed up at the referral hospital. Of the 530 patients who initiated direct-acting antiviral therapy, 515 (97·2%) completed treatment. Subsequently, 466 (90·5%) of 515 patients completed follow-up, and 459 (98·5%) of 466 achieved a sustained virological response at 12 weeks after treatment. Two (0·4%) adverse events (fatigue [n=1] and stomach upset [n=1]) and five (0·9%) serious adverse events (infection [n=2], cardiovascular disease [n=1], and panic attack [n=1], with data missing for one of the causes of serious adverse events) were reported among patients who initiated treatment. All serious adverse events were deemed to be unrelated to therapy. This pilot project showed that a highly simplified, decentralised model of HCV care can be integrated within a rural public health system in a low-income or middle-income country, while maintaining high patient retention, treatment efficacy, and safety. The project delivered care via accessible, decentralised primary health centres, using non-specialist clinical staff, thereby enhancing the efficient use of limited resources and maximising the potential to test and treat individuals living with HCV infection. Médecins Sans Frontières.

Interventions for treatment of COVID-19: Second edition of a living systematic review with meta-analyses and trial sequential analyses (The LIVING Project).

Interventions for treatment of COVID-19: Second edition of a living systematic review with meta-analyses and trial sequential analyses (The LIVING Project).

Targeting synovial fibroblast proliferation in rheumatoid arthritis (TRAFIC): an open-label, dose-finding, phase 1b trial.

SummaryBackgroundCurrent rheumatoid arthritis therapies target immune inflammation and are subject to ceiling effects. Seliciclib is an orally available cyclin-dependent kinase inhibitor that suppresses proliferation of synovial fibroblasts—cells not yet targeted in rheumatoid arthritis. Part 1 of this phase 1b/2a trial aimed to establish the maximum tolerated dose of seliciclib in patients with active rheumatoid arthritis despite ongoing treatment with TNF inhibitors, and to evaluate safety and pharmacokinetics.MethodsPhase 1b of the TRAFIC study was a non-randomised, open-label, dose-finding trial done in rheumatology departments in five UK National Health Service hospitals. Eligible patients (aged ≥18 years) fulfilled the 1987 American College of Rheumatology (ACR) or the 2010 ACR–European League Against Rheumatism classification criteria for rheumatoid arthritis and had moderate to severe disease activity (a Disease Activity Score for 28 joints [DAS28] of ≥3·2) despite stable treatment with anti-TNF therapy for at least 3 months before enrolment. Participants were recruited sequentially to a maximum of seven cohorts of three participants each, designated to receive seliciclib 200 mg, 400 mg, 600 mg, 800 mg, or 1000 mg administered in 200 mg oral capsules. Sequential cohorts received doses determined by a restricted, one-stage Bayesian continual reassessment model, which determined the maximum tolerated dose (the primary outcome) based on a target dose-limiting toxicity rate of 35%. Seliciclib maximum concentration (Cmax) and area under the plasma concentration time curve 0–6 h (AUC0–6) were measured. This study is registered with ISRCTN, ISRCTN36667085.FindingsBetween Oct 8, 2015, and Aug 15, 2017, 37 patients were screened and 15 were enrolled to five cohorts and received seliciclib, after which the trial steering committee and the data monitoring committee determined that the maximum tolerated dose could be defined. In addition to a TNF inhibitor, ten (67%) enrolled patients were taking conventional synthetic disease modifying antirheumatic drugs. The maximum tolerated dose of seliciclib was 400 mg, with an estimated dose-limiting toxicity probability of 0·35 (90% posterior probability interval 0·18–0·52). Two serious adverse events occurred (one acute kidney injury in a patient receiving the 600 mg dose and one drug-induced liver injury in a patient receiving the 400 mg dose), both considered to be related to seliciclib and consistent with its known safety profile. 65 non-serious adverse events occurred during the trial, 50 of which were considered to be treatment related. Most treatment-related adverse events were mild; 20 of the treatment-related non-serious adverse events contributed to dose-limiting toxicities. There were no deaths. Average Cmax and AUC0–6 were two-times higher in participants developing dose-limiting toxicities.InterpretationThe maximum tolerated dose of seliciclib has been defined for rheumatoid arthritis refractory to TNF blockade. No unexpected safety concerns were identified to preclude ongoing clinical evaluation in a formal efficacy trial.FundingUK Medical Research Council, Cyclacel, Research into Inflammatory Arthritis Centre (Versus Arthritis), and the National Institute of Health Research Newcastle and Birmingham Biomedical Research Centres and Clinical Research Facilities.

Efficacy of a Combination of Conservative Therapies vs an Education Comparator on Clinical Outcomes in Thumb Base Osteoarthritis

A combination of conservative treatments is commonly used in clinical practice for thumb base osteoarthritis despite limited evidence for this approach. To determine the efficacy of a 6-week combination of conservative treatments compared with an education comparator. Randomized, parallel trial with 1:1 allocation ratio among people aged 40 years and older with symptomatic and radiographic thumb base osteoarthritis in a community setting in Australia. The intervention group (n = 102) received education on self-management and ergonomic principles, a base-of-thumb splint, hand exercises, and diclofenac sodium, 1%, gel. The comparator group (n = 102) received education on self-management and ergonomic principles alone. Intervention use was at participants' discretion from 6 to 12 weeks. Hand function (Functional Index for Hand Osteoarthritis; 0-30) and pain (visual analog scale; 0-100 mm) were measured at week 6 (primary time point) and week 12. An α of .027 was used at week 6 to account for co-primary outcomes. Of the 204 participants randomized, 195 (96%) and 194 (95%) completed follow-ups at 6 and 12 weeks, respectively; the mean (SD) age of the population was 65.6 (8.1) years, and 155 (76.0%) were female. At week 6, hand function improved significantly more in the intervention group than the comparator (between-group difference, -1.7 units; 97.3% CI, -2.9 to -0.5; P = .002). This trend was sustained at 12 weeks (-2.4 units; 95% CI, -3.5 to -1.3; P < .001). Pain scores improved similarly at week 6 (between-group difference, -4.2 mm; 97.3% CI, -11.3 to 3.0; P = .19). At week 12, pain reduction was significantly greater in the intervention group (-8.6 mm; 95% CI, -15.2 to -2.0; P = .01). There were 34 nonserious adverse events, all in the intervention group-mostly skin reactions and exercise-related pain exacerbations. In this randomized clinical trial of people with thumb base osteoarthritis, combined treatments provided small to medium and potentially clinically beneficial effects on hand function but not pain. Australian New Zealand Clinical Trials Registry Identifier: ACTRN12616000353493.

Medical cannabis for the treatment of fibromyalgia syndrome: a retrospective, open-label case series

BackgroundThe use of cannabis for treating fibromyalgia syndrome (FMS) has not been comprehensively investigated. Thus, we have assessed the efficacy and adverse events (AEs) of short- and long-term medical cannabis (MC) treatment for FMS.MethodsData were obtained from medical reports archived in the pain clinic of Ponderano (Italy; retrospective study). FMS patients, who were resistant to conventional therapy, received licensed MC with various Δ-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) content, as powdered whole flowers (decoction or vaporization) or oil extracts. Demographic and clinical parameters, including Numerical Rating Scale (NRS), Oswestry Disability Index (ODI), Hospital Anxiety and Depression Scale, Widespread Pain Index (WPI), Severity Score (SyS), and side effects, were obtained after 1, 3, and 12 months. Data were analyzed with Wilcoxon signed-rank tests for paired data.ResultsThirty-eight patients were included. Thirty, 18, and 12 patients continued therapy for 1, 3, and 12 months, respectively. Significant improvements (p < 0.01) were observed in NRS, ODI, WPI, and SyS at 1 month; in NRS, ODI, and WPI at 3 months; and in NRS, ODI, and SyS at 12 months. Therapy was interrupted by 17 patients (48.6%) owing to nonserious AEs according to the FDA. The most common side effects were mental confusion (37%), dizziness (14%), nausea/vomiting (14%), and restlessness/irritation (14%). The median daily dose of milled flowers administered as THC-dominant MC and hybrid MC (with similar THC/CBD ratio) was 200 mg/day and 400 mg/day, respectively. After 3 months of titration, the median content of THC administered with THC-dominant MC cultivars was 46.2 mg, and of THC + CBD administered as a hybrid MC cultivar, was 23.6 mg + 38 mg. At 3 months, median THC content administered in the oil extract of the THC-dominant MC cultivars was 9.7 mg, while that of THC + CBD administered in the oil extract of the hybrid MC cultivars was 1.8 mg + 2 mg.ConclusionsMC may represent an alternative treatment for patients with FMS who are unresponsive to conventional therapy. However, its application may be limited by the incidence of nonserious AEs.

Effect of High-Intensity Strength Training on Knee Pain and Knee Joint Compressive Forces Among Adults With Knee Osteoarthritis

Thigh muscle weakness is associated with knee discomfort and osteoarthritis disease progression. Little is known about the efficacy of high-intensity strength training in patients with knee osteoarthritis or whether it may worsen knee symptoms. To determine whether high-intensity strength training reduces knee pain and knee joint compressive forces more than low-intensity strength training and more than attention control in patients with knee osteoarthritis. Assessor-blinded randomized clinical trial conducted at a university research center in North Carolina that included 377 community-dwelling adults (≥50 years) with body mass index (BMI) ranging from 20 to 45 and with knee pain and radiographic knee osteoarthritis. Enrollment occurred between July 2012 and February 2016, and follow-up was completed September 2017. Participants were randomized to high-intensity strength training (n = 127), low-intensity strength training (n = 126), or attention control (n = 124). Primary outcomes at the 18-month follow-up were Western Ontario McMaster Universities Osteoarthritis Index (WOMAC) knee pain (0 best-20 worst; minimally clinically important difference [MCID, 2]) and knee joint compressive force, defined as the maximal tibiofemoral contact force exerted along the long axis of the tibia during walking (MCID, unknown). Among 377 randomized participants (mean age, 65 years; 151 women [40%]), 320 (85%) completed the trial. Mean adjusted (sex, baseline BMI, baseline outcome values) WOMAC pain scores at the 18-month follow-up were not statistically significantly different between the high-intensity group and the control group (5.1 vs 4.9; adjusted difference, 0.2; 95% CI, -0.6 to 1.1; P = .61) or between the high-intensity and low-intensity groups (5.1 vs 4.4; adjusted difference, 0.7; 95% CI, -0.1 to 1.6; P = .08). Mean knee joint compressive forces were not statistically significantly different between the high-intensity group and the control group (2453 N vs 2512 N; adjusted difference, -58; 95% CI, -282 to 165 N; P = .61), or between the high-intensity and low-intensity groups (2453 N vs 2475 N; adjusted difference, -21; 95% CI, -235 to 193 N; P = .85). There were 87 nonserious adverse events (high-intensity, 53; low-intensity, 30; control, 4) and 13 serious adverse events unrelated to the study (high-intensity, 5; low-intensity, 3; control, 5). Among patients with knee osteoarthritis, high-intensity strength training compared with low-intensity strength training or an attention control did not significantly reduce knee pain or knee joint compressive forces at 18 months. The findings do not support the use of high-intensity strength training over low-intensity strength training or an attention control in adults with knee osteoarthritis. ClinicalTrials.gov Identifier: NCT01489462.

Influence of cytochrome P450 (CYP) 2C8 polymorphisms on the efficacy and tolerability of artesunate\u2010amodiaquine treatment of uncomplicated Plasmodium falciparum malaria in Zanzibar

BackgroundThe anti-malarial drug, amodiaquine, a commonly used, long-acting partner drug in artemisinin-based combination therapy, is metabolized to active desethyl-amodiaquine (DEAQ) by cytochrome P450 2C8 (CYP2C8). The CYP2C8 gene carries several polymorphisms including the more frequent minor alleles, CYP2C8*2 and CYP2C8*3. These minor alleles have been associated with decreased enzymatic activity, slowing the amodiaquine biotransformation towards DEAQ. This study aimed to assess the influence of these CYP2C8 polymorphisms on the efficacy and tolerability of artesunate–amodiaquine (AS–AQ) treatment for uncomplicated Plasmodium falciparum malaria in Zanzibar.MethodsDried blood spots on filter paper were collected from 618 children enrolled in two randomized clinical trials comparing AS–AQ and artemether-lumefantrine in 2002–2005 in Zanzibar. Study participant were under five years of age with uncomplicated falciparum malaria. Human CYP2C8*2 and CYP2C8*3 genotype frequencies were determined by PCR-restriction fragment length polymorphism. Statistical associations between CYP2C8*2 and/or CYP2C8*3 allele carriers and treatment outcome or occurrence of adverse events were assessed by Fisher’s exact test.ResultsThe allele frequencies of CYP2C8*2 and CYP2C8*3 were 17.5 % (95 % CI 15.4–19.7) and 2.7 % (95 % CI 1.8–3.7), respectively. There was no significant difference in the proportion of subjects carrying either CYP2C8*2 or CYP2C8*3 alleles amongst those with re-infections (44.1 %; 95 % CI 33.8–54.8) or those with recrudescent infections (48.3 %; 95 % CI 29.4–67.5), compared to those with an adequate clinical and parasitological response (36.7 %; 95 % CI 30.0-43.9) (P = 0.25 and P = 0.31, respectively). However, patients carrying either CYP2C8*2 or CYP2C8*3 alleles were significantly associated with an increased occurrence of non-serious adverse events, when compared with CYP2C8 *1/*1 wild type homozygotes (44.9 %; 95 % CI 36.1–54.0 vs. 28.1 %; 95 % CI 21.9–35.0, respectively; P = 0.003).ConclusionsCYP2C8 genotypes did not influence treatment efficacy directly, but the tolerability to AS–AQ may be reduced in subjects carrying the CYP2C8*2 and CYP2C8*3 alleles. The importance of this non-negligible association with regard to amodiaquine-based malaria chemotherapy warrants further investigation.

Efficacy of low glycemic index diet therapy (LGIT) in children aged 2–8 years with drug-resistant epilepsy: A randomized controlled trial

BackgroundA classic ketogenic diet, even though effective in children with drug-resistant epilepsy is not tolerated well by them and cumbersome to prepare. Low glycemic index therapy (LGIT), the least restrictive with minimal adverse effects among ketogenic dietary therapies has been proven effective in uncontrolled trials, but a placebo-controlled trial in this regard is still lacking. MethodsIn this open-label randomized controlled study, we randomized children above age two years with drug-resistant epilepsy into two groups (LGIT and control groups). Patients in the LGIT group received an add-on low glycemic index diet for 3 months along with the ongoing antiepileptic drugs and the patients in the control group did not receive any dietary intervention. Seizure frequency was assessed from the seizure diary maintained by the parents. Diet compliance was assessed using the diet diary that was maintained by the parents for three days just before the scheduled monthly visits of the patients. ResultsForty children with drug-refractory epilepsy (20 in each group) were enrolled. While 6/20 children in the LGIT arm have >50 % reduction in seizure frequency, none achieved this in the control arm (p = 0.02). The overall compliance with the low glycemic diet in the intervention group was 88.5 %. Out of six responders to LGIT, one child achieved seizure freedom and one achieved >90 % seizure reduction. Five continued LGIT further for a median duration of 8 months (range-4−12 months) successfully. The number needed to treat for more than 50 % seizure reduction was 3 and for more than 90 % seizure reduction was 10. The mean frequency of seizures for the intervention and control groups at three months of follow-up was not significantly different (p = 0.16), but the change in seizure frequency as compared to baseline was better in the intervention arm (p = 0.01). Three patients in the LGIT arm had non-serious adverse events (lethargy in two, vomiting in one). ConclusionIn children aged 2−8 years with drug-refractory epilepsy, the administration of LGIT along with ongoing anti-seizure medications (ASM) is more efficacious in reducing seizure frequency as compared to ASM alone.

Carbamazepine for Irritability and Aggression after Traumatic Brain Injury: A Randomized, Placebo-Controlled Study.

This study tested the hypothesis that carbamazepine (CBZ) reduces irritability/aggression among individuals >6 months post-traumatic brain injury (TBI). Seventy individuals were enrolled in a parallel-group, randomized, double-blind, placebo-controlled, forced-titration trial of CBZ (n = 35) versus placebo (n = 35). Participants were randomly assigned to receive CBZ or placebo 42 days with outcome assessed at baseline and Day 42. Dose was titrated up to 400 mg CBZ or placebo equivalent two times daily. Symptoms of irritability and aggression were measured using the Neuropsychiatric Inventory Irritability (NPI-I) and Aggression (NPI-A) domains as a composite measure (NPI-I/A). Global impression of change was recorded from participant, observer, and study clinician. The CBZ group did not differ significantly from the placebo group (p = 0.60 and 0.59 for NPI-I/A observer and participant ratings, respectively). High placebo effects were observed with minimal clinically important difference in observer NPI-I/A 57% in CBZ group and 77% in placebo group (p = 0.09). Findings were similar for participant ratings. Eighteen of 35 had therapeutic CBZ level ≥4. Therapeutic sample analysis revealed similar high placebo response and non-significant differences except clinician ratings favoring CBZ. Non-serious adverse events occurred more frequently in the CBZ group with greater nervous system effects. CBZ up to 400 mg two times daily was not superior to placebo at reducing irritability/aggression according observers and participants. Large placebo effects may have masked the detection of differences. Clinician rating metrics suggest benefit, and thus, CBZ should remain a treatment option for the experienced brain injury clinician. Data are provided that may aid treatment decisions.

Long-term effects of weight-reducing diets in people with hypertension.

All major guidelines for antihypertensive therapy recommend weight loss. Dietary interventions that aim to reduce body weight might therefore be a useful intervention to reduce blood pressure and adverse cardiovascular events associated with hypertension. Primary objectives To assess the long-term effects of weight-reducing diets in people with hypertension on all-cause mortality, cardiovascular morbidity, and adverse events (including total serious adverse events, withdrawal due to adverse events, and total non-serious adverse events). Secondary objectives To assess the long-term effects of weight-reducing diets in people with hypertension on change from baseline in systolic blood pressure, change from baseline in diastolic blood pressure, and body weight reduction. For this updated review, the Cochrane Hypertension Information Specialist searched the following databases for randomised controlled trials up to April 2020: the Cochrane Hypertension Specialised Register, CENTRAL (2020, Issue 3), Ovid MEDLINE, Ovid Embase, and ClinicalTrials.gov. We also contacted authors of relevant papers about further published and unpublished work. The searches had no language restrictions. We included randomised controlled trials (RCTs) of at least 24 weeks' duration that compared weight-reducing dietary interventions to no dietary intervention in adults with primary hypertension. Two review authors independently assessed risks of bias and extracted data. Where appropriate and in the absence of significant heterogeneity between studies (P > 0.1), we pooled studies using a fixed-effect meta-analysis. In case of moderate or larger heterogeneity as measured by Higgins I2, we used a random-effects model. This second review update did not reveal any new trials, so the number of included trials remains the same: eight RCTs involving a total of 2100 participants with high blood pressure and a mean age of 45 to 66 years. Mean treatment duration was 6 to 36 months. We judged the risks of bias as unclear or high for all but two trials. No study included mortality as a predefined outcome. One RCT evaluated the effects of dietary weight loss on a combined endpoint consisting of the necessity of reinstating antihypertensive therapy and severe cardiovascular complications. In this RCT, weight-reducing diet lowered the endpoint compared to no diet: hazard ratio 0.70 (95% confidence interval (CI) 0.57 to 0.87). None of the trials evaluated adverse events as designated in our protocol. The certainty of the evidence was low for a blood pressure reduction in participants assigned to weight-loss diets as compared to controls: systolic blood pressure: mean difference (MD) -4.5 mm Hg (95% CI -7.2 to -1.8 mm Hg) (3 studies, 731 participants), and diastolic blood pressure: MD -3.2 mm Hg (95% CI -4.8 to -1.5 mm Hg) (3 studies, 731 participants). We judged the certainty of the evidence to be high for weight reduction in dietary weight loss groups as compared to controls: MD -4.0 kg (95% CI -4.8 to -3.2) (5 trials, 880 participants). Two trials used withdrawal of antihypertensive medication as their primary outcome. Even though we did not consider this a relevant outcome for our review, the results of these RCTs strengthen the finding of a reduction of blood pressure by dietary weight-loss interventions. In this second update, the conclusions remain unchanged, as we found no new trials. In people with primary hypertension, weight-loss diets reduced body weight and blood pressure, but the magnitude of the effects are uncertain due to the small number of participants and studies included in the analyses. Whether weight loss reduces mortality and morbidity is unknown. No useful information on adverse effects was reported in the relevant trials.

A randomized placebo-controlled trial of elafibranor in patients with primary biliary cholangitis and incomplete response to UDCA

Patients with primary biliary cholangitis (PBC) who have an incomplete response to ursodeoxycholic acid remain at risk of disease progression. We investigated the safety and efficacy of elafibranor, a dual PPARα/δ agonist, in patients with PBC. This 12-week, double blind phase 2 trial enrolled 45 adults with PBC who had incomplete response to ursodeoxycholic acid (alkaline phosphatase levels ≥1.67-fold the upper limit of normal (ULN). Patients were randomly assigned to elafibranor-80 mg, elafibranor-120 mg or placebo. The primary end-point was the relative change of ALP at 12 weeks (NCT03124108). Reductions of ALP at 12 weeks were -48.3±14.8% for elafibranor-80 mg (p<0.001 vs placebo), -40.6±17.4% for elafibranor-120 mg (p<0.001) and +3.2±14.8% in the placebo group. The composite endpoint of ALP≤1.67-fold the ULN, decrease of ALP >15% and total bilirubin below the ULN was achieved in 67% patients in the elafibranor-80 mg group and 79% patients in the elafibranor-120 mg group, versus 6.7% patients in the placebo group. Levels of gamma glutamyl transferase decreased by 37.0±25.5% in the elafibranor-80mg group (p<0.001), 40.0±24.1% in the elafibranor-120mg group (p<0.01) compared with no change (+0.2±26.0%) in the placebo group. Levels of disease markers such as IgM, 5'-nucleotidase or hsCRP were likewise reduced from elafibranor. Pruritus was not induced or exacerbated from elafibranor and patients with pruritus at baseline reported less pruritic symptoms at the end of treatment. All possibly drug related non-serious adverse events were mild to moderate. In this randomized phase 2 trial, elafibranor was generally safe and well tolerated and significantly reduced levels of ALP, composite endpoints of bilirubin and ALP, as well as other markers of disease activity in patients with PBC and incomplete response to ursodeoxycholic acid. Data is available from the Study Sponsor Genfit SA. Clinical Trials.gov NCT03124108.

Safety of Andrographis paniculata: A systematic review and meta-analysis.

Andrographis paniculata is one of the commonly used herbal medicines worldwide. Nevertheless, evidences on adverse events (AEs) associated with Andrographis paniculata are very limited. This systematic review and meta-analysis was conducted to estimate and to compare the AE incidence of oral monotherapy Andrographis paniculata with others among patients with upper respiratory tract infection, noninfective diarrhea, and autoimmune disease. Systematic search was performed through six databases from inception until August 2018. Randomized controlled trial (RCT), cohort, or intensive monitoring of AEs was eligible for review if AE incidence was examined. The incidence of AEs was, then, pooled across studies using meta-analysis. Ten RCTs and 3 intensive monitoring studies were included. Incidence of serious AEs was very rare with the pooled incidence (95% CI) from RCTs of 0.02 per 1000 patients (0.0-0.5). However, the incidence of nonserious AEs was considered very common with the pooled incidence (95% CI) from RCTs of 102.6 per 1000 patients (10.7-256.1), and the pooled incidence (95% CI) from intensive monitoring of 34.2 per 1000 patients (0.0-229.6). The most common nonserious AEs were related to gastrointestinal disorder, and skin and subcutaneous disorder system. Like other medicine, Andrographis paniculata can cause some AEs. However, it may be generally safe. Nevertheless, prospective patients who plan to use Andrographis paniculata should be thoroughly advised and closely monitored for common AEs. Due to the increasing use of Andrographis paniculata worldwide, larger studies with adequate methodological quality are warranted to monitor the safety of such product.

Evaluating the safety of oral methylene blue during swallowing assessment: a systematic review

Methylene blue (MB) is frequently administered during fiberoptic endoscopic evaluation of swallowing (FEES) to enhance visualization of pharyngeal bolus transit. However, the safety of MB is being questioned since serious adverse events (AEs) such as hemodynamic instability, hemolysis, and serotonin syndrome were reported. The aim of this study is a systematic analysis of the literature to obtain an evidence-based overview of AEs due to oral administration of MB and to determine its safety as a food dye during swallowing assessment. A systematic literature search was carried out in PubMed, Embase, and Cochrane Library. Two reviewers independently selected articles describing oral administration of MB as a main diagnostic/therapeutic intervention, dosage, and AEs. Expert opinions, conference papers, sample size < 10, and animal studies were excluded. Level of evidence of the included studies was determined. A total of 2264 unduplicated articles were obtained. Seventeen studies met the inclusion criteria with 100% agreement between the two reviewers. Among these, twelve studies were randomized controlled trials. In a pooled population of 1902 patients receiving oral MB, three serious AEs were reported related to MB. Non-serious AEs showed a dose-related trend and were usually mild and self-limiting. A meta-analysis could not be performed as studies were methodologically too heterogeneous. Serious AEs due to oral administration of MB are rare (n = 3, 0.16%). MB-related non-serious AEs are mild, self-limiting, and show a dose-related trend. These findings indicate that it is safe to use small amounts of MB as a food dye during swallowing examinations.

Post-vaccination adverse events in the elderly in the State of São Paulo, Brazil, 2015 to 2017

Vaccination is one of the public health measures that has most contributed to decreasing the incidence of vaccine-preventable diseases. However, vaccines can lead to post-vaccination adverse events. This study thus aimed to analyze the prevalence of post-vaccination adverse events in elderly persons, determine the reported post-vaccination adverse events, identify the vaccines that cause post-vaccination adverse events, and verify the post-vaccination adverse events and vaccines that lead to hospitalizations in the State of São Paulo, Brazil, from 2015 to 2017. This was a descriptive cross-sectional study with a quantitative approach based on notifications of post-vaccination adverse events recorded in the Information System of the National Immunization Program. The results showed that of the 15,196,080 elderly persons that were immunized, there were 207 reports of post-vaccination adverse events, of which 187 (89%) were non-serious adverse events and 15 (8%) due to immunization errors (IE). The majority of the patients were female (86%), white (49%), and from 60 to 69 years of age (70%). Clinical manifestations featured local reactions at the injection site (84%). There were 131 cases (64%) that evolved to cure without sequelae. Two individuals (2%) were hospitalized due to serious adverse events. The first had received adult diphtheria/tetanus (dT), pneumococcal (Pn23), and influenza vaccines, and the second had received Pn23. The post-vaccination adverse events notifications showed incomplete information. In conclusion, notification of post-vaccination adverse events is essential. Health professionals need to be committed to adequate completion of the notification forms, with health surveillance supervision aimed at quality of care for elderly persons with post-vaccination adverse events.

Baricitinib and primary biliary cholangitis

Background and aimsThere is an unmet need for alternative treatments for patients with primary biliary cholangitis (PBC) who do not respond to treatment with ursodeoxycholic acid (UDCA). A proof-of-concept study of baricitinib, an orally administered Janus kinase 1 and 2 inhibitor, was initiated to evaluate its use in PBC patients. Approach and resultsPatients with PBC showing inadequate response or intolerance to UDCA were eligible. This was a randomized, double-blinded placebo-controlled trial. Enrollees were assigned 1:1 to baricitinib (2 mg/day) or placebo. Endpoints included change in alkaline phosphatase (ALP), itch Numeric Rating Score (NRS), and fatigue NRS at 12 weeks post-baseline; exploratory markers included high sensitivity C-reactive protein (hs-CRP) and Enhanced Liver Fibrosis (ELF) score.Due to low enrollment, the study was terminated early. Two patients were enrolled and completed the trial; 1 was randomized to receive baricitinib and 1 to placebo. Over the treatment period, the baricitinib-treated patient demonstrated a 30% decrease in ALP and a 7-point improvement in the itch NRS, but a 2-point increase in the Fatigue NRS. Markers of inflammation and liver fibrosis (hs-CRP and ELF score) also improved over the study period. In contrast, the placebo-treated patient showed no improvement in primary or secondary endpoints. A single non-serious treatment-emergent adverse event of moderate sinusitis was reported by the baricitinib-treated patient at day 47. ConclusionsIn a 12-week trial, a patient with PBC showing inadequate response to treatment with UDCA demonstrated a dramatic response to treatment with baricitinib.

The role of hospital pharmacist from the preparation of Bnt162b2 mRNA vaccine (Comirnaty®/Pfizer-Biontech) to its surveillance

Background. The Coronavirus Disease 2019 (COVID-19) pandemic, caused by a new severe acute respiratory syndrome induced by Coronavirus 2, was first recognized in December 2019, affecting more than 200 countries around the world to date. On 21 December 2020 the European Commission, according to the positive opinion of the European Medicines Agency (EMA), granted conditional marketing authorization in the European Union for the anti-COVID-19 mRNA vaccine Bnt162b2 (Comirnaty®/Pfizer-Biontech). The management, storage, preparation and administration of the Comirnaty® vaccine presents numerous critical points due by the new development platform and the pandemic emergency. These factors, if not well considered, can compromise the quality, efficacy and safety of the vaccine. The present study highlights the decisive role of the hospital pharmacist in the technical-logistical management of the vaccine in the current pandemic situation, from preparation to pharmacovigilance. Materials and methods. The detection of adverse reactions manifested by all employees of the IRCCS Sacro Cuore Don Calabria in Negrar di Valpolicella (VR) vaccinated between 01/01/2021-28/02/2021, are described. A prospective observational study, approved by the Ethics Committee of the hospital, was conducted through the compilation of a short questionnaire for the detection of adverse events after the administration of the first and second dose of vaccine. Results. From the pharmacovigilance analysis of 2030 subjects included in this observational study, only 1 serious adverse event was reported (equal to 0,05% incidence). Differently, the 99,95% of the reports refer to non-serious adverse events, mainly: pain at the injection site, fever, asthenia/fatigue, headache, muscle pain, joint pain, chills and skin rashes. The number of symptomatic subjects is statistically greater after the second vaccine administration and the reported events occur mainly immediately after vaccination, resolving within 48 hours after onset. Conclusions. In the context of the current health emergency, this work demonstrates how the professional supervision implemented by the pharmacist, in the current phase of mass immunization, guarantees the maintenance of the quality, efficacy and safety of the vaccine, respectively through the correct use of asepsis techniques, respect for the cold chain (fundamental element especially for Pfizer vaccine) and post-vaccination surveillance through active vaccinovigilance.

The Efficacy and Safety of Gynomax® XL Vaginal Ovule in the Treatment of Common Vaginal Infections: A Single-Arm Clinical Trial, Gyno-Türk

Objective: The objective of this study was to evaluate the efficacy, safety, and tolerability of Gynomax® XL vaginal ovule in the treatment of bacterial vaginosis (BV), candidal vulvovaginitis (CVV), trichomonal vaginitis (TV), and mixed vaginal infections (MVI). Material and Methods: A total of 98 women diagnosed clinically with BV, CVV, TV, or MVI have completed this study. Patients were given Gynomax® XL for 3 consecutive days, and approximately 10 (+/-5) days after the treatment, a follow-up visit was conducted. In addition to the clinical examinations, vaginal swab samples were collected in both visits for microbiological tests. Results: Based on the clinical diagnosis of the investigators, most of the patients had MVIs (54.1%), followed by BV (24.5%) and CVV (20.4%) at the baseline visit. One (1.0%) patient was diagnosed as having TV. According to the microbiologic examination results, 44 (44.9%) patients had BV, 20 (20.4%) had CVV, and 13 (13.3%) had MVIs. According to the clinical findings, overall complete recovery (CR) was observed in 76.5% of the patients and according to the microbiologic findings, overall CR was observed in 85.7% of the patients. Microbiologic results evaluated by each diagnostic criterion showed that CR was detected in 93.2%, 85.0%, and 61.5% of the patients with BV, CVV, and MVIs, respectively. There were no serious or non-serious adverse events leading to patient withdrawal or treatment discontinuation during this study. Conclusion: Gynomax® XL vaginal ovules administered once daily for three consecutive days provide effective and safe treatment in patients with BV, CVV, and MVIs.