Discontinuation Due To Adverse Events Research Articles

Comparison of brexpiprazole, aripiprazole, and placebo for Japanese major depressive disorder: A systematic review and network meta-analysis.

This systematic review and frequentist network meta-analysis used random-effects models is conducted to determine whether there are differences in the efficacy, acceptability, tolerability, and safety profiles of brexpiprazole (BRE) and aripiprazole (ARI) for Japanese with major depressive disorder (MDD) who were inadequately responsive to antidepressants. Outcome measures were scores on the Montgomery Åsberg Depression Rating Scale (primary), the Clinical Global Impression severity scale, and social functioning scale; the non-response rate; the non-remission rate; all-cause discontinuation; discontinuation due to adverse events (DAE); at least one adverse event (1AE); serious adverse event, akathisia; tremor; weight gain. A literature search identified three double-blind, randomized, placebo-controlled trials. These comprised one BRE study (with a 1 mg/day [BRE1] and a 2 mg/day [BRE2]) and two ARI studies (with a 3 mg/day arm and a flexible-dose arm[within the dosage range approved in Japan]) (n = 1736). Both BRE and ARI demonstrated better efficacy than the placebo. BRE but not ARI had a higher DAE than the placebo. ARI but not BRE had a higher 1AE than the placebo. BRE and ARI had a higher risk of akathisia and weight gain than the placebo. There were no significant differences between BRE and ARI for any of the outcomes. Although BRE1 had good efficacy, it carried risk of weight gain. Although BRE2 also had efficacy, it carried risks of DAE, akathisia, and weight gain. However, the risk of akathisia in BRE2 was reduced by an initial dose of 0.5 mg/day rather than 1.0 mg/day. Overall BRE showed similar utility to ARI and a good risk-benefit balance.

Safety of SABA Monotherapy in Asthma Management: a Systematic Review and Meta-analysis.

Short-acting β2-agonist (SABA) reliever overuse is common in asthma, despite availability of inhaled corticosteroid (ICS)-based maintenance therapies, and may be associated with increased risk of adverse events (AEs). This systematic literature review (SLR) and meta-analysis aimed to investigate the safety and tolerability of SABA reliever monotherapy for adults and adolescents with asthma, through analysis of randomized controlled trials (RCTs) and real-world evidence. An SLR of English-language publications between January 1996 and December 2021 included RCTs and observational studies of patients aged ≥ 12years treated with inhaled SABA reliever monotherapy (fixed dose or as needed) for ≥ 4weeks. Studies of terbutaline and fenoterol were excluded. Meta-analysis feasibility was dependent on cross-trial data comparability. A random-effects model estimated rates of mortality, serious AEs (SAEs), and discontinuation due to AEs (DAEs) for as-needed and fixed-dose SABA treatment groups. ICS monotherapy and SABA therapy were compared using a fixed-effects model. Forty-two studies were identified by the SLR for assessment of feasibility. Final meta-analysis included 24 RCTs. Too few observational studies (n = 2) were available for inclusion in the meta-analysis. One death unrelated to treatment was reported in each of the ICS, ICS + LABA, and fixed-dose SABA groups. No other treatment-related deaths were reported. SAE and DAE rates were < 4%. DAEs were reported more frequently in the SABA treatment groups than with ICS, potentially owing to worsening asthma symptoms being classified as an AE. SAE risk was comparable between SABA and ICS treatments. Meta-analysis of data from RCTs showed that deaths were rare with SABA reliever monotherapy, and rates of SAEs and DAEs were comparable between SABA reliever and ICS treatment groups. When used appropriately within prescribed limits as reliever therapy, SABA does not contribute to excess rates of mortality, SAEs, or DAEs.

Benefit-Risk Assessment of Galcanezumab Versus Placebo for the Treatment of Episodic and Chronic Migraine Using the Metrics of Number Needed to Treat and Number Needed to Harm.

IntroductionSubcutaneous galcanezumab was an effective, well-tolerated preventive treatment for adults with episodic (EM) or chronic migraine (CM) in 4 phase 3 randomized controlled trials: EVOLVE-1, EVOLVE-2, REGAIN, and CONQUER. Number needed to treat (NNT) and to harm (NNH) are metrics of effect size used to evaluate benefit–risk profiles. This study evaluated NNT, NNH, and benefit–risk profiles (measured as likelihood to be helped or harmed, LHH) of galcanezumab 120 mg versus placebo in patients with EM or CM.MethodsPrimary efficacy outcomes were responses defined as ≥ 30%, ≥ 50%, and ≥ 75% reductions from baseline in number of monthly migraine headache days in patients with EM (EVOLVE-1; EVOLVE-2; CONQUER) and CM (REGAIN; CONQUER); corresponding NNTs to achieve respective responses; and corresponding NNHs for discontinuations due to adverse events (DCAEs) among the safety population. Secondary efficacy outcomes were responses for patients with ≥ 2 failed prior preventive treatments due to lack of efficacy and/or for tolerability reasons. All LHHs were based on ≥ 50% response and DCAEs.ResultsDuring double-blind treatment periods with galcanezumab 120 mg, NNT to achieve ≥ 30% and ≥ 50% responses ranged from 4 to 10 and NNT to achieve ≥ 75% responses ranged from 5 to 23 in individual trials. NNH ranged from 93 to 1000, while LHH ranged from 18.6 to 104.6. NNTs were generally more robust among patients with EM than with CM; however, in patients with failure of ≥ 2 prior preventive treatments, NNTs to achieve ≥ 30% and ≥ 50% responses were similar between patients with CM and EM. NNHs were imputed as 1000 for both migraine types. Resulting LHHs were 178.8 (EM) and 127 (CM).ConclusionAcross 4 trials, galcanezumab 120 mg demonstrated a favorable benefit–risk profile versus placebo, based on low NNTs to achieve response and high NNHs associated with DCAEs. LHH values consistently far exceeded 1.Trial Registration NumbersEVOLVE-1: ClinicalTrials.gov identifier, NCT02614183; EVOLVE-2: ClinicalTrials.gov identifier, NCT02614196; REGAIN: ClinicalTrials.gov identifier, NCT02614261; CONQUER: ClinicalTrials.gov identifier, NCT03559257.Supplementary InformationThe online version contains supplementary material available at 10.1007/s12325-021-01848-x.

P182 A systematic literature review and network meta-analysis of the efficacy and safety of ixekizumab versus currently licensed biologics for the treatment of radiographic axSpA

Abstract Background/Aims Patients with radiographic axial spondyloarthritis (rad-axSpA) are often managed using biologic therapies such as TNF-α inhibitors and interleukin-17 inhibitors, including ixekizumab (IXE). Due to a lack of head-to-head trial data, limited evidence exists as to the relative performance of biologic therapies. Therefore, when making evidence-based reimbursement decisions, treatment funding agencies can use network meta-analysis (NMA) to estimate the relative efficacy and safety of each treatment within a network of comparator treatments. Objectives: Demonstrate, by means of NMA, the efficacy and safety of IXE 80 mg administered every four weeks (Q4W) against other approved biologic agents used in the treatment of r-axSpA in a biologic-naïve population. Methods We conducted a systematic literature review in February 2019 to identify relevant studies for inclusion in the NMA. The NMA was based on Bayesian Mixed Treatment Comparisons in keeping with NICE DSU (Decision Support Unit) technical guidance. The base case for this analysis focused on studies with biologic-naïve populations and assessed endpoints including the Assessment of SpondyloArthritis International Society endpoints (ASAS20 and ASAS40), Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) at least 50% improvement (BASDAI50), adverse events (AEs), serious adverse events (SAEs) and treatment discontinuation due to AE (DISCAE). Sensitivity analyses explored the robustness of the base case by including studies where the patient’s prior exposure to biologic therapy was unclear, not stated or mixed (treatment naïve and treatment experienced) and examined the impact of IXE starting dose (80mg v 160mg) on outcomes. Results In total, the systematic literature review included 78 full papers and 27 conference proceedings. Fixed-effect models were chosen, as they had lower deviance information criteria (DICs) and random effects models frequently did not converge. IXE 80 mg Q4W demonstrated superiority to placebo on the ASAS20 (Odds Ratio: 3.72, 95% CI:2.11,6.68), ASAS40 (Odds Ratio: 6.26, 95% CI:3.37,11.69), BASDAI (Mean difference: -1.72, 95% CI:-2.27,-1.17) and the BASDAI 50 (Odds Ratio: 5.40, 95% CI: 2.91, 10.06) as well as the other efficacy measures investigated. IXE and the comparator treatments demonstrated similar efficacy compared to each other. The rate of AEs, SAEs and DISCAE were in line with the existing literature both for IXE and the comparator treatments. Results from the sensitivity analyses were confirmatory for the robustness of the base case results. Conclusion This NMA confirms the efficacy and acceptable safety profile of IXE 80 mg Q4W and other biologics in biologic-naïve patients with active rad-axSpA. The NMA can be used to inform evidence-based decision-making in clinical practice and in payer decisions by including all currently marketed agents and dosages. Disclosure Y. Schymura: Corporate appointments; Yves Schymura is an employ of Eli Lilly and Company. P. Graham-Clarke: Corporate appointments; Peita Louise Graham-Clarke is an employee of Eli Lilly and Company. Shareholder/stock ownership; Peita Louise Graham-Clarke is a minor shareholder of Eli Lilly and Company. S. Liu-Leage: Corporate appointments; Soyi Liu-Leage is an employ of Eli Lilly and Company. Shareholder/stock ownership; Soyi Liu-Leage is a minor shareholder of Eli Lilly and Comapny.

Safety of As-Needed Budesonide-Formoterol in Mild Asthma: Data from the Two Phase III SYGMA Studies.

IntroductionBudesonide-formoterol taken as needed is an emerging treatment for mild asthma.ObjectiveWe used data from the SYGMA studies to assess the safety of As-needed budesonide-formoterol compared with As-needed terbutaline and compared with maintenance budesonide.MethodsSYGMA 1 and 2 were 52-week, double-blind, parallel-group studies in patients aged ≥ 12 years with physician-assessed mild asthma. Patients were randomized to As-needed budesonide-formoterol 200/6 μg, twice-daily budesonide 200 μg as maintenance plus As-needed terbutaline 0.5 mg, and As-needed terbutaline 0.5 mg (SYGMA 1 only). Adverse events (AEs), serious AEs (SAEs), discontinuations due to AEs (DAEs), and study-defined asthma-related discontinuations from corresponding treatment groups in both studies were pooled. SYGMA 1 data were used for comparisons with As-needed terbutaline alone.ResultsThe pooled analysis included 3366 patients in the As-needed budesonide-formoterol group and 3369 in the budesonide maintenance group, with AEs in 40.8% and 42.5% of patients, respectively. Common AEs included viral upper respiratory tract infection (viral URTI) and URTI. SAE, DAE, and asthma-related discontinuation rates were similar with As-needed budesonide-formoterol and maintenance budesonide. Potential local and systemic corticosteroid class effects were reported in ≤ 1% of patients for each budesonide-containing regimen. In SYGMA 1, AEs were more common in the As-needed terbutaline (n = 1277) than As-needed budesonide-formoterol (n = 1277) groups (42.7 vs. 38.0%), as were DAEs (2.9 vs. 0.8%) and asthma-related discontinuations (1.6 vs. 0.3%).ConclusionsBudesonide-formoterol anti-inflammatory reliever therapy is generally well-tolerated in patients with mild asthma and has a safety profile similar to that of daily budesonide. No new safety signals were identified.ClinicalTrial.gov IdentifiersNCT02149199 (SYGMA 1) and NCT02224157 (SYGMA 2).Supplementary InformationThe online version contains supplementary material available at 10.1007/s40264-020-01041-z.

Comparative efficacy, tolerability and safety of dolutegravir and efavirenz 400mg among antiretroviral therapies for first-line HIV treatment: A systematic literature review and network meta-analysis.

BackgroundTo inform World Health Organization (WHO) global guidelines, we updated and expanded the evidence base to assess the comparative efficacy, tolerability, and safety of first-line antiretroviral therapy (ART) regimens.MethodsWe searched Embase, Medline and CENTRAL on 28 February 2020 to update the systematic literature review of clinical trials comparing recommended first-line ART that informed previous WHO guidelines. Outcomes included viral suppression, change in CD4 cell counts, mortality, serious and overall adverse events (AEs), discontinuation, discontinuations due to AEs (DAEs); and new outcomes: drug-resistance, neuropsychiatric AEs, early viral suppression, weight gain and birth outcomes. Comparative effects were assessed through network meta-analyses and certainty in the evidence was assessed using the GRADE framework.FindingsWe identified 156 publications pertaining to 68 trials for the primary population. Relative to efavirenz, dolutegravir had improved odds of viral suppression across all time points (odds ratio [OR]: 1·94; 95% credible interval [CrI]: 1·48–2·56 at 96 weeks); was protective of drug-resistance (OR: 0·13; 95%CrI: 0·04–0·48); and led to fewer discontinuations (OR: 0·58; 95%CrI: 0·48–0·70). Evidence supported dolutegravir use among TB-HIV co-infected persons and pregnant women. Adverse birth outcomes were observed in 33.2% of dolutegravir-managed pregnancies and 35.0% of efavirenz-managed pregnancies. Low-dose efavirenz had comparable efficacy and safety to standard-dose efavirenz, but led to fewer DAEs (OR: 0·70; 95%CrI: 0·50–0·92).InterpretationThe evidence supports choosing dolutegravir in combination with lamivudine/emtricitabine and tenofovir disoproxil fumarate as the preferred first-line regimen and low-dose efavirenz-based regimens as an alternative. Dolutegravir can be considered to be effective, safe and tolerable.FundingWHO.

Acceptability of Acute and Maintenance Pharmacotherapy of Bipolar Disorder: A Systematic Review of Randomized, Double-Blind, Placebo-Controlled Clinical Trials.

The aim of the study was to estimate and rank the risk for the discontinuation due to adverse events (DAEs), 7% or more weight gain (WG), and somnolence during the acute and maintenance treatment of bipolar disorder with a mood stabilizer or an antipsychotic monotherapy. The search of MEDLINE, EMBASE, PsycINFO, and clinicaltrials.gov from the inception to December 31, 2018, provided 32 studies in mania, 16 in bipolar depression, and 13 in maintenance. Data of DAEs, WG, and somnolence from each study were extracted. The risk for these variables of an active treatment relative to placebo was estimated with a number needed to harm (NNH) as a single study and pooled sample. For DAEs, pooled NNH ranged from 19 with carbamazepine to -21 with quetiapine-XR in mania, 11 with quetiapine-IR 600 mg/d to -37 with olanzapine/fluoxetine combination in bipolar depression, and 5 with lithium to -8 with asenapine in maintenance. For WG, pooled NNH ranged from 9 with olanzapine to -78 with aripiprazole in mania, 5 with olanzapine to -112 with lithium in bipolar depression, and 4 with olanzapine to 126 with asenapine in maintenance. For somnolence, pooled NNH was from 5 with carbamazepine to 23 with cariprazine in mania, 3 with quetiapine-XR 300 mg/d to 79 with lurasidone in bipolar depression, and 11 with olanzapine to -49 with aripiprazole in maintenance. All medications studied in bipolar disorder were relatively well tolerated during different phases of treatment; however, the risk for short- and long-term WG and somnolence varied widely among included psychotropics.

Pangenotypic direct acting antivirals for the treatment of chronic hepatitis C virus infection: A systematic literature review and meta-analysis

BackgroundRecent approval and adoption of pangenotypic direct acting antivirals (DAAs) necessitated a revision of the 2015 World Health Organization guidelines for the management of persons with hepatitis C virus (HCV) infection. MethodsWe searched MEDLINE, EMBASE, CENTRAL, and relevant conference proceedings to identify randomized and non-randomized trials, as well as prospective observational studies of DAAs. The proportions of persons with events were pooled for sustained virological response at 12 weeks post-treatment (SVR12), discontinuations due to adverse events (DAEs), serious adverse events (SAEs), and all-cause mortality. Analyses were stratified by HCV genotype and antiviral treatment experience, with subgroup analyses based on presence of cirrhosis and HIV-HCV coinfection. FindingsThe evidence base consisted of 238 publications describing 142 studies. In the overall analysis, which included all persons irrespective of treatment experience or comorbidities, the pooled proportion achieving SVR12 exceeded 0.94 for all pangenotypic regimens across genotypes 1, 2, and 4. Some heterogeneity may have led to lower SVR rates in persons with genotype 3 infection. High SVR12 (>0.90) was observed in persons with genotype 1 infection with cirrhosis, though evidence varied and was limited for genotypes 2–4. Evidence was sparse for persons with HIV–HCV coinfection. All regimens were associated with small proportions of persons with DAEs, SAEs, or all-cause mortality. InterpretationBased on this and other supporting evidence, the WHO issued updated guidelines with a conditional recommendation, based on moderate quality evidence, for the use of pangenotypic DAA regimens for persons with chronic HCV infection aged 18 years and older (July 2018). FundingThis study was funded by the World Health Organization.

Indirect Comparison Using Individual Patient Level Data Comparing Efficacy and Safety of a Daratumumab Monotherapy Vs. EU Approved Comparator Therapies in Patients with Multiple Myeloma

Introduction. Efficacy and safety of daratumumab monotherapy (DARA mono) in relapsed/refractory multiple myeloma (rrMM) has been shown in the single-arm phase I/II trial GEN501 and the single-arm phase II trial SIRIUS (1, 2). Since then, several indirect treatment comparisons of DARA mono versus comparator therapies have been published showing consistent results with an overall survival benefit for DARA mono (3, 4, 5, 6). This analysis compares efficacy and for the first time also safety of DARA mono data versus an international historic control group, adjusting for differences in patient populations based on individual patient level data (IPD).Methods. IPD from the SIRIUS trial and from the International Myeloma Foundation (IMF)-cohort (7), a retrospective, multicenter cohort, were compared using a multivariate Cox proportional hazards model, on the endpoints of efficacy (overall survival (OS)) and safety (discontinuation due to adverse events (DISCONAE)). The IMF-cohort included patients with rrMM who received at least three prior lines of therapy, were refractory to both an immunomodulator (IMiD) and a proteasome inhibitor (PI), and were exposed to an alkylating agent. An inclusion criterion for the historic control group in this analysis was treatment with EU approved regimens. Baseline covariates adjusted for in the regression model included age, gender, prior lines of therapy, albumin, beta-2 microglobulin, prior exposure to pomalidomide and carfilzomib, and PI/IMiD refractory status. Several sensitivity analyses were run, including multiple imputation of missing values.Results. Data from 106 patients treated with DARA mono (16 mg/kg) were available from SIRIUS; 258 patients from the IMF chart review fulfilled the inclusion criteria; most frequent treatment regimens contained pomalidomide plus dexamethasone (PomDex) (n=172), bortezomib (n=31), carfilzomib (n=21), cyclophosphamide (n=14) and lenalidomide (n=9). The adjusted HR for OS was 0.41 [0.25, 0.69], p<0.001, and 0.23 [0.05, 1.00], p=0.050 for DISCONAE, in favor of daratumumab. Results were consistent across a range of sensitivity analyses and were similar when restricting the comparison to DARA vs. PomDex, with HR=0.35 [0.19, 0.64], p<0.001 for OS and 0.20 [0.03, 1.54], p=0.123 for DISCONAE.Conclusions. This comparison using real-world data of rrMM patients suggests improved efficacy and safety for DARA mono compared to approved therapy regimens used in clinical practice, including PomDex.References.Lokhorst, H. M., Plesner, T., Laubach, J. P., Nahi, H., Gimsing, P., Hansson, M., et al. Targeting CD38 With Daratumumab Monotherapy in Multiple Myeloma. The New England Journal of Medicine. 2015.Lonial S, Weiss BM, Usmani SZ, Singhal S, Chari A, Bahlis NJ, et al. Daratumumab Monotherapy in Patients with Treatment-Refractory Multiple Myeloma (SIRIUS): An Open-Label, Randomised, Phase 2 Trial. The Lancet. 2016.Usmani S, Ahmadi T, Ng Y, Lam A, Desai A, Potluri R, Mehra M. Analysis of Real-World Data on Overall Survival in Multiple Myeloma Patients With ≥3 Prior Lines of Therapy Including a Proteasome Inhibitor (PI) and an Immunomodulatory Drug (IMiD), or Double Refractory to a PI and an IMiD. The Oncologist. 2016.Van Sanden S, Ito T, Diels J, Vogel M, Belch A, Oriol A. Comparative Efficacy of Daratumumab Monotherapy and Pomalidomide Plus Low-Dose Dexamethasone in the Treatment of Multiple Myeloma: A Matching Adjusted Indirect Comparison. The Oncologist. 2017.Usmani SZ, Diels J, Ito T, Mehra M, Khan I, Lam A. Daratumumab monotherapy compared with real-world historical control data in heavily pretreated patients with highly refractory multiple myeloma: An adjusted treatment comparison. American Journal of Heamtology. 2017.Jelínek T, Maisnar V, Pour L, Špička I, Minařík J, Gregora E, et al. Adjusted comparison of daratumumab monotherapy versus real-world historical control data from the Czech Republic in heavily pretreated and highly refractory multiple myeloma patients. Current Medical Research an Opinion. 2017.Kumar SK, Dimopoulos MA, Kastritis E, Terpos E, Nahi H, Goldschmidt H, et al. Natural history of relapsed myeloma, refractory to immunomodulatory drugs and proteasome inhibitors: a multicenter IMWG study. Leukemia. 2017. DisclosuresDemmer:Janssen: Employment. Huschens:Janssen: Employment. Potthoff:Janssen: Employment. Tomeczkowski:Janssen: Employment. Englisch:Janssen: Employment. Thilakarathne:Janssen: Employment. Diels:Janssen: Employment. Kumar:AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Research Funding; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Durie:Celgene: Consultancy; Amgen: Consultancy; Takeda: Consultancy; Janssen: Consultancy. Eisele:Janssen: Employment.

Treatment discontinuation and tolerability as a function of dose and titration of duloxetine in the treatment of major depressive disorder.

PurposeWe sought to better understand how dose and titration with duloxetine treatment may impact tolerability and treatment discontinuation in patients with major depressive disorder.Patients and methodsWe investigated Phase III duloxetine trials. Group 1 was a single placebo-controlled study with a 20 mg initial dose and a slow titration to 40 and 60 mg. Group 2 was a single study with a 40 mg initial dose and final “active” doses of 40 and 60 mg (5 mg control group), with 1-week titration. Group 3 consisted of eight placebo-controlled studies with starting doses of 40, 60, and 80 mg/day with minimal titration (final dose 40–120 mg/day). Tolerability was measured by rate of discontinuation due to adverse events (DCAE).ResultsThe DCAE in Group 1 were 3.6% in the 60 mg group, 3.3% in the 40 mg group, and 3.2% in the placebo group. In Group 2, the DCAE were 15.0% in the 60 mg group, 8.1% in the 40 mg group, and 4.9% in the 5 mg group. In Group 3, the DCAE were 9.7% and 4.2% in the duloxetine and placebo groups, respectively.ConclusionThis study suggests that starting dose and titration may have impacted tolerability and treatment discontinuation. A lower starting dose of duloxetine and slower titration may contribute to improving treatment tolerability for patients with major depressive disorder.

Important clinical features of atypical antipsychotics in acute bipolar depression that inform routine clinical care: a review of pivotal studies with number needed to treat.

English-language literature cited in MEDLINE from January, 1980 to October 30, 2014 was searched by using terms of antipsychotic, generic and brand names of atypical antipsychotics, "bipolar depression/bipolar disorder", "placebo", and "trial". The parameters of response (≥50% improvement on MADRS, Montgomery-Asberg Depression Rating Scale total score), remission (either ≤12 or 8 on MADRS total score at endpoint), discontinuation due to adverse events (DAEs), somnolence, ≥7% weight gain, overall extrapyramidal side-effects (EPSs), and akathisia, were extracted from originally published primary outcome papers. The number needed to treat to benefit (NNT) for response and remission or harm (NNH) for DAEs or other side effects relative to placebo were estimated and presented with the estimate and 95% confidence interval. Olanzapine monotherapy, olanzapine-fluoxetine combination (OFC), quetiapine-IR monotherapy, quetiapine-XR monotherapy, lurasidone monotherapy, and lurasidone adjunctive therapy were superior to placebo with NNTs for responses of 11-12, 4, 7-8, 4, 4-5, and 7, and NNTs for remission of 11-12, 4, 5-11, 7, 6-7, and 6, respectively. There was no significant difference between OFC and lamotrigine, and between aripiprazole or ziprasidone and placebo in response and remission. Olanzapine monotherapy, quetiapine-IR, quetiapine-XR, aripiprazole, and ziprasidone 120-160 mg/day had significantly increased risk for DAEs with NNHs of 24, 8-14, 9, 12, and 10, respectively. For somnolence, quetiapine-XR had the smallest NNH of 4. For ≥7% weight gain, olanzapine monotherapy and OFC had the smallest NNHs with both of 5. For akathisia, aripiprazole had the smallest NNH of 5. These findings suggest that among the FDA-approved agents including OFC, quetiapine-IR and -XR, lurasidone monotherapy and adjunctive therapy to a mood stabilizer, the differences in the NNTs for response and remission are small, but the differences in NNHs for DAEs and common side-effects are large. Therefore, the selection of an FDA-approved atypical antipsychotic for bipolar depression should be based upon safety and tolerability.

PGI1 - Comparative efficacy and safety of golimumab, infliximab and adalimumab for the treatment of moderate to severe ulcerative colitis: A bayesian indirect treatment comparison meta-analysis

To compare the relative efficacy and safety of golimumab, infliximab and adalimumab for the treatment of moderate-to-severe ulcerative colitis using indirect treatment comparison (ITC) meta-analysis. A systematic literature search identified five randomized controlled trials. Outcomes of interest included clinical remission, clinical response, mucosal healing, sustained remission/response, serious adverse events (SAEs), and discontinuation due to adverse events (DAEs). Data was synthesized using Bayesian indirect treatment comparison (ITC) meta-analysis. The analysis incorporated advanced intention-to-treat with baseline priors to account for the alternative design of the golimumab trial. After the induction phase, each treatment had significantly greater efficacy than placebo all endpoints, with the exception of adalimumab for mucosal healing. No statistical differences were observed between golimumab and infliximab. Adalimumab had significantly lower efficacy measures compared to infliximab for clinical remission (odds ratio [OR] 0.42, 95% credible interval [CrI] 0.17-0.97), clinical response (OR 0.45, 95% CrI 0.23-0.89), and mucosal healing (OR 0.46, 95% CrI 0.25-0.84) after the induction period. During the maintenance phase, each biologic agent exhibited significantly greater efficacy compared to placebo for clinical remission, clinical response, and mucosal healing. Golimumab 100mg was significantly better than adalimumab for clinical response (OR 1.80, 95% CrI 1.01-3.21) and mucosal healing at 54 weeks (OR 1.88, 95% CrI 1.01-3.49). No statistical differences were observed between adalimumab and infliximab. Both golimumab 100mg and infliximab were significantly better than adalimumab in terms of sustained clinical response (OR 2.40, 95% CrI 1.17-4.86 and OR 1.93, 95% CrI 1.04-4.06), respectively. For SAEs, there were no statistical differences between any of the biologics and placebo. Although all biologics were generally safe, golimumab 100mg had statistically significantly higher DAEs when compared to adalimumab (OR 2.09, 95% CrI 1.07-4.17). In the context of ITC meta-analysis, both golimumab and infliximab appear to demonstrate superior efficacy-safety profiles compared with adalimumab.

Safety profile of protein kinase inhibitors in rheumatoid arthritis: systematic review and meta-analysis

ObjectiveTo summarise the adverse events (AE) reported in patients with rheumatoid arthritis (RA) treated with protein kinase inhibitors (PKi), and identify family and molecule-related AEs.MethodsSystematic review of the PKi used...

Safety of budesonide/formoterol maintenance and reliever therapy in asthma trials

The safety of long-acting beta(2)-agonists (LABAs) in asthma is debated. This study examined the safety of the inhaled corticosteroid (ICS)/LABA combination budesonide/formoterol dry powder inhaler used as maintenance and reliever therapy versus combination treatments based on guideline recommendations. Safety data from six double-blind, randomised clinical trials (RCTs) in asthma where budesonide/formoterol was used as maintenance and reliever therapy for at least 6 months were reviewed (N=14 346). All-cause mortality and asthma-related serious adverse events (SAEs) (co-primary endpoints), overall and cardiac SAEs, and discontinuations due to adverse events (DAEs) were assessed. Estimated Mantel-Haenszel (MH) relative risks (RR) with this regimen versus comparators were calculated. There was no increase in all-cause mortality with budesonide/formoterol maintenance and reliever therapy (four deaths [0.07%] versus nine [0.10%]; pooled MH RR 0.70, 95% confidence interval [CI] 0.21-2.30). Asthma-related SAEs were reduced with budesonide/formoterol maintenance and reliever therapy: 41 (0.73%) versus 121 (1.38%); pooled MH RR 0.59, 95% CI 0.42-0.85. All-cause and asthma-related DAEs were also reduced with budesonide/formoterol maintenance and reliever therapy: pooled MH RR 0.60 (95% CI 0.46-0.79) and 0.43 (0.28-0.68), respectively. Overall and cardiac-related SAEs were comparable between treatment groups: pooled MH RR 0.96 (95% CI 0.82-1.14) and 1.26 (0.72-2.22), respectively. Budesonide/formoterol dry powder inhaler maintenance and reliever therapy was well tolerated in RCTs versus fixed-dose alternatives and not associated with increased risk of death or cardiac-related SAEs and DAEs, and asthma-related SAEs and DAEs were significantly reduced. Given the limitations of RCTs, particularly exclusion of patients with co-morbidities, ongoing surveillance is appropriate.

Discontinuation of antihypertensive drugs due to adverse events: a systematic review and meta-analysis.

We conducted a systematic review of randomized, controlled, monotherapy trials since 1990 of oral antihypertensive agents in patients with essential hypertension. Our objective was to quantify the frequency of discontinuation of antihypertensive agents due to adverse events from a meta-analysis of the studies. A total of 190 studies met inclusion criteria. The highest frequency of discontinuations due to adverse events (DAEs) occurred with calcium channel blockers (6.7%) and alpha-adrenergic blockers (6.0%); the lowest with diuretics and angiotensin receptor blockers (each 3.1%). Only in calcium channel blocker studies was the frequency of DAEs greater in treated patients than in patients receiving placebo, but the difference was not significant. This systematic review suggests that the frequency of DAEs in monotherapy antihypertensive trials varies across drug classes and should be considered when choosing drugs for patients with essential hypertension.