Assessment of Saxagliptin Efficacy: Meta-Analysis of 14 Phase 2 and 3 Clinical Trials.
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ABSTRACT: Introduction
This meta-analysis of data from 14 phase 2 and 3, double-blind, randomized, controlled 12- and 24-week studies (N = 4632) summarizes saxagliptin efficacy in patients with type 2 diabetes (T2D) across treatment regimens.Methods
Patients received saxagliptin 5 mg/d or control as either monotherapy (n = 1196 vs placebo), add-on therapy (n = 2139 vs placebo and n = 514 vs uptitrated sulfonylurea), or initial combination therapy (n = 619 vs control monotherapy). Patients with renal impairment received saxagliptin 2.5 mg/d or placebo (n = 164).Results
Mean baseline glycated hemoglobin (A1C) ranged from 8.07% to 9.43% for the saxagliptin and control groups across treatment regimens. A1C reduction from baseline was greater with saxagliptin versus control for all studies combined (mean treatment difference [95% CI]: -0.55% [-0.63%, -0.47%]) and when used as monotherapy (-0.52% [-0.63, -0.40%]), add-on (-0.55% [-0.69%, -0.40%] vs placebo; -0.72% [-0.88%, -0.56%] vs uptitrated sulfonylurea), initial combination therapy (-0.54% [-0.73%, -0.35%] vs control monotherapy), and in patients with renal impairment (-0.42% [-0.75%, -0.09%]). Similar reductions in A1C versus control were noted for patients <65 years (-0.55% [-0.67%, -0.43%]) and ≥65 years (-0.54% [-0.69%, -0.38%]) and for men (-0.54% [-0.69%, -0.40%]) and women (-0.55% [-0.64%, -0.47%]) across treatment regimens. More patients achieved A1C <7% (39% vs 23%) and A1C ≤6.5% (24% vs 14%) with saxagliptin than with placebo or active-control treatment. Saxagliptin versus control was associated with a reduction in glucagon area under the curve (AUC) from baseline and increases in insulin AUC, C-peptide AUC, and the homeostasis model assessment of β-cell function.Conclusion
Results of this meta-analysis demonstrate the consistency of saxagliptin efficacy in different subgroups of patients with T2D across treatment regimens.Funding
AstraZeneca.
SUBMITTER: Sjostrand M
PROVIDER: S-EPMC5446386 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Acinetobacter infections, especially multidrug-resistant (MDR) Acinetobacter infections, are a global health problem. This study aimed to describe clinical outcomes in patients with confirmed Acinetobacter spp. isolates who were treated with tigecycline in randomized clinical trials.Data from 14 multinational, randomized (open-label or double-blind), and active-controlled (except one) Phase III and IV studies were analyzed using descriptive statistics.A total of 174 microbiologically evaluable patients with Acinetobacter spp. infections (including MDR infections) were identified, and 95 received tigecycline to treat community-acquired pneumonia (CAP), diabetic foot infections (DFIs), hospital-acquired pneumonia (HAP), complicated intra-abdominal infections (cIAIs), infections with resistant pathogens (RPs), or complicated skin and skin-structure infections. The rate of cure of tigecycline for most indications was 70%-80%, with the highest (88.2%) in cIAIs. The rate of cure of the comparators was generally higher than tigecycline, but within each indication the 95% CIs for clinical cure for each treatment group overlapped. For most Acinetobacter isolates, the minimum inhibitory concentration of tigecycline was 0.12-2 ?g/mL, with seven at 4 ?g/mL and one at 8 ?g/mL. The cure rate by tigecycline was 50% (95% CI 12.5%-87.5% in CAP) to 88.2% (95% CI 66.2%-97.1% in cIAIs) for all Acinetobacter, and 72.7% (95% CI 54.5%-93.2% in HAP) to 100% (95% CI 25%-100.0% in cIAIs) for MDR Acinetobacter. For the comparators, it was 83.8% (95% CI 62.8%-95.9% in HAP) to 100% (95% CI 75%-100% in cIAIs and 25%-100.0% in RPs) and 88% (95% CI 66%-97% in HAP) to 100% (95% CI 25%-100% in cIAIs and 75%-100% in DFIs), respectively.These findings suggest that with appropriate monitoring, tigecycline may be a useful consideration for Acinetobacter infections alone or in combination with other anti-infective agents when other therapies are not suitable.
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Project description:BackgroundA systematic review of early clinical outcomes in tuberculosis was undertaken to determine ranking of efficacy of drugs and combinations, define variability of these measures on different endpoints, and to establish the relationships between them.MethodsStudies were identified by searching PubMed, Medline, Embase, LILACS (Latin American and Caribbean Health Sciences Literature), and reference lists of included studies. Outcomes were early bactericidal activity results over 2, 7, and 14 days, and the proportion of patients with negative culture at 8 weeks.ResultsOne hundred thirty-three trials reporting phase 2A (early bactericidal activity) and phase 2B (culture conversion at 2 months) outcomes were identified. Only 9 drug combinations were assessed on >1 phase 2A endpoint and only 3 were assessed in both phase 2A and 2B trials.ConclusionsThe existing evidence base supporting phase 2 methodology in tuberculosis is highly incomplete. In future, a broader range of drugs and combinations should be more consistently studied across a greater range of phase 2 endpoints.
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Project description:The impact of a personalized cancer treatment strategy (ie, matching patients with drugs based on specific biomarkers) is still a matter of debate.We reviewed phase II single-agent studies (570 studies; 32,149 patients) published between January 1, 2010, and December 31, 2012 (PubMed search). Response rate (RR), progression-free survival (PFS), and overall survival (OS) were compared for arms that used a personalized strategy versus those that did not.Multivariable analysis (both weighted multiple linear regression and random effects meta-regression) demonstrated that the personalized approach, compared with a nonpersonalized approach, consistently and independently correlated with higher median RR (31% v 10.5%, respectively; P < .001) and prolonged median PFS (5.9 v 2.7 months, respectively; P < .001) and OS (13.7 v 8.9 months, respectively; P < .001). Nonpersonalized targeted arms had poorer outcomes compared with either personalized targeted therapy or cytotoxics, with median RR of 4%, 30%, and 11.9%, respectively; median PFS of 2.6, 6.9, and 3.3 months, respectively (all P < .001); and median OS of 8.7, 15.9, and 9.4 months, respectively (all P < .05). Personalized arms using a genomic biomarker had higher median RR and prolonged median PFS and OS (all P ? .05) compared with personalized arms using a protein biomarker. A personalized strategy was associated with a lower treatment-related death rate than a nonpersonalized strategy (median, 1.5% v 2.3%, respectively; P < .001).Comprehensive analysis of phase II, single-agent arms revealed that, across malignancies, a personalized strategy was an independent predictor of better outcomes and fewer toxic deaths. In addition, nonpersonalized targeted therapies were associated with significantly poorer outcomes than cytotoxic agents, which in turn were worse than personalized targeted therapy.
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Project description:ImportanceBullying is a prevalent and modifiable risk factor for mental health disorders. Although previous studies have supported the effectiveness of anti-bullying programs; their population impact and the association of specific moderators with outcomes are still unclear.ObjectiveTo assess the effectiveness of school anti-bullying interventions, their population impact, and the association between moderator variables and outcomes.Data sourcesA search of Ovid MEDLINE, ERIC, and PsycInfo databases was conducted using 3 sets of search terms to identify randomized clinical trials (RCTs) assessing anti-bullying interventions published from database inception through February 2020. A manual search of reference lists of articles included in previous systematic reviews and meta-analyses was also performed.Study selectionThe initial literature search yielded 34 798 studies. Included in the study were articles that (1) assessed bullying at school; (2) assessed the effectiveness of an anti-bullying program; (3) had an RCT design; (4) reported results; and (5) were published in English. Of 16 707 studies identified, 371 met the criteria for review of full-text articles; 77 RCTs were identified that reported data allowing calculation of effect sizes (ESs). Of these, 69 independent trials were included in the final meta-analysis database.Data extraction and synthesisRandom-effects and meta-regression models were used to derive Cohen d values with pooled 95% CIs as estimates of ES and to test associations between moderator variables and ES estimates. Population impact number (PIN), defined as the number of children in the total population for whom 1 event may be prevented by an intervention, was used as an estimate of the population impact of universal interventions targeting all students, regardless of individual risk.Main outcomes and measuresThe main outcomes are the effectiveness (measured by ES) and the population impact (measured by the PIN) of anti-bullying interventions on the following 8 variable categories: overall bullying, bullying perpetration, bullying exposure, cyberbullying, attitudes that discourage bullying, attitudes that encourage bullying, mental health problems (eg, anxiety and depression), and school climate as well as the assessment of potential assocations between trial or intervention characteristics and outcomes.ResultsThis study included 77 samples from 69 RCTs (111 659 participants [56 511 in the intervention group and 55 148 in the control group]). The weighted mean (range) age of participants in the intervention group was 11.1 (4-17) years and 10.8 (4-17) years in the control group. The weighted mean (range) proportion of female participants in the intervention group was 49.9% (0%-100%) and 50.5% (0%-100%) in the control group. Anti-bullying interventions were efficacious in reducing bullying (ES, -0.150; 95% CI, -0.191 to -0.109) and improving mental health problems (ES, -0.205; 95% CI, -0.277 to -0.133) at study end point, with PINs for universal interventions that target the total student population of 147 (95% CI, 113-213) and 107 (95% CI, 73-173), respectively. Duration of intervention was not statistically significantly associated with intervention effectiveness (mean [range] duration of interventions, 29.4 [1 to 144] weeks). The effectiveness of anti-bullying programs did not diminish over time during follow-up (mean [range] follow-up, 30.9 [2-104] weeks).Conclusions and relevanceDespite the small ESs and some regional differences in effectiveness, the population impact of school anti-bullying interventions appeared to be substantial. Better designed trials that assess optimal intervention timing and duration are warranted.
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Project description:We conducted meta-analyses of findings from randomized, placebo-controlled, short-term trials for acute mania in manic or mixed states of DSM (III-IV) bipolar I disorder in 56 drug-placebo comparisons of 17 agents from 38 studies involving 10,800 patients. Of drugs tested, 13 (76%) were more effective than placebo: aripiprazole, asenapine, carbamazepine, cariprazine, haloperidol, lithium, olanzapine, paliperdone, quetiapine, risperidone, tamoxifen, valproate, and ziprasidone. Their pooled effect size for mania improvement (Hedges' g in 48 trials) was 0.42 (confidence interval (CI): 0.36-0.48); pooled responder risk ratio (46 trials) was 1.52 (CI: 1.42-1.62); responder rate difference (RD) was 17% (drug: 48%, placebo: 31%), yielding an estimated number-needed-to-treat of 6 (all p<0.0001). In several direct comparisons, responses to various antipsychotics were somewhat greater or more rapid than lithium, valproate, or carbamazepine; lithium did not differ from valproate, nor did second generation antipsychotics differ from haloperidol. Meta-regression associated higher study site counts, as well as subject number with greater placebo (not drug) response; and higher baseline mania score with greater drug (not placebo) response. Most effective agents had moderate effect-sizes (Hedges' g=0.26-0.46); limited data indicated large effect sizes (Hedges' g=0.51-2.32) for: carbamazepine, cariprazine, haloperidol, risperidone, and tamoxifen. The findings support the efficacy of most clinically used antimanic treatments, but encourage more head-to-head studies and development of agents with even greater efficacy.
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Project description:BackgroundUsing a machine learning approach, the study investigated if specific baseline characteristics could predict which psoriatic arthritis (PsA) patients may gain additional benefit from a starting dose of secukinumab 300 mg over 150 mg. We also report results from individual patient efficacy meta-analysis (IPEM) in 2049 PsA patients from the FUTURE 2 to 5 studies to evaluate the efficacy of secukinumab 300 mg, 150 mg with and without loading regimen versus placebo at week 16 on achievement of several clinically relevant difficult-to-achieve (higher hurdle) endpoints.MethodsMachine learning employed Bayesian elastic net to analyze baseline data of 2148 PsA patients investigating 275 predictors. For IPEM, results were presented as difference in response rates versus placebo at week 16.ResultsMachine learning showed secukinumab 300 mg has additional benefits in patients who are anti-tumor necrosis factor-naive, treated with 1 prior anti-tumor necrosis factor agent, not receiving methotrexate, with enthesitis at baseline, and with shorter PsA disease duration. For IPEM, at week 16, all secukinumab doses had greater treatment effect (%) versus placebo for higher hurdle endpoints in the overall population and in all subgroups; 300-mg dose had greater treatment effect than 150 mg for all endpoints in overall population and most subgroups.ConclusionsMachine learning identified predictors for additional benefit of secukinumab 300 mg compared with 150 mg dose. Individual patient efficacy meta-analysis showed that secukinumab 300 mg provided greater improvements compared with 150 mg in higher hurdle efficacy endpoints in patients with active PsA in the overall population and most subgroups with various levels of baseline disease activity and psoriasis.
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