Mixed Treatment Comparison Analysis Research Articles

Effects of Aerobic Exercise and Mind-Body Exercise in Parkinson’s Disease: A Mixed-Treatment Comparison Analysis

Background/Objectives: Aerobic exercise and mind-body exercise, are vital for improving motor and non-motor functional performance of Parkinson’s disease (PD). However, evidence-based recommendations on which type of exercise is most suitable for each individual are still lacking. Therefore, we conduct a network meta-analysis to assess the relative efficacy of aerobic and mind-body exercise on motor function and non-motor symptoms in Parkinson’s disease and to determine which of these therapies are the most suitable.Design: A network meta-analysis and dose-response analysis.Setting and Participants: Medline, Embase (all via Ovid), and the Cochrane Central Register of Controlled Trials were comprehensively searched for related trials through April 2021.Measurements: Study quality was evaluated using the Cochrane Risk of Bias Tool. The effect sizes of continuous outcomes were calculated using mean differences (MDs) or standardized mean differences (SMDs). A network meta-analysis with a frequentist approach was conducted to estimate the efficacy and probability rankings of the therapies. The dose-response relationship was determined based on metaregression and SUCRA.Results: Fifty-two trials with 1971 patients evaluating six different therapies were identified. For the UPDRS-motor score and TUG score, yoga all ranked highest (SUCRA = 92.8%, 92.6%, respectively). The SUCRA indicated that walking may best improve the BBS score (SUCRA = 90.2%). Depression, cognitive and activities of daily living scores were significantly improved by yoga (SUCRA: 86.3, 95.1, and 79.5%, respectively). In the dose-response analysis, 60-min sessions, two times a week might be the most suitable dose of yoga for reducing the UPDRS-motor score of PD patients.Conclusion: Yoga and walking are important options for increasing functional mobility and balance function, and yoga might be particularly effective for decreasing depressive symptoms and cognitive impairment and improving activities of daily living in PD. The potential optimal dose of yoga for enhancing motor ability in PD patients is 60-min sessions, two times a week.Registration: PROSPERO CRD42021224823.

Evaluation of Tooth Sensitivity of In-office Bleaching with Different Light Activation Sources: A Systematic Review and a Network Meta-analysis.

A systematic review and network meta-analysis were performed to answer the following research question: Are there differences in the risk and the intensity of tooth sensitivity (TS) among eight light activation systems for in-office bleaching in adults? Randomized controlled trials (RCTs) that compared at least two different in-office bleaching light activations were included. The risk of bias (RoB) was evaluated with the RoB tool version 1.0 from the Cochrane Collaboration tool. A random-effects Bayesian mixed treatment comparison (MTC) model was used independently for high- and low-concentration hydrogen peroxide. The certainty of the evidence was evaluated using the GRADE (Grading of Recommendations, Assessment, Development and Evaluations) approach. A comprehensive search was performed in PubMed, Bridge Base Online (BBO), Latin American and Caribbean Health Sciences Literature database (LILACS), Cochrane Library, Scopus, Web of Science, and grey literature without date and language restrictions on April 23, 2017 (updated on September 26, 2019). Dissertations and theses, unpublished and ongoing trials registries, and IADR (International Association for Dental Research) abstracts (2001-2019) were also searched. After title and abstract screening and the removal of duplicates, 32 studies remained. Six were considered to be at low RoB, three had high RoB, and the remaining had an unclear RoB. The MTC analysis showed no significant differences among the treatments in each network. In general, the certainty of the evidence was graded as low due to unclear RoB and imprecision. There is no evidence that the risk and intensity of TS are affected by light activation during in-office bleaching.

Improving Glycemic Control in Type 2 Diabetes Using Mobile Applications and e-Coaching: A Mixed Treatment Comparison Network Meta-Analysis.

This study compared the effectiveness of glycemic control among usual care, care management using a mobile application (app), and management using an app with additional e-coaching for patients with type 2 diabetes mellitus (T2DM) using a mixed treatment comparison (MTC) network meta-analysis (NMA). A systematic search for published randomized controlled trials (RCTs) was conducted, which included Pubmed, Web of Science, Cochrane Central Register of Controlled Trials, CINAL, Koreamed, KMbase, and ScienceOn, until October 2020. Among the 10,391 studies identified after removing duplicates, 14 RCTs were finally included in the MTC NMA. Data extraction and methodological quality assessment using version 2 of the Cochrane tool for assessing the risk-of-bias in randomized trials (RoB 2) was performed. The comparative efficacy was analyzed using the random-effects NMA based on a frequentist model by the intervention group and main outcome variables. At the 3-month follow-up after each intervention, a comparison of the P-scores revealed the app plus e-coaching intervention to be the most effective method for reducing the HbA1c level in a homogeneous gender ratio group (P-score 0.92). At the 6-month follow-up period, app intervention was the best in reducing the HbA1c level in the homogeneous gender ratio and under 60 years of age group (P-score 1.00). Based on MTC analysis using the data from published RCTs, mobile apps or apps with e-coaching interventions for T2DM patients were more effective in improving the HbA1c values, FBS, and hypoglycemia frequency than usual care. Nevertheless, further research will be needed to clarify the effects of adding e-coaching to the app. Research Registry UIN (reviewregistry780).

Effectiveness of interventions for the reversal of a metabolic syndrome diagnosis: An update of a meta-analysis of mixed treatment comparison studies

ResumenIntroducción. El conocer las intervenciones más efectivas para revertir el síndrome metabólico es clave para el diseño de estrategias clínicas de prevención de enfermedades como la diabetes mellitus de tipo 2 y la enfermedad cardiovascular.Objetivo. Sintetizar el tamaño del efecto de las intervenciones disponibles para revertir un diagnóstico de síndrome metabólico. Materiales y métodos. Se hizo la búsqueda en Embase y Medline, incluyendo los ensayos clínicos en los que la variable “respuesta” se definía como la reversión del diagnóstico del síndrome metabólico. Se categorizaron las intervenciones en cuatro dimensiones: 1) estilo de vida (dieta y ejercicio); 2) farmacia; 3) combinación de estilo de vida y farmacia, y 4) grupos de control; finalmente, se hizo una comparación mixta de tratamientos.Resultados. Se detectaron dos estudios adicionales a los incluidos en el metaanálisis publicado por Dunkley, et al., en el 2012. Se estimó que las intervenciones relacionadas con el estilo de vida tuvieron 2,61 veces (intervalo de credibilidad entre 1,00 y 5,47) más probabilidades de revertir el síndrome metabólico que las de los grupos de control y las relacionadas con los tratamientos farmacéuticos, una probabilidad de 3,39 veces más que las del grupo de control, pero con un intervalo de credibilidad entre 0,81 y 9,99. Las intervenciones sobre el estilo de vida tuvieron 1,59 veces más probabilidades de revertir el síndrome metabólico que las del tratamiento farmacéutico. Conclusión. Las estrategias basadas en la dieta y la actividad física de las personas, tuvieron una mayor probabilidad de ser más efectivas para revertir el diagnóstico de síndrome metabólico.

Adverse pregnancy outcomes between the anti-malarial drugs: Is there a difference between the drugs recommended by World Health Organization? Results of a mixed treatment comparison analysis of randomized clinical trials and cohort studies.

Data regarding the relative safety profile of anti-malarial drugs in pregnancy is sparse mainly limited by the absence of head-to-head clinical trials. The present study is a network meta-analysis of safety of anti-malarial drugs used to treat malaria in pregnant women. A thorough literature search using the search strategy "Malaria [tiab] AND (Pregnant [tiab] OR Pregnancy [tiab])" was carried out for either randomized controlled trials or prospective cohort studies in pregnant malarial women prescribed any of the recommended anti-malarial drugs by World Health Organization (WHO) and that have reported adverse pregnancy outcomes such as miscarriage, still birth, and neonatal deaths. Odds ratio with 95% confidence interval was used as the effect estimate. Random-effects model and Markov Chain Monte Carlo simulation method was used to generate pooled estimates. Sensitivity analysis was performed excluding data from first trimester and GRADE approach was used to categorize the quality of evidence. A total of 1242 papers were obtained with the search strategy, of which seven evaluating 10 treatment arms in a total of 5510 participants were included in the present meta-analysis. The pooled estimates revealed significantly lower risks of abortion with quinine and artemisinin-lumefantrine compared to dihydroartemisinin-piperaquine, artesunate with mefloquine and artesunate with amodiaquine. But when a cohort study that was conducted in the first trimester of pregnancy was excluded, no significant differences were observed in the risk of abortion between the anti-malarial drugs. No significant differences in the risk of either stillbirths or neonatal deaths were observed with any of the drugs. The quality of evidence was found to be very low due to serious limitations in both the precision and indirectness. WHO recommended anti-malarials in pregnancy have similar risk profiles with regard to abortion, stillbirth and neonatal deaths.

Evaluating the cost-effectiveness of secukinumab in moderate-to-severe psoriasis: a Japanese perspective

Aim: To evaluate the cost-effectiveness of secukinumab, a fully human anti-interleukin-17A monoclonal antibody, compared to other clinically used biologics (adalimumab, infliximab, and ustekinumab) in Japan for the treatment of moderate-to-severe psoriasis from the healthcare system (total costs) and patient co-payment (using different frequencies of drug purchase) perspectives.Methods: A decision-tree (first year)/Markov model (subsequent years), with an annual cycle, was developed. The model adopted a 5-year time horizon. Efficacy inputs were obtained from a mixed-treatment comparison analysis, and other model inputs were collected from published literature and local Japanese sources. Model outcomes included quality-adjusted life years (QALYs) and an incremental cost-effectiveness ratio (ICER) in terms of cost per QALY gained. The annual discounting rate of 2% was applied to both costs and outcomes.Results: Results for the healthcare system perspective showed that secukinumab had the highest number of quality-adjusted life years (QALYs) (4.07) vs other biologics, dominated ustekinumab and infliximab, and the ICER of secukinumab compared to adalimumab was ¥8,418,222/QALY gained. In the patient co-payment perspective with the monthly purchase of drugs, ustekinumab had the lowest co-payment cost, followed by infliximab, adalimumab, and secukinumab. In the patient co-payment perspective with a once every 3 months purchase of secukinumab and adalimumab, the co-payment costs of secukinumab, adalimumab, and ustekinumab became comparable, and infliximab had the highest co-payment cost.Limitations: Only short-term efficacy data was modeled, as there was a lack of data on long-term outcomes. Treatment sequencing was restricted to first-line biologic treatment. Drop-out rates for comparators were assumed to be equivalent to secukinumab in the absence of available data.Conclusions: Secukinumab is a cost-efficient treatment for moderate-to-severe psoriasis, providing greater health outcomes to patients at lower total costs compared to infliximab and ustekinumab, as well as comparable patient co-payment relative to other biologic treatments.

Growth factors for diabetic foot ulcers: mixed treatment comparison analysis of randomized clinical trials.

Topical growth factors accelerate wound healing in patients with diabetic foot ulcers (DFU). Due to the absence of head-to-head comparisons, we carried out Bayesian network meta-analysis to compare the efficacy and safety of growth factors. Using an appropriate search strategy, randomized controlled trials on topical growth factors compared with standard of care in patients with DFU, were included. Proportion of patients with complete healing was the primary outcome. Odds ratio (95% confidence interval) was used as the effect estimate and random effects model was used for both direct and indirect comparisons. Markov Chain Monte Carlo simulation was used to obtain pooled estimates. Rankogram was generated based on surface under the cumulative ranking curve (SUCRA). A total of 26 studies with 2088 participants and 1018 events were included. The pooled estimates for recombinant epidermal growth factor (rhEGF), autologous platelet rich plasma (PRP), recombinant human platelet-derived growth factor (rhPDGF) were 5.72 [3.34, 10.37], 2.65 [1.60, 4.54] and 1.97 [1.54, 2.55] respectively. SUCRA for rhEGF was 0.95. Sensitivity analyses did not reveal significant changes from the pooled estimates and rankogram. No differences were observed in the overall risk of adverse events between the growth factors. However, the growth factors were observed to lower the risk of lower limb amputation compared to standard of care. To conclude, rhEGF, rhPDGF and autologous PRP significantly improved the healing rate when used as adjuvants to standard of care, of which rhEGF may perform better than other growth factors. The strength of most of the outcomes assessed was low and the findings may not be applicable for DFU with infection or osteomyelitis. The findings of this study needs to be considered with caution as the results might change with findings from head-to-head studies.

Sublingual, transdermal and intravenous patient-controlled analgesia for acute post-operative pain: systematic literature review and mixed treatment comparison

Objective: To conduct a systematic literature review (SLR) and quantitative analysis to assess the comparative efficacy and safety of the sufentanil sublingual tablet system (SSTS) against other available patient controlled analgesia (PCA) options for post-operative analgesia.Methods: An SLR was conducted for studies published between 2004 and 2016. Due to study heterogeneity, subgroup analyses were conducted controlling for differences in imputation methods for missing values, baseline pain severity, and type of surgery. Where sufficient data was available, a mixed treatment comparison (MTC) was performed.Results: The MTC and subgroup analyses used 13 studies. In direct meta-analysis, there was a statistically significant difference in favor of SSTS compared with intravenous (IV) PCA (morphine) at 24 hours for the patient global assessment (PGA) scores of “good” or “excellent”. For the Pain Intensity Score, there were numerical but not statistically significant differences in favor of the SSTS versus IV PCA (morphine) and the patient controlled transdermal system (PCTS) (fentanyl) in the MTC at 6 hours (standardized mean difference −0.27 [credible interval −2.78, 2.09] and −0.36 [−3.89, 3.03], respectively). The onset of pain relief was earlier with the SSTS versus IV PCA (morphine) as shown by the Pain Intensity Difference. Likewise, the onset was earlier compared with PCTS (fentanyl) where data was available. There was a significant difference in favor of SSTS compared with IV PCA (morphine) and with PCTS (fentanyl) for any adverse event, and numerical improvements for withdrawals due to adverse events.Conclusions: This meta-analysis shows that SSTS is an option for non-invasive management of moderate-to-severe post-operative pain which can be more effective, faster in onset and better tolerated than IV PCA (morphine) and PCTS (fentanyl).

Efficacy and safety of glucagon-like peptide-1 receptor agonists in type 2 diabetes: A systematic review and mixed-treatment comparison analysis.

To compare efficacy and safety of glucagon-like peptide-1 receptor agonists (GLP-1RAs) in people with type 2 diabetes. We electronically searched, up to June 3, 2016, published randomized clinical trials lasting between 24 and 32 weeks that compared a GLP-1RA (albiglutide, dulaglutide, twice-daily exenatide and once-weekly exenatide, liraglutide, lixisenatide, semaglutide and taspoglutide) with placebo or another GLP-1RA. Data on cardiometabolic and safety outcomes were analysed using a mixed-treatment comparison meta-analysis. A total of 34 trials (14 464 participants) met the inclusion criteria; no published data for semaglutide were available. Compared with placebo, all GLP-1RAs reduced glycated haemoglobin (HbA1c) and fasting plasma glucose (FPG) levels (reductions ranged from -0.55% and -0.73 mmol/L, respectively, for lixisenatide to -1.21% and -1.97 mmol/L, respectively, for dulaglutide). There were no differences within short-acting (twice-daily exenatide and lixisenatide) or long-acting (albiglutide, dulaglutide, once-weekly exenatide, liraglutide and taspoglutide) groups. Compared with twice-daily exenatide, dulaglutide treatment was associated with the greatest HbA1c and FPG reduction (0.51% and 1.04 mmol/L, respectively), followed by liraglutide (0.45% and 0.93 mmol/L, respectively) and once-weekly exenatide (0.38% and 0.85 mmol/L, respectively); similar reductions were found when these 3 agents were compared with lixisenatide. Compared with placebo, all GLP-1RAs except albiglutide reduced weight and increased the risk of hypoglycaemia and gastrointestinal side effects, and all agents except dulaglutide and taspoglutide reduced systolic blood pressure. When all GLP-1RAs were compared with each other, no clinically meaningful differences were observed in weight loss, blood pressure reduction or hypoglycaemia risk. Albiglutide had the lowest risk of nausea and diarrhoea and once-weekly exenatide the lowest risk of vomiting. The RCTs in the present analysis show that all GLP-1RAs improve glycaemic control, reduce body weight and increase the risk of adverse gastrointestinal symptoms compared with placebo. Although there were no differences when short-acting agents were compared with each other or when long-acting agents were compared with each other, dulaglutide, liraglutide and once-weekly exenatide were superior to twice-daily exenatide and lixisenatide at lowering HbA1c and FPG levels. There were no differences in hypoglycaemia between these 3 agents, whilst once-weekly exenatide had the lowest risk of vomiting. These results, along with patient's preferences and individualized targets, should be considered when selecting a GLP-1RA.

TCT-450 Bare Metal Stent, Durable Polymer Drug Eluting Stent, or Biodegradable Polymer Drug Eluting Stent in Patients with Diabetes Mellitus - A Mixed Treatment Comparison Analysis of 63,940 Patient-Years of Follow-up from Randomized Trials

TCT-450 Bare Metal Stent, Durable Polymer Drug Eluting Stent, or Biodegradable Polymer Drug Eluting Stent in Patients with Diabetes Mellitus - A Mixed Treatment Comparison Analysis of 63,940 Patient-Years of Follow-up from Randomized Trials

A mixed treatment comparison to compare the efficacy and safety of botulinum toxin treatments for cervical dystonia.

A systematic pair-wise comparison of all available botulinum toxin serotype A and B treatments for cervical dystonia (CD) was conducted, as direct head-to-head clinical trial comparisons are lacking. Five botulinum toxin products: Dysport® (abobotulinumtoxinA), Botox® (onabotulinumtoxinA), Xeomin® (incobotulinumtoxinA), Prosigne® (Chinese botulinum toxin serotype A) and Myobloc® (rimabotulinumtoxinB) have demonstrated efficacy for managing CD. A pair-wise efficacy and safety comparison was performed for all toxins based on literature-reported clinical outcomes. Multi-armed randomized controlled trials (RCTs) were identified for inclusion using a systematic literature review, and assessed for comparability based on patient population and efficacy outcome measures. The Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) was selected as the efficacy outcome measurement for assessment. A mixed treatment comparison (MTC) was conducted using a Bayesian hierarchical model allowing indirect comparison of the interventions. Due to the limitation of available clinical data, this study only investigated the main effect of toxin treatments without explicitly considering potential confounding factors such as gender and formulation differences. There was reasonable agreement between the number of unconstrained data points, residual deviance and pair-wise results. This research suggests that all botulinum toxin serotype A and serotype B treatments were effective compared to placebo in treating CD, with the exception of Prosigne. Based on this MTC analysis, there is no significant efficacy difference between Dysport, Botox, Xeomin and Myobloc at week four post injection. Of the adverse events measured, neither dysphagia nor injection site pain was significantly greater in the treatment or placebo groups.

Once-daily fluticasone furoate/vilanterol versus twice daily combination therapies in asthma-mixed treatment comparisons of clinical efficacy.

BackgroundFluticasone furoate (FF)/vilanterol (VI) is a once-daily inhaled corticosteroid (ICS)/long-acting beta2 agonist (LABA) combination. FF/VI, 92/22mcg and 184/22mcg, are approved in Europe as maintenance therapy in persistent asthma. We report data from mixed treatment comparisons (MTC) of once-daily FF/VI against established twice-daily ICS/LABA combination therapies on clinical efficacy outcomes.MethodsData from 31 parallel-group randomised controlled trials (RCTs) of ICS/LABA, of ≥8 weeks’ duration in patients aged ≥12 years with asthma, identified by systematic review, were analysed using covariate-adjusted Bayesian hierarchical models for four efficacy outcomes (primary analysis). Lung function, assessed by change from baseline morning peak expiratory flow (PEF) (n = 18 studies) and forced expiratory volume in 1 s (FEV1) (n = 28), was the outcome of primary interest. Secondary objectives were assessment of relative efficacy in terms of exacerbation rates (n = 6) and health status (n = 7). Overall, 24 different treatment arms were included in the MTC; we report findings comparing FF/VI (92/22mcg and 184/22mcg) with fluticasone propionate/salmeterol (FP/SAL) (250/50mcg and 500/50mcg) and budesonide/formoterol (BUD/FORM) (320/9mcg and 640/18mcg).ResultsFor PEF (margin = 12 l/min), FF/VI 92/22mcg demonstrated ≥94 % probability and FF/VI 184/22mcg >99 % probability of non-inferiority to corresponding doses of both FP/SAL and BUD/FORM. For FEV1 (margin = 100 ml), FF/VI demonstrated ≥98 % (92/22mcg) and >99 % (184/22mcg) probability of non-inferiority to both FP/SAL and BUD/FORM. Findings for exacerbations were inconclusive due to lack of data: FF/VI 92/22mcg demonstrated 74 % and 82 % probability of non-inferiority (margin = 10 %) to FP/SAL 250/50mcg and BUD/FORM 320/9mcg, respectively. For Asthma Quality of Life Questionnaire (AQLQ) score, FF/VI 92/22mcg demonstrated >99 % and 90 % probability of non-inferiority (margin = 0.25) to FP/SAL 250/50mcg and BUD/FORM 320/9mcg. Data were unavailable to assess non-inferiority of FF/VI 184/22mcg on exacerbations or AQLQ.ConclusionsBoth strengths of once-daily FF/VI in asthma were comparable with corresponding doses of twice-daily FP/SAL and BUD/FORM in terms of lung function in this MTC analysis. FF/VI 92/22mcg was comparable with FP/SAL and BUD/FORM on AQLQ, but exacerbation results were inconclusive. Model limitations include disconnected treatment networks and variability across studies. Our data support previous RCT findings suggesting that the efficacy of once-daily FF/VI in improving lung function and health status in asthma is comparable with twice-daily ICS/LABAs.Electronic supplementary materialThe online version of this article (doi:10.1186/s40733-015-0016-0) contains supplementary material, which is available to authorized users.

A Bayesian missing data framework for generalized multiple outcome mixed treatment comparisons.

Bayesian statistical approaches to mixed treatment comparisons (MTCs) are becoming more popular because of their flexibility and interpretability. Many randomized clinical trials report multiple outcomes with possible inherent correlations. Moreover, MTC data are typically sparse (although richer than standard meta-analysis, comparing only two treatments), and researchers often choose study arms based upon which treatments emerge as superior in previous trials. In this paper, we summarize existing hierarchical Bayesian methods for MTCs with a single outcome and introduce novel Bayesian approaches for multiple outcomes simultaneously, rather than in separate MTC analyses. We do this by incorporating partially observed data and its correlation structure between outcomes through contrast-based and arm-based parameterizations that consider any unobserved treatment arms as missing data to be imputed. We also extend the model to apply to all types of generalized linear model outcomes, such as count or continuous responses. We offer a simulation study under various missingness mechanisms (e.g., missing completely at random, missing at random, and missing not at random) providing evidence that our models outperform existing models in terms of bias, mean squared error, and coverage probability then illustrate our methods with a real MTC dataset. We close with a discussion of our results, several contentious issues in MTC analysis, and a few avenues for future methodological development.

Efficacy of biological agents administered as monotherapy in rheumatoid arthritis: a Bayesian mixed-treatment comparison analysis.

BackgroundBiological agents provide an important therapeutic alternative for rheumatoid arthritis patients refractory to conventional disease-modifying antirheumatic drugs. Few head-to-head comparative trials are available.PurposeThe aim of this meta-analysis was to compare the relative efficacy of different biologic agents indicated for use as monotherapy in rheumatoid arthritis.MethodsA systemic literature search was performed on electronic databases to identify articles reporting double-blind randomized controlled trials investigating the efficacy of biologic agents indicated for monotherapy. Efficacy was assessed using American College of Rheumatology (ACR) 20, 50, and 70 criteria at 16–24 weeks. Relative efficacy was estimated using Bayesian mixed-treatment comparison models. Outcome measures were expressed as odds ratio and 95% credible intervals.ResultsTen randomized controlled trials were selected for data extraction and analysis. Mixed-treatment comparison analysis revealed that tocilizumab offered 100% probability of being the best treatment for inducing an ACR20 response versus placebo, methotrexate, adalimumab, or etanercept. Likewise, for ACR50 and ACR70 outcome responses, tocilizumab had a 99.8% or 98.7% probability of being the best treatment, respectively, compared to other treatments or placebo. Tocilizumab increased the relative probability of being the best treatment (vs methotrexate) by 3.2-fold (odds ratio: 2.1–3.89) for all ACR outcomes.ConclusionTocilizumab offered the greatest possibility of obtaining an ACR20, ACR50, and ACR70 outcome vs other monotherapies or placebo.

TNF-alpha inhibitors for ankylosing spondylitis.

TNF-alpha inhibitors for ankylosing spondylitis.

Sa1795 An Indirect Comparisons Analysis of TNF Inhibitors vs. Selective Adhesion Molecule Inhibitors in the Induction of Response in Ulcerative Colitis

Introduction: Five biologic medications have been proven to be efficacious to treat Ulcerative Colitis (UC), three tumor necrosis factor inhibitors (infliximab, adalimumab, and golimumab) and two Selective Adhesion Molecule (SAM) inhibitors (vedolizumab and etrolizumab). The vast majority of evidence supporting their individual efficacy is based on randomized controlled trials (RCTs) with placebo as the comparator arm. We performed a network metaanalysis (NMA) to determine the comparative efficacy of these biologic medications for the induction of clinical response in the treatment of ulcerative colitis Methods: Studies were extracted from an electronic literature search of PubMed, MEDLINE and EMBASE of all relevant RCTs. 9 RCTs, including 3,265 patients, were identified. The main outcome of interest for efficacy: induction of response, defined as a decrease from baseline in the total Mayo score by at least 3 points and a relative decrease by at least 30% with an accompanying decrease in the rectal bleeding subscore of at least 1 point or an absolute rectal bleeding subscore of 0 or 1. There were several outcomes of interest for safety, primarily serious infections, serious adverse events and adverse events causing discontinuation of the drug. For each outcome, a fixed-effects meta-analysis was employed to compare each drug to placebo. A mixed-treatment comparisons analysis was then used to compare each of these drugs to one another indirectly. Calculation of the probability that each treatment is best was implemented using the Bayesian Markov chain Monte Carlo method. Results: Patients taking Adalimumab had a 67% reduced likelihood of inducing response compared to Infliximab (RR 0.43 95% CI 0.27-0.72). In terms of rank probability, Infliximab had the highest probability of inducing response compared to Adalimumab and Vedolizumab. Overall, TNF inhibitors had a higher rank probability of inducing response compared to SAM inhibitors. In terms of adverse events, SAM inhibitors had a higher rank probability of causing adverse events when compared to TNF inhibitors. The degree of incoherence was low for all outcomes. Conclusion: This NMA to date is the first to compare the two groups of biologics, TNF inhibitors and SAM inhibitors including the new SAM inhibitoretrolizumab in the induction of response with different efficacy outcomes. The results of the study showed that TNF inhibitors seem to be more efficacious in inducing response in ulcerative colitis when compared to SAM inhibitors.

Sa1796 Diet-Induced Secretion of Incretins Is Regulated by Nutrients in the Stomach

Introduction: Five biologic medications have been proven to be efficacious to treat Ulcerative Colitis (UC), three tumor necrosis factor inhibitors (infliximab, adalimumab, and golimumab) and two Selective Adhesion Molecule (SAM) inhibitors (vedolizumab and etrolizumab). The vast majority of evidence supporting their individual efficacy is based on randomized controlled trials (RCTs) with placebo as the comparator arm. We performed a network metaanalysis (NMA) to determine the comparative efficacy of these biologic medications for the induction of clinical response in the treatment of ulcerative colitis Methods: Studies were extracted from an electronic literature search of PubMed, MEDLINE and EMBASE of all relevant RCTs. 9 RCTs, including 3,265 patients, were identified. The main outcome of interest for efficacy: induction of response, defined as a decrease from baseline in the total Mayo score by at least 3 points and a relative decrease by at least 30% with an accompanying decrease in the rectal bleeding subscore of at least 1 point or an absolute rectal bleeding subscore of 0 or 1. There were several outcomes of interest for safety, primarily serious infections, serious adverse events and adverse events causing discontinuation of the drug. For each outcome, a fixed-effects meta-analysis was employed to compare each drug to placebo. A mixed-treatment comparisons analysis was then used to compare each of these drugs to one another indirectly. Calculation of the probability that each treatment is best was implemented using the Bayesian Markov chain Monte Carlo method. Results: Patients taking Adalimumab had a 67% reduced likelihood of inducing response compared to Infliximab (RR 0.43 95% CI 0.27-0.72). In terms of rank probability, Infliximab had the highest probability of inducing response compared to Adalimumab and Vedolizumab. Overall, TNF inhibitors had a higher rank probability of inducing response compared to SAM inhibitors. In terms of adverse events, SAM inhibitors had a higher rank probability of causing adverse events when compared to TNF inhibitors. The degree of incoherence was low for all outcomes. Conclusion: This NMA to date is the first to compare the two groups of biologics, TNF inhibitors and SAM inhibitors including the new SAM inhibitoretrolizumab in the induction of response with different efficacy outcomes. The results of the study showed that TNF inhibitors seem to be more efficacious in inducing response in ulcerative colitis when compared to SAM inhibitors.

Long Term Outcomes of First Line Tyrosine Kinase Inhibitors for Chronic Phase Chronic Myeloid Leukemia: A Mixed-Treatment Comparison

Background: Tyrosine kinase inhibitors (TKI) are associated with marked improvements in molecular response and survival compared with previous therapies for patients with chronic myelogenous leukemia (CML) in chronic phase (CP). We previously reported efficacy and safety of TKI at 12-month follow-up (Firwana et. al.JCO. 2014; 32(15_suppl): 7054). Here, we summarize the evidence of TKI efficacy and safety of TKI, comparing them directly and in-directly, in the mature follow-up for patients with newly diagnosed CP-CML.Methods: We included randomized controlled trials (RCTs) evaluating TKI in adults with newly diagnosed CP-CML. TKI (imatinib, dasatinib and nilotinib) were included if used as an initial treatment. Studies on bosutinib were excluded as it is only approved in the US for the treatment of CP-CML after failure of initial therapy. Studies that included patients with accelerated- or blast-phase CML, intolerant or resistant patients to first-line treatment, those on IFN-α, older agents or stem cell transplantation were excluded. Main outcomes are efficacy, represented by major molecular response (MMR, ≤ 0.1% BCR-ABLIS) and deeper molecular responses (MR4.5, ≤ 0.0032%IS), survival, represented by overall survival (OS) and progression free survival (PFS), and safety represented by medication discontinuation rate due to adverse events. Latest period of reporting outcome data were considered. As available trials provides direct comparison with imatinib, with no head-to-head trials to compare other TKI, we conducted a mixed treatment comparison (MTC) analysis which pools evidence from direct and indirect comparisons to facilitate simultaneous inference regarding all treatments. Bayesian mixed-treatment comparison method was used to rank TKI in terms of effectiveness.Results: Four landmark trials reported in 15 published articles and conference abstracts were identified involving 1647 patients with CP-CML. Follow-up times ranged from 3 months to 6 years. Table-1 depicts the results of MTC for imatinib, dasatinib and nilotinib. MTC analysis demonstrated superiority of both nilotinib and dasatinib over imatinib in terms of efficacy and safety. Nilotinib ranked first in efficacy with better improvement in MMR and MR4.5 at 48-month follow-up despite its different regimens, followed by dasatinib. Dasatinib has the highest medication discontinuation rate due to adverse events or drug-related toxicity. Among TKI, nilotinib was found to have the best survival profile; however, it was statistically nonsignificant.Conclusion: Both nilotinib and dasatinib are associated with significantly better efficacy and safety profiles compared to imatinib. At 48-month follow-up period, nilotinib ranked first to achieve MMR and MR4.5, with lower discontinuation rate due to adverse events. This analysis shows that new generation TKI are not only showing faster response, but also maintaining a more potent one through longer follow up period. It is important to note out that MTC is not a substitute for well conducted RCTs investigating direct comparisons.Table-1:Results of mixed treatment comparison for imatinib, dasatinib and nilotinib using fixed-effect Bayesian method.ComparisonMean risk difference (95% CrI) compared to from reference standard (Imatinib)Rank*MMRMR 4.5PFSOSDiscontinuation due to adverse events48 months48 months36 months48 months48 monthsImatinibReferenceReferenceReferenceReferenceReference4Dasatinib0.62 (0.26 to 1.01)0.32 (-0.05 to 0.69)0.21 (-0.43 to 0.85)0.17 (-0.49 to 0.83)0.59 (-0.05 to 1.25)3Nilotinib 3000.92 (0.56 to 1.28)0.81 (0.45 to 1.18)1.02 (0.24 to 1.86)0.19 (-0.51 to 0.89)-0.11 (-0.66 to 0.43)1Nilotinib 4000.76 (0.41 to 1.12)0.68 (0.31 to 1.05)0.05 (-0.57 to 0.65)0.81 (0.01 to 1.67)0.30 (-0.20 to 0.81)2*Reported rank is valid for all outcomes, except for PFS and OS, where Nilotinib 400 ranks #1 and Nilotinib 300 ranks #2. Also, for rate of medication discontinuation due to adverse events, Dasatinib has the highest rate for discontinuation, followed by Nilotinib, both doses.Abbreviations: CrI, credible intervals; MMR, major molecular response, BCR-ABLIS ≤ 0.1%; MR4, deeper molecular responses, BCR-ABLIS ≤ 0.0032%; PFS, progression free survival; OS, overall survival. DisclosuresNo relevant conflicts of interest to declare.

An Indirect Comparisons Analysis of Biologic Medications in the Maintenance of Response and Remission in Crohn’s Disease

Introduction: Five biologic medications are approved to treat Crohn’s disease (CD), 3 tumor necrosis factor inhibitors (infliximab, adalimumab, and certolizumab pegol) and 2 selective adhesion molecule (SAM) inhibitors (natalizumab and vedolizumab). The vast majority of evidence supporting their individual efficacies is based on randomized controlled trials (RCTs) with placebo as the comparator arm. We performed a network meta-analysis (NMA) to determine the comparative efficacy of these biologic medications in maintaining a clinical response (defined by a decrease in Crohn’s disease activity index by more than 70 points) and remission (defined by a decrease in Crohn’s disease activity index by more than 150 points) at weeks 20 and 24. Methods: Studies were extracted from a electronic literature search of PubMed, MEDLINE and EMBASE of all relevant RCT’s. Twelve RCT’s, including 3,519 patients, were identified. There were 2 outcomes of interest: efficacy in maintaining response and remission at 20 and 24 weeks. There were several outcomes of interest for safety, such as serious infections, abdominal abscess and death. For each outcome, a fixed-effects meta-analysis was used. A mixed-treatment comparisons analysis was then utilized to compare each of these drugs to one another indirectly. Calculation of the probability that each treatment is best was implemented using the Bayesian Markov chain Monte Carlo method. Results: In terms of maintenance of response at 20 weeks, patients taking natalizumab had a 90% (RR 0.10; 95% confidence interval [CI] 0.02-0.59) reduced likelihood of maintaining response when compared to adalimumab. In terms of maintenance of remission at 20 weeks vedolizumab had a 66% reduced likelihood of maintenance of remission when compared to adalimumab (RR 0.34; 95% CI 0.13-0.70). Regarding maintenance of response and remission at 24 weeks, similar outcomes of superiority of adalimumab over certolizumab and vedolizumab were noted although not statistically significant. In terms of rank probability adalimumab had a 71% chance of being the option most likely to maintain response and 72% chance of maintaining remission at 24 weeks. No statistical significance was noted comparing one drug to another in terms of safety. The degree of incoherence was low for all outcomes. Conclusion: This NMA was the first comparison to include all approved biologic medications, including SAM inhibitors-natalizumab and vedolizumab to compare maintenance of response and remission with different efficacy outcomes. Based on the above statistical analysis, adalimumab may be considered a superior option to other biologic medications for maintaining response and remission at 20 weeks.

An Indirect Comparisons Analysis of Biologic Medications in the Induction of Response and Remission in Crohn’s Disease

Introduction: Five biologic medications are approved to treat Crohn’s disease (CD), 3 tumor necrosis factor inhibitors (infliximab, adalimumab, and certolizumab pegol) and 2 selective adhesion molecule (SAM) inhibitors (natalizumab and vedolizumab). The vast majority of evidence supporting their individual efficacies is based on randomized controlled trials (RCTs) with placebo as the comparator arm. We performed a network meta-analysis (NMA) to determine the comparative efficacy of these biologic medications for the induction of clinical response and remission at 2 and 4 weeks. Methods: Studies were extracted from an electronic literature search of PubMed, MEDLINE and EMBASE of all relevant RCTs. Ten RCTs, including 4,425 patients, were identified. Two outcomes were of interest for efficacy: induction of response, defined by a decrease in Crohn’s disease activity index (CDAI) of at least 70 points from baseline, and remission, defined as a CDAI <150, at week 2 and 4. For each outcome, a fixed-effects meta-analysis was employed to compare each drug to placebo. A mixedtreatment comparisons analysis was then used to compare each of these drugs to one another indirectly. Calculation of the probability that each treatment is best was implemented using the Bayesian Markov chain Monte Carlo method. Results: Response induction at 2 weeks: patients taking natalizumab had a 86% reduced likelihood of inducing response compared to infliximab (RR 0.14 95% confidence interval[CI] 0.05-0.40) and patients on vedolizumab had a 85% reduced likelihood of inducing response compared to Infliximab (RR 0.15 95% CI 0.04-0.48). Response induction at 4 weeks: patients taking natalizumab had a 69% reduced likelihood of achieving response compared to adalimumab (RR 0.31 95% CI 0.08-0.88) and patients taking vedolizumab had a 85% reduced likelihood of induction of response compared to adalimumab (RR 0.15 95% CI 0.03-0.56). Remission at 2 weeks: patients on natalizumab had a 92% reduced likelihood of achieving remission at 2 weeks compared to infliximab (RR 0.08 95% CI 0.01-0.60). Remission at 4 weeks: natalizumab had a 88% reduced likelihood of achieving remission compared to Infliximab (RR 0.12 95% CI 0.02-0.68). The degree of incoherence was low for all outcomes. In terms of rank probability, infliximab had the highest probability of inducing response and remission at 2 and 4 weeks. Conclusion: This NMA was the first comparison to include all approved biologic medications, including SAM inhibitors-natalizumab and vedolizumab to compare induction of response and remission with different efficacy outcomes. The results of the study showed that TNF inhibitors infliximab and adalimumab seem to be more efficacious in inducing response at 2 and 4 weeks when compared to SAM inhibitors.