Bucher Method Research Articles

PDB6 Indirect Treatment Comparison (ITC) of ULTRA-RAPID Lispro Insulin (URLI) Versus FAST-Acting Insulin Aspart (FASTER ASPART) in Patients with Type 1 Diabetes (T1DM)

An ITC was performed to estimate between-treatment differences in the efficacy and safety of URLi and faster aspart in adults with T1DM. A systematic literature search identified randomised controlled trials examining the efficacy and safety of URLi or faster aspart. No head-to-head trials of these insulins were identified. Key trials identified for URLi (PRONTO-T1D; URLi versus insulin lispro) and faster aspart (onset 1 and 8; faster aspart versus insulin aspart), with basal insulin, reported the endpoints (including primary endpoints) at 26 weeks. The Bucher method was used to perform ITC; clinical equivalence was assumed for the insulin lispro and insulin aspart treatment arms (ITC anchor point). ITC endpoints included changes from baseline in HbA1c, post-prandial glucose (PPG) excursions (1 to 4 hours, following a mixed-meal tolerance test), weight, and incidence of severe hypoglycaemia. ITC of URLi versus faster aspart showed a mean difference (MD) of 0.01% (95% confidence interval [CI] -0.09%; 0.11%) for HbA1c change from baseline at 26 weeks; the 95% CI was within the non-inferiority margin (0.4%). Reduction in PPG excursions (mmol/L) were larger with URLi versus faster aspart at all timepoints, statistically significantly greater from 2 hours onwards (MD: 2 hours, -1.22 [-1.93; -0.51] p<0.01; 3 hours, -1.41 [-2.19; -0.64] p<0.01; 4 hours, -0.87 [-1.66; -0.09] p=0.03). No significant between-treatment differences were observed regarding weight increase (treatment difference -0.36 [-0.81; 0.10] kg) or odds and probability of severe hypoglycaemia (odds ratio for URLi versus faster aspart: 1.08 [0.55, 2.12], risk ratio 1.07 [0.57; 2.03]). URLi demonstrated non-inferiority in lowering HbA1c at week 26 and superiority in reducing PPG excursions at 2, 3 and 4 hours versus faster aspart in adults with T1DM. Weight increase and severe hypoglycaemia did not differ significantly between URLi and faster aspart.

Comparative effectiveness of improvement in pain and physical function for baricitinib versus adalimumab, tocilizumab and tofacitinib monotherapies in rheumatoid arthritis patients who are naïve to treatment with biologic or conventional synthetic disease-modifying antirheumatic drugs: a matching-adjusted indirect comparison

ObjectiveTo compare improvement in pain and physical function for patients treated with baricitinib, adalimumab, tocilizumab and tofacitinib monotherapy from randomised, methotrexate (MTX)-controlled trials in conventional synthetic disease-modifying antirheumatic drugs (csDMARDs)/biologic...

Indirect Comparison of Combined BRAF and MEK Inhibition in Melanoma Patients with Elevated Baseline Lactate Dehydrogenase.

The approval of BRAF and MEK inhibitors has significantly improved treatment outcomes for patients with BRAF-mutated metastatic melanoma. The 3 first-line targeted therapy trials have provided similar results, and thus the identification of predictive biomarkers may generate a more precise basis for clinical decision-making. Elevated baseline lactate dehydrogenase (LDH) has already been determined as a strong prognostic factor. Therefore, this indirect analysis compared subgroups with elevated baseline LDH across the pivotal targeted therapy trials co-BRIM, COMBI-v and COLUMBUS part 1. The Bucher method was used to compare progression-free survival, objective response rate and overall survival indirectly. The results show a non-significant risk reduction for progression in the subgroup with elevated baseline LDH receiving vemurafenib plus cobimetinib compared with dabrafenib plus trametinib and encorafenib plus binimetinib. Although an indirect comparison, these data might provide some guidance for treatment recommendations in melanoma patients with elevated LDH.

Overall Survival of Glasdegib in Combination with Low-Dose Cytarabine and Azacitidine By Bone Marrow Blasts Among Adult Patients with Previously Untreated Acute Myeloid Leukemia: Comparative Effectiveness Using Indirect Treatment Comparisons

Introduction Acute myeloid leukemia (AML) is an orphan disease with one of the lowest five-year survival rates among myeloid malignancies in United States adults. Older AML patients face a much lower 5-year survival rate than their younger counterparts (8% for those aged 60-65 years vs. 38% for those under 45 years). Current therapies are limited and historically include low-dose cytarabine (LDAC), decitabine, azacitidine (AZA) and best supportive care. A phase II randomized study (Cortes et al, 2019) among previously untreated AML patients who are not eligible for intensive chemotherapy demonstrated improved overall survival (OS) in patients treated with glasdegib (GLAS) in combination with low-dose cytarabine (LDAC) compared to patients receiving LDAC alone. There are two trials comparing AZA with conventional care regimens that report data by bone marrow blasts (BMB) count: Fenaux et al. (2010) for patients with 20-30% BMB and Dombret et al (2015) for patients with over 30% BMB. In clinical practice, AZA may be restricted to the 20-30% BMB population, which is important to consider when comparing treatment options. Therefore, as there are currently no head-to-head comparisons for GLAS+LDAC vs AZA, two separate indirect treatment comparisons (ITCs) were performed in different BMB populations (i.e., 20-30% and &gt;30% BMB). ITCs is an accepted method to support evidence-based comparative effectiveness decision making and ultimately help to optimize treatment and outcomes of patients with previously untreated AML. Method ITCs were conducted in a classical frequentist statistical framework based on the Bucher method. Patient-level data of the Cortes study (data-cut: January 2017) was divided into two subgroups in terms of BMBs, 20-30% (n=30) and &gt;30% (n=80) to match the patient population of Fenaux et al (n=34) and Dombret et al (n=399) accordingly. GLAS+LDAC and AZA were compared in terms of overall survival and results were reported in terms of hazard ratio (HR) with corresponding 95% confidence intervals (95% CI). AZA was chosen as the reference treatment in the ITC. Results In the 20-30% BMB population, the estimated OS HR of GLAS-LDAC in comparison to AZA was 0.46 (95% CI: 0.10-2.14). In the &gt;30% BMB population, the estimated OS HR of GLAS-LDAC in comparison to AZA was 0.61 (95% CI: 0.35-1.08). Conclusion These ITCs suggest that GLAS+LDAC is trending towards being a better treatment option for improving OS in patients with AML compared with AZA, irrespective of the level BMB. These results are consistent with previously published ITC results for this treatment comparison. The results of this ITC should, however, be interpreted with caution due to methodological limitations. First, the relatively small number of patients and deaths result in high uncertainty (as exemplified by the 95% CIs) and, second, patient baseline characteristics (including cytogenetic risk, ECOG status and de novo status) between trial arms and over the different trials were either imbalanced or not reported. While more research is needed, current evidence suggests that GLAS+LDAC may be the preferred treatment option for previously untreated AML patients irrespective of BMB levels. Disclosures Van Beekhuizen: Ingress-health: Consultancy, Other: funding from Pfizer. Bell:Pfizer Inc.: Employment, Equity Ownership. Gezin:Ingress-health: Consultancy, Other: funding from Pfizer. Cappelleri:Pfizer: Employment, Equity Ownership. Heeg:Ingress-Health: Employment. Selya-Hammer:Pfizer Inc: Employment, Equity Ownership. Charaan:Pfizer Inc: Employment, Equity Ownership. Chan:Pfizer Inc: Employment, Equity Ownership.

PNS311 PREDICTIVE-ADJUSTED INDIRECT COMPARISON (PAIC): A NOVEL METHOD FOR POPULATION-ADJUSTED INDIRECT COMPARISON

Population-adjusted indirect comparison methods are increasingly used to compare treatment outcomes across separate clinical trials and to inform health technology assessment. A novel method for population-adjusted comparisons, predictive-adjusted indirect comparison (PAIC), is presented and a comprehensive simulation study is carried out. The rationale behind PAIC is the following: Individual-level data are used to model the link between an outcome and the available prognostic variables and effect modifiers via a generalised linear model. Then, a large number of pseudo-populations are generated by forward sampling from the published aggregate-level values. The outcomes for a trial conducted in a population exchangeable with that of the trial with aggregate-level data are predicted. The simulated datasets are used to estimate an unbiased average treatment effect. A comprehensive simulation study has been carried out where the statistical properties of PAIC are evaluated and benchmarked against those of other recently proposed approaches for population-adjustment (MAIC and STC). The comparative vulnerability of each population-adjustment method to failures in assumptions/model specification is also assessed and compared to that of standard indirect comparison approaches such as the Bucher method. PAIC consistently produces less biased and more accurate estimates across and within scenarios. All population-adjustment methods provide unbiased estimates when all effect modifiers are accounted for and when these interact with treatment in the same way in both trials. PAIC and STC are less biased than MAIC under effect modifier misspecification. The Bucher method is the gold standard when covariates are balanced but is clearly biased and inappropriate when they are not. MAIC displays large variance over replicates as weighting considerably reduces the effective sample size. Population-adjustment methods should be used with caution as their assumptions seem hard to be met in practice. Notwithstanding, PAIC is a very useful tool for comparative effectiveness research without head-to-head trials.

PND2 INDIRECT COMPARISON OF THE EFFICACY OF FREMANEZUMAB VERSUS ERENUMAB IN EPISODIC MIGRAINE PATIENTS WHO HAD FAILED 2-4 PRIOR MIGRAINE PREVENTIVE TREATMENTS

This analysis compared the efficacy of the migraine preventive treatments fremanezumab and erenumab in patients with episodic migraine (EM) who had failed 2-4 prior migraine preventive treatments/classes using an indirect treatment comparison approach. Two trials were identified: the FOCUS study of fremanezumab in migraine patients failing 2-4 prior migraine preventive treatment classes and the LIBERTY study of erenumab in migraine patients failing 2-4 prior migraine preventive treatments. In FOCUS, patients were randomized to 12 weeks of double-blind monthly fremanezumab 225mg, quarterly fremanezumab 675mg, or placebo. In LIBERTY, patients were randomized to 12 weeks of double-blind monthly erenumab 140mg or placebo. The Bucher method was used to estimate relative treatment effects of fremanezumab and erenumab, based on reductions in monthly migraine days (MMD), in patients with EM who had failed 2-4 prior migraine preventive treatments/classes. The effects of fremanezumab relative to erenumab were estimated using the direct estimates of each of these treatments against placebo from their respective trials. Compared to erenumab, reductions from baseline in MMD over 12 weeks were significantly greater for quarterly fremanezumab and monthly fremanezumab (mean difference vs erenumab [95% CI], both 1.2 [0.1, 2.2] MMD; both P<0.05). Significantly greater reductions from baseline in MMD were also observed within the first 4 weeks of treatment compared to erenumab for both quarterly fremanezumab (1.8 [0.5, 3.1] MMD; P<0.01) and monthly fremanezumab (1.7 [0.4, 3.0] MMD; P<0.05). Compared to erenumab, proportions of patients who experienced ≥50% reductions in MMD were generally greater for fremanezumab versus placebo at all evaluated time points, although differences did not reach statistical significance. The results of this indirect treatment comparison indicate that, in EM patients failing 2-4 prior migraine preventive treatments/classes, fremanezumab treatment resulted in significantly greater reductions in MMD over 4 and 12 weeks as compared to erenumab treatment.

PSY4 A SYSTEMATIC LITERATURE REVIEW AND INDIRECT COMPARISON OF IRON ISOMALTOSIDE AND FERRIC CARBOXYMALTOSE IN IRON DEFICIENCY ANAEMIA AFTER FAILURE OR INTOLERANCE OF ORAL IRON TREATMENT

Iron deficiency anemia (IDA) arises when iron losses or requirements exceed absorption, and is often multifactorial in its etiology. Intravenous (IV) is the preferred mode of iron administration in certain groups of patients with IDA, as the efficacy of oral iron is limited by gastrointestinal (GI) absorption and can result in adverse GI symptoms and treatment discontinuation. The aim of the present study was to evaluate the relative efficacy of two high-dose IV iron formulations: iron isomaltoside (IIM) and ferric carboxymaltose (FCM) in patients with IDA. Literature databases were systematically searched to identify randomized controlled trials (RCTs) comparing IIM with FCM in patients with IDA, and RCTs of IIM and FCM with common comparators in order to conduct an indirect treatment comparison (ITC). An ITC of IIM and FCM was ultimately conducted via iron sucrose, employing the Bucher method and evaluating change from baseline hemoglobin and proportion of patients achieving a clinically-relevant response. The systematic literature review identified no direct RCT comparisons of IIM and FCM that had reported results, 5 RCTs of IIM (4 versus oral iron and 1 versus iron sucrose), and 14 RCTs of FCM (11 versus oral iron and 3 versus iron sucrose). Change from baseline hemoglobin significantly favored IIM with a mean difference of +0.249 g/dL (95% confidence interval 0.072-0.426 g/dL) with IIM relative to FCM. Based on an ITC via iron sucrose, IIM would result in a larger increase from baseline hemoglobin than FCM. The proportion of patients achieving clinically-relevant response was not significantly different, but directionally favored IIM over FCM. Due to the heterogeneity between the studies included in the ITC, direct comparisons of IIM and FCM would be needed to confirm these findings.

PP131 Omalizumab And Ciclosporin For Chronic Spontaneous Urticaria

IntroductionOmalizumab and ciclosporin are recommended in international clinical guidelines for treating antihistamine-resistant chronic spontaneous urticaria (CSU). This meta-analysis aimed to evaluate their comparative efficacy and safety to inform local treatment practices in Singapore.MethodsThe PubMed and EMBASE databases were searched for randomized controlled trials (RCTs) published up to October 2018 involving omalizumab or ciclosporin as an add-on therapy to H1-antihistamines for CSU. Key outcomes were changes in weekly Urticaria Activity Score (UAS7), adverse events, and health-related quality of life. Pairwise meta-analysis was conducted for each outcome. Owing to differences in trial designs and patient characteristics across the studies, a random effects model was employed. In the absence of head-to-head trials, the Bucher method of adjusted indirect comparison was used to estimate the comparative effectiveness between omalizumab and ciclosporin, with placebo as the common comparator.ResultsEight omalizumab and two ciclosporin placebo-controlled RCTs comprising 1,740 patients were selected. The magnitude of treatment effect for omalizumab was dose-dependent across all efficacy outcomes: 300 mg was superior to 150 mg. Omalizumab 300 mg, although statistically significantly better than placebo for all efficacy outcomes at week 12, did not achieve clinical significance for all measures. The mean change in UAS7 was statistically better for ciclosporin than for placebo (one RCT) at week 4. The indirect comparison between omalizumab and ciclosporin showed no statistically significant differences for mean change in UAS7. Omalizumab had a more favorable short-term safety profile than ciclosporin, but long-term safety data were lacking.ConclusionsBoth omalizumab and ciclosporin were effective in treating CSU, compared with placebo. However, results of the indirect comparison should be interpreted with caution. On the basis of limited available evidence, and taking into account the similar place in therapy of omalizumab and ciclosporin, the results may be considered acceptable to confirm the clinical comparability of the drugs an add-on to H1-antihistamines for CSU.

An indirect treatment comparison of the efficacy of patisiran and tafamidis for the treatment of hereditary transthyretin-mediated amyloidosis with polyneuropathy

ABSTRACTBackground: Hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis) is a progressive, life-threatening disease. Until recently, tafamidis was the only approved pharmacotherapy. Patisiran significantly improved polyneuropathy and quality of life (QoL) in the phase III APOLLO trial. In the absence of direct comparisons, this analysis aimed to evaluate the comparative efficacy of tafamidis and patisiran in hATTR amyloidosis with polyneuropathy.Research design and methods: Randomized controlled trial evidence for tafamidis was identified by systematic literature review. Indirect treatment comparisons were performed using the standard pairwise Bucher method for endpoints used in both APOLLO and the tafamidis Fx-005 trial: change from baseline in Neuropathy Impairment Score-lower limbs (NIS-LL), Norfolk QoL-Diabetic Neuropathy questionnaire (QoL-DN), NIS-LL response, and mBMI vs. placebo. Inter-trial population differences were assessed by sensitivity analysis.Results: The base-case analysis (FAP Stage 1 APOLLO patients vs. intent-to-treat Fx-005 population) suggested patisiran had a greater treatment effect vs. tafamidis for all endpoints, with significant improvements in mean change in NIS-LL (–5.49) and QoL-DN (–13.10) from baseline to Month 18. Similar trends were observed in all sensitivity analyses.Conclusions: In the absence of direct comparisons, this analysis suggests patisiran has a greater treatment effect than tafamidis in patients with hATTR amyloidosis with polyneuropathy.

A generalized pairwise modelling framework for network meta-analysis.

Indirect comparison methods are used to measure the effect of two treatments that were each compared against a similar control group in a meta-analysis. The network meta-analysis method extends this to multiple treatments which are assessed simultaneously. Currently, there exist Bayesian and multivariate modelling approaches to these analyses, but these are computationally intensive and rely on assumptions that may not be valid in practice. Here we introduce a generalized pairwise modelling (GPM) framework for network meta-analysis, so named as it is based on the repeated application of adjusted indirect comparisons, also known as the Bucher method. The validity of this method hinges on the sufficient similarity of the common control node (transitivity), and for the application in the GPM framework this requirement extends to all common nodes used to make an indirect comparison estimate. Apart from the assumption of sufficient similarity, the GPM framework assumes only standard arithmetic and statistical rules making it more robust when compared with existing methods for network meta-analysis. A software program (MetaXL; www.epigear.com) is available to run this framework, so it is easily accessible to researchers.

Alternative Weighting Approaches for Anchored Matching-Adjusted Indirect Comparisons via a Common Comparator

BackgroundAdjusted indirect comparisons (anchored via a common comparator) are an integral part of health technology assessment. These methods are challenged when differences between studies exist, including inclusion/exclusion criteria, outcome definitions, patient characteristics, as well as ensuring the choice of a common comparator. ObjectivesMatching-adjusted indirect comparison (MAIC) can address these challenges, but the appropriate application of MAICs is uncertain. Examples include whether to match between individual-level data and aggregate-level data studies separately for treatment arms or to combine the arms, which matching algorithm should be used, and whether to include the control treatment outcome and/or covariates present in individual-level data. ResultsResults from seven matching approaches applied to a continuous outcome in six simulated scenarios demonstrated that when no effect modifiers were present, the matching methods were equivalent to the unmatched Bucher approach. When effect modifiers were present, matching methods (regardless of approach) outperformed the Bucher method. Matching on arms separately produced more precise estimates compared with matching on total moments, and for certain scenarios, matching including the control treatment outcome did not produce the expected effect size. The entropy balancing approach was used to determine whether there were any notable advantages over the method proposed by Signorovitch et al. When unmeasured effect modifiers were present, no approach was able to estimate the true treatment effect. ConclusionsCompared with the Bucher approach (no matching), the MAICs examined demonstrated more accurate estimates, but further research is required to understand these methods across an array of situations.

Optimizing acupuncture treatment for dry eye syndrome: a systematic review

sBackgroundIn a former meta-analysis review, acupuncture was considered a potentially effective treatment for dry eye syndrome (DES), but there were heterogeneities among the outcomes. We updated the meta-analysis and conducted subgroup analysis to reduce the heterogeneity and suggest the most effective acupuncture method based on clinical trials.MethodsWe searched for randomized controlled trials (RCTs) in 10 databases (MEDLINE, EMBASE, CENTAL, AMED, SCOPUS, CNKI, Wangfang database, Oriental Medicine Advanced Searching Integrated System (OASIS), Koreamed, J-stage) and searched by hand to compare the effects of acupuncture and artificial tears (AT). We also conducted subgroup analysis by (1) method of intervention (acupuncture only or acupuncture plus AT), (2) intervention frequency (less than 3 times a week or more than 3 times a week), (3) period of treatment (less than 4 weeks or more than 4 weeks), and (4) acupoints (BL1, BL2, ST1, ST2, TE23, Ex-HN5). The Bucher method was used for subgroup comparisons.ResultsNineteen studies with 1126 patients were included. Significant improvements on the Schirmer test (weighted mean difference[WMD], 2.14; 95% confidence interval[CI], 0.93 to 3.34; p = 0.0005) and break up time (BUT) (WMD, 0.98; 95% CI, 0.79 to 1.18; p < 0.00001) were reported. In the subgroup analysis, acupuncture plus AT treatment had a weaker effect in BUT but a stronger effect on the Schirmer test and a better overall effect than acupuncture alone. For treatment duration, treatment longer than 1 month was more effective than shorter treatment. With regard to treatment frequency, treatment less than three times a week was more effective than more frequent treatment. In the acupoint analysis, acupuncture treatment including the BL2 and ST1 acupoints was less effective than treatment that did not include them. None of those factors reduced the heterogeneity.ConclusionsAcupuncture was more effective than AT in treating DES but showed high heterogeneity. Intervention differences did not influence the heterogeneity.

Systematic literature review and indirect treatment comparisons (ITC) of glasdegib (GLAS) plus low dose ara-c (LDAC) versus a hypomethylating agent (HMA) for previously untreated acute myeloid leukemia (AML) patients ineligible for intensive chemotherapy (NIC).

e18526 Background: In a randomized phase 2 study, GLAS, an oral, smoothened inhibitor, combined with LDAC, showed significantly better overall survival (OS) vs LDAC alone in previously untreated AML NIC patients. HMAs azacitidine (AZA) and decitabine (DEC) are considered current standard of care in this population. An ITC was conducted to compare OS for GLAS+LDAC vs. AZA and DEC, respectively. Methods: Embase, MEDLINE, Cochrane database, and conference abstracts (ASCO, ESMO and ASH) were systematically searched through 12/2016 for relevant RCTs of GLAS, AZA and DEC in AML patients ineligible for IC. Classical frequentist ITC using the Bucher method was used to indirectly compare OS hazards ratios with 95% confidence intervals (CI) using LDAC as the common comparator. Results: Four studies met inclusion criteria: AZA Fenaux 2010, N (treatment/ comparator) = 14/20, AZA Dombret 2015, N = 241/158, DEC: Kantarjian 2012, N = 242/243, and GLAS+LDAC: Cortes 2016, N = 88/44. Upon review of baseline characteristics, Fenaux 2010 was excluded based on major population differences (% bone marrow blasts). Three studies contributed data to ITC based on comparable populations: age, cytogenic risk and OS of comparator were similar among studies: age 75/73/76 years old, poor cytogenic risk 34%/37%/39%, OS of the comparator 6.4/5.0/4.3 months in AZA/DEC/GLAS+LDAC, respectively. In the ITC, GLAS+LDAC showed significantly better OS HR vs. AZA and DEC (0.51 and 0.56 respectively) (Table). Conclusions: Using ITC, treatment with GLAS+LDAC yielded significantly better OS HR than AZA and DEC in previously untreated AML patients ineligible for treatment with IC. Limitations include mixed IC &amp; NIC population for the AZA trial, and mixed comparator arm of both LDAC and BSC for the DEC trial. Analyses using patient-level data matching baseline characteristics across studies may enable more robust ITC. [Table: see text]

Randomized controlled trials in relapsed/refractory follicular lymphoma: a systematic review and meta-analysis.

This systematic literature review evaluated the clinical efficacy and safety of interventions used in relapsed/refractory follicular lymphoma. Primary efficacy outcomes were objective response rate, progression-free survival and overall survival. Safety endpoints were grade 3/4 toxicities, serious adverse events and withdrawals or deaths due to toxicity. Studies were selected if they were randomized controlled trials reporting on the efficacy or safety of treatments for relapsed or refractory follicular lymphoma, and if outcomes were reported separately from trials that included other lymphoid neoplasms. We used the Bucher method for conducting adjusted indirect comparisons within a meta-analysis. We identified 10 randomized controlled trials of treatments for relapsed/refractory follicular lymphoma. The most prominent drug investigated (alone or in combination) was rituximab. Most trials did not report median overall survival. Two trials reported median event-free survival (range, 1.2-23.2 months). Six of ten trials reported objective response rate (range, 9-93%). Meta-analysis showed only one statistically significant result: rituximab + bortezomib yielded a significantly higher objective response rate than rituximab monotherapy (relative risk, 1.28; 95% confidence interval, 1.11-1.47). Otherwise, there were no discernable differences in overall survival or progression-free survival, partly due to insufficient reporting of results in the clinical trials. The relatively small number of randomized controlled trials, few overlapping treatment arms, and variability in the randomized controlled trial features and in the endpoints studied complicate the formal comparison of therapies for relapsed/refractory follicular lymphoma. Additional well-designed randomized controlled trials are needed to fully understand the relative outcomes of older and more recently developed therapies.

An indirect comparison of HbA1c treatment effect with albiglutide and exenatide 2.0 mg QW using the Bucher method.

No head-to-head comparisons exist between once-weekly (QW) glucagon-like peptide-1 receptor agonists; accordingly, this indirect comparison was conducted to evaluate the comparative efficacy of QW albiglutide vs QW exenatide. Following a systematic literature search, it was determined that HARMONY 7 and DURATION 6, Phase III trials for albiglutide and exenatide, respectively, were similar in study design and baseline characteristics and included a common comparator arm, making them suitable for an indirect comparison using the Bucher method. The primary endpoint of change from baseline in glycated hemoglobin (HbA1c) with albiglutide 50 mg QW and exenatide 2.0 mg QW was compared and tested for noninferiority. The indirect comparison showed a treatment difference of 0.0% (95% confidence interval: −0.189% to 0.189%) in mean change in HbA1c from baseline, and albiglutide 50 mg was noninferior to exenatide 2.0 mg QW at the noninferiority margin of 0.3%. In the absence of a head-to-head trial, these results can be used in pharmacoeconomic analysis and to inform health technology assessment and clinical decision making.

Indirect treatment comparison of belatacept versus tacrolimus from a systematic review of immunosuppressive therapies for kidney transplant patients

Objective: End-stage renal disease is the final and irreversible stage in chronic kidney disease, leading to patient mortality, unless managed by dialysis or transplantation (the treatment of choice). This study aimed to compare a currently recommended immunosuppressive treatment, tacrolimus, against a newer treatment, belatacept, using indirect treatment comparison (ITC) techniques since no head-to-head randomized controlled trials (RCTs) comparing tacrolimus against belatacept currently exist. Methods: ITC was employed to calculate estimates for the relative risks and mean difference of tacrolimus against belatacept. The choice of the Bucher ITC model was driven by the available data and the simple indirect treatment comparison involving three treatments was considered appropriate. Results: The results of the indirect analysis showed no significant differences between belatacept and tacrolimus treatments for mortality and graft loss. The acute rejection rate was significantly lower with tacrolimus (Prograf* and Advagraf) compared with belatacept (0.22 [0.13, 0.39] to 0.44 [0.20, 0.99]). Conclusions: The results of this systematic review and meta-analysis suggests that tacrolimus is significantly superior to belatacept in terms of acute rejection outcomes but comparable for graft and patient survival. Further research should include a properly designed clinical trial comparing tacrolimus against belatacept directly. Limitations: These include variations in terms of clinical and design differences among the trials, weaknesses in the Bucher method and the lack of long-term clinical trial data with tacrolimus to compare with the recent long-term (7 years) belatacept trial data.

First-line therapy for non-transplant eligible patients with multiple myeloma: direct and adjusted indirect comparison of treatment regimens on the existing market in Germany.

The purpose of this study was to compare approved first-line therapies for patients with multiple myeloma. A systematic literature search for phase III randomized controlled trials (RCTs) comparing first-line chemotherapies approved in Germany and recommended by guidelines at the time of study design was conducted. Random-effects meta-analysis (MA) was used for direct and the Bucher method for adjusted indirect treatment comparison. One RCT comparing melphalan and prednisone plus bortezomib (VMP) vs. melphalan and prednisone (MP) and six RCTs comparing MP plus thalidomide (MPT) vs. MP were analysed. For MPT vs. MP, an individual patient data (IPD) MA was used for sensitivity analyses. VMP and MPT were superior to MP regarding efficacy endpoints (VMP vs. MP, overall survival (OS): hazard ratio (HR) 0.70, 95% confidence interval (CI) 0.57-0.86; progression-free survival (PFS): HR 0.56, 0.39-0.79; complete response (CR), risk-ratio (RR) for non-response: 0.70, 0.65-0.75; MPT vs. HR 0.83, 0.66-1.03; PFS: HR 0.67, 0.56-0.81; CR, RR for non-response 0.92, 0.88-0.95); but had a higher risk of developing any grade 3-4 adverse events (AEs) (VMP vs. MP: RR 1.13, 1.06-1.20; MPT vs. MP: RR 2.06, 1.43-2.98). The indirect comparison of VMP vs. MPT via MP showed a statistically not significant advantage for VMP regarding survival outcomes (OS: HR 0.85, 0.63-1.14; PFS: HR 0.83, 0.56-1.23) and a significant advantage regarding CR (RR for non-response 0.76, 0.70-0.83) and AEs (RR 0.55, 0.38-0.80). Treatment comparisons using results of IPD MA yielded similar effect sizes. VMP and MPT seem more effective than MP, VMP was superior to MPT regarding response criteria and AEs. Our results may best be confirmed by a head-to-head trial of VMP vs. MPT.

A systematic review of randomised controlled trials of radiotherapy for localised prostate cancer

BackgroundProstate cancer is the second most frequently diagnosed cancer and the sixth leading cause of cancer death in males. A systematic review of randomised controlled trials (RCTs) of radiotherapy and other non-pharmacological management options for localised prostate cancer was undertaken. MethodsA search of thirteen databases was carried out until March 2014. RCTs comparing radiotherapy (brachytherapy (BT) or external beam radiotherapy (EBRT)) to other management options i.e. radical prostatectomy (RP), active surveillance, watchful waiting, high intensity focused ultrasound (HIFU), or cryotherapy; each alone or in combination, e.g. with adjuvant hormone therapy (HT), were included.Methods followed guidance by the Centre for Reviews and Dissemination and the Cochrane Collaboration. Indirect comparisons were calculated using the Bucher method. ResultsThirty-six randomised controlled trials (RCTs, 134 references) were included. EBRT, BT and RP were found to be effective in the management of localised prostate cancer. While higher doses of EBRT seem to be related to favourable survival-related outcomes they might, depending on technique, involve more adverse events, e.g. gastrointestinal and genitourinary toxicity. Combining EBRT with hormone therapy shows a statistically significant advantage regarding overall survival when compared to EBRT alone (Relative risk 1.21, 95% confidence interval 1.12–1.30). Aside from mixed findings regarding urinary function, BT and radical prostatectomy were comparable in terms of quality of life and biochemical progression-free survival while favouring BT regarding patient satisfaction and sexual function.There might be advantages of EBRT (with/without HT) compared to cryoablation (with/without HT). No studies on HIFU were identified. ConclusionsBased on this systematic review, there is no strong evidence to support one therapy over another as EBRT, BT and RP can all be considered as effective monotherapies for localised disease with EBRT also effective for post-operative management. All treatments have unique adverse events profiles. Further large, robust RCTs which report treatment-specific and treatment combination-specific outcomes in defined prostate cancer risk groups following established reporting standards are needed. These will strengthen the evidence base for newer technologies, help reinforce current consensus guidelines and establish greater standardisation across practices.

Comparison of glucose lowering effect of metformin and acarbose in type 2 diabetes mellitus: a meta-analysis.

BackgroundMetformin is the first-line oral hypoglycemic agent for type 2 diabetes mellitus recommended by international guidelines. However, little information exists comparing it with acarbose which is also commonly used in China. This study expanded knowledge by combining direct and indirect evidence to ascertain the glucose lowering effects of both drugs.MethodsPubMed (1980- December 2013) and China National Knowledge Infrastructure databases (1994-January 2014) were systematically searched for eligible randomized controlled trials from Chinese and English literatures. Meta-analysis was conducted to estimate the glucose lowering effects of metformin vs. acarbose, or either of them vs. common comparators (placebo or sulphonylureas), using random- and fixed-effect models. Bucher method with indirect treatment comparison calculator was applied to convert the summary estimates from the meta-analyses into weighted-mean-difference (WMD) and 95% confidence intervals (CIs) to represent the comparative efficacy between metformin and acarbose.ResultsA total of 75 studies were included in the analysis. In direct comparison (8 trials), metformin reduced glycosylated hemoglobin (HbA1c) by 0.06% more than acarbose, with no significant difference (WMD,-0.06%; 95% CI, -0.32% to 0.20%). In indirect comparisons (67 trials), by using placebo and sulphonylureas as common comparators, metformin achieved significant HbA1c reduction than acarbose, by -0.38% (WMD,-0.38%, 95% CI, -0.736% to -0.024%) and -0.34% (WMD, -0.34%, 95% CI, -0.651% to -0.029%) respectively.ConclusionThe glucose lowering effects of metformin monotherapy and acarbose monotherapy are the same by direct comparison, while metformin is a little better by indirect comparison. This implies that the effect of metformin is at least as good as acarbose's.

A systematic review of post first-line treatments for advanced gastrointestinal stromal tumor (GIST): Direct pairwise meta-analyses and indirect comparisons.

195 Background: Treatment for metatastatic or unresectable GIST is with imatinib. The majority of patients eventually acquire imatinib resistance, prompting the development of a growing number of agents as post-first-line treatment. Currently no studies directly compare these treatments. Methods: A systematic review was performed through MEDLINE, EMBASE, CENTRAL, and ASCO meeting abstracts up to July 2014 to identify randomized controlled trials that included GIST patients who were previously treated with a first-line chemotherapy for advanced disease. Progression-free survival (PFS) and overall survival (OS) with 95% credible regions were extracted using the Parmar method. Direct pairwise meta-analyses and indirect comparisons using the Bucher method were performed. Results: Four studies were identified for the systematic review. 1 study (n=312) showed that sunitinib in the second-line setting (vs. placebo) improved PFS but not OS. 3 studies (n=528) examined the third-line setting (imatinib resumption vs. placebo; regorafenib vs. placebo; nilotinib vs. best supportive care with or without imatinib or sunitinib). Of the 3 third-line studies, there was significant heterogeneity between placebo-controlled trials and the non-placebo controlled trial (I2= 98%). Direct pairwise meta-analysis using random-effects of the 2 placebo-controlled studies showed that the PFS hazard ratio (HR) was 0.63 (0.22-0.61, p=0.0001), whereas the PFS HR for the non-placebo controlled study was 0.90 (0.65-1.26, p=0.56). These 2 HRs are different statistically (interaction: p=0.002). Indirect comparisons of imatinib resumption vs. regorafenib suggested that the PFS HR was 0.59 (0.31-1.11, p=0.10), trending in favor of regorafenib. OS HRs were not significant for direct or indirect comparison in the third-line setting. Conclusions: The number and size of completed phase III studies and the lack of a standard comparator arm limit the use of direct and indirect comparison methods to determine the best therapeutic option for patients who have progressed on imatinib. At this time, clinicians should interpret the available evidence at an individual level.