Search

Additional file 3: Appendix C. Results of the stage III/IV subgroup analyses. Table C.1. Stage III/IV population – constant hazard ratios estimated from fixed-effects network meta-analysis for recurrence-free/disease-free survival. Table C.2. Stage III/IV population – constant hazard ratios estimated from fixed-effects network meta-analysis for distant metastasis-free survival

Additional file 1: Appendix A. Systematic literature review details and results. Figure A.1. Study selection flow diagram of updated SLR (May 2019). Table A.1. Study selection criteria to identify trials for the systematic literature review. Table A.2. Search strategy for EMBASE (EMBASE 1974 to October 11, 2017; Search executed: October 12, 2017). Table A.3. Search strategy for MEDLINE (Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations, Ovid MEDLINE(R) Daily and Ovid MEDLINE(R) 1946 to Present; Search executed: October 12, 2017). Table A.4. Search strategy for Cochrane Register of Controlled Trials (Cochrane Register of Controlled Trials September 2017; Search executed: October 12, 2017). Table A.5. Search strategy for EMBASE (EMBASE 1974 to 2018 May 07; Search executed: May 8, 2018). Table A.6. Search strategy for MEDLINE (Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations, Ovid MEDLINE(R) Daily and Ovid MEDLINE(R) 1946 to Present; Search executed: May 8, 2018). Table A.7. Search strategy for Cochrane Register of Controlled Trials (Cochrane Register of Controlled Trials March 2018; Search executed: May 8, 2018). Table A.8. Search strategy for EMBASE (EMBASE 1974 to 2019 April 30; Search executed: May 1, 2019). Table A.9. Search strategy for MEDLINE (Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations, Ovid MEDLINE(R) Daily and Ovid MEDLINE(R) 1946 to Present; Search executed: May 1, 2019). Table A.10. Search strategy for Cochrane Register of Controlled Trials (Cochrane Register of Controlled Trials April 2019; Search executed: May 1, 2019). Table A.11. Patient characteristics in randomized controlled trials included in network meta-analyses. Table A.12. Cochrane risk of bias assessment of randomized controlled trials included in the feasibility assessment. Table A.13. Safety data from randomized controlled trials included in the feasibility assessment

Additional file 4: Appendix D. Safety analyses. Figure D.1. Network diagrams of randomized controlled trials for subgroup. Table D.1. Stage II/III/IV population – odds ratios estimated from fixed-effects network meta-analysis for grade 3/4 adverse events analysis of safety outcomes. Table D.2. Stage II/III/IV population – odds ratios estimated from fixed-effects network meta-analysis for discontinuations due to adverse events. Table D.3. Stage II/III/IV population – odds ratios estimated from fixed-effects network meta-analysis for discontinuations

Objectives In the field of relapsed or refractory multiple myeloma (RRMM), between-trial or indirect comparisons are required to estimate relative treatment effects between competing interventions based on the available evidence. Two approaches are frequently used in RRMM: network meta-analysis (NMA) and unanchored matching-adjusted indirect comparison (MAIC). The objective of the current study was to evaluate the relevance and credibility of published NMA and unanchored MAIC studies aiming to estimate the comparative efficacy of treatment options for RRMM. Methods Twelve relevant studies were identified in the published literature (n = 7) and from health technology assessment agencies (n = 5). Data from trials were extracted to identify between-trial differences that may have biased results. Credibility of the performed analyses and relevance of the research questions were critically appraised using the International Society for Pharmacoeconomics and Outcomes Research (ISPOR) checklist and feedback based on consultations with clinical experts. Results The identified studies concerned NMAs of randomized controlled trials (RCTs; n = 7), unanchored MAICs (n = 4), or both types of analyses (n = 1). According to clinical expert consultation, the majority of the identified NMAs did not consider differences in prior therapies or treatment duration across the RCTs included in the analyses, thereby compromising the relevance. Conclusion Based on the results and feedback from clinicians, the majority of NMAs did not consider prior treatment history or treatment duration, which resulted in nonrelevant comparisons. Furthermore, it may have compromised the credibility of the estimates owing to differences in effect-modifiers between the different trials. Pairwise comparisons by means of unanchored MAICs require clear justification given the reliance on non-randomized comparisons.

Background Approved first-line treatments for patients with BRAF V600–mutant advanced melanoma include nivolumab (a programmed cell death protein 1 inhibitor) plus ipilimumab (a cytotoxic T lymphocyte antigen-4 inhibitor; NIVO+IPI) and the BRAF/MEK inhibitors dabrafenib plus trametinib (DAB+TRAM), encorafenib plus binimetinib (ENCO+BINI), and vemurafenib plus cobimetinib (VEM+COBI). Results from prospective randomized clinical trials (RCTs) comparing these treatments have not yet been reported. This analysis evaluated the relative efficacy and safety of NIVO+IPI versus DAB+TRAM, ENCO+BINI, and VEM+COBI in patients with BRAF-mutant advanced melanoma using a matching-adjusted indirect comparison (MAIC). Patients and methods A systematic literature review identified RCTs for DAB+TRAM, ENCO+BINI, and VEM+COBI in patients with BRAF-mutant advanced melanoma. Individual patient-level data for NIVO+IPI were derived from the phase III CheckMate 067 trial (BRAF-mutant cohort) and restricted to match the inclusion/exclusion criteria of the comparator trials. Treatment effects for overall survival (OS) and progression-free survival (PFS) were estimated using Cox proportional hazards and time-varying hazard ratio (HR) models. Safety outcomes (grade 3 or 4 treatment-related adverse events) with NIVO+IPI and the comparators were compared. Results In the Cox proportional hazards analysis, NIVO+IPI showed improved OS compared with DAB+TRAM (HR = 0.53; 95% confidence interval [CI], 0.39-0.73), ENCO+BINI (HR = 0.60; CI, 0.42-0.85), and VEM+COBI (HR = 0.50; CI, 0.36-0.70) for the overall study period. In the time-varying analysis, NIVO+IPI was associated with significant improvements in OS and PFS compared with the BRAF/MEK inhibitors 12 months after treatment initiation. There were no significant differences between NIVO+IPI and BRAF/MEK inhibitor treatment from 0 to 12 months. Safety outcomes favored DAB+TRAM over NIVO+IPI, whereas NIVO+IPI was comparable to VEM+COBI. Conclusion Results of this MAIC demonstrated durable OS and PFS benefits for patients with BRAF-mutant advanced melanoma treated with NIVO+IPI compared with BRAF/MEK inhibitors, with the greatest benefits noted after 12 months., Highlights • First-line treatments for BRAF V600-mutant melanoma include NIVO+IPI and BRAF/MEK inhibitors. • Results from prospective RCTs comparing NIVO+IPI and BRAF/MEK inhibitors have not yet been reported. • This MAIC evaluated NIVO+IPI versus BRAF/MEK inhibitors for BRAF-mutant advanced melanoma. • OS and PFS benefits were noted with NIVO+IPI versus BRAF/MEK inhibitors beginning at 12 months. • These findings may provide information relevant to the selection of treatments for BRAF-mutant advanced melanoma.

In newly diagnosed multiple myeloma (MM), patients ineligible for front-line autologous stem cell transplantation (ASCT), melphalan and prednisone (MP) with thalidomide (MPT) or bortezomib (VMP) are standard first-line therapeutic options. Despite new treatment regimens incorporating bortezomib or lenalidomide, MM remains incurable. The FIRST study demonstrated significant improvement in progression-free survival (PFS) and overall survival (OS) for the combination of lenalidomide and low-dose dexamethasone (Rd) until progression vs. MPT in transplant-ineligible ndMM patients. However, to date no head-to-head randomized controlled trials (RCTs) have compared Rd or MPT versus VMP. We conducted a network meta-analysis using RCTs identified through a systematic literature review to evaluate the relative efficacy of Rd versus other regimens on survival endpoints in previously untreated MM patients ineligible for ASCT. In this analysis, Rd was associated with a significant PFS and survival advantage versus other first-line treatments (VMP, MPT, MP), challenging the role of alkylators in this setting.

Background Targeted and checkpoint inhibitor therapies for advanced melanoma have led to major improvements in overall survival (OS). Using long-term evidence, the objective was to estimate the relative efficacy of nivolumab plus ipilimumab (NIVO+IPI) vs. relevant comparators among treatment-naive patients with advanced, unresectable stage III/IV melanoma. Methods A systematic literature review of randomized controlled trials (RCTs) of first-line advanced melanoma therapies was conducted in November 2018. Key comparators were immunotherapies (NIVO+IPI; NIVO; pembrolizumab [PEM]), and BRAF+MEK inhibitors (dabrafenib + trametinib [DAB+TRAM]; encorafenib + binimetinib [ENC+BIN]; vemurafenib + cobimetinib [VEM+COB]). Bayesian network meta-analysis (NMA) models were used to estimate comparative OS. The NMAs used models of constant (overall) hazard ratio (HR) over time, and fractional polynomials to estimate time-varying HR, along with 95% credible intervals (CrI). Subgroup analyses and alternate models were explored to evaluate effect modification of immunotherapies by BRAF-mutation status. Results In total, 12 RCTs formed the network of evidence for OS (maximum follow-up: 30 to 60 months). For NIVO+IPI vs. each BRAF+MEK inhibitor, the HR decreased steadily over time. The hazard of death was similar by 6 months and lower at 12 months; thereafter, NIVO+IPI was associated with a significantly reduced hazard of death. At 18 months, HRs for NIVO+IPI vs. each BRAF+MEK inhibitor ranged from 0.45 to 0.52; by 42 months (longest duration of observed data for BRAF+MEK inhibitors), HRs were 0.24 to 0.29 (all CrIs Conclusions NIVO+IPI confers similar or sustained improvements in long-term OS compared with immunotherapies and BRAF+MEK inhibitors. Legal entity responsible for the study The authors. Funding Bristol-Myers Squibb. Disclosure P. Mohr: Honoraria (self), To manually add email to ESMO: To manually add email to ESMO. K. Toor: Full / Part-time employment, KT is an employee of Precision Xtract. Precision Xtract received funding for this project from Bristol-Myers Squibb: Precision Xtract. S. Goring: Advisory / Consultancy, SG acted as a consultant to Precision Xtract. Precision Xtract received funding for this project from Bristol-Myers Squibb: Precision Xtract. K. Chan: Full / Part-time employment, KC is an employee of Precision Xtract. Precision Xtract received funding for this project from Bristol-Myers Squibb: Precision Xtract. M. Besada: Full / Part-time employment, MB is an employee of Precision Xtract. Precision Xtract received funding for this project from Bristol-Myers Squibb: Precision Xtract. H.M. Johnson: Advisory / Consultancy: Bristol-Myers Squibb. A. Moshyk: Shareholder / Stockholder / Stock options, Full / Part-time employment: Bristol-Myers Squibb. S. Kotapati: Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options, Full / Part-time employment: Bristol-Myers Squibb.

Aim: To conduct a systematic review and meta-analysis to determine the risk of cardiovascular events and all-cause mortality associated with sulphonylureas (SUs) vs other glucose lowering drugs in patients with T2DM (T2DM. Materials and methods: A systematic review of Medline, Embase, Cochrane and clinicaltrials.gov was conducted for studies comparing SUs with placebo or other antihyperglycaemic drugs in patients with T2DM. A cloglog model was used in the Bayesian framework to obtain comparative hazard ratios (HRs) for the different interventions. For the analysis of observational data, conventional fixed-effect pairwise meta-analyses were used. Results: The systematic review identified 82 randomized controlled trials (RCTs) and 26 observational studies. Meta-analyses of RCT data showed an increased risk of all-cause mortality and cardiovascular-related mortality for SUs compared with all other treatments combined (HR 1.26, 95% confidence interval [CI] 1.10-1.44 and HR 1.46, 95% CI 1.21-1.77, respectively). The risk of myocardial infarction was significantly higher for SUs compared with dipeptidyl peptidase-4 (DPP-4) inhibitors and sodium-glucose co-transporter-2 inhibitors (HR 2.54, 95% CI 1.14-6.57 and HR 41.80, 95% CI 1.64-360.4, respectively). The risk of stroke was significantly higher for SUs than for DPP-4 inhibitors, glucagon-like peptide-1 agonists, thiazolidinediones and insulin. Conclusions: The present meta-analysis showed an association between SU therapy and a higher risk of major cardiovascular disease-related events compared with other glucose lowering drugs. Results of ongoing RCTs, which should be available in 2018, will provide definitive results on the risk of cardiovascular events and all-cause mortality associated with SUs vs other antihyperglycaemic drugs.

Summary Aim: To conduct a network meta-analysis (NMA) to determine the comparative efficacy, as measured by sustained virological response (SVR), between boceprevir (BOC), telaprevir (TEL), faldaprevir (FAL), simeprevir (SIM) and sofosbuvir (SOF) in combination with peginterferon–ribavirin (PR) against a control of PR. Design: A literature search was conducted to identify randomized controlled trials (RCTs) including adult patients with hepatitis C virus genotype 1 who were naive to any prior therapy. RCTs assessing standard duration therapy (SDT) or response-guided therapy (RGT) BOC, TEL, FAL, SIM or SOF in combination with PR against a control of PR were eligible for inclusion. All RCTs must have provided SVR at either 12 or 24 weeks post-therapy cessation. Results: We included nine RCTs. All direct-acting antivirals (DAAs) were found to perform better than PR. Additionally, SDT FAL was found to be better than the 240 mg RGT FAL regimen with the PR lead-in. A sensitivity analysis excluding RCTs with only SVR at 12 weeks was consistent with the results of the primary analysis. A sensitivity analysis removing an RCT assessing SIM that reported SVR of >60% in the PR control group additionally found that RGT SIM was superior to the 240 mg RGT FAL regimen with the PR lead-in. Discussion: Our analyses indicate that SDT and RGT regimens of DAAs plus PR do not differ greatly in terms of SVR among treatment-naive hepatitis C genotype 1 patients. More advanced Bayesian network meta-analyses are likely needed to incorporate a comprehensive evidence base, expanding beyond randomized clinical trials.

Background Second-generation antipsychotics are commonly prescribed for pediatric patients with schizophrenia and schizophrenia spectrum disorders despite their lack of approval for use in children. Although considered a safer alternative to first-generation antipsychotics, there is evidence to suggest that second-generation antipsychotics may be associated with some adverse events as well as an increase in prolactin levels. The purpose of this review is to examine the risk of prolactin-related adverse events in pediatric patients using antipsychotics and to quantify changes in prolactin for this population. Methods Literature searches were conducted in Medline, Embase, the Cochrane Central Register of Controlled Trials, and PsycINFO databases, supplemented with review of select gray literature to identify both randomized controlled trials and observational studies on pediatric patients prescribed antipsychotic medications for schizophrenia or schizophrenia spectrum disorders. Using a narrative approach, data on adverse events were recorded and changes from baseline in prolactin were pooled, where possible, from the randomized trials. Change from baseline in prolactin was evaluated for each treatment, as well as in comparison to placebo and to other treatments. Where data was available, these changes were evaluated separately for male and female patients. Results Six randomized controlled trials and five observational studies, all examining the effects of second-generation antipsychotics, were selected. Literature reporting the effects of risperidone, quetiapine, aripiprazole, olanzapine, and paliperidone was identified, with varying doses. Prolactin-related adverse events were sparsely reported across studies. In evidence gathered from randomized controlled trials, risperidone, olanzapine, and two doses of paliperidone (3–5 mg/day and 6–12 mg/day) were associated with increased prolactin levels compared to baseline. With the exception of paliperidone, similar trends were observed in males and females, separately. The findings of the observational evidence served to both complement and run contrary to the randomized trials, with discrepancies attributed to differences in patient and treatment characteristics. Conclusions No definitive conclusions between second-generation antipsychotic use and prolactin-related adverse events can be made based on the available literature. While some trends in prolactin level changes emerged, this was based on few trials with small sample sizes. Future investigations should emphasize reporting on treatment safety. Trial registration PROSPERO CRD42014009506. Electronic supplementary material The online version of this article (doi:10.1186/s12887-016-0710-y) contains supplementary material, which is available to authorized users.

Introduction Migraine headache is a neurological disorder whose attacks are associated with nausea, vomiting, photophobia and phonophobia. Treatments for migraine aim to either prevent attacks before they have started or relieve attacks (abort) after onset of symptoms and range from complementary therapies to pharmacological interventions. A number of treatment-related adverse events such as somnolence, fatigue, and chest discomfort have previously been reported in association with triptans. The comparative tolerability of available agents for the abortive treatment of migraine attacks has not yet been systematically reviewed and quantified. Methods We performed a systematic literature review and Bayesian network meta-analysis for comparative tolerability of treatments for migraine. The literature search targeted all randomized controlled trials evaluating oral abortive treatments for acute migraine over a range of available doses in adults. The primary outcomes of interest were any adverse event, treatment-related adverse events, and serious adverse events. Secondary outcomes were fatigue, dizziness, chest discomfort, somnolence, nausea, and vomiting. Results Our search yielded 141 trials covering 15 distinct treatments. Of the triptans, sumatriptan, eletriptan, rizatriptan, zolmitriptan, and the combination treatment of sumatriptan and naproxen were associated with a statistically significant increase in odds of any adverse event or a treatment-related adverse event occurring compared with placebo. Of the non-triptans, only acetaminophen was associated with a statistically significant increase in odds of an adverse event occurring when compared with placebo. Overall, triptans were not associated with increased odds of serious adverse events occurring and the same was the case for non-triptans. For the secondary outcomes, with the exception of vomiting, all triptans except for almotriptan and frovatriptan were significantly associated with increased risk for all outcomes. Almotriptan was significantly associated with an increased risk of vomiting, whereas all other triptans yielded non-significant lower odds compared with placebo. Generally, the non-triptans were not associated with decreased tolerability for the secondary outcomes. Discussion In summary, triptans were associated with higher odds of any adverse event or a treatment-related adverse event occurring when compared to placebo and non-triptans. Non-significant results for non-triptans indicate that these treatments are comparable with one another and placebo regarding tolerability outcomes.

Figure S1. Evaluation of RCTs with the Cochrane risk of bias assessment. (PDF 267Â kb)

Aim To conduct a network meta-analysis (NMA) to establish the comparative efficacy of infliximab, adalimumab and golimumab for the treatment of moderately to severely active ulcerative colitis (UC). Design A systematic literature search identified five randomized controlled trials for inclusion in the NMA. One trial assessed golimumab, two assessed infliximab and two assessed adalimumab. Outcomes included clinical response, clinical remission, mucosal healing, sustained clinical response and sustained clinical remission. Innovative methods were used to allow inclusion of the golimumab trial data given the alternative design of this trial (i.e., two-stage re-randomization). Results After induction, no statistically significant differences were found between golimumab and adalimumab or between golimumab and infliximab. Infliximab was statistically superior to adalimumab after induction for all outcomes and treatment ranking suggested infliximab as the superior treatment for induction. Golimumab and infliximab were associated with similar efficacy for achieving maintained clinical remission and sustained clinical remission, whereas adalimumab was not significantly better than placebo for sustained clinical remission. Golimumab and infliximab were also associated with similar efficacy for achieving maintained clinical response, sustained clinical response and mucosal healing. Finally, golimumab 50 and 100 mg was statistically superior to adalimumab for clinical response and sustained clinical response, and golimumab 100 mg was also statistically superior to adalimumab for mucosal healing. Conclusion The results of our NMA suggest that infliximab was statistically superior to adalimumab after induction, and that golimumab was statistically superior to adalimumab for sustained outcomes. Golimumab and infliximab appeared comparable in efficacy.

To determine the short-term costs per sustained remission and sustained response of three tumor necrosis factor inhibitors (infliximab, adalimumab, and golimumab) in comparison to conventional therapy for the treatment of moderately-to-severely active ulcerative colitis.A probabilistic Markov model was developed. This included an 8-week induction period, and 22 subsequent 2-week cycles (up to 1 year). The model included three disease states: remission, response, and relapse. Costs were from a Canadian public payer perspective. Estimates for the additional cost per 1 year of sustained remission and sustained response were obtained.Golimumab 100 mg provided the lowest cost per additional remission ($935) and cost per additional response ($701) compared with conventional therapy. Golimumab 50 mg yielded slightly higher costs than golimumab 100 mg. Infliximab was associated with the largest additional number of estimated remissions and responses, but also higher cost at $1975 per remission and $1311 per response. Adalimumab was associated with the largest cost per remission ($7430) and cost per response ($2361). The cost per additional remission and cost per additional response associated with infliximab vs golimumab 100 mg was $14,659 and $4753, respectively.The results suggest that the additional cost of 1 full year of remission and response are lowest with golimumab 100 mg, followed by golimumab 50 mg. Although infliximab has the highest efficacy, it did not exhibit the lowest cost per additional remission or response. Adalimumab produced the highest cost per additional remission and response.

Background: Aboriginal representation in Canadian correctional institutions has increased rapidly over the past decade. We calculated “years of life lost to incarceration” for Aboriginal and non-Aboriginal Canadians. Methods Incarceration data from provincial databases were used conjointly with demographic data to estimate rates of incarceration and years of life lost to provincial incarceration in (BC) and federal incarceration, by Aboriginal status. We used the Sullivan method to estimate the years of life lost to incarceration. Results Aboriginal males can expect to spend approximately 3.6 months in federal prison and within BC spend an average of 3.2 months in custody in the provincial penal system. Aboriginal Canadians on average spend more time in custody than their non-Aboriginal counterparts. The ratio of the Aboriginal incarceration rate to the non-Aboriginal incarceration rate ranged from a low of 4.28 in Newfoundland and Labrador to a high of 25.93 in Saskatchewan. Rates of incarceration at the provincial level were highest among Aboriginals in Manitoba with an estimated rate of 1377.6 individuals in prison per 100,000 population (95% confidence interval [CI]: 1311.8 – 1443.4). Conclusions The results indicate substantial differences in life years lost to incarceration for Aboriginal versus non-Aboriginal Canadians. In light of on-going prison expansion in Canada, future research and policy attention should be paid to the public health consequences of incarceration, particularly among Aboriginal Canadians.

Kristian Thorlund,1–3 Eric Druyts,1,4 Kabirraaj Toor,1,5 Jeroen P Jansen,1,6 Edward J Mills1,3 1Redwood Outcomes, Vancouver, BC, 2Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, ON, Canada; 3Stanford Prevention Research Center, Stanford University, Stanford, CA, USA; 4Department of Medicine, Faculty of Medicine, 5School of Population and Public Health, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada; 6Department of Public Health and Community Medicine, Tufts University, Boston, MA, USA Introduction: Network meta-analysis (NMA) is an extension of conventional pairwise meta-analysis that allows for simultaneous comparison of multiple interventions. Well-established drug class efficacies have become commonplace in many disease areas. Thus, for reasons of ethics and equipoise, it is not practical to randomize patients to placebo or older drug classes. Unique randomized clinical trial designs are an attempt to navigate these obstacles. These alternative designs, however, pose challenges when attempting to incorporate data into NMAs. Using ulcerative colitis as an example, we illustrate an example of a method where data provided by these trials are used to populate treatment networks. Methods: We present the methods used to convert data from the PURSUIT trial into a typical parallel design for inclusion in our NMA. Data were required for three arms: golimumab 100 mg; golimumab 50 mg; and placebo. Golimumab 100 mg induction data were available; however, data regarding those individuals who were nonresponders at induction and those who were responders at maintenance were not reported, and as such, had to be imputed using data from the rerandomization phase. Golimumab 50 mg data regarding responses at week 6 were not available. Existing relationships between the available components were used to impute the expected proportions in this missing subpopulation. Data for placebo maintenance response were incomplete, as all induction nonresponders were assigned to golimumab 100 mg. Data from the PURSUIT trial were combined with ACT-1 and ULTRA-2 trial data to impute missing information. Discussion: We have demonstrated methods for converting results from alternative study designs to more conventional parallel randomized clinical trials. These conversions allow for indirect treatment comparisons that are informed by a wider array of evidence, adding to the precision of estimates. Keywords: adaptive, network meta-analysis, indirect treatment comparison, ulcerative colitis, golimumab