The example of the analysis of a collection of trials in diabetes consisting of a sparsely connected network of 10 treatments is used to make some points about approaches to analysis. In particular various graphical and tabular presentations, both of the network and of the results are provided and the connection to the literature of incomplete blocks is made. It is clear from this example that is inappropriate to treat the main effect of trial as random and the implications of this for analysis are discussed. It is also argued that the generalisation from a classic random-effect meta-analysis to one applied to a network usually involves strong assumptions about the variance components involved. Despite this, it is concluded that such an analysis can be a useful way of exploring a set of trials.
ObjectivesREGULATE trial was designed to compare the efficacy and safety of benfluorex versus pioglitazone in type 2 diabetes mellitus (DM) patients.MethodsDouble-blind, parallel-group, international, randomised, non-inferiority trial. More than half of the 196 participating centres were primary care centres. Patients eligible had type 2 DM uncontrolled on sulfonylurea. 846 were randomised. They received study treatment for 1 year. 423 patients were allocated to benfluorex (150 to 450 mg/day) and 423 were allocated to pioglitazone (30 to 45 mg/day). Primary efficacy criterion was HbA1c. Safety assessment included blinded echocardiographic evaluation of cardiac and valvular status.Results At baseline, patients were 59.1±10.5 years old with HbA1c 8.3±0.8%, and DM duration 7.1±6.0 years. During the study, mean HbA1c significantly decreased in both groups (benfluorex: from 8.30±0.80 to 7.77±1.31 versus pioglitazone: from 8.30±0.80 to 7.45±1.30%). The last HbA1c value was significantly lower with pioglitazone than with benfluorex (p<0.001) and non-inferiority of benfluorex was not confirmed (p = 0.19). Among the 615 patients with assessable paired echocardiography (310 benfluorex, 305 pioglitazone), 314 (51%) had at least one morphological valvular abnormality and 515 (84%) at least one functional valvular abnormality at baseline. Emergent morphological abnormalities occurred in 8 patients with benfluorex versus 4 with pioglitazone (OR 1.99), 95% CI (0.59 to 6.69). Emergent regurgitation (new or increased by one grade or more) occurred more frequently with benfluorex (82 patients, 27%) than with pioglitazone (33 patients, 11%) (OR 2.97), 95% CI (1.91 to 4.63) and were mainly rated grade 1; grade 2 (mild) was detected in 2 patients with benfluorex and 3 with pioglitazone. There was no moderate or severe regurgitation.ConclusionAfter 1 year of exposure, our results show a 2.97 fold increase in the incidence of valvular regurgitation with benfluorex and provide evidence for the valvular toxicity of this drug.Trial registration www.controlled-trials.com ISRCTN 27354239. isrctn27354239
Objectives The treatment paradigm in newly diagnosed multiple myeloma (NDMM) is evolving toward individualized, risk‐directed, and longer duration of therapy (DOT). The objective of this study was to describe treatment patterns and outcomes in non‐transplant NDMM in four European countries. Methods This retrospective chart review included adults with NDMM diagnosed between January 1, 2012, and December 31, 2013 (early cohort), or April 1, 2016, and March 31, 2017 (recent cohort). Results Among 836 patients, molecular testing was performed in 21% and 35% patients of early vs recent cohorts; proteasome inhibitor (PI)/alkylator combinations were the principal first‐line (1 L) therapy (39% vs 43%). Use of immunomodulatory drug (IMID)/alkylator combinations declined from early to recent cohort (26% vs 13%) but IMID (7% vs 16%) use increased. Few patients (5%) received 1 L maintenance therapy. Two‐thirds of patients were treated with a fixed duration intent, with a median 7‐month 1 L DOT and progression‐free survival (PFS) of 32.8 months in the early cohort. Both 1 L DOT and PFS were longer with oral compared to injectable regimens. Conclusions Although frontline treatment patterns changed significantly, 1 L DOT is short. The uptake of molecular testing and 1 L maintenance is low. These results highlight areas of unmet need in NDMM.
This systematic review and meta-analysis aimed to determine the effectiveness of brentuximab vedotin (BV) in relapsed/refractory classical Hodgkin lymphoma (R/R cHL) in the clinical practice setting using most recent results. A total of 32 observational studies reporting on treatment patterns, overall response rate (ORR), complete response (CR) rate, progression-free survival (PFS), overall survival (OS), and adverse events were found. After four cycles, a random-effect model yielded pooled ORR and CR rates of 62.6% (95% confidence interval (CI): 56.0-68.9; I 2 ¼ 9.7%) and 32.9% (95% CI, 20.8-46.3, I 2 ¼ 64.8%), respectively. Regarding survival, 1-year, 2-year, and 5year PFS ranged from 52.1% to 63.2%, 45.2% to 56.2%, and 31.9% to 33.0%, respectively. OS rates were 68.2-82.7%, 58.0-81.9%, and 58.0-62.0%, respectively. Most common adverse events were hematological toxicities (neutropenia: 13.3-23%, anemia: 8.8-39.0%, and thrombocytopenia: 4-4.6%), and grade 3 peripheral neuropathy (3.3-7.3%). This study supports the effectiveness and safety of BV in R/R cHL patients in the real-world setting.
Background It is becoming increasingly important in the treatment of MM to improve our understanding of routine clinical practice and of the effectiveness of new agents and regimens outside the clinical trial setting. UVEA-IXA is a European, multicenter, observational, longitudinal cohort study of RRMM pts who received therapy with ixazomib, the first oral proteasome inhibitor (PI), at MM specialist centers via an Early Access Program (EAP) in 8 European countries (Czech Republic, Greece, Hungary, Italy, Slovakia, Slovenia, Spain, UK). Ixazomib was available in Europe via the EAP from Nov 2015, when it was initially approved in the US in combination with lenalidomide and dexamethasone for the treatment of MM pts who have received ≥1 prior therapy, until European approval in Nov 2016. Approvals were based on the results of the phase 3 TOURMALINE-MM1 study (Moreau NEJM 2016). We report data from the second interim analysis of pts enrolled in the UVEA-IXA study. Methods The UVEA-IXA observation period comprises two parts: a retrospective chart review, starting from ixazomib therapy initiation in the EAP, followed by a 1-yr prospective follow-up period from the date of chart abstraction, with data captured quarterly per local regulations. Pts eligible for the UVEA-IXA study were adult MM pts in biochemical and/or symptomatic relapse after 1-3 prior lines of therapy, who had not received any anti-MM therapy for >3 cycles (except steroids) at the time of ixazomib therapy initiation, and who had an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0-2. Lenalidomide- or PI-refractory (disease progression on treatment or within 60 d after last dose) pts were excluded from UVEA-IXA. The primary endpoints of UVEA-IXA were response (per International Myeloma Working Group criteria) and progression-free survival (PFS; from ixazomib therapy initiation in the EAP to first documented disease progression/death during the observation period). Results A total of 359 pts were enrolled into UVEA-IXA. At data cutoff (May 22, 2020), 302 pts were evaluable for analysis; 55% were male; median age at enrollment was 68 yrs (range 36-92), with 39% aged ≥70 yrs. At the time of initiating ixazomib therapy, 36/117 (31%) pts had International Staging System (ISS) stage III disease, and 61/301 (20%) had an ECOG PS of 2; 60% of all evaluable pts had ≥1 comorbidity, including hypertension (26%), renal disease (23%), and diabetes (10%). Median time from MM diagnosis was 37.0 mos (range 4.9-231.7), and 39%, 43%, and 18% of pts had received 1, 2, and 3 prior lines of therapy. These included (in any line) bortezomib (89%), thalidomide (52%), transplant (47%), melphalan (22%), lenalidomide (17%), carfilzomib (5%), and pomalidomide (2%). The median follow-up period among 295 pts with available data was 24.9 mos (range 0.2-49.3); of all evaluable pts, 160 (53%) discontinued the study (of these, 88% discontinued due to death). Pts received ixazomib for a median of 10.8 mos (range 0.2-49.3), and most pts also received lenalidomide (97%) and dexamethasone (96%). Among 275 pts with data on best response, the overall response rate (ORR) was 60% (Table 1). Median PFS was 15.6 mos (95% CI 11.8-20.0; Figure). Ixazomib and lenalidomide dose reductions and discontinuations are summarized in Table 2. In 187 pts who received ≥4 cycles of ixazomib, rates of any-grade, grade ≥3, and serious adverse events (AEs) were 60%, 33%, and 23%; the most common AEs of any grade were diarrhea and thrombocytopenia (14% each), rash (7%), peripheral neuropathy (6%), and nausea/vomiting (5%); the most common grade ≥3 AE was thrombocytopenia (6%). Conclusions Data from the second interim analysis of UVEA-IXA demonstrate that ixazomib-based therapy is effective outside the clinical trial setting, with an ORR of 60% and a median PFS of 15.6 mos. Compared with TOURMALINE-MM1 pts (ixazomib arm; ORR 78%, median PFS 20.6 mos), UVEA-IXA pts have higher rates of ECOG PS 2 (20% vs 5%) and ISS stage III MM (31% vs 12%), and had received more prior therapies (61% vs 38% had ≥2 prior therapies). The most common AEs were gastrointestinal and hematologic AEs, in line with the well-characterized and manageable safety profile of ixazomib, although data are not directly comparable with clinical trial safety data due to the retrospective/infrequent prospective collection schedule. Ixazomib-based therapy is an effective and tolerable treatment option outside the clinical trial setting. Disclosures Ludwig: Celgene: Speakers Bureau; Amgen: Other: Advisory Boards, Research Funding, Speakers Bureau; Takeda: Research Funding; Seattle Genetics: Other: Advisory Boards; Janssen: Other: Advisory Boards, Speakers Bureau; Bristol Myers: Other: Advisory Boards, Speakers Bureau; Sanofi: Other: Advisory Boards, Speakers Bureau. Terpos:Genesis: Research Funding; Sanofi: Honoraria; Genesis: Honoraria; Amgen: Honoraria; Janssen: Honoraria; Takeda: Honoraria; Janssen: Research Funding; Takeda: Research Funding; BMS: Honoraria; Amgen: Research Funding; Celgene: Honoraria. Mateos:Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Honoraria; Regeneron: Honoraria, Membership on an entity's Board of Directors or advisory committees. Boccadoro:Mundipharma: Research Funding; Amgen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria; Bristol-Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Kishore:Celgene: Other. Ramasamy:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BMS: Consultancy, Research Funding, Speakers Bureau; Takeda: Consultancy, Research Funding, Speakers Bureau; Oncopeptides: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding. Fernandez:MediNeos Observational Research: Current Employment. Ferri:MediNeos Observational Research: Current Employment. Bent-Ennakhil:Takeda Pharmaceuticals International AG: Current Employment. Zomas:Takeda Pharmaceuticals International AG: Current Employment. Gavini:Takeda Pharmaceuticals International AG: Current Employment. Hajek:Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharma MAR: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Oncopeptides: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding.
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