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Treatment switching frequently occurs in clinical trials due to ethical reasons. Intent-to-treat analysis without adjusting for switching yields biased and inefficient estimates of the treatment effects. In this paper, we propose a class of semiparametric semi-competing risks transition survival models to accommodate two-way time-varying switching. Theoretical properties of the proposed method are examined. An efficient expectation–maximization algorithm is derived to obtain maximum likelihood estimates and model diagnostic tools. Existing software is used to implement the algorithm. Simulation studies are conducted to demonstrate the validity of the model. The proposed method is further applied to data from a clinical trial with patients having recurrent or metastatic squamous-cell carcinoma of head and neck.

In a pragmatic trial involving older persons with treatment-resistant depression, augmentation of existing antidepressants with aripiprazole was better than augmentation with bupropion or a switch to bupropion.

This Grading of Recommendations Assessment, Development and Evaluation (GRADE) concept article offers systematic reviewers, guideline authors, and other users of evidence assistance in addressing randomized trial situations in which interventions or comparators differ from those in the target people, interventions, comparators, and outcomes. To clarify what GRADE considers under indirectness of interventions and comparators, we focus on a particular example: when comparator arm participants receive some or all aspects of the intervention management strategy (treatment switching). An interdisciplinary panel of the GRADE working group members developed this concept article through an iterative review of examples in multiple teleconferences, small group sessions, and e-mail correspondence. After presentation at a GRADE working group meeting in November 2022, attendees approved the final concept paper, which we support with examples from systematic reviews and individual trials. In the presence of safeguards against risk of bias, trials provide unbiased estimates of the effect of an intervention on the people as enrolled, the interventions as implemented, the comparators as implemented, and the outcomes as measured. Within the GRADE framework, differences in the people, interventions, comparators, and outcomes elements between the review or guideline recommendation targets and the trials as implemented constitute issues of indirectness. The intervention or comparator group management strategy as implemented, when it differs from the target comparator, constitutes one potential source of indirectness: Indirectness of interventions and comparators—comparator group receipt of the intervention constitutes a specific subcategory of said indirectness. The proportion of comparator arm participants that received the intervention and the apparent magnitude of effect bear on whether one should rate down, and if one does, to what extent. Treatment switching and other differences between review or guideline recommendation target interventions and comparators vs. interventions and comparators as implemented in otherwise relevant trials are best considered issues of indirectness.

Tyrosine kinase inhibitors (TKIs) have vastly improved long-term outcomes for patients with chronic myeloid leukemia (CML). After imatinib (a first-generation TKI), second- and third-generation TKIs were developed. With five TKIs (imatinib, dasatinib, bosutinib, nilotinib, and ponatinib) targeting BCR :: ABL approved in most countries, and with the recent approval of asciminib in the USA, treatment decisions are complex and require assessment of patient-specific factors. Optimal treatment strategies for CML continue to evolve, with an increased focus on achieving deep molecular responses. Using clinically relevant case studies developed by the authors of this review, we discuss three major scenarios from the perspective of international experts. Firstly, this review explores patient-specific characteristics that affect decision-making between first- and second-generation TKIs upon initial diagnosis of CML, including patient comorbidities. Secondly, a thorough assessment of therapeutic options in the event of first-line treatment failure (as defined by National Comprehensive Cancer Network and European LeukemiaNet guidelines) is discussed along with real-world considerations for monitoring optimal responses to TKI therapy. Thirdly, this review illustrates the considerations and importance of achieving treatment-free remission as a treatment goal. Due to the timing of the writing, this review addresses global challenges commonly faced by hematologists treating patients with CML during the COVID-19 pandemic. Lastly, as new treatment approaches continue to be explored in CML, this review also discusses the advent of newer therapies such as asciminib. This article may be a useful reference for physicians treating patients with CML with second-generation TKIs and, as it is focused on the physicians’ international and personal experiences, may give insight into alternative approaches not previously considered.

Randomised trials with long-term follow-up can provide estimates of the long-term effects of health interventions. However, analysis of long-term outcomes in randomised trials may be complicated by problems with the administration of treatment such as non-adherence, treatment switching and co-intervention, and problems obtaining outcome measurements arising from loss to follow-up and death of participants. Methods for dealing with these issues that involve conditioning on post-randomisation variables are unsatisfactory because they may involve the comparison of non-exchangeable groups and generate estimates that do not have a valid causal interpretation. We describe approaches to analysis that potentially provide estimates of causal effects when such issues arise. Brief descriptions are provided of the use of instrumental variable and propensity score methods in trials with imperfect adherence, marginal structural models and g-estimation in trials with treatment switching, mixed longitudinal models and multiple imputation in trials with loss to follow-up, and a sensitivity analysis that can be used when trial follow-up is truncated by death or other events. Clinical trialists might consider these methods both at the design and analysis stages of randomised trials with long-term follow-up.

IntroductionAtomoxetine, a first-line treatment option for ADHD, is affected by pharmacogenetic (PGx) variation of the drug-metabolizing enzyme CYP2D6. Despite the recommendation of CYP2D6 testing, the use of PGx-guided dosing remains low in Denmark.ObjectivesWe investigated wide-ranging clinical outcomes in atomoxetine users in association with PGx variability.MethodsWe analyzed 6,798 individuals (55% children) with a first prescription for atomoxetine identified from the Danish population-based iPSYCH case-cohort study linking biobank information with Danish registers. Individuals were categorized based on their single-nucleotide-polymorphism-based CYP2D6 genotype into normal (NM), intermediate (IM), and poor metabolizer (PM). Clinical outcomes included treatment switching, discontinuation, psychiatric inpatient-, outpatient-, and emergency contact, suicide attempt/self-harm, sleep problem, and depression. Individuals’ CYP2D6-status could change due to drug-drug-interactions of weak, intermediate, or strong-CYP2D6 inhibitors (phenoconversion), which we accounted for by time-varying phenotype assessment. Incidence rate ratios (IRR) were estimated using Poisson regression analyses and adjusted for a wide range of potential confounders and covariates.ResultsOver two-thirds of the individuals had a hospital diagnosis of ADHD at the first atomoxetine prescription. The distribution of CYP2D6 phenotypes was similar in children and adults. IM/PM children had a significantly higher risk of a sleeping problem compared with NM children (IRR 1.25, 95% CI 1.01-1.54). Compared with NM adults, those with IM/PM had a higher risk of switching (1.15, 95% CI 0.98-1.35).ConclusionsThis is the first study showing the potential impact of PGx variability on clinical outcomes of atomoxetine users in a population-based setting, highlighting the utility of PGx testing.DisclosureNo significant relationships.

Combining biologicals or Janus kinase inhibitors (JAKis) with conventional medications and switching therapies is common in moderate-to-severe inflammatory bowel disease (IBD) treatment. This study assessed the use of conventional medications, treatment continuation, switching, and factors associated with switching during IBD maintenance therapy with subcutaneous (SC) biologicals or JAKis. This Finnish nationwide, retrospective registry study included adult Crohn's disease (CD) and ulcerative colitis (UC) patients on SC biological/JAKi maintenance therapy (≥6 months on treatment) during 2003-2023. Pharmacy dispensation data were collected from The Social Insurance Institution. Among 7,707 individuals, use of corticosteroids (CS), immunosuppressants (IS) and 5-aminosalicylates (5-ASA) was less common after SC biological/JAKi initiation. At 24 months, treatment continuation rates were 51-57% for adalimumab, golimumab, ustekinumab and tofacitinib (in UC); and 71-80% for infliximab, vedolizumab and ustekinumab (in CD). Overall, 16% of treatments were switched-most commonly from golimumab (28%), tofacitinib (24%) and adalimumab (21%) to ustekinumab (42% of switches) or vedolizumab (17% of switches). Prior golimumab (adjusted OR, 1.73; 95% CI, 1.42-2.09) or tofacitinib (1.48; 1.16-1.86) use was associated with a higher risk of switching (p<0.001), while prior infliximab (0.12; 0.09-0.16), vedolizumab (0.35; 0.26-0.46), IS (0.52; 0.45-0.57), or 5-ASA (0.62; 0.55-0.70) use was associated with lower risk (p<0.001). Treatment continuation rates during maintenance reached up to 80%. Most switches involved a different mode-of-action. While conventional medications were tapered, IS and 5-ASA may support treatment continuation.

BackgroundIn CheckMate 9LA, nivolumab plus ipilimumab with chemotherapy prolonged overall survival (OS) versus chemotherapy regardless of tumor PD-L1 expression or histology. We report updated efficacy and safety in all randomized patients with a minimum 4-year follow-up and an exploratory treatment-switching adjustment analysis in all treated patients who received chemotherapy and subsequent immunotherapy.MethodsAdults with stage IV/recurrent non-small cell lung cancer (NSCLC), no sensitizing EGFR/ALK alterations, and ECOG performance status ≤1 were randomized 1:1 to nivolumab 360 mg every 3 weeks plus ipilimumab 1 mg/kg every 6 weeks with chemotherapy (two cycles) or chemotherapy (four cycles, with optional maintenance pemetrexed for the nonsquamous population). Assessments included OS, progression-free survival, and objective response rate. Exploratory analyses included efficacy by tumor PD-L1 expression and histology and in patients who discontinued nivolumab plus ipilimumab with chemotherapy due to treatment-related adverse events (TRAEs), and a treatment-switching adjustment analysis using inverse probability of censoring weighting.ResultsWith a 47.9-month minimum follow-up for OS, nivolumab plus ipilimumab with chemotherapy continued to prolong OS over chemotherapy in all randomized patients (HR 0.74, 95% CI 0.63 to 0.87; 4-year OS rate: 21% versus 16%), regardless of tumor PD-L1 expression (HR (95% CI): PD-L1<1%, 0.66 (0.50 to 0.86) and ≥1%, 0.74 (0.60 to 0.92)) or histology (squamous, 0.64 (0.48 to 0.84) and non-squamous, 0.80 (0.66 to 0.97)). In patients who discontinued all components of nivolumab plus ipilimumab with chemotherapy due to TRAEs (n=61), the 4-year OS rate was 41%. With treatment-switching adjustment for the 36% of patients receiving subsequent immunotherapy in the chemotherapy arm, the estimated HR of nivolumab plus ipilimumab with chemotherapy versus chemotherapy was 0.66 (95% CI 0.55 to 0.80). No new safety signals were observed.ConclusionsIn this 4-year update, patients treated with nivolumab plus ipilimumab with chemotherapy continued to have long-term, durable efficacy benefit over chemotherapy regardless of tumor PD-L1 expression and/or histology. A greater estimated relative OS benefit was observed after adjustment for subsequent immunotherapy use in the chemotherapy arm. These results further support nivolumab plus ipilimumab with chemotherapy as a first-line treatment for patients with metastatic/recurrent NSCLC, including those with tumor PD-L1<1% or squamous histology, populations with high unmet needs.

Efanesoctocog alfa is a first-in-class high-sustained factor VIII (FVIII) replacement therapy. In the phase III XTEND-1 (NCT04161495) study, once-weekly efanesoctocog alfa prophylaxis (50 IU/kg) was well-tolerated and achieved high-sustained factor levels in the normal to near-normal range (>40%) for most of the week. To report outcomes in previously treated participants with severe haemophilia A aged ⩾12 years from an observational study who switched to efanesoctocog alfa prophylaxis during XTEND-1. Paired assessment of participants from an observational study who enrolled in the phase III XTEND-1 study. Seventy-eight participants switched from marketed standard half-life (SHL) or extended half-life (EHL) FVIII prophylaxis to once-weekly efanesoctocog alfa prophylaxis (50 IU/kg). Endpoints included annualized bleed rates (ABRs), treatment of bleeding episodes, injection frequency and FVIII consumption. Pre-study, 44 (56%) and 34 (44%) participants received SHL FVIII or EHL FVIII prophylaxis, respectively. In the overall population, a significant reduction in ABR from 2.96 to 0.69 (  < 0.0001) was observed following the switch to efanesoctocog alfa prophylaxis as well as reductions in spontaneous, traumatic, joint and spontaneous joint ABRs (  < 0.0001). Significant reductions in mean weekly injection frequency were observed, from 2.8 to 1.0 in the SHL FVIII cohort (  < 0.0001) and from 1.8 to 1.0 in the EHL FVIII cohort (  < 0.0001). Mean annualized factor consumption reduced by 47% in the SHL FVIII cohort and 30% in the EHL FVIII cohort. Collectively, the results of this post hoc analysis demonstrate the benefits of once-weekly efanesoctocog alfa prophylaxis over SHL or EHL FVIII prophylaxis on bleed rates, injection frequency and consumption. Observational study: 242HA201/OBS16221; XTEND-1: NCT04161495 (https://clinicaltrials.gov/study/NCT04161495).

Background Treatment switching in randomised controlled trials (RCTs) is a problem for health technology assessment when substantial proportions of patients switch onto effective treatments that would not be available in standard clinical practice. Often statistical methods are used to adjust for switching: these can be applied in different ways, and performance has been assessed in simulation studies, but not in real-world case studies. We assessed the performance of adjustment methods described in National Institute for Health and Care Excellence Decision Support Unit Technical Support Document 16, applying them to an RCT comparing panitumumab to best supportive care (BSC) in colorectal cancer, in which 76% of patients randomised to BSC switched onto panitumumab. The RCT resulted in intention-to-treat hazard ratios (HR) for overall survival (OS) of 1.00 (95% confidence interval [CI] 0.82–1.22) for all patients, and 0.99 (95% CI 0.75–1.29) for patients with wild-type KRAS (Kirsten rat sarcoma virus). Methods We tested several applications of inverse probability of censoring weights (IPCW), rank preserving structural failure time models (RPSFTM) and simple and complex two-stage estimation (TSE) to estimate treatment effects that would have been observed if BSC patients had not switched onto panitumumab. To assess the performance of these analyses we ascertained the true effectiveness of panitumumab based on: (i) subsequent RCTs of panitumumab that disallowed treatment switching; (ii) studies of cetuximab that disallowed treatment switching, (iii) analyses demonstrating that only patients with wild-type KRAS benefit from panitumumab. These sources suggest the true OS HR for panitumumab is 0.76–0.77 (95% CI 0.60–0.98) for all patients, and 0.55–0.73 (95% CI 0.41–0.93) for patients with wild-type KRAS. Results Some applications of IPCW and TSE provided treatment effect estimates that closely matched the point-estimates and CIs of the expected truths. However, other applications produced estimates towards the boundaries of the expected truths, with some TSE applications producing estimates that lay outside the expected true confidence intervals. The RPSFTM performed relatively poorly, with all applications providing treatment effect estimates close to 1, often with extremely wide confidence intervals. Conclusions Adjustment analyses may provide unreliable results. How each method is applied must be scrutinised to assess reliability.