A New Multistate Transition Model For Effect Estimation In Randomized Trials With Treatment Switching And A Cured Subgroup

Background: Many methods, including multistate models, have been proposed in the literature to estimate the treatment effect on overall survival in randomized trials with treatment switching permit after the disease progression. Nevertheless, the cured fraction of patients has not been considered. The cured would never experience the progressive disease, but they may suffer death with a hazard comparable to that of people without the disease. With the mix of the cured subgroup, existing methods yield highly biased effect estimation and fail to reflect the truth in uncured patients. Methods: In this paper, we propose a new multistate transition model to incorporate the cure, progression, treatment switching, and death states during trials. In the proposed model, the probability of cure and the death hazard of the cured are modeled separately. For the not cured patients, the semi-competing risks model is used with the treatment effect evaluated via transitional hazards between states. The particle swarm optimization algorithm is adopted to estimate the model parameters. Results: Extensive simulation studies have been conducted to evaluate the performance of the proposed multistate model and compare it with existing treatment switching adjustment methods. Results show that in all scenarios, the treatment effect estimation of the proposed model is more accurate than that of existing treatment switching adjustment methods. Besides, the application to diffuse large B-cell lymphoma data has also illustrated the superiority of the proposed model.Conclusions: The superiority and robustness of the proposed multistate transition model qualify it to estimate the treatment effect in trials with the treatment switching permit after progression and a cured subgroup.

Antibiotic Prescribing Patterns in Paediatric Primary Care in Italy: Findings from 2012–2018

Comprehensive data are needed to monitor antibiotic prescribing and inform stewardship. We aimed to evaluate the current antibiotic prescribing patterns, including treatment switching and prolongation, in the paediatric primary care setting in Italy. This database study assessed antibiotic prescriptions retrieved from Pedianet, a paediatric primary care database, from 1 January 2012 to 31 December 2018. Descriptive analyses were stratified by diagnosis class, calendar year, and children’s age. Generalized linear Poisson regression was used to assess variation in the prescriptions. In total, 505,927 antibiotic prescriptions were included. From 2012 to 2018, the number of antibiotics per child decreased significantly by 4% yearly from 0.79 in 2012 to 0.62 in 2018. Amoxicillin prescriptions decreased with increasing children’s age, while macrolides and third-generation cephalosporins had the opposite trend. Prescriptions were associated with a diagnosis of upper respiratory infection in 23% of cases, followed by pharyngitis (21%), bronchitis and bronchiolitis (12%), and acute otitis media (12%). Eight percent of treatment episodes were prolonged or switched class, mostly represented by co-amoxiclav, macrolides, and third-generation cephalosporins. Our findings report an overall decrease in antibiotic prescriptions, but pre-schoolers are still receiving more than one antibiotic yearly, and broad-spectrum antibiotics prescription rates remain the highest.

Retrospective Database Analysis: Dose Escalation and Adherence in Patients Initiating Biologics for Ulcerative Colitis

Background: Biologic therapies are often used in patients with ulcerative colitis who are non-responsive to conventional treatments. However, non-response or loss of response to biologics often occurs, leading to dose escalation, combination therapy, and/or treatment switching. We investigated real-world treatment patterns of biologic therapies among patients with ulcerative colitis in the USA. Methods: This study analyzed data from the IBM® MarketScan® Commercial and Medicare Supplemental Databases (medical/pharmacy claims for >250 million patients in the USA) to identify patients with ulcerative colitis initiating a biologic therapy (adalimumab, infliximab, golimumab, or vedolizumab) with 12 months of follow-up post-initiation. Key measures were patient baseline characteristics, dose escalation (average maintenance dose >20% higher than label), adherence (proportion of days covered), and ulcerative colitis-related healthcare costs in the 12 months following biologic therapy initiation. Results: Of 2,331 patients included in the study (adalimumab [N=1,291], infliximab [N=810], golimumab [N=127], vedolizumab [N=103]), 28.1% used concomitant immunosuppressant therapy within 12 months post-initiation. Overall, 23.6% (adalimumab), 34.8% (infliximab), 9.9% (golimumab), and 39.2% (vedolizumab) of patients dose escalated within 12 months. Patients who dose escalated incurred $20,106 higher total ulcerative colitis-related healthcare costs over 12 months than those who did not. Adherence (covariate-adjusted proportion of days covered) ranged from 0.63 to 0.73, and 39.3% of patients discontinued within 12 months (median treatment duration=112 days). Conclusion: Dose escalation was common, and incurred higher costs, in patients with ulcerative colitis initiating biologic therapies. Sub-optimal adherence and/or discontinuation within 12 months of initiation occurred frequently, highlighting the challenges in managing these patients.

A modified weighted log-rank test for confirmatory trials with a high proportion of treatment switching

In confirmatory cancer clinical trials, overall survival (OS) is normally a primary endpoint in the intention-to-treat (ITT) analysis under regulatory standards. After the tumor progresses, it is common that patients allocated to the control group switch to the experimental treatment, or another drug in the same class. Such treatment switching may dilute the relative efficacy of the new drug compared to the control group, leading to lower statistical power. It would be possible to decrease the estimation bias by shortening the follow-up period but this may lead to a loss of information and power. Instead we propose a modified weighted log-rank test (mWLR) that aims at balancing these factors by down-weighting events occurring when many patients have switched treatment. As the weighting should be pre-specified and the impact of treatment switching is unknown, we predict the hazard ratio function and use it to compute the weights of the mWLR. The method may incorporate information from previous trials regarding the potential hazard ratio function over time. We are motivated by the RECORD-1 trial of everolimus against placebo in patients with metastatic renal-cell carcinoma where almost 80% of the patients in the placebo group received everolimus after disease progression. Extensive simulations show that the new test gives considerably higher efficiency than the standard log-rank test in realistic scenarios.

P540 Real-world evidence on treatment switching in patients with moderate-to-severe ulcerative colitis: a systematic review of literature

Background Current approved therapies for the treatment of moderate-to-severe ulcerative colitis (UC) have well-established efficacy; however, some patients may fail to respond or may lose their response over time, resulting in dose escalation or treatment switching. The objective of this systematic literature review was to summarize the real-world evidence on treatment switching in UC and the associated clinical, safety and economic outcomes. Methods A literature search of Embase and MEDLINE (from database inception to August 2020) and conference proceedings (2017 to 2020) was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. The population of interest included adult patients (≥18 years) with UC who experienced treatment switching on anti-tumour necrosis factor alpha agents (anti- TNFα) - (adalimumab [ADA], infliximab [IFX], golimumab [GOL]), vedolizumab (VDZ), tofacitinib (TOFA), and ustekinumab (USTE). Outcomes of interest included all available clinical, safety and economic outcomes. Results Of a total 1593 studies screened, 29 met the eligibility criteria. Of these, 22 (76%) reported switching rates of 4–63% (sample size: 4-1274). A total of 7 studies reported outcomes in populations comprised entirely of switched patients (sample size: 5–76). Figure 1 includes the directed connectivity graph showing the number of studies reporting different switches. IFX to ADA was the most frequently reported switch (n=11 studies;35%). Figure 2 and Table 1 include the number of studies and proportion of patients reporting outcomes following a treatment switch, respectively. Heterogeneity was observed in patient populations, follow-up, and definitions of response/remission. In the short term (4–12 weeks), remission rates of 10–38% have been reported that increased to 49–100% in the long-term (24–57 weeks). In contrast, the clinical response rates decreased over time (30–58% over 4–12 weeks versus 15–56% over 24–57 weeks). Colectomy and corticosteroid-free remission were reported in 0–35% and 18–79% of patients, respectively. Rate of adverse events varied from 13–38%, with a switch to IFX from other anti-TNFs associated with the highest rate. One study reported higher mean quarterly total healthcare costs in patients who switched within anti-TNFs (IFX>ADA, ADA>IFX) compared to those who did not ($15,004 vs $9632). Conclusion Treatment switching in the management of moderate-to-severe UC is common in routine clinical practice and is associated with suboptimal outcomes and potentially increased costs. There remains a need for additional treatment options that provide long-term durable disease control.