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Since the publication of ICH E9 (R1), "Addendum to statistical principles for clinical trials: on choosing appropriate estimands and defining sensitivity analyses in clinical trials," there has been a lot of debate about the hypothetical strategy for handling intercurrent events. Arguments against the hypothetical strategy are twofold: (1) the clinical question has limited clinical/regulatory interest; (2) the estimation may need strong statistical assumptions. In this article, we provide an example of a hypothetical strategy handling use of rescue medications in the acute pain setting. We argue that the treatment effect of a drug that is attributable to the treatment alone is the clinical question of interest and is important to regulators. The hypothetical strategy is important when developing non‐opioid treatment as it estimates the treatment effect due to treatment during the pre‐specified evaluation period whereas the treatment policy strategy does not. Two widely acceptable and non‐controversial clinical inputs are required to construct a reasonable estimator. More importantly, this estimator does not rely on additional strong statistical assumptions and is considered reasonable for regulatory decision making. In this article, we point out examples where estimators for a hypothetical strategy can be constructed without any strong additional statistical assumptions besides acceptable clinical inputs. We also showcase a new way to obtain estimation based on disease specific clinical knowledge instead of strong statistical assumptions. In the example presented, we clearly demonstrate the advantages of the hypothetical strategy compared to alternative strategies including the treatment policy strategy and a composite variable strategy. [ABSTRACT FROM AUTHOR]

Introduction/Background Atopic dermatitis (AD) has different clinical presentations, pathophysiology, comorbidity frequencies, and genetic profiles in adult-onset vs childhood-onset disease. Based on these differences, it is plausible that treatment response would also be different between adult- and childhood-onset AD. Lebrikizumab, a novel, high affinity monoclonal antibody, selectively targeting IL-13 with high affinity and slow dissociation rate, has been approved in the EU, UK, and Japan and is under investigation in the US and elsewhere for the treatment of moderate-to-severe AD. Objectives To evaluate the Week-16 efficacy of lebrikizumab monotherapy by age of AD onset in adults and adolescents with moderate-to-severe AD from ADvocate1 (NCT04146363) and ADvocate2 (NCT04178967), identically-designed, randomized, double-blind, placebo-controlled phase 3 trials. Methods In ADvocate1 and ADvocate2, eligible patients were randomly allocated 2:1 to receive lebrikizumab 250 mg or placebo every 2 weeks. The date of AD onset was collected, and age of onset was calculated accordingly. Patients were stratified by age of AD-onset as ≤2, >2-to-<18, and ≥18 years. Efficacy was assessed at Week 16 with the proportion of patients with Investigator's Global Assessment score of 0 or 1 with ≥2-point improvement (IGA 0,1; the trials' primary endpoint); ≥75% (EASI 75) and ≥90% (EASI 90) improvement in the Eczema Area and Severity Index from baseline; ≥4-point Pruritus Numeric Rating Scale (NRS) improvement from baseline (with baseline score ≥4), and percentage change in total EASI from baseline. Data from patients who received topical or systemic rescue medication or discontinued treatment due to lack of efficacy were imputed as nonresponders or set to baseline values. Data from patients who discontinued treatment for other reasons were set to missing and analyzed by multiple imputation. This was a post-hoc analysis conducted on the modified, pooled intent-to-treat population. Treatment-by-age subgroup interaction was assessed with logistic regression. Binary outcomes were analyzed by the Cochran-Mantel-Haenszel method, and continuous outcomes were analyzed with ANCOVA. Results At baseline, the numbers of patients treated with lebrikizumab and placebo, respectively, were 215 and 117 in the ≤2 years AD-onset subgroup, 178 and 103 in the >2-to-<18 years subgroup, and 171 and 67 in the ≥18 years subgroup. At baseline, the percentages of patients with ≥1 atopic comorbidity were 81% in the ≤2 years subgroup, 74% in the >2-to-<18 years subgroup, and 58% in the ≥18 years subgroup. At Week 16, treatment-by-age subgroup interactions were not significant at the 0.10 level for IGA 0,1; EASI 75; EASI 90; and Pruritus NRS 4-pt improvement. Within each subgroup, a higher proportion of lebrikizumab-treated compared with placebo-treated patients (p<0.001) achieved IGA 0,1 responses (≤2 years: 41% vs. 12%; >2-to-<18 years: 35% vs. 12%; ≥18 years: 38% vs. 12%), EASI 75 responses (≤2 years: 57% vs. 17%; >2-to-<18 years: 51% vs. 16%; ≥18 years: 58% vs. 20%), and EASI 90 responses (≤2 years: 38% vs. 10%; >2-to-<18 years: 32% vs. 9%; ≥18 years: 33% vs. 8%). Additionally, the least-squares mean percentage change from baseline in total EASI score for lebrikizumab and placebo, respectively, was -65% and -26% in the ≤2 years subgroup, -60% and -26% in the >2-to-<18 years subgroup, and -63% and -30% in the ≥18 years subgroup (p<0.001 for lebrikizumab vs. placebo in all subgroups). The proportion of lebrikizumab-treated patients who reported ≥4-point improvement in Pruritus NRS from baseline (baseline ≥4) was greater compared with placebo-treated patients ([N]; ≤2 years: 43% [201] vs. 11% [108]; >2-to-<18 years: 41% [161] vs. 14% [96]; ≥18 years: 45% [154] vs. 12% [60]; p<0.001). Conclusions Regardless of age of AD onset, lebrikizumab was associated with significant improvements in AD signs and symptoms compared with placebo over 16 weeks of treatment. [ABSTRACT FROM AUTHOR]

Aim: We evaluated the safety of baricitinib in an East Asian (EA) patient population with moderate‐to‐severely active rheumatoid arthritis (RA), through an integrated sub‐analysis of data from the overall baricitinib RA clinical program. Methods: Data from EA patients who received any dose of baricitinib from five completed studies (1 Phase 2, 4 Phase 3) and an ongoing long‐term extension study were pooled up to 1 September, 2016. Exposure‐adjusted incidence rates (EAIR) and incidence rates (IRs), both per 100 patient‐years (PY), were calculated. Results: This analysis included 740 EA patients with 1294 PY of total baricitinib exposure (maximum 3.5 years). Overall, 109 patients discontinued baricitinib due to adverse events (AEs); EAIR: 8.4. No deaths were reported in this cohort. Serious AEs were reported by 125 patients (EAIR: 9.7). Serious infections were the most common serious AEs (n = 53, IR: 4.15). IR of herpes zoster infection was 6.2; the majority of events were of mild‐to‐moderate severity. Three cases (IR: 0.23) of tuberculosis were reported. The IRs of malignancy (excluding non‐melanoma skin cancer) was 0.99 and EAIR specifically of lymphoma was 0.1. The IR of major adverse cardiovascular events was 0.26, and deep vein thrombosis was reported in four patients (EAIR: 0.3). Two cases of gastrointestinal perforations (EAIR: 0.2) were reported. Conclusion: Integrated data show that baricitinib is well‐tolerated in EA patients with moderate‐to‐severely active RA in the context of demonstrated efficacy, which is generally consistent with safety results of the overall study population. [ABSTRACT FROM AUTHOR]