Bivariate pseudo-observations for recurrent event analysis with terminal events.

The analysis of recurrent events in the presence of terminal events requires special attention. Several approaches have been suggested for such analyses either using intensity models or marginal models. When analysing treatment effects on recurrent events in controlled trials, special attention should be paid to competing deaths and their impact on interpretation. This paper proposes a method that formulates a marginal model for recurrent events and terminal events simultaneously. Estimation is based on pseudo-observations for both the expected number of events and survival probabilities. Various relevant hypothesis tests in the framework are explored. Theoretical derivations and simulation studies are conducted to investigate the behaviour of the method. The method is applied to two real data examples. The bivariate marginal pseudo-observation model carries the strength of a two-dimensional modelling procedure and performs well in comparison with available models. Finally, an extension to a three-dimensional model, which decomposes the terminal event per death cause, is proposed and exemplified.

The pan-JAK inhibitor delgocitinib in a cream formulation demonstrates dose response in chronic hand eczema in a 16-week randomized phase IIb trial.

BACKGROUND: Chronic hand eczema (CHE) is a burdensome disease, and new well-documented, safe and efficacious treatments are warranted. In a recent CHE phase IIa trial, the pan-Janus kinase (JAK) inhibitor delgocitinib in an ointment formulation was found to be efficacious and well tolerated. OBJECTIVES: This trial assessed the dose response, efficacy and safety of delgocitinib cream in CHE. METHODS: In this double-blind, phase IIb dose-ranging trial, adults with CHE and a recent history of inadequate response or contraindication to topical corticosteroids were randomized to delgocitinib cream 1, 3, 8, 20 mg g-1 or vehicle treatment twice daily for 16 weeks. The primary endpoint was the Investigator's Global Assessment for CHE (IGA-CHE) treatment success [0 (clear) or 1 (almost clear) with a ≥ two-point improvement from baseline to week 16]. Secondary endpoints were the time to IGA-CHE treatment success and changes in Hand Eczema Severity Index (HECSI); other endpoints were itch and pain numerical rating scale (NRS) scores, and Patient's Global Assessment (PaGA) at week 16. RESULTS: Patients (n = 258) were randomized 1 : 1 : 1 : 1 : 1 to delgocitinib cream 1, 3, 8, 20 mg g-1 or vehicle. A significant dose-response relationship was established for IGA-CHE (P < 0.025). IGA-CHE treatment success at week 16 was achieved in 21.2% (1 mg g-1 ), 7.8% (3 mg g-1 ), 36.5% (8 mg g-1 ), 37.7% (20 mg g-1 ) and 8.0% (vehicle) of patients. Delgocitinib 8 and 20 mg g-1 showed a treatment effect against vehicle (P < 0.001). Similarly, there were improvements in HECSI, itch and pain NRS scores, and PaGA. Delgocitinib cream was well tolerated with the majority of adverse events being mild or moderate and considered unrelated to treatment. The most frequently reported adverse events were nasopharyngitis (17.3-29.4% in delgocitinib groups vs. 40% in vehicle group), eczema (5.8-11.3% in delgocitinib groups vs. 16.0% in vehicle group) and headache (3.8-11.5% in delgocitinib groups vs. 4.0% in vehicle group). CONCLUSIONS: In this trial, delgocitinib cream showed a dose-response relationship in terms of efficacy and was well tolerated.