Search

Abstract Background Published in 2019, a new addendum to the ICH E9 guideline presents the estimand framework as a systematic approach to ensure alignment among clinical trial objectives, trial execution/conduct, statistical analyses, and interpretation of results. The use of the estimand framework for describing clinical trial objectives has yet to be extensively considered in the context of patient-reported outcomes (PROs). We discuss the application of the estimand framework to PRO objectives when designing clinical trials in the future, with a focus on PRO outcomes in oncology trial settings as our example. Main We describe the components of an estimand and take a naïve PRO trial objective to illustrate how to apply attributes described in the estimand framework to inform construction of a detailed clinical trial objective and its related estimand. We discuss identifying potential post-randomization events that alter the interpretation of the endpoint or render its observation impossible (also defined as intercurrent events) in the context of PRO endpoints, and the implications of how to handle intercurrent events in the construction of the PRO objective. Using a simple objective statement, “What is the effect of treatment X on patient’s quality of life?”, we build up an example estimand statement and also use a previously published phase III oncology clinical trial to illustrate how an estimand for a PRO objective could have been written to align to the estimate framework. Conclusion The use of the estimand framework, as described in the new ICH E9 (R1) addendum guideline will become a key common framework for developing clinical trial objectives for evaluating effects of treatment. In the context of considering PROs, the framework provides an opportunity to more precisely specify and build the rationale for patient-focused objectives. This will help to ensure that clinical trials used for registration are designed and analysed appropriately, enabling all stakeholders to accurately interpret conclusions about the treatment effects for patient-focused outcomes.

Ulrich Feifel1, Gudrun Wallenstein1, Karl-Ludwig Rominger1, Dirk Trommeshauser2, Juliane Platz21Boehringer Ingelheim Pharma GmbH & Co. KG, Binger Straße 173, 55216 Ingelheim, Germany; 2Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorf Straße 65, 88397 Biberach, GermanyAbstract: Data are presented from two randomized, double-blind, placebo-controlled studies in which the tolerability of tiotropium Respimat® Soft Mist™ Inhaler (SMI), a new-generation, propellant-free device for use in COPD, and the ocular safety of tiotropium were examined. In Study 1, 36 healthy males received tiotropium 8, 16, or 32 µg (n = 9/dose) or placebo (n = 3/dose level), administered once daily via Respimat® SMI for 14 days. Safety and pharmacokinetics were evaluated. In Study 2, 48 healthy males received tiotropium 0.02, 0.04, 0.08, 0.16, 0.28, or 0.40 µg (n = 6/dose) or placebo (n = 2/dose level), applied as two drops to one eye (the highest dose was a significant multiple of a percentage of the proposed Respimat® SMI clinical dose that could be inadvertently deposited in the eye). Ocular parameters were measured over 24 hours. Tiotropium Respimat® SMI at doses up to 32 µg was well tolerated in Study 1; typical dose-dependent anticholinergic adverse events of mild-to-moderate intensity were observed. In Study 2, ocular tiotropium administration did not affect pupil diameter, pupillary reflex, intraocular pressure, or accommodation. Tiotropium Respimat® SMI was well tolerated. Inadvertent ocular exposure to tiotropium up to 0.40 µg is unlikely to result in ocular adverse effects.Keywords: Respimat® Soft Mist™ Inhaler, tiotropium, anticholinergic, chronic obstructive pulmonary disease

This study determined if meloxicam, a selective cyclooxygenase (COX)-2 inhibitor, interferes with the antiplatelet effect of aspirin using platelet aggregation and thromboxane (Tx) B 2 endpoints in healthy volunteers. Eight male and 8 female volunteers participated in this open-label, randomized, two-treatment, two-way crossover trial. Treatment 1 was meloxicam (15 mg qd) over 4 days, and then aspirin (100 mg qd) was ingested 2 hours after meloxicam for an additional 7 days. Blood samples were taken 2, 6, and 24 hours after the last dose. Treatment 2 consisted of only aspirin (100 mg) over 2 days. Samples were taken at the same time points. Each subject received both treatments with a 2-week washout between the treatment periods. Treatments were safe and well tolerated. The initial 4-day treatment with meloxicam had no effect on platelet aggregation but reduced serum TxB 2 by 64% ± 19%. Addition of aspirin (100 mg qd) for 7 days resulted in complete inhibition of aggregation and TxB 2 for 24 hours. Two-day treatment with only 100 mg aspirin also resulted in complete inhibition of platelet aggregation and TxB 2. These results indicate that meloxicam does not affect the ability of aspirin to inhibit COX-1 in platelets, thereby allowing aspirin to effectively prevent platelet aggregation and reduce TxB 2 levels, and that meloxicam is selective for COX-2. [ABSTRACT FROM AUTHOR]