TABLE 5.

Phase IIb study.

Study ID short title	Main objectives	Study design	Device, dosing regimen, duration	Treatments (number of subjects)	Population (N randomized)	Primary measure(s)	References
COPD
PIONEER	Efficacy, safety, and tolerability	Multicenter, randomized, double-blind, double-dummy, placebo- and active-controlled, parallel group, dose ranging	NEXThaler® Twice-daily (BID) 24 weeks	Tanimilast: Dose 1: 400 µg BID	N = 1,130 moderate or severe COPD patients with a history of exacerbation on maintenance with LABA therapy	Primary efficacy variable: Predose FEV1 at week 12, Main secondary efficacy variables: COPD exacerbation, PROs, Blood biomarkers, Safety variables: AEs, ADRs, vital signs, 12-lead ECGs, routine laboratory values	Singh et al. (2020c)
				Dose 2: 800 µg BID
				Dose 3: 1,200 µg BID
				Dose 4: 1,600 µg BID
				Budesonide DPI
				400 µg BID
				Matched placebo BID
Main outcomes; Efficacy: No difference versus placebo were observed for any dose of tanimilast or for the active control budesonide on pre-dose FEV1 at 12 and 24 weeks or on PROs. Clinically relevant reductions in the COPD exacerbation rate (moderate or severe) were observed with all the tanimilast doses on top of LABA compared to placebo (LABA alone); from 13 to 28% for the highest dose. A post hoc analysis on subgroup populations showed an enriched effect in terms of exacerbation rate reduction in the subgroups of patients with chronic bronchitis; this effect increased further in patient with chronic bronchitis and blood eosinophils ≥150 cells/μL reaching statistically significance for the 800 and 1,600 μg BID doses. A significant reduction of systemic level of SP-D for all doses of tanimilast (but not for budesonide) was observed in comparison with placebo. Safety: All the doses well tolerated. The incidence of known PDE4 inhibitor class effects (e.g., gastrointestinal) was low and comparable to that of the placebo group