*2.2. Search Strategy*

The protocol of this synthesis of the current literature has been registered to the international prospective register of systematic reviews (PROSPERO, Protocol ID: CRD42022336605), and performed in agreement with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols (PRISMA-P) [15], with the relative flow diagram reported in Figure 1. This study satisfied all the recommended items reported by the PRISMA 2020 checklist [16].

The PICO (Patient problem, Intervention, Comparison, and Outcome) framework was applied to develop the literature search strategy and question, as previously reported [17]. Namely, the "Patient problem" included asthmatic patients; the "Intervention" regarded investigational agents in Phase I and II CTs; the "Comparison" was performed with respect to placebo (PCB) and/or active comparators; the assessed "Outcomes" were lung function, symptoms control, blood eosinophil count (BEC), fractioned exhaled nitric oxide (FENO), exacerbations and hospitalisations, the use of rescue medications, and quality of life (QoL).

A comprehensive literature search was performed for Phase I and II CTs, written in English and investigating the impact of investigational treatments in patients with asthma. The search was performed in ClinicalTrials.gov in order to provide relevant studies available within the past 5 years (from May 2017 to May 2022).

The term "asthma" was searched for the disease, "Interventional Studies (Clinical Trials)" was selected for the study type, "Terminated" and "Completed" were chosen for

the recruitment status, and "Early Phase I", "Phase I", and "Phase II" were selected in the Additional Criteria of the Advanced Search in the ClinicalTrials.org database.

**Figure 1.** PRISMA 2020 flow diagram for the identification of the RCTs included in the qualitative and quantitative syntheses. PRISMA: Preferred Reporting Items for Systematic Reviews and Meta-Analyses; RCT: randomised controlled trial.
