Peter G. Gibson

Objective: The Breathing for Life Trial (BLT) was a multicentre randomised controlled trial testing the hypothesis that a fractional exhaled nitric oxide-based intervention to guide asthma therapy in pregnancy improves perinatal outcomes. While BLT was negative based on selected outcomes, the conduct of the trial over 7 years showed potential for assessing the broader research impacts and returns on investment in BLT. The aim of this study was to retrospectively assess and report on the impact and value of BLT to show accountability for the research investment in what was deemed a 'negative' trial. Methods: The Framework to Assess the Impact from Translational health research (FAIT) was selected as the preferred method. FAIT combines three validated methods, including a modified Payback framework, an economic analysis of return on investment and a narrative account of the impact generated from the research. Data collection was done via document analysis of BLT administrative and research records and review of relevant websites/databases. Results: BLT delivered a return on investment of $6.7 million in leveraged grants, fellowships and consultancies and conservatively returned $2.44 for every dollar invested. The research trained and upskilled 18 midwives and obstetricians in evidence-based asthma management in pregnancy and improved research capability of six PhD students. Specialised equipment purchased by BLT is now being repurposed to undertake other research in regional Australia, saving further research investment. Of the 1200 mothers who were part of BLT, 508 now have written asthma plans, 268 had a clinically significant improvement in their asthma control score and the proportion who improved their asthma plan knowledge increased by 58 percentage points from 12 to 70%. Conclusions: This case example in the developing field of impact assessment illustrates how researchers can use evidence to demonstrate and report more broadly on the impact of and returns on research investment in a clinical trial.

Background: Although clinical trials have documented the oral corticosteroid (OCS)-sparing effect of biologics in patients with severe asthma, little is known about whether this translates to a reduction of new-onset OCS-related adverse outcomes. Objective: To compare the risk of developing new-onset OCS-related adverse outcomes between biologic-initiators and non-initiators. Methods: This was a longitudinal cohort study using pooled data from the International Severe Asthma Registry (ISAR; 16 countries) and the Optimum Patient Care Research database (OPCRD; UK). For biologic-initiators, the index date was the date of biologic-initiation. For non-initiators, it was the date of enrolment (for ISAR) or a random medical appointment date (for OPCRD). Inverse-probability-of-treatment-weighting was used to improve comparability between groups and weighted Cox proportional hazard models were used to estimate the hazard ratios (HR) of developing OCS-related adverse outcomes for up to five years from the index date. Results: 42,908 patients were included. Overall, 27.3% and 4.7% of biologic-initiators and non-initiators were long-term OCS users (daily intake ≥90 consecutive days in year pre-index), with a mean prednisolone-equivalent daily dose of 10.2 mg and 6.2 mg, respectively. Compared to non-initiators, biologic-initiators had decreased rate of developing any OCS-related adverse outcome (HR [95% CI]: 0.82 [0.72-0.93]; p=0.002), primarily driven by reduced rate of developing diabetes (0.62 [0.45-0.87]; p=0.006]), major cardiovascular events (0.65 [0.44-0.97]; p=0.034), and anxiety/depression (0.68 [0.55-0.85]; p=0.001]). There were no significant differences in the rates of new-onset cataract (HR: 0.77 [95% CI: 0.47-1.25]), sleep apnea (HR: 0.82 [95% CI: 0.78-1.41]), or other OCS-related AOs assessed (e.g. osteoporosis). The results were consistent across both datasets. Conclusions: Our findings highlight the role for biologics in preventing new-onset OCS-related adverse outcomes in patients with severe asthma.

Type 2 (T2) low asthma is characterized by the absence of T2-mediated eosinophilic airway inflammation. The diagnosis and prevalence of T2-low asthma are complicated by the absence of specific biomarkers, varied cut-offs of existing biomarkers and biomarker suppression by corticosteroids. The substantial disease burden of T2-low asthma can be attributed to comorbidities, including obesity. T2-low asthma phenotypes include late-onset, aging-related, obesity-related, as well as neutrophilic and paucigranulocytic subtypes. Emerging evidence suggests that T2-low asthma may be more prevalent in mild to moderate asthma compared to severe asthma. Furthermore, the exacerbation phenotype in most patients with severe T2-low asthma may change to T2-high during an exacerbation, while the long-term prognosis in T2-low severe asthma remains unclear. Clinical management strategies for T2-low asthma include addressing comorbidities and risk factors, optimizing inhaled/oral corticosteroid dose, and considering other potential add-on therapies, including azithromycin, anti-thymic stromal lymphopoietin therapy and bronchial thermoplasty. Azithromycin is a promising treatment option, showing potential to induce clinical remission in up to 50% of patients with T2-low uncontrolled asthma and demonstrates the therapeutic potential of targeting microbial dysbiosis in T2-low asthma. Future directions include biologics targeting IL33 pathways, and Glucagon-Like Peptide 1 (GLP-1) and Gastric Inhibitory Polypeptide (GIP) receptor agonists in obesity-related T2-low asthma. Further research is needed to optimize management strategies for T2-low asthma phenotypes.

Background: For severe asthma (SA) management, real-world evidence on the effects of biologic therapies in reducing the burden of oral corticosteroid (OCS) use is limited. Objective: To estimate the efficacy of biologic initiation on total OCS (TOCS) exposure in SA patients from real-world specialist and primary care settings. Methods: From the International Severe Asthma Registry (ISAR, specialist care) and the Optimum Patient Care Research Database (OPCRD, primary care, UK), adult biologic initiators were identified and propensity score-matched with non-initiators (ISAR, 1:1; OPCRD, 1:2). The impact of biologic initiation on TOCS (including bursts for exacerbations) daily dose in the first and second year follow-up period was estimated using multivariable generalized linear models. Results: Among 5663 patients (ISAR 48%, OPCRD 52%), the odds ratios (ORs) of biologic initiators achieving TOCS cessation in the first and second year of follow-up were 2.38 (95% CI, 1.87-3.04) and 2.11 (95% CI, 1.65-2.70), whereas the ORs of low (0-5mg) TOCS intake were 1.62 (95% CI, 1.40-1.86) and 1.40 (95% CI, 1.21-1.61) respectively. Compared to non-initiators, biologic initiators had a substantially higher chance of achieving >75% reduction from baseline (OR [95% CI]: 2.35 [2.06-2.68] and 1.53 [1.35-1.73] in first and second year, respectively). These findings remained persistent and robust, when analyses were repeated with one country setting removed at a time. Conclusions: Biologic initiation in SA patients led to substantial reduction in TOCS exposure, in particular in the first year. Future analyses will explore the impact on OCS-related adverse health events.

Asthma characterization using blood eosinophil count (BEC) (among other biomarkers and clinical indices) is recommended in severe asthma (SA), but the masking effect of oral corticosteroids (OCS), makes this challenging. Our aim was to explore the effect of OCS use (both intermittent [iOCS] and long-term [LTOCS]) prior to biologic initiation on SA phenotype and biomarker profile in real-life and to characterize the burden of SA among patients prescribed LTOCS by biomarker profile. This was a registry-based cohort study, including data from 23 countries collected between 2003 and 2023 and shared with the Internatonal Severe Asthma Registry (ISAR). Patients with SA were categorized into 3 cohorts, those with: (i) no prescription for OCS, (ii) prescription(s) for iOCS (ie, ≤90 days in previous 12-months, usually short courses for exacerbations), and (iii) prescriptions for LTOCS (ie, >90 days in previous 12-months). Biomarker distribution (ie, BEC, fractional exhaled nitric oxide [FeNO], and total Immunoglobulin E [IgE]) were quantified in the year prior to biologic initiation in patients with SA according to OCS prescription pattern. Phenotypes were characterized for those prescribed LTOCS according to BEC cut-off (<150 and ≥ 150 cells/μL). Of 4305 patients included, 5.0% (n = 215), 54.1% (n = 2330) and 40.9% (n = 1760) were prescribed no OCS, iOCS, and LTOCS, respectively. The BEC distribution varied by prescription pattern and LTOCS dose (<5 mg to ≥20 mg/day); BEC was <150 cells/μL in 28.6% (n = 369/1288) of LTOCS patients, compared to 19.5% (n = 284/1460) of iOCS patients and 14.0% (n = 21/150) of those in the no OCS group. Median BEC was also significantly lower in the LTOCS versus the iOCS group (310 vs 400 cells/μL; p < 0.001). A similar pattern was noted for IgE, but not FeNO. Among LTOCS patients with BEC <150 cells/μL, 39.9% experienced ≥4 exacerbations, 75.1% had uncontrolled asthma symptoms and 55.9% had evidence of persistent airflow obstruction (compared with 40.9%, 76.2% and 59.5% of those with BEC ≥150 cells/μL, respectively). OCS, whether prescribed intermittently or long term, affect BEC distribution potentially leading to heightened risk of phenotype misclassification and influencing subsequent treatment decisions. FeNO appears to be less susceptible to OCS-induced suppression. Disease burden was high for those in the LTOCS group and was high independent of dose and BEC. Our findings highlight the importance of considering OCS use, even intermittent use, when characterizing SA, and suggests the need for earlier phenotyping and alternative treatment strategies for LTOCS patients with low BEC.