Type-2 Inflammation and Lung Function Changes in the Placebo Arms of Asthma Clinical Trials: Findings from the ORACLE2 Meta-analysis
Bibliographic record
Abstract
Abstract INTRODUCTION: In randomized controlled trials (RCTs), many patients receiving placebo show improvement in clinical outcomes including lung function. Regression to the mean and increased adherence to medication are potential explanatory mechanisms. Given that type-2 inflammation is a treatment-responsive characteristic, we hypothesized that baseline type-2 biomarker levels (blood eosinophil count (BEC) and exhaled nitric oxide (FeNO)) are associated with the magnitude of lung function improvement over time in the placebo groups in RCTs. METHODS: The OxfoRd Asthma attaCk risk scaLE (ORACLE2) patient-level meta-analysis dataset was used to identify prognostic variables associated to lung function changes. The dataset includes control arms of 22 RCTs assessing fixed treatment regimens on asthma exacerbation rates over at least 24 weeks. We excluded open-label RCTs, and we excluded trials missing Forced Expiratory Volume in 1 second (FEV1) at the 52-week follow-up. Multiple imputation by chained equations was used for others missing values in 10 iterations. Lung function change was defined as the change in FEV1 (mL) over one year. Adjusted regression coefficients (aRC)[95% confidence intervals (CI)] were computed using linear regression. Interactions terms between in FeNO and BEC was assessed in this model and restricted cubic spline curves were plotted to visualize the potential interaction. RESULTS: Patients with moderate-to-severe asthma (n=2,675), from 9 RCTs with a placebo arm were included. An improvement in lung function was observed in the placebo group across trials. Factors associated with lung function change (ΔFEV1 (mL)) included (aRC [95%CI]) (Figure A): FeNO (per 10-fold increase: 67 ml [28-107]), age (per 10-year increase: -42 ml [-53--31]), baseline FEV1 (per 10% decrease: 54 ml [44-64]), FEV1 reversibility (per 10% increase: 128 ml [114-142]), and presence of nasal polyposis (40 ml [0-80]). FeNO and BEC have a significant positive interaction (interaction term [95%CI]: 133[24-242]) (Figure B). CONCLUSION: Type 2 inflammatory biomarkers, particularly FeNO, emerged as a factor associated with lung function improvement on placebo in asthma trials. Low adherence in pre-trial among patients with high FeNO may partially explain the observed lung function improvements in this group within the placebo arm of RCTs. Further research is needed to understand the mechanisms underlying this observation and its impact on the outcomes of RCTs. REGISTRATION: PROSPERO-CRD42021245337 JSP&SML= co-primary authors
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.026 | 0.063 |
| Meta-epidemiology (narrow) | 0.002 | 0.001 |
| Meta-epidemiology (broad) | 0.010 | 0.039 |
| Bibliometrics | 0.003 | 0.005 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.003 | 0.001 |
| Open science | 0.002 | 0.002 |
| Research integrity | 0.002 | 0.002 |
| Insufficient payload (model declined to judge) | 0.007 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".