The effect of glycopyrronium and indacaterol, as monotherapy and in combination, on the methacholine dose-response curve of mild asthmatics: a randomized three-way crossover study
Bibliographic record
Abstract
Methacholine dose-response curves illustrate pharmacologic bronchoprotection against methacholine-induced airway hyperresponsiveness and can be used to quantitate changes in airway sensitivity (position), reactivity (slope), and maximal responsiveness following drug administration. Our objective was to determine the influence of single-dose glycopyrronium (long-acting muscarinic antagonist) and indacaterol (ultra-long acting β2 agonist), as monotherapy and in combination, on the methacholine dose-response curve of mild asthmatics and to compare these findings with a non-asthmatic control curve. This was a randomized, double blind, double dummy, three-way crossover study. For asthmatic participants (n = 14), each treatment arm included a baseline methacholine challenge, drug administration, and repeat methacholine challenges at 1, 24, and 48 h. Non-asthmatic control participants (n = 15) underwent a single methacholine challenge and did not receive any study treatment. Methacholine dose-response curves were graphed as the percent fall in forced expiratory volume in 1 s (FEV1) for each methacholine concentration administered. Best-fit curves were then generated. Differences in airway reactivity were calculated through linear regression. Changes in airway sensitivity were assessed as the shift in the provocative concentration of methacholine causing a 20% fall in FEV1. Compared to baseline, all treatments significantly reduced airway sensitivity to methacholine at 1 h post-dose (indacaterol ~1.5 doubling concentrations; glycopyrronium ~5 doubling concentrations; combination ~5 doubling concentrations). Bronchoprotection at 24 and 48 h remained significant with glycopyrronium and combination therapy only. Airway reactivity was not influenced by indacaterol whereas glycopyrronium significantly reduced airway reactivity at all time-points (p = 0.003-0.027). The combination significantly decreased slope at 1 (p = 0.021) and 24 (p = 0.039) hours only. The non-asthmatic control and 1-h glycopyrronium curves are nearly identical. Only the non-asthmatic control and 1-h post-combination therapy curves appeared to generate a true response plateau (three data points within 5%), which occurred at a 14% fall in FEV1. Methacholine dose-response curves differentiate the bronchoprotective mechanisms triggered by different classes of asthma medications. Assessment of bronchoprotection using methacholine dose-response curves may be useful during clinical development of respiratory medications when performing superiority, equivalence, or non-inferiority trials. clinicaltrials.gov ( NCT02953041 ). Retrospectively registered on October 24th 2016.
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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 | 0.002 | 0.002 |
| Meta-epidemiology (narrow) | 0.002 | 0.001 |
| Meta-epidemiology (broad) | 0.006 | 0.002 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.001 | 0.002 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.002 | 0.003 |
| Insufficient payload (model declined to judge) | 0.003 | 0.001 |
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".