Inhaled colistimethate sodium in patients with bronchiectasis and Pseudomonas aeruginosa infection: results of PROMIS-I and PROMIS-II, two randomised, double-blind, placebo-controlled phase 3 trials assessing safety and efficacy over 12 months
Bibliographic record
Abstract
BACKGROUND: Chronic lung infection with Pseudomonas aeruginosa is associated with increased exacerbations and mortality in people with bronchiectasis. The PROMIS-I and PROMIS-II trials investigated the efficacy and safety of 12-months of inhaled colistimethate sodium delivered via the I-neb. METHODS: Two randomised, double-blind, placebo-controlled trials of twice per day colistimethate sodium versus placebo were conducted in patients with bronchiectasis with P aeruginosa and a history of at least two exacerbations requiring oral antibiotics or one requiring intravenous antibiotics in the previous year in hospitals in Argentina, Australia, Belgium, Canada, France, Germany, Greece, Israel, Italy, Netherlands, New Zealand, Poland, Portugal, Spain, Switzerland, the UK, and the USA. Randomisation was conducted through an interactive web response system and stratified by site and long term use of macrolides. Masking was achieved by providing colistimethate sodium and placebo in identical vials. After random assignment, study visits were scheduled for 1, 3, 6, 9, and 12 months (the end of the treatment period); and telephone calls were scheduled for 7 days after random assignment and 2 weeks after the end of treatment. The primary endpoint was the mean annual exacerbation rate. These trials are registered with EudraCT: number 2015-002743-33 (for PROMIS-I) and 2016-004558-13 (for PROMIS-II), and are now completed. FINDINGS: 377 patients were randomly assigned in PROMIS-I (177 to colistimethate sodium and 200 to placebo; in the modified intention-to-treat population, 176 were in the colistimethate sodium group and 197 were in the placebo group) between June 6, 2017, and April 8, 2020. The annual exacerbation rate was 0·58 in the colistimethate sodium group versus 0·95 in the placebo group (rate ratio 0·61; 95% CI 0·46-0·82; p=0·0010). 287 patients were randomly assigned in PROMIS-II (152 were assigned to colistimethate sodium and 135 were assigned to placebo, in the modified intention-to-treat population), between Feb 12, 2018, and Oct 22, 2021. PROMIS-II was then prematurely terminated due to the effect of the COVID-19 pandemic. No significant difference was observed in the annual exacerbation rate between the colistimethate sodium and placebo groups (0·89 vs 0·89; rate ratio 1·00; 95% CI 0·75-1·35; p=0·98). No major safety issues were identified. The overall frequency of adverse events was 142 (81%) patients in the colistimethate sodium group versus 159 (81%) patients in the placebo group in PROMIS-I, and 123 (81%) patients versus 104 (77%) patients in PROMIS-II. There were no deaths related to study treatment. INTERPRETATION: The data from PROMIS-I suggest a clinically important benefit of colistimethate sodium delivered via the I-neb adaptive aerosol delivery system in patients with bronchiectasis and P aeruginosa infection. These results were not replicated in PROMIS-II, which was affected by the COVID-19 pandemic and prematurely terminated. FUNDING: Zambon.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.008 | 0.005 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.003 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.000 | 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 teacher head, 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".