Safety and tolerability of nintedanib in patients with idiopathic pulmonary fibrosis (IPF): pooled data from six clinical trials
Bibliographic record
Abstract
Rationale Nintedanib is an approved treatment for IPF that slows disease progression by reducing the rate of decline in forced vital capacity. To characterize the safety and tolerability of nintedanib, we analyzed adverse events (AEs) based on pooled data from six clinical IPF trials. Methods Data from patients treated with nintedanib 150 mg bid in the 52-week Phase II TOMORROW trial (NCT00514683) and/or open-label extension (NCT01170065), the two 52-week Phase III INPULSIS trials (NCT01335464, NCT01335477) and/or open-label extension INPULSIS-ON (NCT01619085), and a Phase III b trial (placebo-controlled up to 12 months and open-label up to 12 months [NCT01979952]) were pooled. Dose reductions to 100 mg bid and treatment interruptions were allowed to manage AEs. All AEs reported by investigators were coded according to MedDRA. Event rates (ERs) per 100 patient exposure–years were calculated based on AEs with onset within 28 days (14 days in TOMORROW) after the last dose. Results In the 1126 patients the mean (SD) exposure to nintedanib was 27.7 (20.5) months, max. 93.1 months. Total exposure was 2599 patient–years. AEs that led to permanent dose reduction and permanent discontinuation of nintedanib were 12.8 and 23.8 events per 100 patient exposure–years. ERs reported in the pooled population were generally lower than in the INPULSIS trials (Table). Diarrhea was the most frequent AE. Diarrhea led to permanent dose reduction and permanent discontinuation of nintedanib in 17.2% and 8.8% of patients, respectively. Conclusion Data from the largest set of nintedanib-treated patients with IPF analyzed to date demonstrated that nintedanib had a manageable safety and tolerability profile. Diarrhea was the most frequent AE in patients treated with nintedanib, but was managed without treatment discontinuation in most patients. Tab. 1 AE rates per 100 patient exposure–years Nintedanib pooled population (n = 1126) INPULSIS trials Nintedanib (n = 638) Placebo (n = 423) AE rate > 10 per 100 patient exposure–years pooled. *MedDRA term ‘IPF’, incl. disease worsening/IPF exacerbations. Diarrhea 76.5 112.6 25.6 Nausea 18.0 34.9 7.0 Nasopharyngitis 15.1 19.6 22.0 Bronchitis 14.5 15.5 15.0 Cough 13.2 16.1 16.2 Progression of IPF* 12.9 11.8 17.7 Vomiting 11.2 17.1 2.7 Upper respiratory tract infection 10.1 12.1 13.3 * * presented ATS 2018
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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 | 0.021 | 0.012 |
| Meta-epidemiology (narrow) | 0.002 | 0.000 |
| Meta-epidemiology (broad) | 0.005 | 0.008 |
| Bibliometrics | 0.001 | 0.002 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 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".