Abstract 14024: Results of a Phase I / II Multicenter Investigation of Udenafil in Adolescents After Fontan Palliation
Bibliographic record
Abstract
Introduction: Many pediatric clinical trials fail due to use of sub-therapeutic dosing. This phase I / II clinical trial was designed to evaluate the short-term safety, pharmacokinetics (PK), and preliminary efficacy of udenafil, a phosphodiesterase type 5 inhibitor, in adolescents following Fontan palliation to inform dose selection for a phase III clinical trial. Methods: This was a dose escalation trial with 5 dosing cohorts of 6 subjects each at 37.5 mg, 87.5 mg, and 125 mg daily, as well as 37.5 mg and 87.5 mg twice daily (bid) for 5 days. Efficacy testing (echocardiography, exercise stress test, endothelial function assessment) was performed at baseline and on day 5. A control cohort of 6 subjects underwent exercise testing without drug administration. Serum samples for PK analysis were collected on days 6-8. Adverse events (AE) were recorded throughout the 8-day study period and for 3 months thereafter. Comparison between baseline and day 5 testing was performed using ANOVA and visual trend lines. PK analysis was performed using a non-linear mixed effects model. Results: The trial enrolled 36 subjects at a mean age of 15.8 years (58.3% male). Subject characteristics were similar between cohorts. No drug-related serious AEs were reported during the study period, while 24 subjects had non-serious AEs possibly or probably related to study drug. Headache was the most common, occurring in 20 of the 30 subjects. Other possibly or probably medication related side effects occurring in more than one subject included: facial flushing (10 subjects), nasal congestion (7), spontaneous penile erection (6), nausea (3), and abdominal discomfort (2). The 87.5 mg bid cohort achieved the highest steady state serum concentration (172 ng/mL, range 117-202), the highest maximal concentration (506 +/- 188 ng/mL), and the greatest area under the curve for 24 hours (6701 +/- 1591 ng*hr/mL). Efficacy test results did not change significantly in any cohort. Conclusion: Udenafil was safe and well tolerated at all dosing levels while the 87.5 mg bid cohort achieved the highest serum drug level. With a 5-day treatment period and small sample size no significant clinical changes were observed. These data suggest that the 87.5 mg bid regimen may be most appropriate for a Phase III clinical trial.
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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 | 0.001 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.002 |
| 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".