Correction for QT/RR Hysteresis in the Assessment of Drug‐Induced QTc Changes—Cardiac Safety of Gadobutrol
Bibliographic record
Abstract
BACKGROUND: The so-called thorough QT/QTc (TQT) studies required for every new pharmaceutical compound are negative if upper single-sided 95% confidence interval (CI) of placebo and baseline corrected QTc prolongation is <10 ms. This tight requirement has many methodological implications. If the investigated drug has a fast action and ECGs cannot be obtained at stable heart rates, QT/RR hysteresis correction is needed. METHODS: This was used in a TQT study of gadobutrol. The TQT study was a randomized double-blind five-times crossover study of three doses of gadobutrol (0.1, 0.3, and 0.5 mmol/kg) that was placebo and positive effect controlled (moxifloxacin 400 mg). The study enrolled 50 healthy subjects with data of all periods. QT/RR hysteresis was assessed from prestudy exercise test ECGs. Among others, comparisons were made between population heart rate correction without hysteresis considerations and combined population heart rate and hysteresis correction. RESULTS: The highest heart rate increase (placebo and baseline controlled) of 13.1 beats per minute (90% CI 9.9-16.4) occurred 1 minute after the administration of the highest dose of gadobutrol. Without hysteresis consideration, the highest DeltaDeltaQTc were 9.91 ms (90% CI 8.01-11.81) while with hysteresis correction, these values were 7.62 ms (90% CI 6.37-8.87), thus turning a marginally positive TQT study into a negative finding. CONCLUSION: Hence, omitting hysteresis correction from episodes of fast heart rate changes may lead to incorrect conclusions. Despite substantial rate acceleration, accurate hysteresis correction confirms that gadobutrol does not have any effects on cardiac repolarization that would be within the limits of regulatory relevance.
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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 | 0.012 | 0.018 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.000 |
| 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".