Jørgen Matz

Quantitative Analysis of T‐wave Morphology Increases Confidence in Drug‐Induced Cardiac Repolarization Abnormalities: Evidence From the Investigational IKr Inhibitor Lu 35–138

This study investigates repolarization changes induced by a new candidate drug to determine whether a composite electrocardiographic (ECG) measure of T‐wave morphology could be used as a reliable marker to support the evidence of abnormal repolarization, which is indicated by QT interval prolongation. Seventy‐nine healthy subjects were included in this parallel study. After a baseline day during which no drug was given, 40 subjects received an IKr‐blocking antipsychotic compound (Lu 35–138) on 7 consecutive days while 39 subjects received placebo. Resting ECGs were recorded and used to determine a combined measure of repolarization morphology (morphology combination score [MCS]), based on asymmetry, flatness, and notching. Replicate measurements were used to determine reliable change and study power for both measures. Lu 35–138 increased the QTc interval with corresponding changes in T‐wave morphology as determined by MCS. For subjects taking Lu 35–138, T‐wave morphology was a more reliable indicator of IKr inhibition than QTcF (χ2 = 20.3, P = .001). At 80% study power for identifying a 5‐millisecond placebo‐adjusted change from baseline for QTcF, the corresponding study power for MCS was 93%. As a covariate to the assessment of QT interval liability, MCS offered important additive information to the effect of Lu 35–138 on cardiac repolarization.

Covariate analysis of QTc and T-wave morphology: new possibilities in the evaluation of drugs that affect cardiac repolarization

This study adds the dimension of a T‐wave morphology composite score (MCS) to the QTc interval–based evaluation of drugs that affect cardiac repolarization. Electrocardiographic recordings from 62 subjects on placebo and 400 mg moxifloxacin were compared with those from 21 subjects on 160 and 320 mg D,L‐sotalol. T‐wave morphology changes, as assessed by ΔMCS, are larger after 320 mg D,L‐sotalol than after 160 mg D,L‐sotalol; and the changes associated with 160 mg D,L‐sotalol are, in turn, larger than those associated with moxifloxacin and placebo. Covariate analyses of ΔQTc and ΔMCS showed that changes in T‐wave morphology are a significant effect of D,L‐sotalol. By contrast, moxifloxacin was found to have no significant effect on T‐wave morphology (ΔMCS) at any given change in QTc. This study offers new insights into the repolarization behavior of a drug associated with low cardiac risk vs. one associated with a high risk and describes the added benefits of a T‐wave MCS as a covariate to the assessment of the QTc interval.

Effect of nalmefene 20 and 80 mg on the corrected QT interval and T-wave morphology: a randomized, double-blind, parallel-group, placebo- and moxifloxacin-controlled, single-centre study.

BACKGROUND Nalmefene is an orally administered competitive opioid receptor antagonist targeted at reducing alcohol consumption in alcohol-dependent patients. As part of the regulatory requirements for drug approval, the potential of novel compounds for causing unwanted proarrhythmia should be studied in a thoroughly designed clinical QT/corrected QT (QTc) study (International Conference on Harmonisation [ICH] E14 guideline). OBJECTIVE This study was designed to evaluate whether nalmefene 20 and 80 mg/day induced changes in cardiac repolarization biomarkers indicative of proarrhythmia (the QTc interval and T-wave morphology). METHODS This was a prospective, randomized, double-blind, parallel-group, placebo- and moxifloxacin-controlled, single-centre study carried out in a clinical pharmacology unit. The study included 270 healthy male and female subjects (age 18-45 years). The subjects were randomized to a 7-day treatment period of placebo, nalmefene 20 mg/day or nalmefene 80 mg/day, or placebo for 6 days followed by a single dose of moxifloxacin 400 mg on day 7. Serial triplicate ECGs were obtained over a 24-hour period at protocol-defined time-points. The primary protocol-defined endpoint was the largest time-matched baseline- and placebo-adjusted mean difference in the individually heart rate-corrected QT interval (QTcNi) recorded at any of the 12 ECG time-points distributed over a 24-hour period on day 7 of treatment. Secondary endpoints included a similar analysis using the Fridericia- (QTcF) and Bazett-corrected (QTcB) intervals. An explorative analysis included quantitative assessment of T-wave morphology using the T-wave morphology composite score (MCS) to assess for differences between treatment groups and placebo on day 7 of treatment. The frequency of outliers in the QTc intervals, the pharmacokinetics of nalmefene and the tolerability of nalmefene were also assessed. RESULTS Nalmefene was rapidly absorbed with a time to reach maximum plasma concentration of 2.2 hours and a dose-proportionate relationship between dose administered and exposure. The largest baseline- and placebo-adjusted mean changes from baseline in the individualized QTcNi (primary endpoint) were 5.45 ms (90% CI 1.52, 9.37) and 5.57 ms (90% CI 1.62, 9.52) for nalmefene 20 and 80 mg/day, respectively, with study sensitivity confirmed by the expected largest increase in mean QTcNi of 10.15 ms (90% CI 5.67, 14.63) for moxifloxacin. Quantitative assessment using the T-wave MCS demonstrated the largest baseline- and placebo-adjusted increase in MCS to be non-significantly different from the intra-subject variability of triplicate recordings in the placebo group. No deaths or serious adverse events occurred in the study. CONCLUSION This thorough QT/QTc study was a negative study in accordance with the ICH E14 guideline, meaning that nalmefene has no clinically relevant effect on the QTc interval and T-wave morphology. The study predicts no concern over proarrhythmia or need for intensive QTc monitoring with the use of nalmefene in clinical practice.

Effect of Nalmefene 20 and 80 mg on the Corrected QT Interval and T-Wave Morphology

AbstractBackground: Nalmefene is an orally administered competitive opioid receptor antagonist targeted at reducing alcohol consumption in alcohol-dependent patients. As part of the regulatory requirements for drug approval, the potential of novel compounds for causing unwanted proarrhythmia should be studied in a thoroughly designed clinical QT/corrected QT (QTc) study (International Conference on Harmonisation [ICH] E14 guideline). Objective: This study was designed to evaluate whether nalmefene 20 and 80 mg/day induced changes in cardiac repolarization biomarkers indicative of proarrhythmia (the QTc interval and T-wave morphology). Methods: This was a prospective, randomized, double-blind, parallel-group, placebo- and moxifloxacin-controlled, single-centre study carried out in a clinical pharmacology unit. The study included 270 healthy male and female subjects (age 18–45 years). The subjects were randomized to a 7-day treatment period of placebo, nalmefene 20 mg/day or nalmefene 80 mg/day, or placebo for 6 days followed by a single dose of moxifloxacin 400 mg on day 7. Serial triplicate ECGs were obtained over a 24-hour period at protocol-defined time-points. The primary protocol-defined endpoint was the largest time-matched baseline- and placebo-adjusted mean difference in the individually heart rate-corrected QT interval (QTcNi) recorded at any of the 12 ECG time-points distributed over a 24-hour period on day 7 of treatment. Secondary endpoints included a similar analysis using the Fridericia-(QTcF) and Bazett-corrected (QTcB) intervals. An explorative analysis included quantitative assessment of T-wave morphology using the T-wave morphology composite score (MCS) to assess for differences between treatment groups and placebo on day 7 of treatment. The frequency of outliers in the QTc intervals, the pharma-cokinetics of nalmefene and the tolerability of nalmefene were also assessed. Results: Nalmefene was rapidly absorbed with a time to reach maximum plasma concentration of 2.2 hours and a dose-proportionate relationship between dose administered and exposure. The largest baseline- and placebo-adjusted mean changes from baseline in the individualized QTcNi (primary endpoint) were 5.45 ms (90% CI 1.52, 9.37) and 5.57 ms (90% CI 1.62, 9.52) for nalmefene 20 and 80mg/day, respectively, with study sensitivity confirmed by the expected largest increase in mean QTcNi of 10.15 ms (90% CI 5.67, 14.63) for moxifloxacin. Quantitative assessment using the T-wave MCS demonstrated the largest baseline- and placebo-adjusted increase in MCS to be non-significantly different from the intra-subject variability of triplicate recordings in the placebo group. No deaths or serious adverse events occurred in the study. Conclusion: This thorough QT/QTc study was a negative study in accordance with the ICH E14 guideline, meaning that nalmefene has no clinically relevant effect on the QTc interval and T-wave morphology. The study predicts no concern over proarrhythmia or need for intensive QTc monitoring with the use of nalmefene in clinical practice.

Cardiac effects of sertindole and quetiapine: Analysis of ECGs from a randomized double-blind study in patients with schizophrenia

The QT interval is the most widely used surrogate marker for predicting TdP; however, several alternative surrogate markers, such as Tpeak-Tend (TpTe) and a quantitative T-wave morphology combination score (MCS) have emerged. This study investigated the cardiac effects of sertindole and quetiapine using the QTc interval and newer surrogate markers. Data were derived from a 12 week randomized double-blind study comparing flexible dosage of sertindole 12-20mg and quetiapine 400-600mg in patients with schizophrenia. ECGs were recorded digitally at baseline and after 3, 6 and 12 weeks. Between group effects were compared by using a mixed effect model, whereas assessment within group was compared by using a paired t-test. Treatment with sertindole was associated with QTcF and QTcB interval prolongation and an increase in MCS, T-wave asymmetry, T-wave flatness and TpTe. The mean increase in QTcF from baseline to last observation was 12.1ms for sertindole (p<0.001) and -0.5ms for quetiapine (p=0.8). Quetiapine caused no increase in MCS, T-wave asymmetry, T-wave flatness or TpTe compared to baseline. In the categorical analysis, there were 11 patients (9.6%) receiving quetiapine who experienced more than 20ms QTcF prolongation compared with 36 patients (33.3%) in the sertindole group. Sertindole (12-20mg) was associated with moderate QTc prolongation and worsening of T-wave morphology in a study population of patients with schizophrenia. Although, quetiapine (400-600mg) did not show worsening of repolarization measures some individual patients did experience significant worsening of repolarization. Clinical Trials NCT00654706.

Sensitivity of T-wave morphology and the QT interval to small drug-induced electrocardiographic changes

The electrocardiographic QT interval is the only widely used surrogate marker of repolarization abnormality in drug trials. However, numerous basic and clinical studies have provided evidence that disturbed ventricular repolarization is reflected not only in the duration of the QT interval but also in the shape of the electrocardiographic T-wave. Thus, in order to elucidate the full spectrum of drug-induced repolarization changes, it is pertinent to perform a thorough analysis of T-wave morphology changes in addition to measuring the QT interval. We present a computerized method for quantification of drug-induced T-wave morphology changes. Our results provide evidence that the shape of the T-wave can be a more sensitive marker of disturbed repolarization than QT interval prolongation. Effect sizes for T-wave morphology changes, 1.58plusmn0.30 (meanplusmnSD) were 1.8 times larger than those for QTcF, 0.87plusmn0.14, p=0.0013.

The T-peak–T-end Interval as a Marker of Repolarization Abnormality: A Comparison with the QT Interval for Five Different Drugs

Background and ObjectiveThe T-peak to T-end (TpTe) interval has been suggested as an index of transmural dispersion and as a marker of drug-induced abnormal repolarization. In this study, we investigate the relation between TpTe and the QT interval.MethodsElectrocardiograms (ECGs) from five different drugs (sotalol, sertindole, moxifloxacin, nalmefene, and Lu 38-135) and from a placebo group were analyzed. Semi-automatic measurements of T-peak, T-end, and QRS onset were obtained. The TpTe/QT ratio was calculated to investigate the proportional relationship of QT and TpTe.ResultsAlthough a significant increase of both TpTe and QT from baseline is apparent with QT-prolonging drugs, the TpTe/QT ratio remained the same at baseline and after drug administration, thus indicating that prolongation of TpTe is just a fractional part of total QT prolongation. In the presence of notched or flattened T-waves, the uncertainty associated with measurement of the TpTe interval increases. The errors in TpTe for individual subjects may be substantial, thus complicating the use of TpTe for follow-up of individuals.ConclusionsThe duration of the QT interval and TpTe are closely related. Drugs appear to prolong the TpTe interval as a predictable fraction of the total QT prolongation.