Threshold Of Regulatory Concern Research Articles

Dasiglucagon Effects on QTc in Healthy Volunteers: A Randomized, Placebo-Controlled, Dose-Escalation, Double-Blind Study

BackgroundDasiglucagon is a novel glucagon analog that is stable in aqueous formulation and approved for use in severe hypoglycemia. Concentration QTc analyses are critical for assessing risk of drug-induced QTc prolongation and potential for fatal cardiac arrhythmias such as torsades de pointes.ObjectiveThe aim of this study was to determine whether dasiglucagon treatment resulted in any clinically relevant effect on cardiac repolarization in healthy volunteers.MethodsThis double-blind, placebo-controlled, dose-escalation Phase I trial was conducted at a single center in Germany between November 2018 and June 2019. Sixty healthy volunteers aged 18 to 45 years were randomized within dose cohorts to receive intravenous dasiglucagon, intravenous placebo, or subcutaneous dasiglucagon. In the intravenous administration cohorts, doses ranged from 0.03 mg to 1.5 mg. The subcutaneous administration cohort received the approved 0.6 mg dose. In the intravenous administration cohorts, serial electrocardiograms were extracted from continuous Holter monitors at prespecified time points beginning the day before dosing and through 24 hours postdose. Heart rate, PR interval, and QRS duration were evaluated. Concentration-QT analyses corrected by Fridericia's formula (QTcF) were performed using both a linear mixed-effects and a maximum estimated effect (Emax) model.ResultsAt the doses studied, dasiglucagon did not have any clinically relevant effect on heart rate, PR interval, or QRS duration. A minor prolongation of the QTcF interval was observed without any clear dose or concentration dependency. Both the linear and Emax models predicted mean and 90% CIs of placebo-corrected change in QTcF remained below 10 ms (the threshold of regulatory concern), although the linear model did not fit the data well at low dasiglucagon plasma concentrations. In the Emax model, the Emax of dasiglucagon was 3.6 ms (90% CI, 1.23–5.95 ms), and the amount to produce half the effect of Emax) was 426.0 pmol/L (90% CI, −48.8 to 900.71 pmol/L). The treatment effect-specific intercept was −0.44 ms (90% CI, −2.37 to 1.49 ms). The most frequently observed treatment-emergent adverse events reported in the trial were gastrointestinal disorders such as nausea and vomiting.ConclusionsDasiglucagon does not cause clinically relevant QTc prolongation in concentrations up to ≈30,000 pmol/L, a level 5-fold higher than the highest observed plasma concentrations in clinical trials investigating use of the approved 0.6 mg SC dose. ClinicalTrials.gov Identifier: NCT03735225; EudraCT identifier: 2018-002025-32. (Curr Ther Res Clin Exp. 2022; 83:XXX–XXX)

Impact of Daridorexant, a Dual Orexin Receptor Antagonist, on Cardiac Repolarization Following Bedtime Dosing: Results from a Thorough QT Study Using Concentration-QT Analysis.

Daridorexant is a new dual orexin receptor antagonist currently in late-stage clinical development for the treatment of insomnia. This randomized, double-blind, placebo-controlled, four-period crossover study investigated the effect of daridorexant at a therapeutic and supratherapeutic dose on QT interval duration. Thirty-six healthy subjects received single oral doses of daridorexant (50mg; 200mg), moxifloxacin (400mg; open label), and placebo. All treatments were administered at bedtime to mimic therapeutic practice. The primary analysis was based on linear mixed-effects concentration-QT modelling. Triplicate ECG data were extracted from Holter recordings at baseline and until 24h post dosing at time points matching those for pharmacokinetic sampling. Plasma concentrations of daridorexant were determined over 24h. Assay sensitivity was demonstrated based on mean baseline- and placebo-corrected QT interval using Fridericia's formula (ΔΔQTcF) >5ms following moxifloxacin administration (p<0.01). Following daridorexant administration, mean (90% confidence interval, CI) ΔΔQTcF was 1.40ms (0.48; 2.32ms) and 1.84ms (-0.12; 3.79ms) at the Cmax of 747ng/mL (50mg dose) and 1809ng/mL (200mg dose), respectively, i.e., the upper bounds of the CIs were<10ms defined as threshold of regulatory concern. Lack of relevant QT prolongation was confirmed by secondary by-time point analysis and absence of relevant findings in the categorical outlier analysis. Daridorexant was safe and well tolerated and its pharmacokinetics were consistent with previous data. Daridorexant does not impair cardiac repolarization evidenced by absence of relevant QT prolongation at therapeutic and supratherapeutic doses. Clinical Trials Registration ID: NCT04250506.

Confirmation of the cardiac safety of nolasiban in a randomised cohort of healthy female volunteers

Nolasiban is an orally active oxytocin receptor antagonist being developed to increase the efficiency of assisted reproductive technologies. This study evaluated the pharmacokinetics, pharmacodynamics, and cardiac safety of nolasiban in 45 healthy women of child-bearing age. Nolasiban was administered in a fasted state with a standardised lunch served 4.5 h post-dose. Concentration-effect modelling was used to assess the effect of two dosages of nolasiban (900 mg and 1800 mg) on QTc following single-dose administration. We found no significant change in QTc at all tested dosages. Two-sided 90% confidence intervals of geometric mean Cmax for estimated QTc effects of nolasiban were below the threshold of regulatory concern. The sensitivity of the assay to detect small changes in QTc was confirmed by a significant shortening of QTc between 2 and 4 h after consumption of a meal, which served to validate the model. Independent of the nolasiban assessment, this study also explored the effects of sex hormones on ECG parameters, especially QT subintervals. We found a significant relationship between JTpc and oestradiol. Heart rate was negatively correlated with progesterone. This study confirms the cardiovascular safety of nolasiban and describes relationships of sex hormones and ECG parameters.

The IQ‐CSRC Prospective Clinical Phase 1 Study: “Can Early QT Assessment Using Exposure Response Analysis Replace the Thorough QT Study?”

A collaboration between the Consortium for Innovation and Quality in Pharmaceutical Development and the Cardiac Safety Research Consortium has been formed to design a clinical study in healthy subjects demonstrating that the thorough QT (TQT) study can be replaced by robust ECG monitoring and exposure-response (ER) analysis of data generated from First-in-Man single ascending dose (SAD) studies. Six marketed drugs with well-characterized QTc effects were identified in discussions with FDA; five have caused QT prolongation above the threshold of regulatory concern. Twenty healthy subjects will be enrolled in a randomized, placebo-controlled study designed with the intent to have similar power to exclude small QTc effects as a SAD study. Two doses (low and high) of each drug will be given on separate, consecutive days to 9 subjects. Six subjects will receive placebo. Data will be analyzed using linear mixed-effects ER models. Criteria for QT-positive drugs will be the demonstration of an upper bound (UB) of the 2-sided 90% confidence interval (CI) of the projected QTc effect at the peak plasma level of the lower dose above the threshold of regulatory concern (currently 10 ms) and a positive slope of ER relationship. The criterion for QT-negative drug will be an UB of the CI of the projected QTc effect of the higher dose <10 ms. It is expected that a successful outcome in this study will provide evidence supporting replacement of the TQT study with ECG assessments in standard early clinical development studies for a new chemical entity.

Preladenant, a selective adenosine A2A receptor antagonist, is not associated with QT/QTc prolongation

Preladenant is an orally administered adenosine2A (A2A) receptor antagonist in phase III development for Parkinson's disease treatment. This thorough QT/QTc study evaluated its potential effects on cardiac repolarization. This was a randomized, double-blind, positive- and placebo-controlled, four-period crossover study performed under steady-state exposure of clinical and supratherapeutic doses of preladenant (10 mg BID and 100 mg BID, respectively, for 5 days), moxifloxacin (400 mg on day 5), or placebo in 60 healthy adult volunteers. The potential effect on QTcF was measured by the largest upper bound of 95 % one-sided CIs for the mean changes from time-matched baseline ECG recordings compared with placebo. Plasma preladenant concentrations were also determined on day 5. The QTcF difference for moxifloxacin compared with placebo exceeded 5 ms from 1 to 12 h postdose, establishing assay sensitivity. The QTcF interval was similar between the preladenant and placebo treatment groups: the upper bound of the 95 % one-sided CI for the mean difference in QTcF between preladenant and placebo was less than 10 ms at all time points for the supratherapeutic treatment group (1.3 to 5.7 ms, mean difference: -1.3 to 2.7 ms) and the therapeutic treatment group (0.4 to 4.3 ms, mean difference: -2.1 to 1.5 ms), substantially below the threshold of regulatory concern. The supratherapeutic dose (100 mg BID) provided a Cmax margin of 6.1-fold and AUC margin of 6.9-fold, respectively, compared with 10 mg BID. At clinical and supratherapeutic doses, preladenant is not associated with QTc prolongation.

Abstract 1189: Phase I (phI) study evaluating the cardiac safety of oral chemotherapy s-1 in patients (pts) with advanced solid tumors.

Abstract The incidence of cardiotoxicity (CTx) due to 5FU varies in the literature ranging from 1-68% of pts. Angina-like chest pain is the most common symptom of 5FU associated CTx. Cardiac arrhythmias, congestive heart failure, myocardial infarction, dilatative cardiomyopathy, cardiogenic shock, cardiac arrest or sudden death have been also reported. Most cases occur during or following initial treatment (trt) courses. Only 18% of pts developing CTx have a history of underlying cardiac disease. Capecitabine (Oral 5FU) is also associated with a non-negligible incidence (3-9%) of CTx (E. Yeh. JACC 2009). S-1 is a new oral formulation combining a 5FU prodrug (tegafur) and 2 targeted modulators of its metabolism (gimeracil and oteracil) to preserve efficacy and improve safety. We report the results of a European Ph1, evaluating the effect of S-1 on cardiac repolarization evaluated during S-1 trt under controlled conditions with assessment of 24hour (h) Holter monitor (HM) electrocardiograms (ECGs). Study design: Pts received S-1 30mg/m2 dose BID D1 to 14 q3w. This trial investigated the effect of S-1 vs baseline and placebo on cardiac repolarization QTc (corrected QT interval). During cycle 1, pts were assessed via 24h HM ECGs monitoring after each dose of S-1. Results: 56 pts with advanced solid tumors were enrolled and final cardiac safety results analyzed on 49 pts: - The 1-sided 95% upper confidence boundaries for QTc changes were completely within the 10 msec boundaries set by the ICH guideline. - Mean changes relative to placebo (adjusted for baseline) following single-dose of S-1 did not indicate any effect on QTc. -Following multiple dosing with S-1, any mean increases in QTc relative to placebo were below the threshold of regulatory concern. Forty two (75.0%) pts reported 225 adverse events (AEs). Only 5 pts (8.9%) experienced trt-related Grade 3 or higher including anemia, neutropenia and diarrhea. Discontinuation of trt: 1 pt (Hand foot syndrome Gr2). No cardiac SAEs or trt-related AEs were observed. No syncope or arrhythmia reported (Gr1 atrial fibrillation: 1 pt and Gr1 tachycardia: 1 pt, unrelated to trt). S-1 was well-tolerated in heavily treated pts, with no unexpected trt-related AE that resulted in death or AEs leading to discontinuation of trt. Conclusion: No effect on cardiac repolarization was observed among the 49 pts analysed and no cardiac SAE was reported. The good cardiac safety profile of S-1 is also supported by a survey performed in Japan on more than 4,000 pts treated with S-1 (F. Nagashima. IJGC 2005). No more than 0.2% all grades and 0.05% Gr3-4 cardiac events were observed, which compare favorably with the incidences reported for this class of drugs. In the context of published fluoropyrimidines related-cardiotoxicity, S-1 is probably a good option to treat patients efficiently with a low risk of severe cardiac event. Citation Format: Mario Campone, Jean Sébastien Frenel, Mikhail. R Lichinitser, Vera Gorbunova, Fabio Benedetti. Phase I (phI) study evaluating the cardiac safety of oral chemotherapy s-1 in patients (pts) with advanced solid tumors. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1189. doi:10.1158/1538-7445.AM2013-1189

Repeated supratherapeutic dosing of strontium ranelate over 15 days does not prolong QTc interval in healthy volunteers

The study was performed to assess the safety of strontium ranelate in accordance with the ICH, E14 guidelines for QT/QT(c) studies. Its primary objective was to compare supratherapeutic repeated dosing of strontium ranelate (4 g day⁻¹ for 15 days) with placebo on the largest time-matched mean QT(c) variation, from baseline to under treatment values, in healthy subjects. Ninety-six healthy male and female subjects (27.7 ± 7.5 years) were included to receive 1 day of placebo followed by 15 days of supratherapeutic repeated dosing of strontium ranelate (4 g day⁻¹), in a 4 month, randomized, placebo (16 days) and positive-controlled (single dose of moxifloxacin 400 mg preceded by 15 days of placebo), double-blind, double dummy, crossover design. Measurement of QT interval was performed automatically on the ECGs with subsequent manual onscreen over-reading by cardiologists using electronic callipers. The largest time-matched difference in QT(c) I (individual QT correction for heart rate) between moxifloxacin 400 mg and placebo was observed at 2 h post dose (mean [95% CI] 10.62 [7.90, 13.35] ms). For strontium ranelate (4 g day⁻¹) the largest time-matched difference in QT(c) I compared with placebo was observed at 1 h post dose (mean [90% CI] 7.54 [5.17, 9.90] ms). No subject had a QT(c) greater than 480 ms during the study. Both moxifloxacin and strontium ranelate were well tolerated in healthy subjects. The findings of this study demonstrate that the administration of supratherapeutic repeated oral doses of strontium ranelate (4 g day⁻¹ for 15 days) does not lead to a prolongation of the QT/QT(c) interval above the threshold of regulatory concern.

Testing for Positive Control Activity in a Thorough QTc Study*

The ICH E14 guidance (ICH, 2005) recommend that a concurrent positive control should be included in a thorough QTc clinical trial to validate the study. The ICH E14 guidance (ICH, 2005) state that “The positive control should have an effect on the mean QTc interval of about 5 ms (i.e., an effect that is close to the QTc effect that represents the threshold of regulatory concern, around 5 ms)”. This task may be carried out through some statistical tests. The current practice is to test at each time point where QT measurements are collected. This method is usually not efficient. In this article, I discuss two types of statistical procedures. The first one is a local statistical test to make a time-point-specific claim, i.e., to claim a mild QTc effect due to the positive control at some specific time points. A different approach, named as a global test, is also proposed, to make a general claim that the mean difference of the positive control and placebo after baseline adjustment will be about 5 ms without specifying at which time points. An example will be used to illustrate how to apply the two procedures. How to best allocate sample size in a parallel QTc study is also discussed in this paper.