QTcF Interval Research Articles

Clinical analysis of adverse reactions in patients with multidrug-resistant and rifampicin-resistant pulmonary tuberculosis treated with delamanid-containing regimen

Objective: To explore the characteristics of adverse drug reactions during the 24-week therapy with delamanid-containing regimen for patients with multidrug-resistant and rifampicin-resistant pulmonary tuberculosis (MDR/RR-PTB). Methods: The prospective multicenter study was conducted from June 2020 to June 2023. A total of 608 eligible patients with MDR/RR-PTB were enrolled in 26 tuberculosis medical institutions in China including 364 males and 79 females, aged 39.6(19.0-68.0) years. Patients were treated with chemotherapy regimens containing delamanid. Patients were closely supervised during treatment of medication, and all adverse reactions occurring during treatment were monitored and recorded. The clinical characteristics of adverse reactions were evaluated by descriptive analysis. Chi-square test and multivariate logistic regression were used to analyze the related factors of QTcF interval prolongation (QT corrected with Fridericia's formula). Results: Of the 608 patients enrolled in this study, 325 patients (53.5%) reported 710 adverse events within 24 weeks of treatment. The top 6 most common complications were hematological abnormalities (143 patients, 23.5%), QT prolongation (114 patients, 18.8%), liver toxicity (85 patients, 14.0%), gastrointestinal reaction (41 patients, 6.7%), peripheral neuropathy (25 patients, 4.1%) and mental disorders (21 patients, 3.5%). The prolongation of QT interval mostly occurred in the 12th week after the first dose of medication. Serious adverse reactions occurred in 21 patients (3.5%). There were 7 patients (1.2%) with mental disorders, including 2 patients (0.3%) with severe mental disorders. Conclusions: The safety of dalamanid-based regimen in the staged treatment of MDR/RR-PTB patients was generally good, and the incidence of adverse reactions was similar to that reported in foreign studies. This study found that the incidence of QT interval prolongation in Chinese patients was higher than that reported overseas, suggesting that the monitoring of electrocardiogram should be strengthened when using drugs containing delamanid that may cause QT interval prolongation.

Concentration-QTc and cardiac safety analysis of single and multiple zavegepant nasal spray doses in healthy participants to support approval.

Zavegepant is a novel gepant administered as a nasal spray approved in the United States at a 10 mg dose for the acute treatment of migraine with or without aura in adults. The cardiovascular safety of zavegepant nasal spray was assessed in both single-ascending dose (SAD) and multiple-ascending dose (MAD) studies in healthy participants. The SAD study included 72 participants (54 active/18 placebo) who received 0.1-40 mg zavegepant or placebo. The MAD study included 72 participants (56 active/16 placebo) who received 5-40 mg zavegepant or placebo for 1-14 days. Plasma zavegepant pharmacokinetics and electrocardiographic (ECG) parameters (Fridericia-corrected QT interval [QTcF], heart rate, PR interval, ventricular depolarization [QRS], T-wave morphology, and U-wave presence) were analyzed pre- and post-zavegepant administration. Using pooled data from the SAD and MAD studies, the relationship between time-matched plasma zavegepant concentrations and QTc interval was assessed using a linear mixed-effects model to evaluate the potential for QTc interval prolongation. Results showed that single and multiple doses of zavegepant had no significant impact on ECG parameters versus placebo, and there was no concentration-dependent effect on QTcF interval. The estimated slope of the plasma zavegepant concentration-QTcF model was -0.053 ms per ng/mL with a 90% confidence interval of -0.0955 to -0.0110 (p = 0.0415), which is not considered clinically meaningful. At doses up to four times the recommended daily dose, zavegepant does not prolong the QT interval to any clinically relevant extent.

Concentration-QTcF Modeling of Icenticaftor from a Randomized, Placebo- and Positive-Controlled Thorough QT Study in Healthy Participants.

Icenticaftor (QBW251) is a potentiator of the cystic fibrosis transmembrane receptor. Based on its mechanism of action, icenticaftor is expected to provide benefits in patients with chronic obstructive pulmonary disease by restoring mucociliary clearance, which would eventually lead to a reduction of bacterial colonization and related inflammatory cascade. A placebo- and positive-controlled, 4-way crossover thorough QT study was conducted in 46 healthy participants with the objective to assess the effect of therapeutic (300mg twice daily for 6 days) and supratherapeutic (750mg twice daily for 6 days) oral doses of icenticaftor on electrocardiogram parameters, including concentration-corrected QT (QTc) analysis. Moxifloxacin (400mg, oral) was used as a positive control. In the concentration-QTc analysis performed on pooled data from Day 1 and Day 6 (steady state), the estimated population slope was shallow and slightly negative: -0.0012ms/ng/mL. The effect on the Fridericia corrected QT (QTcF) interval (∆ΔQTcF) was predicted to be -1.3milliseconds at the icenticaftor 300-mg twice-daily peak concentration (geometric mean was 1094ng/mL) and -5.5milliseconds at the 750-mg twice-daily peak concentration (geometric mean Cmax was 4529ng/mL) indicated a mild shortening effect of icenticaftor on QTcF interval length. The results of the by-time-point analysis indicated least squares placebo corrected mean ∆∆QTcF across time points ranged from -7.9 to 0.1milliseconds at 1 and 24hours after dosing both on Day 6 in the 750-mg dose group compared with -3.7 to 1.6milliseconds at 1.5 and 24 hours after dosing on Day1 in the 300-mg dose group. Assay sensitivity was demonstrated with moxifloxacin. The large accumulation of exposures, especially the 4.3-fold increase in peak plasma concentration observed at the icenticaftor 750-mg twice-daily dosage compared with Icenticaftor 300mg twice daily (2.3-fold) on Day 6 provided a large concentration range (up to 9540ng/mL) to evaluate the effect of icenticaftor on ΔΔQTcF. Based on the concentration-QTc analysis, an effect on ΔΔQTcF exceeding 10milliseconds can be excluded within the full observed ranges of plasma concentrations on icenticaftor, up to approximately 9540ng/mL. Icenticaftor at the studied doses demonstrated a mild shortening in QTcF, which is unlikely to be of clinical relevance in a therapeutic setting.

Use of Pharmacokinetic and Pharmacodynamic Data to Develop the CDK4/6 Inhibitor Ribociclib for Patients with Advanced Breast Cancer.

Ribociclib is an orally bioavailable, selective cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor. CDK4/6inhibition by ribociclib leads to retinoblastoma tumor suppressor protein (Rb) reactivation, thereby restoring Rb-mediated cell cycle arrest. Ribociclib is approved for the treatment of patients with hormone receptor-positive/human epidermal growth factor receptor-2-negative (HR+/HER2-) advanced breast cancer (ABC), at the dose of 600mg once daily (QD) during cycles of 21days on/7days off, with optional dose reduction to 400 mgand 200mg. Ribociclib is rapidly absorbed with a median time to reach maximum plasma concentration of 2.4h, mean half-life of 32.0h and oral bioavailability of 65.8% at 600mg. It is eliminated mainly by hepatic metabolism (~84% of total elimination), mostly by cytochrome P450 (CYP) 3A4. Age, body weight, race, baseline Eastern Cooperative Oncology Group status, food, mild hepatic impairment, mild-to-moderate renal impairment, proton pump inhibitors, and combination partners (non-steroidal aromatase inhibitors or fulvestrant) have no clinically relevant impact on ribociclib exposure. Ribociclib inhibits CYP3A at 600mg leading to increased exposure of CYP3A substrates. Strong CYP3A inhibitors or inducers increase or decrease, respectively, ribociclib exposure. Exposure-safety and exposure-efficacy analyses support the clinical benefit of the 600mg QD starting dose, with potential individualized dose reductions to 400 mgand 200mg for effective management of the adverse events neutropenia and QTcF interval prolongation, while maintaining efficacy, in patients with HR+/HER2- ABC. Overall, these clinical pharmacology data informed ribociclib dose justification and clinical development, as well as its prescribing information for clinical use in advanced breast cancer patients.

Inhibition of the KCa2 potassium channel in atrial fibrillation: a randomized phase 2 trial

Existing antiarrhythmic drugs to treat atrial fibrillation (AF) have incomplete efficacy, contraindications and adverse effects, including proarrhythmia. AP30663, an inhibitor of the KCa2 channel, has demonstrated AF efficacy in animals; however, its efficacy in humans with AF is unknown. Here we conducted a phase 2 trial in which patients with a current episode of AF lasting for 7 days or less were randomized to receive an intravenous infusion of 3 or 5 mg kg−1 AP30663 or placebo. The trial was prematurely discontinued because of slow enrollment during the coronavirus disease 2019 pandemic. The primary endpoint of the trial was cardioversion from AF to sinus rhythm within 90 min from the start of the infusion, analyzed with Bayesian statistics. Among 59 patients randomized and included in the efficacy analyses, the primary endpoint occurred in 42% (5 of 12), 55% (12 of 22) and 0% (0 of 25) of patients treated with 3 mg kg−1 AP30663, 5 mg kg−1 AP30663 or placebo, respectively. Both doses demonstrated more than 99.9% probability of superiority over placebo, surpassing the prespecified 95% threshold. The mean time to cardioversion, a secondary endpoint, was 47 (s.d. = 23) and 41 (s.d. = 24) minutes for 3 mg kg−1 and 5 mg kg−1 AP30663, respectively. AP30663 caused a transient increase in the QTcF interval, with a maximum mean effect of 37.7 ms for the 5 mg kg−1 dose. For both dose groups, no ventricular arrhythmias occurred and adverse event rates were comparable to the placebo group. AP30663 demonstrated AF cardioversion efficacy in patients with recent-onset AF episodes. KCa2 channel inhibition may be an attractive mechanism for rhythm control of AF that should be studied further in randomized trials. ClinicalTrials.gov registration: NCT04571385.

Diagnostic Accuracy of Single-Lead Electrocardiograms Using the Kardia Mobile App and the Apple Watch 4: Validation Study.

To date, the 12-lead electrocardiogram (ECG) is the gold standard for cardiological diagnosis in clinical settings. With the advancements in technology, a growing number of smartphone apps and gadgets for recording, visualizing, and evaluating physical performance as well as health data is available. Although this new smart technology is innovative and time- and cost-efficient, less is known about its diagnostic accuracy and reliability. This study aimed to examine the agreement between the mobile single-lead ECG measurements of the Kardia Mobile App and the Apple Watch 4 compared to the 12-lead gold standard ECG in healthy adults under laboratory conditions. Furthermore, it assessed whether the measurement error of the devices increases with an increasing heart rate. This study was designed as a prospective quasi-experimental 1-sample measurement, in which no randomization of the sampling was carried out. In total, ECGs at rest from 81 participants (average age 24.89, SD8.58 years; n=58, 72% male) were recorded and statistically analyzed. Bland-Altman plots were created to graphically illustrate measurement differences. To analyze the agreement between the single-lead ECGs and the 12-lead ECG, Pearson correlation coefficient (r) and Lin concordance correlation coefficient (CCCLin) were calculated. The results showed a higher agreement for the Apple Watch (mean deviation QT: 6.85%; QT interval corrected for heart rate using Fridericia formula [QTcF]: 7.43%) than Kardia Mobile (mean deviation QT: 9.53%; QTcF: 9.78%) even if both tend to underestimate QT and QTcF intervals. For Kardia Mobile, the QT and QTcF intervals correlated significantly with the gold standard (rQT=0.857 and rQTcF=0.727; P<.001). CCCLin corresponded to an almost complete heuristic agreement for the QT interval (0.835), whereas the QTcF interval was in the range of strong agreement (0.682). Further, for the Apple Watch, Pearson correlations were highly significant and in the range of a large effect (rQT=0.793 and rQTcF=0.649; P<.001). CCCLin corresponded to a strong heuristic agreement for both the QT (0.779) and QTcF (0.615) intervals. A small negative correlation between the measurement error and increasing heart rate could be found of each the devices and the reference. Smart technology seems to be a promising and reliable approach for nonclinical health monitoring. Further research is needed to broaden the evidence regarding its validity and usability in different target groups.

Imeglimin: A Clinical Pharmacology Review.

Imeglimin (PXL008, EMD-387008, Twymeeg®) is a first-in-class novel oral hypoglycemic agent, launched in Japan, for the treatment of type 2 diabetes mellitus. Its mechanism of action targets mitochondrial bioenergetics to ameliorate insulin resistance and to enhance β-cell function. This review summarizes the properties underlying the pharmacokinetic profile of imeglimin, a small cationic drug belonging to the tetrahydrotriazine chemical class, with a complex mechanism of absorption involving an active transport through organic cation transporters (OCTs). Imeglimin absorption decreases when dose increases due to the saturation of the active uptake transport. Post absorption, imeglimin is rapidly and primarily distributed to organs and tissues, and has a half-life ranging from 9.03 to 20.2h. Plasma protein binding of imeglimin is low, which explains the rapid distribution to the organs observed in all species. Imeglimin is excreted unchanged in urine, indicating a low extent of metabolism. Imeglimin is a substrate of multidrug and toxic compound extrusion (MATE)2-K and a substrate and inhibitor of OCT1, OCT2, and MATE1. Clinical drug-drug interaction studies confirmed the absence of relevant clinical interaction with substrates or inhibitors of these transporters. Overall, the drug-drug interaction potential of imeglimin is low. Its pharmacokinetics profile has also been characterized in special populations, showing no influence of mild and moderate hepatic impairment but an impact of renal function on imeglimin renal clearance. Dosage adjustment is thus required in moderately and severely renally impaired patients. Imeglimin pharmacokinetics was shown to be insensitive to ethnicity and food intake and to have no effect on QTcF interval.

Heart rate stability in a clinical setting and after a short exercise in healthy male volunteers.

Limited data exist on heart rate stabilization in the domiciled nature of phase I clinical studies, particularly when frequent measurements of QT intervals are involved. The present analysis aimed to evaluate heart rate stability in the domiciled nature of, and stabilization after a short exercise. Fifty-six healthy male subjects were included in this analysis. Data during a domiciled clinical setting and after a short exercise were analysed. Mean values of 30 s intervals of collected electrocardiographical data (PR, RR, QT and QTcF intervals) during a 10-min supine resting period in a domiciled nature or after walking up and down three stories (100 steps) were compared to baseline values using paired t-tests or compared to the intrasubject standard deviation. Stable heart rates and stable QTcF intervals observed immediately upon assuming a supine position in the domiciled clinical setting. After the short exercise, PR interval and RR interval were significantly (p < 0.05) shorter for up to 120 s (mean value -9.8 ± 7.2 ms) and 30 s (-160 ± 165 ms, p < 0.05), respectively. QT and QTcF intervals were significantly (p < 0.05) shorter for up to 90 and 120 s postexercise, respectively. Both QT and QTcF intervals stabilized after 2 min, but QT interval remained prolonged while QTcF interval returned to baseline levels. In a clinical setting, male volunteers do not require a waiting period for electrocardiographic parameter normalization. However, accurate measurement of these parameters following a short exercise necessitates a minimum 2-min resting interval.

Characterisation of the Cardiovascular Effects of a Meal: QTcF Assessment and Further Insights into the Physiological Effects

The electrical activity of the heart, characterised by the QT interval on an electrocardiogram (ECG), serves as a crucial parameter for evaluating cardiac health. Variations in the QT interval, particularly when corrected for heart rate using Fridericia's formula (QTcF), have long been of interest in cardiology and play a pivotal role in assessing cardiac safety in clinical trials. Understanding the influence of meals given at different times on QTcF intervals is essential for the accurate execution of Thorough QT (TQT) studies. Moreover, it has been proposed that this meal-related QT interval shortening could serve as a valuable indicator of assay sensitivity in TQT studies or even as a potential integration of TQT investigations into in Phase I/II studies. This study explores the impact of meals on QTcF intervals, specifically in the context of pharmacodynamic studies and TQT investigations. The primary goal is to gain insights into how different meals and baseline calculations affect QTcF changes and their potential implications for cardiac health and the risk of arrhythmias. Recent research has begun shedding light on the intricate relationship between meal composition, timing, and QTcF alterations. Several studies have investigated the effects of various nutrients, such as carbohydrates, fats, and proteins, on QTcF duration, as well as the implications of postprandial changes. These investigations have unveiled the complex interplay between dietary components and the cardiovascular system, raising essential questions about how our dietary choices may influence cardiac electrophysiology. In this comprehensive meta-analysis, we analyse data from nine studies, all conducted in accordance with Good Clinical Practice and ethical standards. These studies were approved by Ethics Committees and Regulatory authorities. Our analysis focuses on ECG assessments, involving the use of 12-lead ECGs recorded electronically and evaluated by certified cardiologists. We apply the Fridericia formula for QT correction (QTcF), as it has been shown to provide more accurate results across different heart rates compared to other correction methods. Our findings confirm existing literature into the impact of meals on QTcF intervals. We observe a consistent shortening of QTcF following breakfast, exceeding 5 milliseconds, which aligns with the positive control requirement defined by ICH E14, thus demonstrating the validity of our approach. In contrast, the effect of lunch is consistently less than 5 milliseconds across various timepoints and studies, indicating differences in the meal-related QTcF changes. Furthermore, our analysis incorporates gender-based assessments, showing that women exhibit a smaller effect than men, which is significant for breakfast and the fasted condition. These results suggest that the observed QTcF effect post-breakfast is a combination of the meal itself and factors unique to the initial day of a study. This insight holds potential for improving the design and interpretation of cardiac safety studies, particularly in Phase I investigations, and may offer the opportunity to explore the removal of positive control agents like Moxifloxacin, thereby reducing exposure to harmful challenge agents and contributing to the global effort to combat antimicrobial resistance (AMR). In conclusion, this meta-analysis advances our understanding of meal-induced QTcF changes and their significance in cardiac safety assessment, offering the prospect of more efficient and patient-focused drug development practices. This not only contributes to enhanced safety but also supports the reduction of antibiotic consumption, a key element in the global fight against AMR.

Effect of Trastuzumab Deruxtecan on QT/QTc Interval and Pharmacokinetics in HER2-Positive or HER2-Low Metastatic/Unresectable Breast Cancer.

HER2-targeted anticancer therapies may be associated with cardiovascular adverse events. This study evaluated effects of the HER2-targeted antibody-drug conjugate trastuzumab deruxtecan (T-DXd, DS-8201a) on QT/QTc interval and its pharmacokinetics. Patients with heavily pretreated, metastatic HER2-expressing breast cancer were enrolled at seven study sites in Japan. T-DXd was administered intravenously at 6.4 mg/kg on day 1 of each 21-day cycle. Primary end points were baseline-adjusted QTcF interval and pharmacokinetics parameters. Key secondary end points included safety events, serum concentration of T-DXd and DXd at the time of electrocardiographic measurements, and antitumor activity parameters. Among 51 total patients, 47 (92.2%) had HER2-low breast cancer (immunohistochemistry 1+ or 2+ and in situ hybridization-negative/equivocal/missing). Pharmacokinetic parameters after a single dose of T-DXd were consistent with previous studies. After multiple doses, T-DXd showed moderate accumulation (accumulation ratio (cycle 3/cycle 1), 1.35), but DXd showed minimal accumulation (1.09). The upper bound of the 90% confidence interval for mean ΔQTcF interval was < 10 ms at all timepoints, and at mean maximum serum concentration was also < 10 ms. Based on concentration-QT analysis, ΔQTcF increased with increasing concentrations of T-DXd and DXd. No clinically meaningful QTcF prolongation was observed. T-DXd had a manageable safety profile and showed antitumor activity in HER2-low breast cancer. In this study, a T-DXd dose of 6.4 mg/kg, higher than the 5.4-mg/kg dose currently approved for breast cancer, was not associated with clinically relevant QTcF prolongation in heavily pretreated patients with HER2-expressing metastatic breast cancer. This study adds to our understanding of T-DXd for treatment of HER2-low breast cancer.

AZD8233 antisense oligonucleotide targeting PCSK9 does not prolong QT interval.

AZD8233 is a proprotein convertase subtilisin/kexin type 9 (PCSK9) antisense oligonucleotide under development for treatment of hypercholesterolaemia. A prespecified concentration-QT analysis was performed based on data from a single ascending dose study that was prospectively designed to act as a TQT study substitute. Subcutaneous single doses ranging from 4 to 120 mg were evaluated in 73 adult healthy male subjects. Time-matched 12-lead digital ECG and plasma concentrations (n = 15) were measured at baseline and up to 48 hours after dose in each subject. The analysis was performed using a linear mixed effect model, where change from baseline QTc (ΔQTc) was a dependent variable and time-matched AZD8233 concentration was an independent variable. The high clinical exposure scenario was defined as 1.7-fold the expected Cmax following an assumed therapeutic dose of 60 mg, which corresponds to AZD8233 plasma concentration of 1.39 μg/mL. Estimated placebo-corrected and baseline-adjusted QTcF interval (ΔΔQTcF) at this concentration was -2.2ms (90% CI: -4.11, -0.28). Furthermore, the upper 90% ΔΔQTcF confidence interval was estimated to be below 10ms at all observed concentrations. As the effect on ΔΔQTcF is below the threshold for regulatory concern (10ms), it can be concluded that AZD8233 does not induce QTcF prolongation at the high clinical exposure scenario.

E2027 Cardiac Safety Evaluation With Concentration-Response Modeling of ECG Data to Inform Dose Selection in Studies in Patients With Dementia With Lewy Bodies.

E2027 is a novel, highly selective and potent inhibitor of phosphodiesterase 9 in development for dementia with Lewy bodies. Cardiac safety assessments for emerging agents are essential to avoid drug-induced QT interval prolongation, which may predispose individuals to potentially fatal ventricular arrhythmias. To evaluate the cardiac safety of E2027 and to inform dose selection for the phase 2 study of E2027 in dementia with Lewy bodies, we evaluated concentration-response modeling of pooled electrocardiogram data. A post hoc concentration-QTc analysis evaluated potential QT effects using data from 2 randomized, double-blind studies in healthy subjects: a single ascending dose (SAD) study and a multiple ascending dose (MAD) study. Daily E2027 doses ranged from 5 to 1200 mg. A linear mixed-effects model was used to establish the relationship between plasma concentrations of E2027 and change from the baseline of QTcF (ΔQTcF). A significant but shallow relationship was observed in the estimated slope of the concentration-ΔQTcF: 0.002 ms/ng/mL (90% confidence interval: 0.0007-0.0031) with a small, nonsignificant treatment effect-specific intercept of -0.6 ms. Based on this pooled concentration-QTc analysis, an effect on the QTcF interval >10 ms can be excluded up to E2027 plasma concentrations of ∼3579 ng/mL, corresponding to a dose at least 4-fold larger than the 50 mg phase 2 dose. This pooled post hoc analysis evaluating cardiac safety of E2027 demonstrated that clinically concerning QTcF prolongation and related cardiac complications are highly unlikely with proposed E2027 doses planned for phase 2.

Efficacy, Safety, and Tolerability of Flexibly Dosed Ziprasidone in Children and Adolescents with Mania in Bipolar I Disorder: A Randomized Placebo-Controlled Replication Study.

Objective: To evaluate the acute efficacy, safety, and tolerability of flexibly dosed ziprasidone in children and adolescents with Bipolar I Disorder (BD-I). Methods: Participants, 10-17 years of age, meeting The Diagnostic and Statistical Manual of Mental Disorders, 5th edition criteria, were randomized 1:1 in a 4-week double-blind (DB) study, to receive ziprasidone (20-80 mg/twice a day) or placebo. Some were then enrolled in a 26-week open-label extension (OLE) study. The primary efficacy measure was the Young Mania Rating Scale (YMRS) total score. Results: A total of 171 participants entered this randomized DB study and 23 continued into the OLE study. The mean (SD) age of the combined sample was 13.4 (2.1) years, 44.4% were male, and 66.7% were white. The demographic characteristics of participants who received ziprasidone (n = 86) or placebo (n = 85) were similar. The primary objective was met: the mean difference for ziprasidone versus placebo in the YMRS total score was -4.23 (95% confidence interval: -7.14 to -1.32; p = 0.005) indicating an effect size of 0.58. The most common adverse events (AEs) in the ziprasidone group were somnolence (31.4%), fatigue (22.1%), and nausea (14%). The mean Fridericia-corrected QT interval (QTcF) intervals in the ziprasidone group were moderately prolonged relative to the placebo group at all study visits. No participants had QTcF intervals ≥480 msec or an increase from baseline ≥60 msec. No AEs indicative of QT prolongation occurred. Weight, body mass index (BMI), and BMI z-scores, and metabolic measures were similar in both treatment groups. The data from the OLE study will be reported separately. Conclusions: Ziprasidone was effective in children and adolescents with BD-I in a manic episode, replicating the results of a previous study with a similar design (Findling et al. 2013). Overall, ziprasidone was safe and well tolerated with no meaningful effects on weight or metabolic parameters. Trial registration: ClinicalTrials.gov. NCT02075047 and NCT03768726.

Safety of prolonged treatment with bedaquiline in programmatic conditions.

Bedaquiline is now considered a first-line medicine for treatment of rifampicin-resistant tuberculosis (RR-TB). We evaluated the safety of treatment with bedaquiline for longer than 190 days in individuals with RR-TB under programmatic conditions.In a prospective cohort study enrolling pulmonary RR-TB patients, we initiated bedaquiline-based treatment at a tertiary hospital in Belarus. We defined standard bedaquiline use as <190 days and prolonged as ≥190 days. We recorded adverse events (AEs) and classified their seriousness and relation to bedaquiline. Our primary outcome in regression analyses was the incidence of serious AEs occurring within 5 months of bedaquiline cessation. We used generalised estimating equations to estimate the adjusted incidence rate ratio (aIRR) of serious AEs between the prolonged and standard bedaquiline groups.We enrolled 113 patients, 83 (73%) of whom received standard and 30 (27%) received prolonged treatment. A total of 2030 AEs occurred during treatment. Of these, 63 (3.1%) were serious AEs occurring within 5 months of bedaquiline cessation; QTcF prolongation was the most common bedaquiline-related serious AE. The incidence of serious AEs per 100 person-months was 5.4 (3.9 to 7.2) in the standard group and 4.4 (2.6 to 7.0) in the prolonged group. In adjusted analyses, serious AEs were no different (aIRR: 0.82, 95% CI 0.42–1.61) in the prolonged group. One patient in the standard bedaquiline group died of acute cardiopulmonary failure deemed possibly related to bedaquiline.Prolonged use of bedaquiline under programmatic conditions appears safe. Clinicians should carefully monitor QTcF interval since its prolongation was commonly observed.

Pharmacological profile of ALKS 7119, an investigational compound evaluated for the treatment of neuropsychiatric disorders, in healthy volunteers.

AimsALKS 7119 is a novel compound with in vitro affinity highest for the SERT, and for μ receptor, α1A‐adrenoceptor, α1B‐adrenoceptor, NMDA receptor and sigma non‐opioid intracellular receptor 1. This first‐in‐human study evaluated safety and PK/PD effects of single ascending doses (SAD) of ALKS 7119 in healthy males and compared effects with neurotransmitter modulators with partially overlapping targets.MethodsIn 10 cohorts (n = 10 subjects each), PK, safety and PD (NeuroCart tests, measuring neurophysiologic effects [pupillometry, pharmaco‐EEG (pEEG)], visuomotor coordination, alertness, [sustained] attention [saccadic peak velocity, adaptive tracking], subjective drug effects [VAS Bowdle and VAS Bond and Lader] and postural stability [body sway]) were evaluated. Neuroendocrine effects (cortisol, prolactin, growth hormone) were measured. Data were analysed over the 12‐hour post‐dose period using mixed‐effects model for repeated measure (MMRM) with baseline as covariate.ResultsALKS 7119 demonstrated linear PK and was generally well tolerated. QTcF interval increases of 30–60 ms compared to baseline were observed with ALKS 7119 doses of ≥50 mg without related adverse events. Significant increases in left and right pupil/iris ratio were observed at dose levels ≥50 mg (estimate of difference [95% CI], P‐value) (0.04 [0.01; 0.07], P < .01) and (0.06 [0.03; 0.09], P = .01), respectively. From dose levels ≥50 mg significant increases (% change) of serum cortisol (51.7 [8.4; 112.3], P = .02) and prolactin (77.9 [34.2; 135.8], P < .01) were observed.ConclusionIn line with ALKS 7119’s in vitro pharmacological profile, the clinical profile observed in this study is most comparable to SERT inhibition.

ЭФФЕКТИВНОСТЬ И БЕЗОПАСНОСТЬ ДЕЛАМАНИД-СОДЕРЖАЩИХ РЕЖИМОВ У ПАЦИЕНТОВ С ЛЕКАРСТВЕННО УСТОЙЧИВЫМ ТУБЕРКУЛЕЗОМ И КОМОРБИДНОЙ СЕРДЕЧНО-СОСУДИСТОЙ ПАТОЛОГИЕЙ

Aim. To study the effectiveness of treatment with delamanid-containing regimens in patients with multidrug-resistant and extensively drug-resistant tuberculosis and comorbid cardiovascular diseases, to assess the frequency, structure, and severity of adverse events in the cardiovascular system in this group of patients. Materials and methods. The study included 125 adult patients with multidrug and extensive drug resistance who started treatment with delamanid-containing regimens from July 2016 to February 2018 at the Republican Research and Practical Center for Pulmonology and Tuberculosis and six regional anti-TB institutions. The main group included patients with multiple and extensive drug resistance and comorbid cardiovascular diseases (N = 46). The control group included patients with multiple and extensive drug resistance without comorbid cardiovascular diseases (N = 79). The formulation and coding of the diagnosis (the underlying disease and comorbid diseases (conditions)) corresponded to the International Classification of Diseases (ICD) of the 10th revision. Adverse events were classified according to the international dictionary MedDRA (Medical Dictionary for Regulatory Activities). The severity of adverse events classification complied with CTCAE (Common Terminology Criteria for Adverse Events). The severity of adverse events was determined in accordance with the definitions of ICH (The International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use), and the treatment outcomes were identified in accordance with clinical guidelines and WHO recommendations. The study materials were the data from the medical records of the patients in the E-Register "Tuberculosis". Sputum culture conversion was defined as two consecutive negative test results. Treatment outcomes were classified as successful and unsuccessful. For the analysis of adverse events, each event was considered as a unit of analysis both in the aggregate of all adverse events in the cardiovascular system and in groups of patients. Testing of statistical hypotheses was carried out at a critical level of significance p = 0.05, i.e. the difference was considered statistically significant if p &lt; 0.05. Results. The effectiveness of treatment with delamanid-containing regimens in the group of patients with comorbid cardiovascular diseases was 88.0%, sputum conversion after 6 months of treatment (abacillation by culture) was observed in 93.0% of patients in this group, when compared no statistical difference was present in the effectiveness of treatment (p = 3.841) of the patients of the main group and those of the comparison group. In the analysis of long-term results, only one patient with cardiovascular comorbidity (3.0%) had a relapse of tuberculosis more than one year after successful treatment. 78.0% of patients of the main study group (with comorbid cardiovascular diseases) and 70.0% of the comparison group manifested cardiovascular adverse events during treatment. The most common adverse event in both groups was prolongation of the QTcF interval, which was recorded in 37.0% of patients with comorbid cardiovascular diseases and in 42.0% of patients without cardiovascular diseases (p = 0.597). Timely correction and careful monitoring of adverse events made it possible to avoid the development of life-threatening conditions in both groups of patients. In this regard, no withdrawal of anti-tuberculosis drugs was registered due to cardiovascular adverse events, including those due to the prolongation of the QTcF interval. The highest frequency of cardiovascular adverse events was detected during the first month of treatment of patients, then, in the course of treatment, it decreased, which may indirectly indicate the absence of a cumulative cardiotoxic effect of delamanid-containing treatment regimens. Conclusions. Treatment with delamanid-containing regimens in adult patients with multidrug-resistant tuberculosis and comorbid cardiovascular disease was effective and had an overall favorable cardiovascular safety profile comparable to the comparison group. Despite a large number of cardiovascular adverse events, they were manageable at the program level (prevailing at the initial stages of treatment, having light, mild or moderate severity, having been relieved), which made it possible to complete anti-tuberculosis treatment with delamanid-containing regimens.

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)

Pimavanserin for negative symptoms of schizophrenia: results from the ADVANCE phase 2 randomised, placebo-controlled trial in North America and Europe

Negative symptoms of schizophrenia are associated with adverse clinical outcomes, but there are few effective treatments. We aimed to assess the effects of pimavanserin, a selective 5-HT2A inverse agonist and antagonist, on negative symptoms of schizophrenia. The ADVANCE study was a phase 2, 26-week, randomised, double-blind, placebo-controlled study of pimavanserin in stable outpatients with schizophrenia aged 18-55 years with predominant negative symptoms. Patients were randomly assigned (1:1) across 83 sites (18 in North America and 65 in Europe) to receive pimavanserin or placebo daily, added to an ongoing antipsychotic medication, per a computer-generated schedule (stratification by geographical region). Eligible patients had a score of at least 20 on the sum of seven Positive and Negative Syndrome Scale (PANSS) Marder negative factor items (and scores of ≥4 on at least three or ≥5 on at least two of negative symptom items). The starting dosage of 20 mg of pimavanserin or placebo could be adjusted to 34 mg or 10 mg within the first 8 weeks of the study, after which dosage remained stable until the end of the study. Both pimavanserin and placebo were administered orally once daily as two individual tablets (pimavanserin tablets were either 10 mg or 17 mg). The primary endpoint was change in total score using the 16-item Negative Symptom Assessment (NSA-16) from baseline to week 26. Primary outcomes were analysed in patients who received at least one dose of the study drug and had NSA-16 assessments at baseline and at least once post-baseline (full analysis set). Safety outcomes were analysed in patients who had received at least one dose of the study drug. This trial is registered with ClinicalTrials.gov, NCT02970305, and is complete. Between Nov 4, 2016, and April 16, 2019, we randomly assigned 403 patients to pimavanserin (n=201; 131 [65%] male; 187 [93%] White) or placebo (n=202; 137 [68%] male, 186 (92%) White), of whom 400 were included in the efficacy analysis (199 in the pimavanserin group, 201 in the placebo group). Mean age was 37·7 years (SD 9·4) in the pimavanserin group and 36·7 (9·2) years in the placebo group. The change in total NSA-16 score from baseline to week 26 was significantly improved with pimavanserin (least squares mean -10·4 [SE 0·67]) versus placebo (least squares mean -8·5 [0·67]; p=0·043; effect size: 0·211). The number of patients with treatment-emergent adverse events (TEAEs) was similar between groups: 80 (40%) patients experienced TEAEs in the pimavanserin group and 71 (35%) in the placebo group. Most TEAEs were headache (6% [n=13] vs 5% [n=10]) and somnolence (5% [n=11] vs 5% [n=10]). One patient from the placebo group reported severe headache (0·5%), rhinorrhoea (0·5%), cough (0·5%), and influenza (0·5%). In the pimavanserin group, one patient reported severe toothache (0·5%), and two patients had worsening of schizophrenia (1%). Mean change in QTcF interval was higher with pimavanerin (4·5 ms [SD 18·0]) than with placebo (0·0 ms [16·0]). Stable patients with predominant negative symptoms of schizophrenia showed a reduction in negative symptoms after treatment with pimavanserin. However, given the small effect size, further investigation with optimised dosing is warranted to determine the clinical significance of this effect. Acadia Pharmaceuticals.

Diagnostic Value of the TpTe Interval in Children with Ventricular Arrhythmias.

Background: The changes in the period of ventricular repolarization, i.e., QT interval, QTp (Q-Tpeak) and TpTe interval (Tpeak–Tend), make it possible to assess the electrical instability of the heart muscle, which may lead to the development of life-threatening ventricular arrhythmia. The aim of the study was to determine and evaluate the use of differences in T-wave morphology and durations of repolarization period parameters (QT, TpTe) in resting ECGs for children with ventricular arrhythmias. Methods: The retrospective analysis was made of the disease histories of 80 examined children with resting ECGs, which were admitted to the Children’s Cardiology Department. The study group consisted of 46 children aged 4 to 18 with ventricular arrhythmias and the control group consisted of 34 healthy children between 4 and 18 years of age, with no arrhythmias. Results: The duration of the TpTe interval was significantly (p < 0.001) longer in the group of children with ventricular arrhythmia with abnormal T-wave (bactrian/bifid, humid/biphasic) compared to the TpTe interval in children with ventricular arrhythmia with the normal repolarization period. The duration of the TpTe (p < 0.001), QTcB (p < 0.001) and QTcF (p < 0.001) intervals were significantly longer in the group of children with ventricular arrhythmias and with abnormal T-wave compared to the values of the TpTe, QTcB, and QTcF intervals of the control group with normal morphology of the repolarization period. Only the duration of the TpTe interval was significantly (p = 0.020) longer in the group of children with ventricular arrhythmia without clinical symptoms. Conclusions: Children with benign ventricular arrhythmias recorded on a standard ECG with prolonged TpTe and QT intervals and abnormal T-wave morphology require systematic and frequent cardiac check up with long term ECG recordings due to the possibility of future more severe ventricular arrhythmias. Further follow-up studies in even larger groups of patients are necessary to confirm the values of these repolarization parameters in clinical practice.

Vericiguat: a QTc interval study in patients with coronary artery disease

Abstract Background Vericiguat is a soluble guanylate cyclase stimulator developed for the treatment of symptomatic chronic heart failure (HF) in adult patients with ejection fraction less than 45% who had a previous decompensation event. Guidelines on QT studies recommend evaluation of investigational drugs at supratherapeutic exposures in healthy volunteers. We anticipated that supratherapeutic doses of vericiguat would decrease blood pressure. We conducted an adjusted QT study using the therapeutic range of vericiguat in patients with coronary artery disease (CAD), who were expected to be more haemodynamically stable with fewer confounders (e.g., on the electrocardiogram) than a HF population. Purpose To assess the effect of vericiguat 10 mg once-daily on placebo-adjusted change from baseline of the Fridericia-corrected QT interval (QTcF) in patients with stable CAD. Methods This was a randomised, Phase Ib, placebo-controlled, double blind, double-dummy, multicentre study (NCT03504982). Test drug was vericiguat once-daily (up-titrated from 2.5 mg to 5 mg and then to 10 mg [treatments A, B, C] at 14-day intervals). The positive control was moxifloxacin 400 mg (single dose on Day 8 or Day 50 with placebo on other days [treatment D]; Figure). Patients were randomised to one of two sequences. We evaluated QTcF interval prolongation potential of vericiguat at increasing doses up to 10 mg, steady state. We investigated the pharmacokinetics, safety and tolerability of vericiguat. A clinically meaningful effect was defined as a QTcF change from baseline &amp;gt;10 ms relative to placebo. Assay sensitivity for moxifloxacin was confirmed by the lower limit of the 90% confidence interval (CI) of the time-matched, baseline-adjusted mean difference to placebo exceeding 5 ms at &amp;gt;1 time point. Results A total of 74 patients (66 males and 8 females) with CAD, mean (standard deviation) age 63.4 (8.0) years, were included. Mean difference between vericiguat and placebo in QTcF change from baseline (≤7 h post-dose) was &amp;lt;6 ms; no upper limit of the 90% CIs crossed the threshold of 10 ms. Lower limits of the two-sided 90% CI of the differences between moxifloxacin and placebo in QTcF change from baseline were &amp;gt;5 ms at 3 of 4 time points (Table). Peak plasma concentration (Cmax) of vericiguat following administration of vericiguat 10 mg was 322 μg/l and median time of maximum concentration (Tmax) was 4.5 h post-dose, in line with concentrations observed following administration of vericiguat 10 mg to patients with HF [1]. For moxifloxacin 400 mg, Cmax was 1960 μg/l and median Tmax was 3 h post-dose, in line with previously reported values [2]. Vericiguat up to 10 mg was generally safe and well tolerated. Conclusion This study supports the assessment that administration of vericiguat 10 mg is not associated with clinically meaningful QTc prolongation. These data contribute to the overall safety profile of vericiguat for the treatment of patients with HF. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Funding was provided by Bayer AG, Berlin, Germany, and Merck Sharp &amp; Dohme Corp., a subsidiary of Merck &amp; Co., Inc., Kenilworth, NJ, USA QTc study design