Effects of triclabendazole and its metabolite exposure on the heart‐rate–corrected QT intervals: A randomized, placebo‐ and positive‐controlled thorough QT study in healthy individuals

Abstract

Triclabendazole is an effective and well‐tolerated treatment for human fascioliasis. A placebo‐ and positive‐controlled, four‐sequence by four‐period crossover study was conducted in 45 healthy participants to assess the effect of therapeutic (10 mg/kg twice daily [b.i.d.] for 1 day) and supratherapeutic (10 mg/kg b.i.d. for 3 days) oral doses of triclabendazole on corrected QT (QTc) interval prolongation. Moxifloxacin (400 mg, oral) was used as a positive control. The highest mean placebo‐corrected change from baseline in QTcF (ΔΔQTcF) on day 4 with triclabendazole was 9.2 at therapeutic dose ms and 21.7 ms at supratherapeutic dose, at 4 h postdose. The upper limit of the two‐sided 90% confidence interval exceeded 10 ms across all timepoints, except at predose timepoint on day 4 in the therapeutic group indicating that an effect of triclabendazole on cardiac repolarization could not be excluded. However, triclabendazole had no clinically significant effects on heart rate and cardiac conduction at the studied doses. In the moxifloxacin group, the mean ΔΔQTcF peak value was 13.7 ms at 3 h on day 4. The assay sensitivity was confirmed. Maximum plasma concentration of triclabendazole, sulfoxide metabolite, and sulfone metabolite occurred at ~3‐, 4‐, and 6‐h postdose, respectively. No deaths, serious adverse events, study discontinuations due to treatment‐emergent adverse events, or clinically relevant abnormalities in laboratory evaluations and vital sign values were observed. This study showed that triclabendazole had no clinically relevant effects on heart rate and cardiac conduction; however, an effect on cardiac repolarization (ΔΔQTcF >10 ms) could not be excluded.

Study Highlights.

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Triclabendazole is an effective, well‐tolerated, and approved treatment for human fascioliasis. Although a transient prolongation of the mean QT and the QTc was reported in some dogs in a 13‐week study, there have been no reports of fainting, syncope, or acute cardiac events in the patients treated with triclabendazole in the clinical trials or in postmarketing reports. To date, cardiotoxic potential (prolongation of QT interval) of triclabendazole has not been investigated in humans.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This is the first study evaluating the cardiotoxic potential, pharmacokinetics, and safety of triclabendazole at therapeutic and supratherapeutic doses in humans.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Drug‐induced prolongation of the QT interval can be pro‐arrhythmic, therefore, as a part of safety assessment of new drugs, thorough QT studies are performed. This study provides information on cardiotoxic potential of triclabendazole in humans.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Another effective drug in human fascioliasis is emetine. However, it has serious cardiotoxic side effects. Triclabendazole is an approved treatment for human fascioliasis and, therefore, the outcome of this study will provide documentary evidence on its safety in humans. This will help decision making in treating physicians.

INTRODUCTION

Triclabendazole, a benzimidazole derivative, is a narrow‐spectrum anthelminthic drug and an effective, well‐tolerated treatment for human fascioliasis (liver fluke infestation). ¹ It was approved for human use in the United States (2019), Egypt (1997), and France (2002), and is the only treatment for fascioliasis recommended by the World Health Organization (WHO 2019), the Pan‐American Health Organization (PAHO 2019), and the US Centers for Disease Control and Prevention (CDC 2019). ² , ³ , ⁴ , ⁵ , ⁶ , ⁷ The mechanism of action has not been fully elucidated, ³ but may include inhibition of microtubule formation or adenylate cyclase activity. After oral administration, absorption of triclabendazole occurs rapidly and it undergoes extensive metabolism first to a sulfoxide and then to a sulfone metabolite. ⁸ The sulfoxide metabolite, which is predominant in human plasma, appears to have a more potent effect on parasite motility than triclabendazole itself. ⁹

Thorough QT (TQT) studies are routinely performed as part of safety assessments of new drugs to characterize the potential for prolongation of the QT interval. Drug‐induced prolongation of QT interval can be pro‐arrhythmic and can result in fatal arrhythmias. ¹⁰ In vitro (hERG channel binding assay and rabbit Purkinje fiber assay) and in vivo preclinical studies showed that triclabendazole has no effect on the cardiac action potential at a concentration of up to 30 μM. However, at higher concentrations (30 μM and 100 μM), the sulfoxide and sulfone metabolites of triclabendazole had an effect on the duration of cardiac action potential (unpublished data, Novartis; for details refer to Appendix S1). Administration of triclabendazole at 39 mg/kg/day (1.1‐times the maximum recommended human dose; calculated based on body‐surface area ¹¹ ) resulted in a transient and statistically insignificant increase in the QT or QTc intervals in some dogs in a 13‐week study. However, transient prolongation of QT and/or QTc intervals was observed in 30% and 40% of the dogs at a single dose of 40 and 100 mg/kg (1.1‐ and 2.7‐times the maximum recommended human dose), respectively, which was thought to be due to high plasma levels of sulfone metabolite in dogs (100‐ and 500‐times, respectively higher when compared with the plasma levels in humans; unpublished data, Novartis).

Although preclinical and in vitro studies showed no clinically relevant effects of triclabendazole and its metabolites on QT prolongation at concentrations equivalent to the human dose, this study evaluated the effect of triclabendazole and its metabolites on cardiac repolarization (as evidenced by the change in QT interval and the heart‐rate‐corrected QT interval), electrocardiogram (ECG) morphology, and on other relevant ECG variables in healthy individuals.

METHODS

Study design

This was a randomized, partially blinded, placebo‐ and moxifloxacin‐controlled, four‐sequence by four‐period, crossover study in healthy individuals. The study was partially blinded due to the lack of matching placebo to moxifloxacin. There was a 21‐day screening period, followed by four sequential treatment periods of 4 days with a washout period of at least 4 days between each treatment period. Eligible individuals were randomized in a ratio of 1:1:1:1 to one of the four treatment sequences chosen to reflect a four‐sequence by four‐period Williams crossover design. A treatment sequence reflected the order of given treatments. All doses of triclabendazole were given 12 h (±30 min) apart (Figure 1). Before entering each of the treatment periods, it was mandatory for participants to meet the eligibility criteria. An end‐of‐study evaluation was performed 4 days after the last study treatment dose, followed by a safety follow‐up call 30 days after the last study treatment dose. Triclabendazole or placebo was administered orally under fed state 30 min after consuming a standard breakfast/meal (~560 kcal) following an overnight fast for at least 10 h. Participants were required to completely consume their meal within 30 min. The treatment was administered 30 min after the start of the meal with ~240 mL (8 fluid ounces) of water. No food was allowed for at least 4 h postdose. Triclabendazole was administered at 10 mg/kg b.i.d. (2 doses given 12 h apart) for 1 day as a therapeutic dose and 10 mg/kg b.i.d. for 3 days as a supratherapeutic dose. The supratherapeutic dose was selected based on available safety and efficacy data for triclabendazole with the dosing regimen higher than the therapeutic dose. The pharmacokinetics, safety, and tolerability of triclabendazole at higher doses (>10 mg/kg b.i.d.) has not been characterized in clinical studies. However, there is limited published evidence of safety and tolerability associated with three divided doses of 10 mg/kg given 12 h apart (10 mg/kg b.i.d. for 3 days) in patients. ¹² It is the highest safe dose studied across the clinical studies and in clinical practice. Even though this dose may not yield higher exposure than the clinically relevant exposure (at 10 mg/kg b.i.d.), this repeated dose (10 mg/kg b.i.d. for 3 days) was suggested as a supratherapeutic dose by the US Food and Drug Administration (FDA), considering triclabendazole resistance and the lack of safety data for doses higher than 10 mg/kg b.i.d. A single dose of moxifloxacin 400 mg (administered orally under fasted conditions following an overnight fast for at least 10 h) was used as a positive control.

FIGURE 1.

Study design. BL, baseline; EoP, end of phase; EoS, end of study; placebo, triclabendazole‐matched placebo; TBZL, triclabendazole. Treatment sequences: ABCD, BDAC, CADB, DCBA.

The study protocol was reviewed and approved by the institutional review board. This study was conducted in accordance with International Conference on Harmonization (ICH) E6 guidelines that have their origin in the Declaration of Helsinki. Written informed consent was obtained from all participants before initiating study‐related procedures. ¹³

Study objectives

The primary objective of this study was to assess the effect of triclabendazole on the baseline‐corrected mean Fredericia corrected QT interval (QTcF), compared with placebo, in healthy individuals. Secondary objectives included assessment of selected ECG parameters (QT, heart rate [HR], PR, and QRS), evaluation of the pharmacokinetics (PK) of triclabendazole and its metabolites (sulfoxide and sulfone), effect of a single dose of moxifloxacin on the baseline‐corrected mean QTcF (ΔQTcF) compared with placebo (ΔΔQTcF), and safety and tolerability of therapeutic and supratherapeutic oral doses of triclabendazole in healthy individuals.

Study participants

Key inclusion criteria

The study participants were healthy women of non‐childbearing potential and/or male participants aged between 18 and 55 years, weighing greater than or equal to 50 kg with a body mass index (BMI) of 18–30 kg/m² (inclusive). Participants had no clinically significant findings on medical history, physical examination, vital signs, and ECG, with oral body temperature 35.0–37.5°C (inclusive), systolic blood pressure greater than or equal to 90 to less than or equal to 139 mmHg, diastolic blood pressure greater than or equal to 50 to less than or equal to 89 mmHg, and pulse rate greater than or equal to 50 to less than or equal to 90 bpm, at screening.

Key exclusion criteria

Individuals were excluded if they (i) used other investigational drugs within five half‐lives of screening, or within 30 days, whichever was longer; or longer if required by local regulations; (ii) had any of the following ECG abnormalities at screening or at each baseline: ECG not in sinus rhythm, HR less than 50 bpm, PR greater than 200 ms, QRS complex greater than 120 ms, QTcF greater than 450 ms (men) or QTcF greater than 470 ms (women), prominent U waves, or any other significant morphological changes that make ECGs unsuitable for QT evaluations; (iii) had known family history or known presence of long QT syndrome at screening or first baseline; and (iv) had undergone any surgery or had a medical condition that significantly altered absorption, distribution, metabolism, and excretion of drugs per the investigators.

ECG assessments

Holter ECG monitoring was performed at baseline on day 1, 1‐h prior to the corresponding morning dose on days 2, 3, and 4, and for 25‐h on day 4 of each treatment period. The ECG monitoring on day 4 started 1 h before dosing and continued over 24 h postdosing. Up to 10 ECG replicates were extracted from Holter ECG monitoring records at prespecified timepoints and transmitted to the selected ECG core laboratory (ERT, USA) for analysis. The ECG variables assessed included HR, RR, PR, QRS, QRS axis, QT, QTcF, and change in ST‐ and T‐wave morphology. All ECGs from a particular participant were read by TQT Plus, an advanced computer‐assisted and statistical process utilized to extract ECGs from continuous recordings collected in the TQT study. The following method of QT interval correction was implemented in this study:

$$\text{Fridericia correction}:\text{QTcF}=\mathrm{QT}/{\left(\mathrm{RR}\right)}^{0.33}.$$

Bioanalytical assessments

The PK analysis set included all participants with at least one available valid PK concentration measurement, who had received at least triclabendazole and had no protocol deviations that would impact on PK data.

Blood samples were obtained from all participants predose and at 1, 2, 3, 4, 6, 8, 12, and 24 h after last dose administration (on day 4). Samples were collected into vacutainers containing K₂EDTA. Triclabendazole and metabolites (sulfoxide and sulfone) were determined by a validated liquid chromatography and tandem mass spectrometry using protein precipitation method with sample volume of 0.05 mL. The lower limit of quantitation was 1 ng/mL for all analytes. A noncompartmental PK analysis was performed using Phoenix WinNonlin (version 8.0) after multiple doses (day 4). The PK parameters peak plasma concentrations (C _max), time to C _max (T _max), terminal‐phase half‐life (t _½), area under the concentration–time curves from time 0 to ~24 h (AUC_0–24h) were determined from plasma concentration–time data.

Safety assessments

The safety analysis set included all participants who received any study treatment (triclabendazole, placebo, and moxifloxacin). Safety assessments included clinical laboratory evaluations, 12‐lead safety ECG, 25‐h Holter ECG monitoring, vital sign measurements, height and weight measurements, and physical examinations.

Statistical assessments

The sample size was chosen to, in the absence of QT prolongation, observe with high probability a negative “TQT/QTc study” following the ICH guidelines ¹⁴ , ¹⁵ (i.e., to demonstrate that the upper limit of the 2‐sided 90% confidence interval [CI] for the largest mean difference between triclabendazole and placebo on QTcF was smaller than 10 ms). Assuming a one‐sided 5% significance level, a within‐participant standard deviation (SD) of 7 ms for change‐from‐baseline QTcF (ΔQTcF) for all treatment groups, and a true mean difference of 3 ms in ΔQTcF between triclabendazole and placebo, a sample size of 31 evaluable participants provided 90% power to demonstrate that the upper limit of the two‐sided 90% CIs for the difference in ΔQTcF between triclabendazole and placebo would fall below 10 ms for up to 10 postdose timepoints. ¹⁶ A sample size of 36 participants was to be enrolled to obtain 31 evaluable participants who would complete the study. QTcF value was obtained from the median of the replicate ECG measurements at each timepoint. The mean baseline value was obtained by calculating the average of the replicate QTcF values collected at 0, 0.25, 0.5, 0.75, and at 1‐h predose on day 1 of each period. The primary analysis of change from period specific baseline in QTcF was based on a linear mixed‐effects model with ΔQTcF as the dependent variable; treatment, sequence, time (as a categorical variable), period, and the treatment‐by‐time interaction as fixed effects, and period‐specific baseline QTcF as a covariate. The model also included a participant random effect. At each postdose timepoint, the change from mean baseline and two‐sided 90% CI for the mean difference between each of the active treatments (therapeutic and supratherapeutic dose of triclabendazole) and placebo was provided. It was to be concluded that there was no triclabendazole‐induced effect on the QTc interval if all two sided 90% CI upper limits of the mean difference at all the time points were less than 10 ms. For the characterization of moxifloxacin (positive control), the mean difference with placebo was extracted at three preplanned timepoints (1, 2, and 3 h postdose) on day 4 from the linear mixed effects model. The Hochberg approach was used to control possible inflation of the type I error rate due to multiple testing. ¹⁷ Under this approach, the three timepoints were in descending order according to their unadjusted P value, and corresponding two‐sided 90%, 95%, and 96.7% CIs were computed for the ordered timepoints, respectively. If any of the three CI lower limits exceeded the 5 ms threshold, then assay sensitivity was claimed.

RESULTS

Overall, 45 (36 men and 9 women) participants with a mean (SD) age of 39.5 (8.9) years and a mean (SD) BMI of 26.4 (2.6) kg/m² were enrolled in this study. Most participants (62.2%) were of African American ethnicity (Table 1). A total of 31 (68.9%) participants completed the study. Fourteen (31.1%) discontinued the study: eight because of physician decision; three were lost to follow‐up, two discontinued due to adverse events (AEs), and one participant withdrew consent (Table S1).

TABLE 1.

Demographic and baseline characteristics.

Characteristic	Statistics	Total N = 45
Age (years)	Mean (SD)	39.5 (8.9)
	Median	40.0
	Range	23–55
Sex	Male	36.0 (80.0)
	Female	9.0 (20.0)
Race	Black or African American	28.0 (62.2)
	White	17 (37.8)
Ethnicity	Hispanic or Latino	15.0 (33.3)
	Not Hispanic or Latino	30.0 (66.7)
Weight (kg)	Mean (SD)	81.0 (11.2)
	Median	81.0
	Range	60.1–107.4
Height (cm)	Mean (SD)	175.0 (9.4)
	Median	175.0
	Range	153.0–195.0
Body mass index (kg/m2)	Mean (SD)	26.4 (2.6)
	Median	26.5
	Range	19.4–29.8

Abbreviation: SD, standard deviation.

Primary pharmacodynamic results

Mean ΔQTcF ranged from −0.8 to 3.3 ms and 7.1 to 14.1 ms with therapeutic and supratherapeutic doses of triclabendazole, respectively, whereas mean ΔQTcF with placebo ranged from −9.6 to −4.7 ms across postdose timepoints. As shown in Figure 2a, the mean placebo‐corrected ΔQTcF (ΔΔQTcF) in the therapeutic dose group ranged from 4.9 ms (90% CI: 2.20–7.61) at predose (prior to the last dose) to 9.2 ms (90% CI: 6.30–12.18) at 4 h on day 4. At the supratherapeutic dose on day 4, ΔΔQTcF ranged from 13.3 ms (90% CI: 10.05–16.58) at 1 h postdose to 21.7 ms (90% CI: 18.71–24.66) at 4 h postdose. The upper limit of the two‐sided 90% CI exceeded 10 ms across all timepoints in the therapeutic and supratherapeutic groups, except at the predose (prior to last dose) timepoint on day 4 in the therapeutic group. A single dose of moxifloxacin (400 mg) caused an increase in the baseline‐corrected QTcF compared with placebo, with a mean ΔΔQTcF peak value of 13.7 ms (90% CI: 10.26–17.12) at 3 h (Figure 2a). Assay sensitivity was shown by the lower limit of the two‐sided 95% and 96.7% adjusted for multiplicity CI being greater than 5 ms at 2 h (7.93 ms) and at 3 h (9.23 ms) postdose, respectively.

FIGURE 2.

Placebo‐corrected mean change from baseline in (a) QTcF (ΔΔQTcF), (b) HR (ΔΔHR), (c) PR (ΔΔPR), and (d) QRS (ΔΔQRS) across timepoints on day 4 (PD analysis set). BID, twice daily; CI, confidence interval; HR, heart rate; LS, least squares; msec, millisecond; PD, pharmacodynamics; TBZL, triclabendazole.

Results of categorical analysis of predefined ECG events are presented in Table 2. No participants had a new treatment‐emergent QTcF greater than 480 ms or a ΔQTcF greater than 60 ms. One participant in the therapeutic dose group and two participants in the supratherapeutic dose group showed QTcF greater than 450 to less than or equal to 480 ms at one and five timepoints, respectively. QTcF greater than 450 to less than or equal to 480 ms was observed in one participant in the moxifloxacin group (at 5 timepoints) and in no participants in the placebo group. ΔΔQTcF greater than 30 to less than 60 ms was observed in two participants (at 3 timepoints) and six participants (at 15 timepoints) in the therapeutic and supratherapeutic group, respectively, and in no participants in the moxifloxacin and placebo groups. In the triclabendazole treatment groups, one participant had a negative T‐wave at one timepoint in the therapeutic dose group and one participant in the supratherapeutic group had a biphasic T‐wave at six timepoints. In the placebo group, one participant had a negative T‐wave at two timepoints and one participant had a treatment‐emergent U‐wave at eight timepoints.

TABLE 2.

Analysis of predefined ECG events.

	Category	TBZL 10 mg/kg b.i.d. for 1 day	TBZL 10 mg/kg b.i.d. for 3 days	Moxifloxacin	Placebo
Participants	Total	38	37	37	38
	ΔQTcF >30 and ≤60 ms	2 (5.3%)	6 (16.2%)	0	0
	ΔQTcF >60 ms	0	0	0	0
	QTcF >450 and ≤480 ms	1 (2.6%)	2 (5.4%)	1 (2.7%)	0
	QTcF >480 and ≤500 ms	0	0	0	0
	QTcF >500 ms	0	0	0	0
Timepoint	Total	338	323	330	332
	ΔQTcF >30 and ≤60 ms	3 (0.9%)	15 (4.6%)	0	0
	ΔQTcF >60 ms	0	0	0	0
	QTcF >450 and ≤480 ms	1 (0.3%)	5 (1.5%)	5 (1.5%)	0
	QTcF >480 and ≤500 ms	0	0	0	0
	QTcF >500 ms	0	0	0	0

Abbreviations: b.i.d., twice daily; ECG, electrocardiogram; QTcF, Fredericia corrected QT interval; TBZL, triclabendazole.

Secondary pharmacodynamic results

Baseline ECG parameters were within the expected range for a healthy population with mean HR 60.5–69.9 bpm, mean QTcF 398.6–404.6 ms, mean PR 153.0–157.1 ms, and mean QRS 105.7–106.3 ms across the treatment groups.

The mean baseline‐corrected HR (∆HR) and PR (∆PR) on triclabendazole treatment followed the pattern observed on placebo. The mean placebo‐corrected ΔHR (ΔΔHR) across treatments and postdose timepoints on day 4 ranged from −2.0 bpm to 2.9 bpm (Figure 2b). The mean placebo‐corrected ΔPR (ΔΔPR) on day 4 in triclabendazole treatment groups was −2.5 ms and 0.7 ms at 3 h postdose on the therapeutic dose and supratherapeutic dose, respectively (Figure 2c). The mean ∆QRS was small, and the mean ΔΔQRS was within ±1.6 ms across all postdose timepoints (Figure 2d).

Pharmacokinetic results

The mean (SD) plasma concentration‐time profile of triclabendazole and its sulfoxide and sulfone metabolites after 1 day of dosing (second dose) and 3 days of dosing (sixth dose) is shown in Figure 3. The C _max of triclabendazole, triclabendazole sulfoxide, and triclabendazole sulfone were attained at ~3 h, 4 h, and 6 h, respectively. With increasing doses, from the second to sixth dose, both peak and total exposures for all three analytes increased. The mean C _max of triclabendazole, triclabendazole sulfoxide, and triclabendazole sulfone was 1.85‐, 1.94‐, and 2.26‐fold higher, respectively, after the sixth dose compared with the second dose. The mean exposure (AUC_0‐24h) of triclabendazole, triclabendazole sulfoxide, and triclabendazole sulfone were 2.50, 2.83, and 3.25‐fold, respectively, higher after the sixth dose compared to the second dose. Overall, the exposures (C _max and AUC_0–24h) after the second and sixth doses showed moderate‐to‐high interindividual variability across all three analytes (≥25.8%–120.4%; Table 3).

FIGURE 3.

Triclabendazole plasma concentration‐time profiles – combined analytes (PK analysis set). BID, twice daily; PK, pharmacokinetics; TBZL, triclabendazole.

TABLE 3.

Exposure of triclabendazole, sulfoxide, and sulfone.

PK parameters	10 mg/kg b.i.d. for 1 day (N = 38)			10 mg/kg b.i.d. for 3 days (N = 37)
	TBZL	TBZL Sulfoxide	TBZL Sulfone	TBZL	TBZL Sulfoxide	TBZL Sulfone
T max a (h)	3.02 [1.02; 6.02]	4.02 [2.02; 8.02]	6.02 [2.03; 24.02]	3.02 [2.02; 8.02]	4.02 [3.00; 8.03]	6.03 [0.00; 12.05]
C max (ng/mL)	770 (44.2%)	28,200 (30.1%)	2030 (111.5%)	843 (52.6%)	36,800 (25.8%)	2990 (60.4)
AUC0–24h (h*ng/mL)	4870 (42.2%)	369,000 (41.2%)	34,200 (120.4%)	6340 (48.3%)	534,000 (36.5%)	54,600 (73.2%)
t 1/2 (h)	9.93 (23.3%)	8.39 (36.2%)	9.09 (37.9%)	14.5 (40.4)	9.11 (38.4%)	11.9 (62.3)

Abbreviations: AUC_0–24h, area under the concentration–time curves from time 0 to ~24 hours; b.i.d., twice daily; C _max, peak plasma concentration; h, hour; max, maximum; min, minimum; PK, pharmacokinetic; TBZL, triclabendazole; T _max, t _1/2, terminal‐phase half‐life.

^a For T _max, only median, minimum, and maximum are displayed.

Safety results

No deaths, serious AEs (SAEs), or study discontinuations due to treatment‐emergent AEs were reported. Overall, the most frequent AEs by system organ class were gastrointestinal disorders and skin and subcutaneous tissue disorders, each in five participants (11.1%). The most commonly reported AEs by preferred term were headache in four participants (8.9%) and dermatitis in three participants (6.7%). Two participants had AEs related to coronavirus disease 2019 (COVID‐19) that led to discontinuation from the study. The incidence of AEs was observed to be higher in the triclabendazole (10 mg/kg b.i.d. for 3 days) treatment group (Table 4). There were no severe AEs; 11.1% of participants had AEs of moderate intensity. There were no clinically significant changes in individual hematology, biochemistry, and urine analysis parameters. No clinically significant effect on HR, and cardiac conduction was found during the study; however, an effect on ΔΔQTcF exceeding 10 ms could not be excluded.

TABLE 4.

Treatment‐emergent AEs.

	Placebo N = 38 n (%)	TBZL 10 mg/kg b.i.d. For 1 day  N = 38 n (%)	TBZL 10 mg/kg b.i.d. For 3 days N = 38 n (%)	Moxifloxacin 400 mg o.d. N = 37 n (%)	Total N = 45 n (%)
Participants with at least one AE	5 (13.2)	5 (13.2)	8 (21.1)	3 (8.1)	15 (33.3)
Preferred team
Headache	1 (2.6)	0	3 (7.9)	1 (2.7)	4 (8.9)
Dermatitis contact	1 (2.6)	2 (5.3)	0	1 (2.7)	3 (6.7)
Bowel movement irregularity	0	1 (2.6)	1 (2.6)	0	2 (4.4)
Cough	0	0	2 (5.3)	0	2 (4.4)
Nausea	0	0	2 (5.3)	0	2 (4.4)
SARS‐CoV‐2 test positive	1 (2.6)	0	1 (2.6)	0	2 (4.4)
Chest discomfort	0	0	1 (2.6)	0	1 (2.2)
Constipation	0	0	1 (2.6)	0	1 (2.2)
Coronavirus infection	1 (2.6)	0	0	0	1 (2.2)
Feeling hot	0	0	1 (2.6)	0	1 (2.2)
Feeling of relaxation	1 (2.6)	0	0	0	1 (2.2)
Insomnia	0	1 (2.6)	0	0	1 (2.2)
Pruritus	0	0	1 (2.6)	0	1 (2.2)
Rash maculo‐papular	0	0	1 (2.6)	0	1 (2.2)
Seasonal allergy	0	0	0	1 (2.7)	1 (2.2)
Skin irritation	0	1 (2.6)	0	0	1 (2.2)
Skin laceration	1 (2.6)	0	0	0	1 (2.2)
Torticollis	1 (2.6)	0	0	0	1 (2.2)
Vomiting	0	0	1 (2.6)	0	1 (2.2)

Note: A participant with multiple AEs is courted only once in the “at least one AE” now. A participant with multiple AEs is courted only for that preferred term and treatment. Arranged in descending order of frequency (in total group) and alphabetically by preferred term.

Abbreviations: AEs, adverse events; b.i.d., twice daily; o.d., once daily; SARS‐CoV‐2, severe acute respiratory syndrome coronavirus 2; TBZL, triclabendazole.

DISCUSSION

The present study investigated the ECG effects of triclabendazole in healthy participants at therapeutic and supratherapeutic doses. The results of this study showed that triclabendazole had no clinically significant effect on HR and cardiac conduction. Drug‐induced QT prolongation leads to major safety considerations for the development of new therapeutic candidates. ¹⁰ The cardiotoxic or QT prolonging potential of benzimidazole anthelmintic compounds (like albendazole, mebendazole, and triclabendazole) has not formally been investigated in humans. Cardiovascular effects of triclabendazole were previously investigated in nonclinical studies using in vitro and in vivo models. In the nonclinical studies, triclabendazole showed no prolongation of QTc interval to any clinically relevant extent at human equivalent doses.

This study was conducted according to the ICH‐E14 guidance for evaluating the potential of drugs from QT/QTc prolongation in healthy male and female participants, using a four‐sequence by four‐period Williams crossover design. Study assay sensitivity was confirmed with the positive control single‐dose moxifloxacin. Considering the primary objective, this study was designed to determine the effect of triclabendazole on the baseline‐corrected mean QTcF interval as compared to placebo at steady state (day 4 after 6 doses) for supratherapeutic dose and after two doses on day 4 for therapeutic dose by timepoint analysis, as described in ICH E14 guidance. Data from all 45 participants (36 men and 9 women) who received triclabendazole were included in the analysis. Twelve‐lead ECGs were extracted from Holter records at predefined timepoints prior to dosing and serially paired with PK samples on day 1 and day 4 of each period.

In the present study, following the administration of therapeutic and supratherapeutic doses of triclabendazole, the mean ΔQTcF ranged from −0.8 to 3.3 ms and 7.1–14.1 ms, respectively. The effect of placebo on ΔQTcF varied from −9.6 to −4.7 ms across postdose timepoints. Triclabendazole at the studied doses had no clinically relevant effect on HR and cardiac conduction (i.e., the PR and QRS intervals). However, an effect on cardiac repolarization, as evidenced by ΔΔQTcF exceeding 10 ms, could not be excluded in the therapeutic and supratherapeutic groups. Plots and results from the HR change indicated similar ΔHR across all treatments and it was concluded that fixed standard correction factor (i.e., Fridericia) was adequate to eliminate the underlying HR effect on the QT intervals, regardless of the concentration of triclabendazole. Assay sensitivity was confirmed by the effect of moxifloxacin on ΔΔQTcF.

To support the primary objective of whether triclabendazole causes change in the ΔΔQTcF in healthy participants, the PKs of 10 mg/kg triclabendazole and its major metabolites were evaluated on day 4 after b.i.d. dosing for 1 day and b.i.d. dosing for 3 days. As expected, peak and total exposures (C _max and AUC_0–24h) of all three analytes increased with increasing doses (second to sixth dose), the rank order of exposures being triclabendazole sulfoxide > triclabendazole sulfone > triclabendazole. In addition, the exposures showed moderate to high interindividual variability across all three analytes (≥25.8% to 120.4%). Mean C _max values of triclabendazole 10 mg/kg b.i.d. for 1 day and 10 mg/kg b.i.d. for 3 days are 425‐ and 388‐fold lower than the highest concentration (30 μM) that has shown no affinity to the hERG channel.

The safety and tolerability profiles of triclabendazole and moxifloxacin were consistent with their known clinical profiles and there were no unexpected findings. No deaths or SAEs were reported in this study. There were no clinically relevant findings in clinical laboratory evaluations and vital sign values.

In conclusion, this study showed that triclabendazole and moxifloxacin were well‐tolerated at therapeutic and supratherapeutic doses with no new safety concerns. However, an effect on cardiac repolarization as evidenced by ∆∆QTcF exceeding 10 ms could not be excluded in the therapeutic and supratherapeutic groups.

AUTHOR CONTRIBUTIONS

W.T.P., V.K.V., J.L., K.S.N., C.G., A.T., and G.R.I. wrote the manuscript. W.T.P., V.K.V., and K.Z. designed the research. W.T.P., C.G., A.T., J.L., and G.R.I. performed the research. W.T.P., V.K.V., J.L., K.S.N., and G.R.I. analyzed the data.

FUNDING INFORMATION

This work was supported by Novartis Pharma AG.

CONFLICT OF INTEREST STATEMENT

All authors are employees of Novartis.

Supporting information

Appendix S1

Prince WT, Venishetty VK, Lecot J, et al. Effects of triclabendazole and its metabolite exposure on the heart‐rate–corrected QT intervals: A randomized, placebo‐ and positive‐controlled thorough QT study in healthy individuals. Clin Transl Sci. 2023;16:1758‐1767. doi: 10.1111/cts.13564