A Study to Test the Cardiac Effects of Padsevonil in Healthy Study Participants

Study Overview
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Brief Summary
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The purpose of the study is to evaluate the effects on cardiac repolarization of high-dose padsevonil (PSL) in comparison to placebo in healthy study participants.

Official Title
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A Single-Center, Randomized, Placebo-Controlled, 3 Treatment Period Crossover Study to Assess the Effect of Padsevonil on Cardiac Repolarization (QTc Interval) (Using Moxifloxacin as a Positive Control) in Healthy Study Participants

Conditions
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Healthy Study Participants

Intervention / Treatment
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* Drug: Padsevonil
* Drug: Moxifloxacin
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participant must be 18 to 55 years of age inclusive, at the time of signing the informed consent form (ICF) Participant who is overtly healthy as determined by medical evaluation including medical history, physical examination, laboratory tests, and cardiac monitoring Body weight of at least 50 kilogram (kg) (males) or 45 kg (females) and body mass index (BMI) within the range 18 to 30 kg/m2 (inclusive) Male and/or female: A male study participant must agree to use contraception during the Treatment Period and for at least 90 days after the last dose of study medication and refrain from donating sperm during this period A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies: Not a woman of childbearing potential (WOCBP) OR A WOCBP who agrees to follow the contraceptive guidance during the Treatment Period and for at least 90 days after the last dose of study medication Exclusion Criteria: Participant has a known hypersensitivity to any components of the study medication or comparative drugs as stated in this protocol or history of tendon pathology secondary to use of quinolone antibiotics Participant has a history of unexplained syncope or a family history of sudden death due to long QT syndrome Participant has a present condition of respiratory or cardiovascular disorders, eg, cardiac insufficiency, coronary heart disease, hypertension, arrhythmia, tachyarrhythmia, or myocardial infarction Past or intended use of over-the-counter (OTC) or prescription medication including herbal medications within 2 weeks or 5 half-lives prior to dosing. Participant has used hepatic enzyme-inducing drugs (eg, glucocorticoids, phenobarbital, isoniazid, phenytoin, rifampicin, etc) within 2 months prior to the first dose of study medication Participant has previously received padsevonil (PSL) in this or any other study Participant has any clinically relevant electrocardiogram (ECG) finding at the Screening Visit or at Baseline. Participant has an abnormality in the 12-lead ECG that, in the opinion of the Investigator, increases the risks associated with participating in the study. In addition, any participant with any of the following findings will be excluded: QT interval corrected for heart rate using the Fridericia method (QTcF) ≥450 ms (on mean of triplicate ECG recordings); Other conduction abnormalities (defined as PR interval >220 ms); QRS interval >109 ms; Any rhythm other than sinus rhythm; Any history of Wolff-Parkinson-White Syndrome, Brugada Syndrome, unexplained syncope, or ventricular tachycardia; Family history of QTc prolongation or of unexplainable sudden death at <50 years of age Participant has made a blood or plasma donation or has had a comparable blood loss (>450 mL) within 30 days prior to the Screening Visit. Blood donation during the study is not permitted

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Padsevonil<br>Study participants randomized to this arm will receive assigned doses of padsevonil twice daily. On Day 8 padsevonil will be administered in the morning, and placebo will administered in the evening. | Drug: Padsevonil<br>* Pharmaceutical form: Film-coated tablet Route of administration: Oral use Study participants will receive padsevonil in a pre-specified dosing sequence during the Treatment Period<br>Drug: Placebo<br>* Pharmaceutical form: Film-coated tablet Route of administration: Oral use Study participants will receive placebo in a pre-specified sequence during the Treatment Period to match padsevonil and maintain the blinding<br>|
| Placebo Comparator: Placebo<br>Study participants randomized to this arm will receive placebo twice daily to maintain the blinding. | Drug: Placebo<br>* Pharmaceutical form: Film-coated tablet Route of administration: Oral use Study participants will receive placebo in a pre-specified sequence during the Treatment Period to match padsevonil and maintain the blinding<br>|
| Active Comparator: Moxifloxacin<br>Study participants randomized to this arm will receive padsevonil-placebo twice daily. On Day 8 placebo will be administered in the morning, and moxifloxacin will administered in the evening. | Drug: Moxifloxacin<br>* Pharmaceutical form: Film-coated tablet Route of administration: Oral use Study participants will receive moxifloxacin once during the Treatment Period<br>Drug: Placebo<br>* Pharmaceutical form: Film-coated tablet Route of administration: Oral use Study participants will receive placebo in a pre-specified sequence during the Treatment Period to match padsevonil and maintain the blinding<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Placebo-corrected Change From Baseline in QTcF on Day 8 for Padsevonil | Placebo-corrected change from Baseline in corrected QT interval (QTc), based on Fridericia's correction (QTcF) method (ΔΔQTcF) evaluated during the Target Dose Day of the padsevonil and placebo Treatment Periods, using linear mixed-effects model analysis. | Day 8 : 0.75, 0.5, 0.25 hours predose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24 hours postdose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Placebo-corrected Change From Baseline in QTcF After a Single Dose of Moxifloxacin on Day 8 | Placebo-corrected change from Baseline in corrected QT interval (QTc), based on Fridericia's correction (QTcF) method (ΔΔQTcF) evaluated during the Target Dose Day of the moxifloxacin and placebo Treatment Periods, using linear mixed-effects model analysis. | Day 8 : 0.75, 0.5, 0.25 hours predose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24 hours postdose | 
| Placebo-corrected Change From Baseline in Heart Rate (HR) Interval on Day 1 | Placebo-corrected change from Baseline in HR, (ΔΔHR) evaluated during the Target Dose Day of the padsevonil/moxifloxacin and placebo Treatment Periods, using linear mixed-effects model analysis. | Day 1 : 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours postdose | 
| Placebo-corrected Change From Baseline in Heart Rate (HR) Interval on Day 8 | Placebo-corrected change from Baseline in HR, (ΔΔHR) evaluated during the Target Dose Day of the padsevonil/moxifloxacin and placebo Treatment Periods, using linear mixed-effects model analysis. | Day 8 : 0.75, 0.5, 0.25 predose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24 hours postdose | 
| Placebo-corrected Change From Baseline for PR Interval on Day 1 | Placebo-corrected change from Baseline in PR, (ΔΔPR) evaluated during the Target Dose Day of the padsevonil/moxifloxacin and placebo Treatment Periods, using linear mixed-effects model analysis. | Day 1 : 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours postdose | 
| Placebo-corrected Change From Baseline for PR Interval on Day 8 | Placebo-corrected change from Baseline in PR, (ΔΔPR) evaluated during the Target Dose Day of the padsevonil/moxifloxacin and placebo Treatment Periods, using linear mixed-effects model analysis. | Day 8 : 0.75, 0.5, 0.25 predose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24 hours postdose | 
| Placebo-corrected Change From Baseline for QRS Interval on Day 1 | Placebo-corrected change from Baseline for QRS interval, (ΔΔQRS) evaluated during the Target Dose Day of the padsevonil/moxifloxacin and placebo Treatment Periods, using linear mixed-effects model analysis. | Day 1 : 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours postdose | 
| Placebo-corrected Change From Baseline for QRS Interval on Day 8 | Placebo-corrected change from Baseline for QRS interval, (ΔΔQRS) evaluated during the Target Dose Day of the padsevonil/moxifloxacin and placebo Treatment Periods, using linear mixed-effects model analysis. | Day 8 : 0.75, 0.5, 0.25 predose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24 hours postdose | 
| Number of Participants With Treatment-emergent Changes for T-wave Morphology and U-wave Presence | Number of Participants with treatment-emergent changes of electrocardiogram waveforms as T-waves and U-waves. If a given morphology occurs multiple times at a given time point, that occurrence was only counted 1 time for that time point. If more than 1 morphology type was observed at a given time point, both morphology types were counted. A subject can appear in more than 1 category. | Day 8 : 0.75, 0.5, 0.25 hours predose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24 hours postdose | 
| Change From Baseline in QTcF Evaluated at Drug-specific Tmax for Padsevonil | Change from Baseline in QTcF (ΔQTcF) evaluated at drug-specific tmax (Δtmax) for padsevonil, using an analysis of variance (ANOVA) mixed-effect model. | Day 8 : 0.75, 0.5, 0.25 hours predose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 18 hours postdose | 
| Change From Baseline in QTcF Evaluated at Drug-specific Tmax for Metabolite 1 | Change from Baseline in QTcF (ΔQTcF) evaluated at drug-specific tmax (Δtmax) for metabolite 1, using an analysis of variance (ANOVA) mixed-effect model. | Day 8 : 0.75, 0.5, 0.25 hours predose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 18 hours postdose | 
| Change From Baseline in QTcF Evaluated at Drug-Specific Tmax for Metabolite 2 | Change from Baseline in QTcF (ΔQTcF) evaluated at drug-specific tmax (Δtmax) for metabolite 2, using an analysis of variance (ANOVA) mixed-effect model. | Day 8 : 0.75, 0.5, 0.25 hours predose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 18 hours postdose | 
| Maximum Observed Plasma Concentration at Steady State (Cmax, ss) for Padsevonil | Cmax,ss: Maximum observed plasma concentration of padsevonil at steady state. | Day 8: 0.5 hours predose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 18 hours postdose | 
| Time of Observed Maximum Concentration (Tmax) at Steady State for Padsevonil | tmax: Time of observed maximum plasma concentration at steady state. | Day 8: 0.5 hours predose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 18 hours postdose | 
| Area Under the Plasma Concentration Time Curve (AUCtau) at Steady State for Padsevonil | AUCtau: Area under the plasma concentration time curve over a dosing interval at steady state. | Day 8: 0.5 hours predose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 18 hours postdose | 
| Percentage of Participants With Adverse Events From Baseline to Safety Follow-up (up to Day 67) | An Adverse Event is any untoward medical occurrence in a subject or trial subject that is administered a drug or biologic (medicinal product) or that is using a medical device. The event does not necessarily have a causal relationship with that treatment or usage. | From Baseline to Safety Follow-up (up to Day 67) | 
| Percentage of Participants With Serious Adverse Events From Baseline to Safety Follow-up (up to Day 67) | A Serious Adverse Event (SAE) is any untoward medical occurrence that at any dose: Results in death Is life-threatening Requires in patient hospitalization or prolongation of existing hospitalization Is a congenital anomaly or birth defect Is infection that requires treatment parenteral antibiotics Other important medical events which based on medical or scientific judgement may jeopardize the patients, or may require medical or surgical intervention to prevent any of the above. | From Baseline to Safety Follow-up (up to Day 67) | 
| Percentage of Participants With Treatment Related Adverse Events From Baseline to Safety Follow-up (up to Day 67) | An Adverse Event (AE) is any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product, which does not necessarily have a causal relationship with this treatment. An AE could therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. | From Baseline to Safety Follow-up (up to Day 67) | 
| Percentage of Participants With Adverse Events Leading to Discontinuation of the Study From Baseline to Safety Follow-up (up to Day 67) | An Adverse Event is any untoward medical occurrence in a subject or trial subject that is administered a drug or biologic (medicinal product) or that is using a medical device. The event does not necessarily have a causal relationship with that treatment or usage. The results of this Primary Outcome Measure are summarized from the Adverse Event pages of the Case Report Forms. | From Baseline to Safety Follow-up (up to Day 67) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Healthy study participants, Padsevonil, Moxifloxacin, Cardiac repolarization