A Study to Test the Pharmacodynamic, Pharmacokinetic, Safety, and Tolerability of Padsevonil in Healthy Study Participants Receiving Either Ethanol or Cannabidiol

Study Overview
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Brief Summary
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The purpose of the study is to evaluate the pharmacodynamic (PD) interaction between steady-steady treatment with padsevonil (PSL) and Ethanol and the pharmacokinetic (PK) interaction between stead-state treatment with PSL and cannabidiol (CBD).

Official Title
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A Double-Blind, Placebo-Controlled, Randomized, Single-Center, Cross-Over Study to Investigate the Pharmacodynamic, Pharmacokinetic, Safety, and Tolerability Profiles of Padsevonil in Healthy Study Participants Receiving Either Ethanol or Cannabidiol

Conditions
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Healthy Participants

Intervention / Treatment
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* Drug: Padsevonil
* Drug: Placebo (PSL)


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 Participants who are overtly healthy as determined by medical evaluation including medical history, physical examination, laboratory tests, and cardiac monitoring Participant must have previous experience with alcohol consumption and, therefore, must be familiar with the effects and able to tolerate social amounts of alcohol Participant has a body weight of at least 50 kg (males) or 45 kg (females) and body mass index (BMI) within the range 18 to 30 kg/m2 (inclusive) Participants are male or female: A male participant must agree to use contraception as detailed in the protocol during the treatment period and for at least 7 days after the last dose of study treatment 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 1 of the following conditions applies: Not a woman of childbearing potential (WOCBP) as defined n the protocol OR A WOCBP who agrees to follow the contraceptive guidance in the protocol during the Treatment Period and for at least 90 days after the last dose of study treatment Exclusion Criteria: Participant has history or presence of cardiovascular, respiratory, hepatic, renal, gastrointestinal, endocrinological, hematological, or neurological disorders capable of significantly altering the absorption, metabolism, or elimination of drugs; constituting a risk when taking the study intervention; or interfering with the interpretation of data Participant has a history of chronic alcohol or drug abuse within the previous 6 months or the presence of drug or alcohol dependency at Screening or Day -1 or tests positive for alcohol and/or drugs at Screening or Day -1 Participant has a known hypersensitivity to any components of the study medication or comparative drugs (and/or an investigational device) as stated in this protocol Participant has a history of unexplained syncope or a family history of sudden death due to long QT syndrome Participant has lymphoma, leukemia, or any malignancy within the past 5 years except for basal cell or squamous epithelial carcinomas of the skin that have been resected with no evidence of metastatic disease for 3 years Participant has past or intended use of over-the-counter or prescription medication including herbal medications within 2 weeks or 5 half-lives prior to dosing Participant has used hepatic enzyme-inducing drugs within 2 months prior to dosing Participant has alanine transaminase (ALT), aspartate aminotransferase (AST), or alkaline phosphatase (ALP) >1.0x upper limit of normal (ULN) Participant has current or chronic history of liver disease or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones) Participant has any clinically relevant electrocardiogram (ECG) finding at the Screening Visit or at Baseline Participant has the presence of hepatitis B surface antigen (HBsAg) at Screening or within 3 months prior to dosing Participant has a positive hepatitis C antibody test result at Screening or within 3 months prior to starting study intervention Participant has a positive human immunodeficiency virus (HIV) antibody test

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: Part A: Padsevonil and Ethanol<br>Subjects will be randomized to receive Padsevonil and Ethanol. | Drug: Padsevonil<br>* Padsevonil will be administered in predefined dosages.<br>|
| Placebo Comparator: Part A: Padsevonil and Ethanol-Placebo<br>Subjects will be randomized to receive Padsevonil and Ethanol-Placebo. | Drug: Padsevonil<br>* Padsevonil will be administered in predefined dosages.<br>|
| No Intervention: Part A: Ethanol and Ethanol-Placebo<br>Subjects will be randomized to receive Ethanol and Ethanol-Placebo. | |
| No Intervention: Part A: Ethanol-Placebo and Ethanol<br>Subjects will be randomized to receive Ethanol and Ethanol-Placebo. | |
| Experimental: Part B: Padsevonil and Cannabidiol<br>Subjects will be randomized to receive Padsevonil and Cannabidiol. | Drug: Padsevonil<br>* Padsevonil will be administered in predefined dosages.<br>|
| Placebo Comparator: Part B: Padsevonil-Placebo and Cannabidiol<br>Subjects will be randomized to receive Padsevonil-Placebo and Cannabidiol. | Drug: Placebo (PSL)<br>* Placebo will be provided matching Padsevonil to maintain the blinding.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Smooth Pursuit Eye Movements on Day 1 of Period 1 or Day 3 of Period 2 During Part A | Smooth pursuit to assess eye movement coordination and attention to evaluate the ethanol effect. The average percentage of smooth pursuit for all stimulus frequencies was used as a parameter. Participants received either ethanol or placebo on Day 1 of Period 1 or on Day 3 of Period 2. Therefore, the results were summarized by treatment. | Predose, 0.5, 1, 2, 3, 4, 5, 6, 8 and 10 hours postdose on Day 1 of Period 1 or Day 3 of Period 2 | 
| Percentage of Smooth Pursuit Eye Movements on Day 5 of Period 4 or Day 7 of Period 5 During Part A | Smooth pursuit to assess eye movement coordination and attention to evaluate the ethanol effect. The average percentage of smooth pursuit for all stimulus frequencies was used as a parameter. Participants received either ethanol or placebo on Day 5 of Period 4 or Day 7 of Period 5. Therefore, the results were summarized by treatment. | Predose, 0.5, 1, 2, 3, 4, 5, 6, 8 and 10 hours postdose on Day 5 of Period 4 or Day 7 of Period 5 | 
| Maximum Observed Plasma Concentration at Steady State (Cmax,ss) of Padsevonil During Part B | Cmax is maximum observed plasma concentration at steady state of padsevonil. | Predose up to 12 hours postdose | 
| Maximum Observed Plasma Concentration at Steady State (Cmax,ss) of Cannabidiol During Part B | Cmax is maximum observed plasma concentration at steady state of CBD. | Predose up to 12 hours postdose | 
| Area Under the Curve Over a Dosing Interval (AUCtau) of Padsevonil During Part B | AUCtau is the area under the curve over a dosing interval of padsevonil. | Predose up to 12 hours post dose | 
| Area Under the Curve Over a Dosing Interval (AUCtau) of Cannabidiol During Part B | AUCtau is the area under the curve over a dosing interval of CBD. | Predose up to 12 hours postdose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Breath Concentration of Ethanol Over Time on Day 1 of Period 1 or Day 3 of Period 2 During Part A | Continuous infusion of ethanol began with a 30 minute loading phase (prior to 0 hours) and was continued for 5 hours with adjustments during the infusion. Participants received either ethanol on Day 1 of Period 1 or on Day 3 of Period 2. Therefore, the results were summarized by treatment. | -0.4, -0.3, -0.2, -0.16, -0.08, Predose, 0.16, 0.3, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7 and 8 hours postdose on Day 1 of Period 1 or on Day 3 of Period 2 | 
| Breath Concentration of Ethanol Over Time on Day 5 of Period 4 or Day 7 of Period 5 During Part A | Continuous infusion of ethanol began with a 30 minute loading phase (prior to 0 hours) and was continued for 5 hours with adjustments during the infusion. Participants received either ethanol on Day 5 of Period 4 or Day 7 of Period 5. Therefore, the results were summarized by treatment. | -0.4, -0.3, -0.2, -0.16, -0.08, Predose, 0.16, 0.3, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7 and 8 hours postdose on Day 5 of Period 4 or Day 7 of Period 5 | 
| Maximum Observed Plasma Concentration at Steady State (Cmax,ss) of Padsevonil During Part A | Cmax,ss is the maximum observed plasma concentration at steady state of padsevonil. | Predose, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8 and 12 hours postdose on Day 5 | 
| Area Under the Curve Over a Dosing Interval (AUCtau) of Padsevonil During Part A | AUC0-tau is the area under the curve over a dosing interval of padsevonil. | Predose, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8 and 12 hours postdose on Day 5 | 
| Half-life (t1/2) of Padsevonil During Part B | t1/2 is the apparent terminal half-life of padsevonil. | Predose up to 12 hours postdose | 
| Half-life (t1/2) of Cannabidiol During Part B | t1/2 is the apparent terminal half-life of CBD. | Predose up to 12 hours postdose | 
| Apparent Total Body Clearance at Steady State (CLss/F) of Padsevonil During Part B | CLss/F is the apparent total body clearance at steady state following extravascular administration of padsevonil. | Predose up to 12 hours postdose | 
| Apparent Total Body Clearance at Steady State (CLss/F) of Cannabidiol During Part B | CLss/F is the apparent total body clearance at steady state following extravascular administration of CBD. | Predose up to 12 hours postdose | 
| Percentage of Smooth Pursuit Eye Movements During Part B | Smooth pursuit to assess eye movement coordination and attention to evaluate the ethanol effect. The average percentage of smooth pursuit for all stimulus frequencies was used as a parameter. | Treatment Period 1: Screening, Day 1 and Day 2 | 
| Saccadic Peak Velocity to Assess Sedation on Day 1 of Period 1 or Day 3 of Period 2 During Part A | Sixteen saccades were recorded with interstimulus intervals varying randomly. Average values of latency (reaction time), saccadic peak velocity of all correct saccades, and inaccuracy of all saccades were used as parameters. Participants received either ethanol or placebo on Day 1 of Period 1 or on Day 3 of Period 2. Therefore, the results were summarized by treatment. | Predose, 0.5, 1, 2, 3, 4, 5, 6, 8 and 10 hours postdose on Day 1 of Period 1 or Day 3 of Period 2 | 
| Saccadic Peak Velocity to Assess Sedation on Day 5 of Period 4 or Day 7 of Period 5 During Part A | Sixteen saccades were recorded with interstimulus intervals varying randomly. Average values of latency (reaction time), saccadic peak velocity of all correct saccades, and inaccuracy of all saccades were used as parameters. Participants received either ethanol or placebo on Day 5 of Period 4 or Day 7 of Period 5. Therefore, the results were summarized by treatment. | Predose, 0.5, 1, 2, 3, 4, 5, 6, 8 and 10 hours postdose on Day 5 of Period 4 or Day 7 of Period 5 | 
| Saccadic Peak Velocity to Assess Sedation During Part B | Sixteen saccades were recorded with interstimulus intervals varying randomly. Average values of latency (reaction time), saccadic peak velocity of all correct saccades, and inaccuracy of all saccades were used as parameters. | Treatment Period 1: Screening, Day 1 and Day 2 | 
| Adaptive Tracking to Assess Visuo-Motor Control and Vigilance on Day 1 of Period 1 or Day 3 of Period 2 During Part A | The adaptive tracking test was performed as originally described by Borland and Nicholson (Borland and Nicholson, 1984). Performance was scored after a fixed period of 3.5 minutes and reflected visuo-motor control and vigilance. The average performance scores were used in the analysis. Participants received either ethanol or placebo on Day 1 of Period 1 or on Day 3 of Period 2. Therefore, the results were summarized by treatment. | Predose, 0.5, 1, 2, 3, 4, 5, 6, 8 and 10 hours postdose on Day 1 of Period 1 or Day 3 of Period 2 | 
| Adaptive Tracking to Assess Visuo-Motor Control and Vigilance on Day 5 of Period 4 or Day 7 of Period 5 During Part A | The adaptive tracking test was performed as originally described by Borland and Nicholson (Borland and Nicholson, 1984). Performance was scored after a fixed period of 3.5 minutes and reflected visuo-motor control and vigilance. The average performance scores were used in the analysis. Participants received either ethanol or placebo on Day 5 of Period 4 or Day 7 of Period 5. Therefore, the results were summarized by treatment. | Predose, 0.5, 1, 2, 3, 4, 5, 6, 8 and 10 hours on Day 5 of Period 4 or Day 7 of Period 5 | 
| Adaptive Tracking to Assess Visuo-Motor Control and Vigilance During Part B | The adaptive tracking test was performed as originally described by Borland and Nicholson (Borland and Nicholson, 1984). Performance was scored after a fixed period of 3.5 minutes and reflected visuo-motor control and vigilance. | Treatment Period 1: Screening, Day 1 and Day 2 | 
| Body Sway to Assess Postural Stability on Day 1 of Period 1 or Day 3 of Period 2 During Part A | Body Sway test measured the study participant's body movements in a single direction. Body sway was measured by CHCR NeuroCart. Study participants were asked to stand erect and motionless with their eyes closed. The amplitude and direction of any Body Sway was recorded for 1 minute. Participants received either ethanol or placebo on Day 1 of Period 1 or on Day 3 of Period 2. Therefore, the results were summarized by treatment. | Predose, 0.5, 1, 2, 3, 4, 5, 6, 8 and 10 hours postdose on Day 1 of Period 1 or Day 3 of Period 2 | 
| Body Sway to Assess Postural Stability on Day 5 of Period 4 or Day 7 of Period 5 During Part A | Body Sway test measured the study participant's body movements in a single direction. Body sway was measured by CHCR NeuroCart. Study participants were asked to stand erect and motionless with their eyes closed. The amplitude and direction of any Body Sway was recorded for 1 minute. Participants received either ethanol or placebo on Day 5 of Period 4 or Day 7 of Period 5. Therefore, the results were summarized by treatment. | Predose, 0.5, 1, 2, 3, 4, 5, 6, 8 and 10 hours on Day 5 of Period 4 or Day 7 of Period 5 | 
| Body Sway to Assess Postural Stability During Part B | Body Sway test measured the study participant's body movements in a single direction. Body sway was measured by CHCR NeuroCart. Study participants were asked to stand erect and motionless with their eyes closed. The amplitude and direction of any Body Sway was recorded for 1 minute. | Treatment Period 1: Screening, Day 1 and Day 2 | 
| Number of Participants With Adverse Events During Part A | An adverse event (AE) was any untoward medical occurrence in a participant or trial participant 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 Screening up to the Safety Follow-up visit of Part A (up to Day 26) | 
| Number of Participants With Adverse Events During Part B | An AE was any untoward medical occurrence in a participant or trial participant 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 Screening up to the Safety Follow-up visit of Part B (up to Day 66) | 
| Number of Participants With Serious Adverse Events During Part A | A serious adverse event (SAE) was any untoward medical occurrence that at any dose resulted in death, is life-threatening, required in patient hospitalization or prolongation of existing hospitalization, is a congenital anomaly or birth defect, is an infection that requires treatment parenteral antibiotics, other important medical events which based on medical or scientific judgement may jeopardize the participants, or may require medical or surgical intervention to prevent any of the above. | From Screening up to the Safety Follow-up visit of Part A (up to Day 26) | 
| Number of Participants With Serious Adverse Events During Part B | A SAE was any untoward medical occurrence that at any dose resulted in death, is life-threatening, required in patient hospitalization or prolongation of existing hospitalization, is a congenital anomaly or birth defect, is an infection that requires treatment parenteral antibiotics, other important medical events which based on medical or scientific judgement may jeopardize the participants, or may require medical or surgical intervention to prevent any of the above. | From Screening up to the Safety Follow-up visit of Part B (up to Day 66) | 
| Number of Participants With Treatment-related Adverse Events During Part A | Treatment-related adverse event was an adverse event for which a causal relationship between the product and the occurrence is suspected. | From Baseline up to Safety Follow-up visit of Part A (up to Day 26) | 
| Number of Participants With Treatment-related Adverse Events During Part B | Treatment-related adverse event was an adverse event for which a causal relationship between the product and the occurrence is suspected. | From Baseline up to Safety Follow-up visit of Part B (up to Day 66) | 
| Number of Participants With Adverse Events Leading to Discontinuation of the Study During Part A | An AE was any untoward medical occurrence in a participant or clinical investigation participant 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 Screening up to Safety Follow-up visit of Part A (up to Day 26) | 
| Number of Participants With Adverse Events Leading to Discontinuation of the Study During Part B | An AE was any untoward medical occurrence in a participant or clinical investigation participant 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 Screening up to Safety Follow-up visit of Part B (up to Day 66) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Ethanol, Cannabidiol, Padsevonil