Study to Evaluate the Effect of Coadministered Erythromycin on the Pharmacokinetics and Safety of Padsevonil

Sponsor
UCB Biopharma S.P.R.L. (Industry)
Overall Status
Completed
CT.gov ID
NCT03480243
Collaborator
(none)
28
1
1
4.2
6.7

Study Details

Study Description

Brief Summary

The purpose of this study is to evaluate and compare the Pharmacokinetics (PK) of concomitant administration of Padsevonil (PSL) in the presence and absence of erythromycin in healthy study participants.

Condition or Disease Intervention/Treatment Phase
Phase 1

Study Design

Study Type:
Interventional
Actual Enrollment :
28 participants
Allocation:
N/A
Intervention Model:
Sequential Assignment
Masking:
None (Open Label)
Primary Purpose:
Basic Science
Official Title:
An Open-label, Fixed-sequence Study in Healthy Study Participants to Evaluate the Effect of Coadministered Erythromycin on the Pharmacokinetics and Safety of Padsevonil
Actual Study Start Date :
Mar 27, 2018
Actual Primary Completion Date :
Aug 2, 2018
Actual Study Completion Date :
Aug 2, 2018

Arms and Interventions

Arm Intervention/Treatment
Experimental: Padsevonil and Erythromycin

Treatment Period 1 (Day 1 to Day 11): Padsevonil 100 mg twice daily (bid) on Day 1 to Day 4 Padsevonil 100 mg single dose on Day 5 1 week of wash-out (from evening of Day 5 to Day 11) Treatment Period 2 (Day 12 to 22): Padsevonil 100 mg twice daily (bid) on Day 12 to Day 15 Padsevonil 100 mg single dose on Day 16 1 week of wash-out (from evening of Day 16 to Day 22) Treatment Period 3 (Day 23 to Day 38): Erythromycin 500 mg twice daily (bid) on Day 23 to Day 25 Padsevonil 100 mg bid and erythromycin 500 mg bid on Day 26 to Day 32 Padsevonil 100 mg single dose on Day 33 Erythromycin 500 mg twice daily (bid) on Day 33 to Day 36 Erythromycin 500 mg single dose on Day 37

Drug: Padsevonil (UCB0942)
Pharmaceutical Form: film-coated tablet Route of Administration: Oral use

Drug: Erythromycin
Pharmaceutical Form: film-coated tablet Route of Administration: Oral use

Outcome Measures

Primary Outcome Measures

  1. Maximum Observed Plasma Concentration (Cmax) of Padsevonil for Single Dose [Predose and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 8, and 12 hours postdose on Day 1, 12, and 26]

    Cmax: The maximum observed plasma concentration of padsevonil for single dose . Cmax was expressed in nanograms per milliliter (ng/mL).

  2. Area Under the Plasma Concentration-time Curve From Time Zero to 12 Hours (AUC(0-12)) of Padsevonil for Single Dose [Predose and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 8, and 12 hours postdose on Day 1, 12, and 26]

    AUC(0-12): The area under the plasma concentration-time curve from time zero to 12 hours of padsevonil for single dose . AUC(0-12) was expressed in hours times nanograms per milliliter (hours*ng/mL).

  3. Maximum Observed Steady-state Plasma Concentration (Cmax, ss) of Padsevonil for Multiple Doses [Blood samples were taken at specific time points from pre-dose to 72 hours post last dose of Padsevonil (PSL) (Treatment Period 1 and 2); from pre-dose to 120 hours post last dose of PSL (Treatment Period 3)]

    Cmax, ss: The maximum observed steady-state plasma concentration of padsevonil for multiple doses. Cmax, ss was expressed in nanograms per millilitre (ng/mL).

  4. Area Under the Plasma Concentration-time Curve Over a Dosing Interval (12 Hours) (AUCtau) of Padsevonil for Multiple Doses [Blood samples were taken at specific time points from pre-dose to 72 hours post last dose of Padsevonil (PSL) (Treatment Period 1 and 2); from pre-dose to 120 hours post last dose of PSL (Treatment Period 3)]

    AUCtau: The area under the plasma concentration-time curve over a dosing interval (12 hours) of padsevonil for multiple doses. AUC(tau) was expressed in hours times nanograms per millilitre (hours*ng/mL).

Secondary Outcome Measures

  1. Time of Maximum Plasma Concentration (Tmax) of Padsevonil for Single Dose [Blood samples were taken at specific time points from pre-dose to 12 hours post first dose of Padsevonil for each Treatment Period]

    Tmax: The time of maximum plasma concentration of padsevonil for single dose. Tmax was expressed in hours (h).

  2. Minimum Observed Plasma Concentration (Cmin) of Padsevonil for Single Dose [Blood samples were taken at specific time points from pre-dose to 12 hours post first dose of Padsevonil for each Treatment Period]

    Cmin: The minimum observed plasma concentration of padsevonil for single dose. Cmin was expressed in nanograms per millilitre (ng/mL).

  3. Time of Maximum Plasma Concentration (Tmax) of Padsevonil for Multiple Doses [Blood samples were taken at specific time points from pre-dose to 72 hours post last dose of Padsevonil (PSL) (Treatment Period 1 and 2); from pre-dose to 120 hours post last dose of PSL (Treatment Period 3)]

    Tmax: The time of maximum plasma concentration of padsevonil for multiple doses. Tmax was expressed in hours (h).

  4. Apparent Terminal Elimination Half-life at Steady-state (t1/2,ss) of Padsevonil for Multiple Doses in Plasma [Blood samples were taken at specific time points from pre-dose to 72 hours post last dose of Padsevonil (PSL) (Treatment Period 1 and 2); from pre-dose to 120 hours post last dose of PSL (Treatment Period 3)]

    t½,ss: The apparent terminal elimination half-life at steady-state of padsevonil for multiple doses in plasma. t1/2, ss was expressed in hours (h).

  5. Predose Observed Plasma Concentration (Ctrough) of Padsevonil for Multiple Doses [Blood samples were taken at specific time points from pre-dose to 72 hours post last dose of Padsevonil (PSL) (Treatment Period 1 and 2); from pre-dose to 120 hours post last dose of PSL (Treatment Period 3)]

    Ctrough: The predose observed plasma concentration of padsevonil for multiple doses. Ctrough was expressed in nanograms per millilitre (ng/mL).

  6. Apparent Total Clearance at Steady-state (CL/Fss) of Padsevonil for Multiple Doses in Plasma [Blood samples were taken at specific time points from pre-dose to 72 hours post last dose of Padsevonil (PSL) (Treatment Period 1 and 2); from pre-dose to 120 hours post last dose of PSL (Treatment Period 3)]

    CL/Fss: The apparent total clearance at steady-state of padsevonil for multiple doses in plasma. CL/Fss was expressed in milliliters per hour (mL/hour).

  7. Apparent Elimination Rate Constant (Lambdaz) of Padsevonil for Multiple Doses in Plasma [Blood samples were taken at specific time points from pre-dose to 72 hours post last dose of Padsevonil (PSL) (Treatment Period 1 and 2); from pre-dose to 120 hours post last dose of PSL (Treatment Period 3)]

    lambdaz: The apparent elimination rate constant of padsevonil for multiple doses in plasma. Lambdaz was expressed in liters per hour (l/hour).

  8. Maximum Observed Plasma Concentration (Cmax) of Padsevonil Metabolites (1 and 2) for Single Dose [Blood samples were taken at specific time points from pre-dose to 12 hours post first dose of Padsevonil for each Treatment Period]

    Cmax: The maximum plasma concentration of padsevonil metabolites (1 and 2) for single dose. Cmax was expressed in nanograms per milliliter (ng/mL).

  9. Area Under the Plasma Concentration-time Curve From Time Zero to 12 Hours (AUC(0-12)) of Padsevonil Metabolites (1 and 2) for Single Dose [Blood samples were taken at specific time points from pre-dose to 12 hours post first dose of Padsevonil for each Treatment Period]

    AUC(0-12): The area under the plasma concentration-time curve from time zero to 12 hours of padsevonil metabolites (1 and 2) for single dose. AUC(0-12) was expressed in hours times nanograms per milliliter (hours*ng/mL).

  10. Area Under the Plasma Concentration-time Curve Over a Dosing Interval (12 Hours) (AUCtau) of Padsevonil Metabolites (1 and 2) for Multiple Doses [Blood samples were taken at specific time points from pre-dose to 72 hours post last dose of Padsevonil (PSL) (Treatment Period 1 and 2); from pre-dose to 120 hours post last dose of PSL (Treatment Period 3)]

    AUCtau: The area under the plasma concentration-time curve over a dosing interval (12 hours) of padsevonil metabolites (1 and 2) for multiple doses. AUCtau was expressed in hours times nanograms per milliliter (hours*ng/mL).

  11. Maximum Observed Steady-state Plasma Concentration (Cmax, ss) of Padsevonil Metabolites (1 and 2) for Multiple Doses [Blood samples were taken at specific time points from pre-dose to 72 hours post last dose of Padsevonil (PSL) (Treatment Period 1 and 2); from pre-dose to 120 hours post last dose of PSL (Treatment Period 3)]

    Cmax, ss: The maximum observed steady-state plasma concentration of padsevonil metabolites (1 and 2) for multiple doses. Cmax, ss was expressed in nanograms per millilitre (ng/mL).

  12. Metabolite-to-parent Ratio for Cmax of Padsevonil Metabolites (1 and 2) in Plasma [Blood samples were taken at specific time points from pre-dose to 12 hours post dose of Padsevonil for each Treatment Period]

    Metabolite-to-parent ratio calculated as: Cmax of padsevonil metabolites (1 and 2) divided by Cmax of padsevonil following a single dose in plasma. Metabolite-to-parent ratio for Cmax was expressed as ratio.

  13. Metabolite-to-parent Ratio for AUC(0-12) of Padsevonil Metabolites (1 and 2) in Plasma [Blood samples were taken at specific time points from pre-dose to 12 hours post first dose of Padsevonil for each Treatment Period]

    Metabolite-to-parent ratio calculated as: AUC(0-12)of padsevonil metabolites (1 and 2) divided by AUC(0-12) of padsevonil following a single dose in plasma. Metabolite-to-parent ratio for AUC(0-12) was expressed as ratio.

  14. Metabolite-to-parent Ratio for AUCtau of Padsevonil Metabolites (1 and 2) in Plasma [Blood samples were taken at specific time points from pre-dose to 72 hours post last dose of Padsevonil (PSL) (Treatment Period 1 and 2); from pre-dose to 120 hours post last dose of PSL (Treatment Period 3)]

    Metabolite-to-parent ratio calculated as: AUCtau of padsevonil metabolites (1 and 2) divided by AUCtau of padsevonil following multiple dosing in plasma. Metabolite-to-parent ratio for AUCtau was expressed as ratio.

  15. Renal Clearance (CLr) of Padsevonil and Metabolites (1 and 2) for Single Dose in Urine [Urine samples were taken 0 to 12 hours post first dose of Padsevonil during each Treatment Period]

    CLr: The renal clearance of padsevonil and its metabolites (1 and 2) for single dose in urine. CLr was expressed in milliliters per hour (mL/hour).

  16. Renal Clearance (CLr) of Padsevonil and Metabolites (1 and 2) for Multiple Doses in Urine [Urine samples were taken 0 to 12 hours, 12 to 24 hours,and 24 to 48 hours post last PSL dose during Treatment Period 1 and 2; 0 to 12 hours, 12 to 24 hours, 24 to 48 hours, 48 to 72 hours, and 72 to 96 hours post last dose of PSL during Treatment Period 3]

    CLr: The renal clearance of padsevonil and its metabolites (1 and 2) for multiple doses in urine. CLr was expressed in milliliters per hour (mL/hour).

  17. Cumulative Amount (Ae) of Padsevonil and Metabolites (1, 2, and 3) Excreted Into the Urine for Single Dose [Urine samples were taken 0 to 12 hours post first dose of Padsevonil during each Treatment Period]

    Ae: The cumulative amount of padsevonil and its metabolites (1, 2, and 3) excreted into the urine for single dose. Ae was expressed in milligrams (mg).

  18. Cumulative Amount (Ae) of Padsevonil and Metabolites (1, 2, and 3) Excreted Into the Urine for Multiple Doses [Urine samples were taken 0 to 12 hours, 12 to 24 hours,and 24 to 48 hours post last PSL dose during Treatment Period 1 and 2; 0 to 12 hours, 12 to 24 hours, 24 to 48 hours, 48 to 72 hours, and 72 to 96 hours post last dose of PSL during Treatment Period 3]

    Ae: The cumulative amount of padsevonil and its metabolites (1, 2, and 3) excreted into the urine for multiple doses. Ae was expressed in milligrams (mg).

  19. Fraction (fe) of Padsevonil and Metabolites (1, 2, and 3) Excreted Into the Urine for Single Dose [Urine samples were taken 0 to 12 hours post first dose of Padsevonil during each Treatment Period]

    fe: The fraction of padsevonil or metabolites (1, 2, and 3) excreted into the urine for single dose. fe was expressed in percentage (%).

  20. Fraction (fe) of Padsevonil and Metabolites (1, 2, and 3) Excreted Into the Urine for Multiple Doses [Urine samples were taken 0 to 12 hours, 12 to 24 hours,and 24 to 48 hours post last PSL dose during Treatment Period 1 and 2; 0 to 12 hours, 12 to 24 hours, 24 to 48 hours, 48 to 72 hours, and 72 to 96 hours post last dose of PSL during Treatment Period 3]

    fe: The fraction of padsevonil and its metabolites (1, 2, and 3) excreted into the urine for multiple doses. fe was expressed in percentage (%).

  21. Formation Clearance (CLform) of Padsevonil Metabolites (1, 2, and 3) in the Urine for Single Dose [Urine samples were taken 0 to 12 hours post first dose of Padsevonil during each Treatment Period]

    CLform: The formation clearance of padsevonil metabolites (1, 2, and 3) in the urine for single dose. CLform was expressed in milliliters per hour (mL/hour).

  22. Formation Clearance (CLform) of Padsevonil Metabolites (1, 2, and 3) in the Urine for Multiple Doses [Urine samples were taken 0 to 12 hours, 12 to 24 hours,and 24 to 48 hours post last PSL dose during Treatment Period 1 and 2; 0 to 12 hours, 12 to 24 hours, 24 to 48 hours, 48 to 72 hours, and 72 to 96 hours post last dose of PSL during Treatment Period 3]

    CLform: The formation clearance of padsevonil metabolites (1, 2, and 3) in the urine for multiple doses. CLform was expressed in milliliters per hour (mL/hour).

  23. Percentage of Participants Experiencing Treatment-Emergent Serious Adverse Events (SAEs) During the Study [From beginning of the first Treatment Period (Day 1) to the Safety Follow-up Visit (up to 48 days )]

    An 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 an 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.

  24. Percentage of Participants Experiencing Treatment-Emergent Non-serious Adverse Events (AEs) During the Study [From beginning of the first Treatment Period (Day 1) to the Safety Follow-up Visit (up to 48 days )]

    Treatment-emergent Adverse Events (TEAEs) were defined as those events which started on or after the date of first dose of UP0057 IMP, or events in which severity worsened on or after the date of first dose of UP0057 study medication.

Eligibility Criteria

Criteria

Ages Eligible for Study:
18 Years to 55 Years
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
Yes
Inclusion Criteria:
  • Study participant is male or female and between 18 and 55 years of age (inclusive)

  • Study participant is of a body weight of at least 50 kg for males and 45 kg for females, as determined by a body mass index (BMI) between 18 and 30 kg/m^2

  • Female study participants use an efficient form of contraception for the duration of the study (unless menopausal). Hormonal contraception may be susceptible to an interaction with the Investigational Medicinal Product (IMP), which may reduce the efficacy of the contraception method. The potential for reduced efficacy of any hormonal contraception methods requires that a barrier method (preferably male condom) also be used

  • Study participant has clinical laboratory test results within the local reference ranges or values are considered as not clinically relevant by the investigator and approved by the UCB Study Physician

  • Study participant has Blood Pressure (BP) and pulse rate within normal range in supine position after 10 minutes of rest

  • Male study participant agrees that, during the study period, when having sexual intercourse with a woman of childbearing potential, he will use an efficient barrier contraceptive (condom plus spermicide) AND that the respective partner will use an additional efficient contraceptive method

Exclusion Criteria:
  • Study participant has previously received Investigational Medicinal Product (IMP) in this study

  • Study participant has participated in another study of an IMP (or a medical device) within the previous 3 months before Screening (or within 5 half-lives for the IMP, whichever is longer) or is currently participating in another study of an IMP (or a medical device)

  • Study participant has a history of drug or alcohol dependency within the previous 6 months or tests positive for alcohol (breath test) and/or drugs of abuse (urine test) at the Screening Visit or at any time during confinement

  • Study participant has made a blood or plasma donation or has had a comparable blood loss (>400 mL) within the last 3 months prior to the Screening Visit

  • Study participant smokes more than 5 cigarettes per day (or equivalent) or has done so within 6 months prior to the Screening Visit

  • Study participant is taking any concomitant medication currently or within 2 weeks prior to the first day of dosing with the exception of paracetamol (acetaminophen)

  • Study participant has any clinically relevant Electrocardiogram (ECG) finding at the Screening Visit or confinement

  • Study participant has a history within the last 5 years or present condition of malignancy, with the exception of basal cell carcinoma

  • Female study participant tests positive for pregnancy, plans to get pregnant during the participation in the study, or who is breastfeeding

Contacts and Locations

Locations

Site City State Country Postal Code
1 Up0057 001 London United Kingdom

Sponsors and Collaborators

  • UCB Biopharma S.P.R.L.

Investigators

  • Study Director: UCB Cares, 001 844 599 2273 (UCB)

Study Documents (Full-Text)

More Information

Publications

None provided.
Responsible Party:
UCB Biopharma S.P.R.L.
ClinicalTrials.gov Identifier:
NCT03480243
Other Study ID Numbers:
  • UP0057
  • 2017-004694-13
First Posted:
Mar 29, 2018
Last Update Posted:
Jul 12, 2021
Last Verified:
Jun 1, 2021
Studies a U.S. FDA-regulated Drug Product:
No
Studies a U.S. FDA-regulated Device Product:
No
Keywords provided by UCB Biopharma S.P.R.L.
Additional relevant MeSH terms:

Study Results

Participant Flow

Recruitment Details The study started to enroll patients in March 2018 and concluded in August 2018.
Pre-assignment Detail Participant Flow refers to the Full Analysis Set (FAS).
Arm/Group Title Padsevonil and/or Erythromycin
Arm/Group Description The study participants received treatment as follows: Treatment Period 1: From Day 1 to Day 11: Padsevonil 100 mg twice daily (bid) on Day 1 to Day 4 Padsevonil 100 mg single dose on Day 5 1 week of wash-out (from evening of Day 5 to Day 11). Treatment Period 2: From Day 12 to Day 22: Padsevonil 100 mg bid on Day 12 to Day 15 Padsevonil 100 mg single dose on Day 16 1 week of wash-out (from evening of Day 16 to Day 22). Treatment Period 3: From Day 23 to 37 Treatment Period 3a: -Erythromycin 500 mg bid on Day 23 to Day 25. Treatment Period 3b: Padsevonil 100 mg bid and erythromycin 500 mg bid on Day 26 to Day 32 Padsevonil 100 mg single dose on Day 33 Erythromycin 500 mg bid on Day 33. Treatment Period 3c: - Erythromycin 500 mg bid on Day 34 to Day 37.
Period Title: Padsevonil (Period 1)
STARTED 28
COMPLETED 28
NOT COMPLETED 0
Period Title: Padsevonil (Period 1)
STARTED 28
COMPLETED 27
NOT COMPLETED 1
Period Title: Padsevonil (Period 1)
STARTED 27
COMPLETED 27
NOT COMPLETED 0
Period Title: Padsevonil (Period 1)
STARTED 27
COMPLETED 26
NOT COMPLETED 1
Period Title: Padsevonil (Period 1)
STARTED 26
COMPLETED 26
NOT COMPLETED 0

Baseline Characteristics

Arm/Group Title Padsevonil and/or Erythromycin
Arm/Group Description The study participants received treatment as follows: Treatment Period 1: From Day 1 to Day 11: Padsevonil 100 mg twice daily (bid) on Day 1 to Day 4 Padsevonil 100 mg single dose on Day 5 1 week of wash-out (from evening of Day 5 to Day 11). Treatment Period 2: From Day 12 to Day 22: Padsevonil 100 mg bid on Day 12 to Day 15 Padsevonil 100 mg single dose on Day 16 1 week of wash-out (from evening of Day 16 to Day 22). Treatment Period 3: From Day 23 to 37 Treatment Period 3a: -Erythromycin 500 mg bid on Day 23 to Day 25. Treatment Period 3b: Padsevonil 100 mg bid and erythromycin 500 mg bid on Day 26 to Day 32 Padsevonil 100 mg single dose on Day 33 Erythromycin 500 mg bid on Day 33. Treatment Period 3c: - Erythromycin 500 mg bid on Day 34 to Day 37.
Overall Participants 28
Age (Count of Participants)
<=18 years
0
0%
Between 18 and 65 years
28
100%
>=65 years
0
0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]
36.7
(8.3)
Sex: Female, Male (Count of Participants)
Female
3
10.7%
Male
25
89.3%
Race/Ethnicity, Customized (Count of Participants)
Asian
2
7.1%
Black
1
3.6%
White
24
85.7%
Missing
1
3.6%

Outcome Measures

1. Primary Outcome
Title Maximum Observed Plasma Concentration (Cmax) of Padsevonil for Single Dose
Description Cmax: The maximum observed plasma concentration of padsevonil for single dose . Cmax was expressed in nanograms per milliliter (ng/mL).
Time Frame Predose and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 8, and 12 hours postdose on Day 1, 12, and 26

Outcome Measure Data

Analysis Population Description
The Pharmacokinetic Per-Protocol Set (PK-PPS) was a subset of the FAS, consisting of those study participants who had no important protocol deviations affecting the PK parameters and for whom a sufficient number of samples were available to determine at least 1 PK parameter. As per the planned analysis, data was summarized by treatment periods.
Arm/Group Title Padsevonil (Period 1) (PK-PPS) Padsevonil (Period 2) (PK-PPS) Padsevonil and Erythromycin (Period 3b) (PK-PPS)
Arm/Group Description The study participants, of a single cohort, received Padsevonil during the Treatment Period 1 as follows: From Day 1 to Day 11: Padsevonil 100 mg bid on Day 1 to Day 4 Padsevonil 100 mg single dose on Day 5 1 week of wash-out (from evening of Day 5 to Day 11). Study participants formed the Pharmacokinetic-Per Protocol Set (PK-PPS). The study participants, of a single cohort, received Padsevonil during the Treatment Period 2 as follows: From Day 12 to Day 22: Padsevonil 100 mg bid on Day 12 to Day 15 Padsevonil 100 mg single dose on Day 16 1 week of wash-out (from evening of Day 16 to Day 22). Study participants formed the PK-PPS. The study participants, of a single cohort, received Padsevonil and Erythromycin during the second part of the Treatment Period 3b as follows: Padsevonil 100 mg bid and erythromycin 500 mg bid on Day 26 to Day 32 Padsevonil 100 mg single dose on Day 33 Erythromycin 500 mg bid on Day 33. Study participants formed the PK-PPS.
Measure Participants 28 28 27
Geometric Mean (Geometric Coefficient of Variation) [ng/mL]
366.6
(38.8)
385.3
(40.9)
697.4
(46.9)
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Padsevonil (Period 1) (PK-PPS), Padsevonil and Erythromycin (Period 3b) (PK-PPS)
Comments The analysis of variance model included the fixed effects period (1, 2 or 3b) and participant as a random effect.
Type of Statistical Test Other
Comments
Statistical Test of Hypothesis p-Value
Comments
Method
Comments
Method of Estimation Estimation Parameter Cmax Estimate Ratio
Estimated Value 1.90
Confidence Interval (2-Sided) 90%
1.59 to 2.27
Parameter Dispersion Type:
Value:
Estimation Comments
Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Padsevonil (Period 2) (PK-PPS), Padsevonil and Erythromycin (Period 3b) (PK-PPS)
Comments The analysis of variance model included the fixed effects period (1, 2 or 3b) and participant as a random effect.
Type of Statistical Test Other
Comments
Statistical Test of Hypothesis p-Value
Comments
Method
Comments
Method of Estimation Estimation Parameter Cmax Estimate Ratio
Estimated Value 1.81
Confidence Interval (2-Sided) 90%
1.51 to 2.16
Parameter Dispersion Type:
Value:
Estimation Comments
2. Primary Outcome
Title Area Under the Plasma Concentration-time Curve From Time Zero to 12 Hours (AUC(0-12)) of Padsevonil for Single Dose
Description AUC(0-12): The area under the plasma concentration-time curve from time zero to 12 hours of padsevonil for single dose . AUC(0-12) was expressed in hours times nanograms per milliliter (hours*ng/mL).
Time Frame Predose and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 8, and 12 hours postdose on Day 1, 12, and 26

Outcome Measure Data

Analysis Population Description
The Pharmacokinetic Per-Protocol Set (PK-PPS) was a subset of the FAS, consisting of those study participants who had no important protocol deviations affecting the PK parameters and for whom a sufficient number of samples were available to determine at least 1 PK parameter. As per the planned analysis, data was summarized by treatment periods.
Arm/Group Title Padsevonil (Period 1) (PK-PPS) Padsevonil (Period 2) (PK-PPS) Padsevonil and Erythromycin (Period 3b) (PK-PPS)
Arm/Group Description The study participants, of a single cohort, received Padsevonil during the Treatment Period 1 as follows: From Day 1 to Day 11: Padsevonil 100 mg bid on Day 1 to Day 4 Padsevonil 100 mg single dose on Day 5 1 week of wash-out (from evening of Day 5 to Day 11). Study participants formed the Pharmacokinetic-Per Protocol Set (PK-PPS). The study participants, of a single cohort, received Padsevonil during the Treatment Period 2 as follows: From Day 12 to Day 22: Padsevonil 100 mg bid on Day 12 to Day 15 Padsevonil 100 mg single dose on Day 16 1 week of wash-out (from evening of Day 16 to Day 22). Study participants formed the PK-PPS. The study participants, of a single cohort, received Padsevonil and Erythromycin during the second part of the Treatment Period 3b as follows: Padsevonil 100 mg bid and erythromycin 500 mg bid on Day 26 to Day 32 Padsevonil 100 mg single dose on Day 33 Erythromycin 500 mg bid on Day 33. Study participants formed the PK-PPS.
Measure Participants 28 28 27
Geometric Mean (Geometric Coefficient of Variation) [hours*ng/mL]
1428
(40.7)
1571
(41.8)
2576
(47.0)
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Padsevonil (Period 1) (PK-PPS), Padsevonil and Erythromycin (Period 3b) (PK-PPS)
Comments The analysis of variance model included the fixed effects period (1, 2 or 3b) and participant as a random effect.
Type of Statistical Test Other
Comments
Statistical Test of Hypothesis p-Value
Comments
Method
Comments
Method of Estimation Estimation Parameter AUC Estimate Ratio
Estimated Value 1.80
Confidence Interval (2-Sided) 90%
1.50 to 2.17
Parameter Dispersion Type:
Value:
Estimation Comments
Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Padsevonil (Period 2) (PK-PPS), Padsevonil and Erythromycin (Period 3b) (PK-PPS)
Comments The analysis of variance model included the fixed effects period (1, 2 or 3b) and participant as a random effect.
Type of Statistical Test Other
Comments
Statistical Test of Hypothesis p-Value
Comments
Method
Comments
Method of Estimation Estimation Parameter AUC Estimate Ratio
Estimated Value 1.64
Confidence Interval (2-Sided) 90%
1.36 to 1.97
Parameter Dispersion Type:
Value:
Estimation Comments
3. Primary Outcome
Title Maximum Observed Steady-state Plasma Concentration (Cmax, ss) of Padsevonil for Multiple Doses
Description Cmax, ss: The maximum observed steady-state plasma concentration of padsevonil for multiple doses. Cmax, ss was expressed in nanograms per millilitre (ng/mL).
Time Frame Blood samples were taken at specific time points from pre-dose to 72 hours post last dose of Padsevonil (PSL) (Treatment Period 1 and 2); from pre-dose to 120 hours post last dose of PSL (Treatment Period 3)

Outcome Measure Data

Analysis Population Description
The Pharmacokinetic Per-Protocol Set (PK-PPS) was a subset of the FAS, consisting of those study participants who had no important protocol deviations affecting the PK parameters and for whom a sufficient number of samples were available to determine at least 1 PK parameter. As per the planned analysis, data was summarized by treatment periods. Here, number of participants were included who were evaluable for the assessment.
Arm/Group Title Padsevonil (Period 1) (PK-PPS) Padsevonil (Period 2) (PK-PPS) Padsevonil and Erythromycin (Period 3b) (PK-PPS)
Arm/Group Description The study participants, of a single cohort, received Padsevonil during the Treatment Period 1 as follows: From Day 1 to Day 11: Padsevonil 100 mg bid on Day 1 to Day 4 Padsevonil 100 mg single dose on Day 5 1 week of wash-out (from evening of Day 5 to Day 11). Study participants formed the Pharmacokinetic-Per Protocol Set (PK-PPS). The study participants, of a single cohort, received Padsevonil during the Treatment Period 2 as follows: From Day 12 to Day 22: Padsevonil 100 mg bid on Day 12 to Day 15 Padsevonil 100 mg single dose on Day 16 1 week of wash-out (from evening of Day 16 to Day 22). Study participants formed the PK-PPS. The study participants, of a single cohort, received Padsevonil and Erythromycin during the second part of the Treatment Period 3b as follows: Padsevonil 100 mg bid and erythromycin 500 mg bid on Day 26 to Day 32 Padsevonil 100 mg single dose on Day 33 Erythromycin 500 mg bid on Day 33. Study participants formed the PK-PPS.
Measure Participants 28 28 26
Geometric Mean (Geometric Coefficient of Variation) [ng/mL]
475.0
(38.4)
473.9
(43.7)
1010
(45.7)
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Padsevonil (Period 1) (PK-PPS), Padsevonil and Erythromycin (Period 3b) (PK-PPS)
Comments The analysis of variance model included the fixed effects period (1, 2 or 3b) and participant as a random effect.
Type of Statistical Test Other
Comments
Statistical Test of Hypothesis p-Value
Comments
Method
Comments
Method of Estimation Estimation Parameter Cmax,ss Estimate Ratio
Estimated Value 2.13
Confidence Interval (2-Sided) 90%
1.77 to 2.55
Parameter Dispersion Type:
Value:
Estimation Comments
Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Padsevonil (Period 2) (PK-PPS), Padsevonil and Erythromycin (Period 3b) (PK-PPS)
Comments The analysis of variance model included the fixed effects period (1, 2 or 3b) and participant as a random effect.
Type of Statistical Test Other
Comments
Statistical Test of Hypothesis p-Value
Comments
Method
Comments
Method of Estimation Estimation Parameter Cmax,ss Estimate Ratio
Estimated Value 2.13
Confidence Interval (2-Sided) 90%
1.78 to 2.56
Parameter Dispersion Type:
Value:
Estimation Comments
4. Primary Outcome
Title Area Under the Plasma Concentration-time Curve Over a Dosing Interval (12 Hours) (AUCtau) of Padsevonil for Multiple Doses
Description AUCtau: The area under the plasma concentration-time curve over a dosing interval (12 hours) of padsevonil for multiple doses. AUC(tau) was expressed in hours times nanograms per millilitre (hours*ng/mL).
Time Frame Blood samples were taken at specific time points from pre-dose to 72 hours post last dose of Padsevonil (PSL) (Treatment Period 1 and 2); from pre-dose to 120 hours post last dose of PSL (Treatment Period 3)

Outcome Measure Data

Analysis Population Description
The Pharmacokinetic Per-Protocol Set (PK-PPS) was a subset of the FAS, consisting of those study participants who had no important protocol deviations affecting the PK parameters and for whom a sufficient number of samples were available to determine at least 1 PK parameter. As per the planned analysis, data was summarized by treatment periods. Here, number of participants were included who were evaluable for the assessment.
Arm/Group Title Padsevonil (Period 1) (PK-PPS) Padsevonil (Period 2) (PK-PPS) Padsevonil and Erythromycin (Period 3b) (PK-PPS)
Arm/Group Description The study participants, of a single cohort, received Padsevonil during the Treatment Period 1 as follows: From Day 1 to Day 11: Padsevonil 100 mg bid on Day 1 to Day 4 Padsevonil 100 mg single dose on Day 5 1 week of wash-out (from evening of Day 5 to Day 11). Study participants formed the Pharmacokinetic-Per Protocol Set (PK-PPS). The study participants, of a single cohort, received Padsevonil during the Treatment Period 2 as follows: From Day 12 to Day 22: Padsevonil 100 mg bid on Day 12 to Day 15 Padsevonil 100 mg single dose on Day 16 1 week of wash-out (from evening of Day 16 to Day 22). Study participants formed the PK-PPS. The study participants, of a single cohort, received Padsevonil and Erythromycin during the second part of the Treatment Period 3b as follows: Padsevonil 100 mg bid and erythromycin 500 mg bid on Day 26 to Day 32 Padsevonil 100 mg single dose on Day 33 Erythromycin 500 mg bid on Day 33. Study participants formed the PK-PPS.
Measure Participants 28 28 26
Geometric Mean (Geometric Coefficient of Variation) [hours*ng/mL]
2049
(41.1)
2274
(47.1)
5073
(55.9)
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Padsevonil (Period 1) (PK-PPS), Padsevonil and Erythromycin (Period 3b) (PK-PPS)
Comments The analysis of variance model included the fixed effects period (1, 2 or 3b) and participant as a random effect.
Type of Statistical Test Other
Comments
Statistical Test of Hypothesis p-Value
Comments
Method
Comments
Method of Estimation Estimation Parameter AUCtau Estimate Ratio
Estimated Value 2.48
Confidence Interval (2-Sided) 90%
2.02 to 3.03
Parameter Dispersion Type:
Value:
Estimation Comments
Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Padsevonil (Period 2) (PK-PPS), Padsevonil and Erythromycin (Period 3b) (PK-PPS)
Comments The analysis of variance model included the fixed effects period (1, 2 or 3b) and participant as a random effect.
Type of Statistical Test Other
Comments
Statistical Test of Hypothesis p-Value
Comments
Method
Comments
Method of Estimation Estimation Parameter AUCtau Estimate Ratio
Estimated Value 2.23
Confidence Interval (2-Sided) 90%
1.82 to 2.73
Parameter Dispersion Type:
Value:
Estimation Comments
5. Secondary Outcome
Title Time of Maximum Plasma Concentration (Tmax) of Padsevonil for Single Dose
Description Tmax: The time of maximum plasma concentration of padsevonil for single dose. Tmax was expressed in hours (h).
Time Frame Blood samples were taken at specific time points from pre-dose to 12 hours post first dose of Padsevonil for each Treatment Period

Outcome Measure Data

Analysis Population Description
The Pharmacokinetic Per-Protocol Set (PK-PPS) was a subset of the FAS, consisting of those study participants who had no important protocol deviations affecting the PK parameters and for whom a sufficient number of samples were available to determine at least 1 PK parameter. As per the planned analysis, data was summarized by treatment periods.
Arm/Group Title Padsevonil (Period 1) (PK-PPS) Padsevonil (Period 2) (PK-PPS) Padsevonil and Erythromycin (Period 3b) (PK-PPS)
Arm/Group Description The study participants, of a single cohort, received Padsevonil during the Treatment Period 1 as follows: From Day 1 to Day 11: Padsevonil 100 mg bid on Day 1 to Day 4 Padsevonil 100 mg single dose on Day 5 1 week of wash-out (from evening of Day 5 to Day 11). Study participants formed the Pharmacokinetic-Per Protocol Set (PK-PPS). The study participants, of a single cohort, received Padsevonil during the Treatment Period 2 as follows: From Day 12 to Day 22: Padsevonil 100 mg bid on Day 12 to Day 15 Padsevonil 100 mg single dose on Day 16 1 week of wash-out (from evening of Day 16 to Day 22). Study participants formed the PK-PPS. The study participants, of a single cohort, received Padsevonil and Erythromycin during the second part of the Treatment Period 3b as follows: Padsevonil 100 mg bid and erythromycin 500 mg bid on Day 26 to Day 32 Padsevonil 100 mg single dose on Day 33 Erythromycin 500 mg bid on Day 33. Study participants formed the PK-PPS.
Measure Participants 28 28 27
Median (Full Range) [hours]
3.000
1.500
1.500
6. Secondary Outcome
Title Minimum Observed Plasma Concentration (Cmin) of Padsevonil for Single Dose
Description Cmin: The minimum observed plasma concentration of padsevonil for single dose. Cmin was expressed in nanograms per millilitre (ng/mL).
Time Frame Blood samples were taken at specific time points from pre-dose to 12 hours post first dose of Padsevonil for each Treatment Period

Outcome Measure Data

Analysis Population Description
The Pharmacokinetic Per-Protocol Set (PK-PPS) was a subset of the FAS, consisting of those study participants who had no important protocol deviations affecting the PK parameters and for whom a sufficient number of samples were available to determine at least 1 PK parameter. As per the planned analysis, data was summarized by treatment periods.
Arm/Group Title Padsevonil (Period 1) (PK-PPS) Padsevonil (Period 2) (PK-PPS) Padsevonil and Erythromycin (Period 3b) (PK-PPS)
Arm/Group Description The study participants, of a single cohort, received Padsevonil during the Treatment Period 1 as follows: From Day 1 to Day 11: Padsevonil 100 mg bid on Day 1 to Day 4 Padsevonil 100 mg single dose on Day 5 1 week of wash-out (from evening of Day 5 to Day 11). Study participants formed the Pharmacokinetic-Per Protocol Set (PK-PPS). The study participants, of a single cohort, received Padsevonil during the Treatment Period 2 as follows: From Day 12 to Day 22: Padsevonil 100 mg bid on Day 12 to Day 15 Padsevonil 100 mg single dose on Day 16 1 week of wash-out (from evening of Day 16 to Day 22). Study participants formed the PK-PPS. The study participants, of a single cohort, received Padsevonil and Erythromycin during the second part of the Treatment Period 3b as follows: Padsevonil 100 mg bid and erythromycin 500 mg bid on Day 26 to Day 32 Padsevonil 100 mg single dose on Day 33 Erythromycin 500 mg bid on Day 33. Study participants formed the PK-PPS.
Measure Participants 28 28 27
Geometric Mean (Geometric Coefficient of Variation) [ng/mL]
2.857
(100.9)
5.643
(147.8)
4.286
(172.5)
7. Secondary Outcome
Title Time of Maximum Plasma Concentration (Tmax) of Padsevonil for Multiple Doses
Description Tmax: The time of maximum plasma concentration of padsevonil for multiple doses. Tmax was expressed in hours (h).
Time Frame Blood samples were taken at specific time points from pre-dose to 72 hours post last dose of Padsevonil (PSL) (Treatment Period 1 and 2); from pre-dose to 120 hours post last dose of PSL (Treatment Period 3)

Outcome Measure Data

Analysis Population Description
The Pharmacokinetic Per-Protocol Set (PK-PPS) was a subset of the FAS, consisting of those study participants who had no important protocol deviations affecting the PK parameters and for whom a sufficient number of samples were available to determine at least 1 PK parameter. As per the planned analysis, data was summarized by treatment periods. Here, number of participants were included who were evaluable for the assessment.
Arm/Group Title Padsevonil (Period 1) (PK-PPS) Padsevonil (Period 2) (PK-PPS) Padsevonil and Erythromycin (Period 3b) (PK-PPS)
Arm/Group Description The study participants, of a single cohort, received Padsevonil during the Treatment Period 1 as follows: From Day 1 to Day 11: Padsevonil 100 mg bid on Day 1 to Day 4 Padsevonil 100 mg single dose on Day 5 1 week of wash-out (from evening of Day 5 to Day 11). Study participants formed the Pharmacokinetic-Per Protocol Set (PK-PPS). The study participants, of a single cohort, received Padsevonil during the Treatment Period 2 as follows: From Day 12 to Day 22: Padsevonil 100 mg bid on Day 12 to Day 15 Padsevonil 100 mg single dose on Day 16 1 week of wash-out (from evening of Day 16 to Day 22). Study participants formed the PK-PPS. The study participants, of a single cohort, received Padsevonil and Erythromycin during the second part of the Treatment Period 3b as follows: Padsevonil 100 mg bid and erythromycin 500 mg bid on Day 26 to Day 32 Padsevonil 100 mg single dose on Day 33 Erythromycin 500 mg bid on Day 33. Study participants formed the PK-PPS.
Measure Participants 28 28 26
Median (Full Range) [hours]
1.750
1.500
2.000
8. Secondary Outcome
Title Apparent Terminal Elimination Half-life at Steady-state (t1/2,ss) of Padsevonil for Multiple Doses in Plasma
Description t½,ss: The apparent terminal elimination half-life at steady-state of padsevonil for multiple doses in plasma. t1/2, ss was expressed in hours (h).
Time Frame Blood samples were taken at specific time points from pre-dose to 72 hours post last dose of Padsevonil (PSL) (Treatment Period 1 and 2); from pre-dose to 120 hours post last dose of PSL (Treatment Period 3)

Outcome Measure Data

Analysis Population Description
The Pharmacokinetic Per-Protocol Set (PK-PPS) was a subset of the FAS, consisting of those study participants who had no important protocol deviations affecting the PK parameters and for whom a sufficient number of samples were available to determine at least 1 PK parameter. As per the planned analysis, data was summarized by treatment periods. Here, number of participants were included who were evaluable for the assessment.
Arm/Group Title Padsevonil (Period 1) (PK-PPS) Padsevonil (Period 2) (PK-PPS) Padsevonil and Erythromycin (Period 3b) (PK-PPS)
Arm/Group Description The study participants, of a single cohort, received Padsevonil during the Treatment Period 1 as follows: From Day 1 to Day 11: Padsevonil 100 mg bid on Day 1 to Day 4 Padsevonil 100 mg single dose on Day 5 1 week of wash-out (from evening of Day 5 to Day 11). Study participants formed the Pharmacokinetic-Per Protocol Set (PK-PPS). The study participants, of a single cohort, received Padsevonil during the Treatment Period 2 as follows: From Day 12 to Day 22: Padsevonil 100 mg bid on Day 12 to Day 15 Padsevonil 100 mg single dose on Day 16 1 week of wash-out (from evening of Day 16 to Day 22). Study participants formed the PK-PPS. The study participants, of a single cohort, received Padsevonil and Erythromycin during the second part of the Treatment Period 3b as follows: Padsevonil 100 mg bid and erythromycin 500 mg bid on Day 26 to Day 32 Padsevonil 100 mg single dose on Day 33 Erythromycin 500 mg bid on Day 33. Study participants formed the PK-PPS.
Measure Participants 28 28 26
Median (Full Range) [hours]
6.465
6.649
8.548
9. Secondary Outcome
Title Predose Observed Plasma Concentration (Ctrough) of Padsevonil for Multiple Doses
Description Ctrough: The predose observed plasma concentration of padsevonil for multiple doses. Ctrough was expressed in nanograms per millilitre (ng/mL).
Time Frame Blood samples were taken at specific time points from pre-dose to 72 hours post last dose of Padsevonil (PSL) (Treatment Period 1 and 2); from pre-dose to 120 hours post last dose of PSL (Treatment Period 3)

Outcome Measure Data

Analysis Population Description
The Pharmacokinetic Per-Protocol Set (PK-PPS) was a subset of the FAS, consisting of those study participants who had no important protocol deviations affecting the PK parameters and for whom a sufficient number of samples were available to determine at least 1 PK parameter. As per the planned analysis, data was summarized by treatment periods. Here, number of participants were included who were evaluable for the assessment.
Arm/Group Title Padsevonil (Period 1) (PK-PPS) Padsevonil (Period 2) (PK-PPS) Padsevonil and Erythromycin (Period 3b) (PK-PPS)
Arm/Group Description The study participants, of a single cohort, received Padsevonil during the Treatment Period 1 as follows: From Day 1 to Day 11: Padsevonil 100 mg bid on Day 1 to Day 4 Padsevonil 100 mg single dose on Day 5 1 week of wash-out (from evening of Day 5 to Day 11). Study participants formed the Pharmacokinetic-Per Protocol Set (PK-PPS). The study participants, of a single cohort, received Padsevonil during the Treatment Period 2 as follows: From Day 12 to Day 22: Padsevonil 100 mg bid on Day 12 to Day 15 Padsevonil 100 mg single dose on Day 16 1 week of wash-out (from evening of Day 16 to Day 22). Study participants formed the PK-PPS. The study participants, of a single cohort, received Padsevonil and Erythromycin during the second part of the Treatment Period 3b as follows: Padsevonil 100 mg bid and erythromycin 500 mg bid on Day 26 to Day 32 Padsevonil 100 mg single dose on Day 33 Erythromycin 500 mg bid on Day 33. Study participants formed the PK-PPS.
Measure Participants 28 28 26
Geometric Mean (Geometric Coefficient of Variation) [ng/mL]
57.03
(69.0)
68.57
(85.1)
182.6
(95.5)
10. Secondary Outcome
Title Apparent Total Clearance at Steady-state (CL/Fss) of Padsevonil for Multiple Doses in Plasma
Description CL/Fss: The apparent total clearance at steady-state of padsevonil for multiple doses in plasma. CL/Fss was expressed in milliliters per hour (mL/hour).
Time Frame Blood samples were taken at specific time points from pre-dose to 72 hours post last dose of Padsevonil (PSL) (Treatment Period 1 and 2); from pre-dose to 120 hours post last dose of PSL (Treatment Period 3)

Outcome Measure Data

Analysis Population Description
The Pharmacokinetic Per-Protocol Set (PK-PPS) was a subset of the FAS, consisting of those study participants who had no important protocol deviations affecting the PK parameters and for whom a sufficient number of samples were available to determine at least 1 PK parameter. As per the planned analysis, data was summarized by treatment periods. Here, number of participants were included who were evaluable for the assessment.
Arm/Group Title Padsevonil (Period 1) (PK-PPS) Padsevonil (Period 2) (PK-PPS) Padsevonil and Erythromycin (Period 3b) (PK-PPS)
Arm/Group Description The study participants, of a single cohort, received Padsevonil during the Treatment Period 1 as follows: From Day 1 to Day 11: Padsevonil 100 mg bid on Day 1 to Day 4 Padsevonil 100 mg single dose on Day 5 1 week of wash-out (from evening of Day 5 to Day 11). Study participants formed the Pharmacokinetic-Per Protocol Set (PK-PPS). The study participants, of a single cohort, received Padsevonil during the Treatment Period 2 as follows: From Day 12 to Day 22: Padsevonil 100 mg bid on Day 12 to Day 15 Padsevonil 100 mg single dose on Day 16 1 week of wash-out (from evening of Day 16 to Day 22). Study participants formed the PK-PPS. The study participants, of a single cohort, received Padsevonil and Erythromycin during the second part of the Treatment Period 3b as follows: Padsevonil 100 mg bid and erythromycin 500 mg bid on Day 26 to Day 32 Padsevonil 100 mg single dose on Day 33 Erythromycin 500 mg bid on Day 33. Study participants formed the PK-PPS.
Measure Participants 28 28 26
Geometric Mean (Geometric Coefficient of Variation) [mL/hour]
48810
(41.1)
43970
(47.1)
19710
(55.9)
11. Secondary Outcome
Title Apparent Elimination Rate Constant (Lambdaz) of Padsevonil for Multiple Doses in Plasma
Description lambdaz: The apparent elimination rate constant of padsevonil for multiple doses in plasma. Lambdaz was expressed in liters per hour (l/hour).
Time Frame Blood samples were taken at specific time points from pre-dose to 72 hours post last dose of Padsevonil (PSL) (Treatment Period 1 and 2); from pre-dose to 120 hours post last dose of PSL (Treatment Period 3)

Outcome Measure Data

Analysis Population Description
The Pharmacokinetic Per-Protocol Set (PK-PPS) was a subset of the FAS, consisting of those study participants who had no important protocol deviations affecting the PK parameters and for whom a sufficient number of samples were available to determine at least 1 PK parameter. As per the planned analysis, data was summarized by treatment periods. Here, number of participants were included who were evaluable for the assessment.
Arm/Group Title Padsevonil (Period 1) (PK-PPS) Padsevonil (Period 2) (PK-PPS) Padsevonil and Erythromycin (Period 3b) (PK-PPS)
Arm/Group Description The study participants, of a single cohort, received Padsevonil during the Treatment Period 1 as follows: From Day 1 to Day 11: Padsevonil 100 mg bid on Day 1 to Day 4 Padsevonil 100 mg single dose on Day 5 1 week of wash-out (from evening of Day 5 to Day 11). Study participants formed the Pharmacokinetic-Per Protocol Set (PK-PPS). The study participants, of a single cohort, received Padsevonil during the Treatment Period 2 as follows: From Day 12 to Day 22: Padsevonil 100 mg bid on Day 12 to Day 15 Padsevonil 100 mg single dose on Day 16 1 week of wash-out (from evening of Day 16 to Day 22). Study participants formed the PK-PPS. The study participants, of a single cohort, received Padsevonil and Erythromycin during the second part of the Treatment Period 3b as follows: Padsevonil 100 mg bid and erythromycin 500 mg bid on Day 26 to Day 32 Padsevonil 100 mg single dose on Day 33 Erythromycin 500 mg bid on Day 33. Study participants formed the PK-PPS.
Measure Participants 28 28 26
Geometric Mean (Geometric Coefficient of Variation) [l\hour]
0.1049
(27.9)
0.1006
(36.2)
0.07975
(34.5)
12. Secondary Outcome
Title Maximum Observed Plasma Concentration (Cmax) of Padsevonil Metabolites (1 and 2) for Single Dose
Description Cmax: The maximum plasma concentration of padsevonil metabolites (1 and 2) for single dose. Cmax was expressed in nanograms per milliliter (ng/mL).
Time Frame Blood samples were taken at specific time points from pre-dose to 12 hours post first dose of Padsevonil for each Treatment Period

Outcome Measure Data

Analysis Population Description
The Pharmacokinetic Per-Protocol Set (PK-PPS) was a subset of the FAS, consisting of those study participants who had no important protocol deviations affecting the PK parameters and for whom a sufficient number of samples were available to determine at least 1 PK parameter. As per the planned analysis, data was summarized by treatment periods.
Arm/Group Title Padsevonil (Period 1) (PK-PPS) Padsevonil (Period 2) (PK-PPS) Padsevonil and Erythromycin (Period 3b) (PK-PPS)
Arm/Group Description The study participants, of a single cohort, received Padsevonil during the Treatment Period 1 as follows: From Day 1 to Day 11: Padsevonil 100 mg bid on Day 1 to Day 4 Padsevonil 100 mg single dose on Day 5 1 week of wash-out (from evening of Day 5 to Day 11). Study participants formed the Pharmacokinetic-Per Protocol Set (PK-PPS). The study participants, of a single cohort, received Padsevonil during the Treatment Period 2 as follows: From Day 12 to Day 22: Padsevonil 100 mg bid on Day 12 to Day 15 Padsevonil 100 mg single dose on Day 16 1 week of wash-out (from evening of Day 16 to Day 22). Study participants formed the PK-PPS. The study participants, of a single cohort, received Padsevonil and Erythromycin during the second part of the Treatment Period 3b as follows: Padsevonil 100 mg bid and erythromycin 500 mg bid on Day 26 to Day 32 Padsevonil 100 mg single dose on Day 33 Erythromycin 500 mg bid on Day 33. Study participants formed the PK-PPS.
Measure Participants 28 28 27
Metabolite 1
166.6
(29.1)
158.7
(34.5)
189.5
(29.8)
Metabolite 2
110.5
(33.4)
94.47
(44.2)
108.3
(49.6)
13. Secondary Outcome
Title Area Under the Plasma Concentration-time Curve From Time Zero to 12 Hours (AUC(0-12)) of Padsevonil Metabolites (1 and 2) for Single Dose
Description AUC(0-12): The area under the plasma concentration-time curve from time zero to 12 hours of padsevonil metabolites (1 and 2) for single dose. AUC(0-12) was expressed in hours times nanograms per milliliter (hours*ng/mL).
Time Frame Blood samples were taken at specific time points from pre-dose to 12 hours post first dose of Padsevonil for each Treatment Period

Outcome Measure Data

Analysis Population Description
The Pharmacokinetic Per-Protocol Set (PK-PPS) was a subset of the FAS, consisting of those study participants who had no important protocol deviations affecting the PK parameters and for whom a sufficient number of samples were available to determine at least 1 PK parameter. As per the planned analysis, data was summarized by treatment periods.
Arm/Group Title Padsevonil (Period 1) (PK-PPS) Padsevonil (Period 2) (PK-PPS) Padsevonil and Erythromycin (Period 3b) (PK-PPS)
Arm/Group Description The study participants, of a single cohort, received Padsevonil during the Treatment Period 1 as follows: From Day 1 to Day 11: Padsevonil 100 mg bid on Day 1 to Day 4 Padsevonil 100 mg single dose on Day 5 1 week of wash-out (from evening of Day 5 to Day 11). Study participants formed the Pharmacokinetic-Per Protocol Set (PK-PPS). The study participants, of a single cohort, received Padsevonil during the Treatment Period 2 as follows: From Day 12 to Day 22: Padsevonil 100 mg bid on Day 12 to Day 15 Padsevonil 100 mg single dose on Day 16 1 week of wash-out (from evening of Day 16 to Day 22). Study participants formed the PK-PPS. The study participants, of a single cohort, received Padsevonil and Erythromycin during the second part of the Treatment Period 3b as follows: Padsevonil 100 mg bid and erythromycin 500 mg bid on Day 26 to Day 32 Padsevonil 100 mg single dose on Day 33 Erythromycin 500 mg bid on Day 33. Study participants formed the PK-PPS.
Measure Participants 28 28 27
Metabolite 1
828.3
(24.2)
824.3
(25.5)
905.6
(29.7)
Metabolite 2
596.5
(39.0)
534.4
(43.9)
599.5
(49.5)
14. Secondary Outcome
Title Area Under the Plasma Concentration-time Curve Over a Dosing Interval (12 Hours) (AUCtau) of Padsevonil Metabolites (1 and 2) for Multiple Doses
Description AUCtau: The area under the plasma concentration-time curve over a dosing interval (12 hours) of padsevonil metabolites (1 and 2) for multiple doses. AUCtau was expressed in hours times nanograms per milliliter (hours*ng/mL).
Time Frame Blood samples were taken at specific time points from pre-dose to 72 hours post last dose of Padsevonil (PSL) (Treatment Period 1 and 2); from pre-dose to 120 hours post last dose of PSL (Treatment Period 3)

Outcome Measure Data

Analysis Population Description
The Pharmacokinetic Per-Protocol Set (PK-PPS) was a subset of the FAS, consisting of those study participants who had no important protocol deviations affecting the PK parameters and for whom a sufficient number of samples were available to determine at least 1 PK parameter. As per the planned analysis, data was summarized by treatment periods. Here, number of participants were included who were evaluable for the assessment.
Arm/Group Title Padsevonil (Period 1) (PK-PPS) Padsevonil (Period 2) (PK-PPS) Padsevonil and Erythromycin (Period 3b) (PK-PPS)
Arm/Group Description The study participants, of a single cohort, received Padsevonil during the Treatment Period 1 as follows: From Day 1 to Day 11: Padsevonil 100 mg bid on Day 1 to Day 4 Padsevonil 100 mg single dose on Day 5 1 week of wash-out (from evening of Day 5 to Day 11). Study participants formed the Pharmacokinetic-Per Protocol Set (PK-PPS). The study participants, of a single cohort, received Padsevonil during the Treatment Period 2 as follows: From Day 12 to Day 22: Padsevonil 100 mg bid on Day 12 to Day 15 Padsevonil 100 mg single dose on Day 16 1 week of wash-out (from evening of Day 16 to Day 22). Study participants formed the PK-PPS. The study participants, of a single cohort, received Padsevonil and Erythromycin during the second part of the Treatment Period 3b as follows: Padsevonil 100 mg bid and erythromycin 500 mg bid on Day 26 to Day 32 Padsevonil 100 mg single dose on Day 33 Erythromycin 500 mg bid on Day 33. Study participants formed the PK-PPS.
Measure Participants 28 28 26
Metabolite 1
1748
(35.1)
1993
(40.8)
2625
(46.1)
Metabolite 2
775.1
(37.4)
813.1
(40.5)
799.0
(38.5)
15. Secondary Outcome
Title Maximum Observed Steady-state Plasma Concentration (Cmax, ss) of Padsevonil Metabolites (1 and 2) for Multiple Doses
Description Cmax, ss: The maximum observed steady-state plasma concentration of padsevonil metabolites (1 and 2) for multiple doses. Cmax, ss was expressed in nanograms per millilitre (ng/mL).
Time Frame Blood samples were taken at specific time points from pre-dose to 72 hours post last dose of Padsevonil (PSL) (Treatment Period 1 and 2); from pre-dose to 120 hours post last dose of PSL (Treatment Period 3)

Outcome Measure Data

Analysis Population Description
The Pharmacokinetic Per-Protocol Set (PK-PPS) was a subset of the FAS, consisting of those study participants who had no important protocol deviations affecting the PK parameters and for whom a sufficient number of samples were available to determine at least 1 PK parameter. As per the planned analysis, data was summarized by treatment periods. Here, number of participants were included who were evaluable for the assessment.
Arm/Group Title Padsevonil (Period 1) (PK-PPS) Padsevonil (Period 2) (PK-PPS) Padsevonil and Erythromycin (Period 3b) (PK-PPS)
Arm/Group Description The study participants, of a single cohort, received Padsevonil during the Treatment Period 1 as follows: From Day 1 to Day 11: Padsevonil 100 mg bid on Day 1 to Day 4 Padsevonil 100 mg single dose on Day 5 1 week of wash-out (from evening of Day 5 to Day 11). Study participants formed the Pharmacokinetic-Per Protocol Set (PK-PPS). The study participants, of a single cohort, received Padsevonil during the Treatment Period 2 as follows: From Day 12 to Day 22: Padsevonil 100 mg bid on Day 12 to Day 15 Padsevonil 100 mg single dose on Day 16 1 week of wash-out (from evening of Day 16 to Day 22). Study participants formed the PK-PPS. The study participants, of a single cohort, received Padsevonil and Erythromycin during the second part of the Treatment Period 3b as follows: Padsevonil 100 mg bid and erythromycin 500 mg bid on Day 26 to Day 32 Padsevonil 100 mg single dose on Day 33 Erythromycin 500 mg bid on Day 33. Study participants formed the PK-PPS.
Measure Participants 28 28 26
Metabolite 1
232.3
(27.1)
258.3
(32.3)
310.3
(46.0)
Metabolite 2
118.6
(29.3)
113.3
(36.8)
101.8
(37.1)
16. Secondary Outcome
Title Metabolite-to-parent Ratio for Cmax of Padsevonil Metabolites (1 and 2) in Plasma
Description Metabolite-to-parent ratio calculated as: Cmax of padsevonil metabolites (1 and 2) divided by Cmax of padsevonil following a single dose in plasma. Metabolite-to-parent ratio for Cmax was expressed as ratio.
Time Frame Blood samples were taken at specific time points from pre-dose to 12 hours post dose of Padsevonil for each Treatment Period

Outcome Measure Data

Analysis Population Description
The Pharmacokinetic Per-Protocol Set (PK-PPS) was a subset of the FAS, consisting of those study participants who had no important protocol deviations affecting the PK parameters and for whom a sufficient number of samples were available to determine at least 1 PK parameter. As per the planned analysis, data was summarized by treatment periods.
Arm/Group Title Padsevonil (Period 1) (PK-PPS) Padsevonil (Period 2) (PK-PPS) Padsevonil and Erythromycin (Period 3b) (PK-PPS)
Arm/Group Description The study participants, of a single cohort, received Padsevonil during the Treatment Period 1 as follows: From Day 1 to Day 11: Padsevonil 100 mg bid on Day 1 to Day 4 Padsevonil 100 mg single dose on Day 5 1 week of wash-out (from evening of Day 5 to Day 11). Study participants formed the Pharmacokinetic-Per Protocol Set (PK-PPS). The study participants, of a single cohort, received Padsevonil during the Treatment Period 2 as follows: From Day 12 to Day 22: Padsevonil 100 mg bid on Day 12 to Day 15 Padsevonil 100 mg single dose on Day 16 1 week of wash-out (from evening of Day 16 to Day 22). Study participants formed the PK-PPS. The study participants, of a single cohort, received Padsevonil and Erythromycin during the second part of the Treatment Period 3b as follows: Padsevonil 100 mg bid and erythromycin 500 mg bid on Day 26 to Day 32 Padsevonil 100 mg single dose on Day 33 Erythromycin 500 mg bid on Day 33. Study participants formed the PK-PPS.
Measure Participants 28 28 27
Metabolite 1
0.4544
(40.6)
0.4119
(45.5)
0.2717
(49.5)
Metabolite 2
0.3015
(66.8)
0.2452
(77.1)
0.1552
(94.3)
17. Secondary Outcome
Title Metabolite-to-parent Ratio for AUC(0-12) of Padsevonil Metabolites (1 and 2) in Plasma
Description Metabolite-to-parent ratio calculated as: AUC(0-12)of padsevonil metabolites (1 and 2) divided by AUC(0-12) of padsevonil following a single dose in plasma. Metabolite-to-parent ratio for AUC(0-12) was expressed as ratio.
Time Frame Blood samples were taken at specific time points from pre-dose to 12 hours post first dose of Padsevonil for each Treatment Period

Outcome Measure Data

Analysis Population Description
The Pharmacokinetic Per-Protocol Set (PK-PPS) was a subset of the FAS, consisting of those study participants who had no important protocol deviations affecting the PK parameters and for whom a sufficient number of samples were available to determine at least 1 PK parameter. As per the planned analysis, data was summarized by treatment periods.
Arm/Group Title Padsevonil (Period 1) (PK-PPS) Padsevonil (Period 2) (PK-PPS) Padsevonil and Erythromycin (Period 3b) (PK-PPS)
Arm/Group Description The study participants, of a single cohort, received Padsevonil during the Treatment Period 1 as follows: From Day 1 to Day 11: Padsevonil 100 mg bid on Day 1 to Day 4 Padsevonil 100 mg single dose on Day 5 1 week of wash-out (from evening of Day 5 to Day 11). Study participants formed the Pharmacokinetic-Per Protocol Set (PK-PPS). The study participants, of a single cohort, received Padsevonil during the Treatment Period 2 as follows: From Day 12 to Day 22: Padsevonil 100 mg bid on Day 12 to Day 15 Padsevonil 100 mg single dose on Day 16 1 week of wash-out (from evening of Day 16 to Day 22). Study participants formed the PK-PPS. The study participants, of a single cohort, received Padsevonil and Erythromycin during the second part of the Treatment Period 3b as follows: Padsevonil 100 mg bid and erythromycin 500 mg bid on Day 26 to Day 32 Padsevonil 100 mg single dose on Day 33 Erythromycin 500 mg bid on Day 33. Study participants formed the PK-PPS.
Measure Participants 28 28 27
Metabolite 1
0.5799
(39.7)
0.5246
(42.8)
0.3515
(48.9)
Metabolite 2
0.4176
(70.0)
0.3401
(78.7)
0.2327
(97.1)
18. Secondary Outcome
Title Metabolite-to-parent Ratio for AUCtau of Padsevonil Metabolites (1 and 2) in Plasma
Description Metabolite-to-parent ratio calculated as: AUCtau of padsevonil metabolites (1 and 2) divided by AUCtau of padsevonil following multiple dosing in plasma. Metabolite-to-parent ratio for AUCtau was expressed as ratio.
Time Frame Blood samples were taken at specific time points from pre-dose to 72 hours post last dose of Padsevonil (PSL) (Treatment Period 1 and 2); from pre-dose to 120 hours post last dose of PSL (Treatment Period 3)

Outcome Measure Data

Analysis Population Description
The Pharmacokinetic Per-Protocol Set (PK-PPS) was a subset of the FAS, consisting of those study participants who had no important protocol deviations affecting the PK parameters and for whom a sufficient number of samples were available to determine at least 1 PK parameter. As per the planned analysis, data was summarized by treatment periods. Here, number of participants were included who were evaluable for the assessment.
Arm/Group Title Padsevonil (Period 1) (PK-PPS) Padsevonil (Period 2) (PK-PPS) Padsevonil and Erythromycin (Period 3b) (PK-PPS)
Arm/Group Description The study participants, of a single cohort, received Padsevonil during the Treatment Period 1 as follows: From Day 1 to Day 11: Padsevonil 100 mg bid on Day 1 to Day 4 Padsevonil 100 mg single dose on Day 5 1 week of wash-out (from evening of Day 5 to Day 11). Study participants formed the Pharmacokinetic-Per Protocol Set (PK-PPS). The study participants, of a single cohort, received Padsevonil during the Treatment Period 2 as follows: From Day 12 to Day 22: Padsevonil 100 mg bid on Day 12 to Day 15 Padsevonil 100 mg single dose on Day 16 1 week of wash-out (from evening of Day 16 to Day 22). Study participants formed the PK-PPS. The study participants, of a single cohort, received Padsevonil and Erythromycin during the second part of the Treatment Period 3b as follows: Padsevonil 100 mg bid and erythromycin 500 mg bid on Day 26 to Day 32 Padsevonil 100 mg single dose on Day 33 Erythromycin 500 mg bid on Day 33. Study participants formed the PK-PPS.
Measure Participants 28 28 26
Metabolite 1
0.8533
(34.9)
0.8766
(38.7)
0.5174
(48.2)
Metabolite 2
0.3783
(63.4)
0.3576
(75.5)
0.1575
(88.5)
19. Secondary Outcome
Title Renal Clearance (CLr) of Padsevonil and Metabolites (1 and 2) for Single Dose in Urine
Description CLr: The renal clearance of padsevonil and its metabolites (1 and 2) for single dose in urine. CLr was expressed in milliliters per hour (mL/hour).
Time Frame Urine samples were taken 0 to 12 hours post first dose of Padsevonil during each Treatment Period

Outcome Measure Data

Analysis Population Description
The Pharmacokinetic Per-Protocol Set (PK-PPS) was a subset of the FAS, consisting of those study participants who had no important protocol deviations affecting the PK parameters and for whom a sufficient number of samples were available to determine at least 1 PK parameter. As per the planned analysis, data was summarized by treatment periods.
Arm/Group Title Padsevonil (Period 1) (PK-PPS) Padsevonil (Period 2) (PK-PPS) Padsevonil and Erythromycin (Period 3b) (PK-PPS)
Arm/Group Description The study participants, of a single cohort, received Padsevonil during the Treatment Period 1 as follows: From Day 1 to Day 11: Padsevonil 100 mg bid on Day 1 to Day 4 Padsevonil 100 mg single dose on Day 5 1 week of wash-out (from evening of Day 5 to Day 11). Study participants formed the Pharmacokinetic-Per Protocol Set (PK-PPS). The study participants, of a single cohort, received Padsevonil during the Treatment Period 2 as follows: From Day 12 to Day 22: Padsevonil 100 mg bid on Day 12 to Day 15 Padsevonil 100 mg single dose on Day 16 1 week of wash-out (from evening of Day 16 to Day 22). Study participants formed the PK-PPS. The study participants, of a single cohort, received Padsevonil and Erythromycin during the second part of the Treatment Period 3b as follows: Padsevonil 100 mg bid and erythromycin 500 mg bid on Day 26 to Day 32 Padsevonil 100 mg single dose on Day 33 Erythromycin 500 mg bid on Day 33. Study participants formed the PK-PPS.
Measure Participants 28 28 27
Padsevonil
27.40
(54.3)
25.80
(73.0)
19.36
(60.2)
Metabolite 1
253.7
(47.8)
283.0
(60.1)
255.0
(53.9)
Metabolite 2
17640
(19.6)
17630
(21.2)
16290
(20.7)
20. Secondary Outcome
Title Renal Clearance (CLr) of Padsevonil and Metabolites (1 and 2) for Multiple Doses in Urine
Description CLr: The renal clearance of padsevonil and its metabolites (1 and 2) for multiple doses in urine. CLr was expressed in milliliters per hour (mL/hour).
Time Frame Urine samples were taken 0 to 12 hours, 12 to 24 hours,and 24 to 48 hours post last PSL dose during Treatment Period 1 and 2; 0 to 12 hours, 12 to 24 hours, 24 to 48 hours, 48 to 72 hours, and 72 to 96 hours post last dose of PSL during Treatment Period 3

Outcome Measure Data

Analysis Population Description
The Pharmacokinetic Per-Protocol Set (PK-PPS) was a subset of the FAS, consisting of those study participants who had no important protocol deviations affecting the PK parameters and for whom a sufficient number of samples were available to determine at least 1 PK parameter. As per the planned analysis, data was summarized by treatment periods. Here, number of participants were included who were evaluable for the assessment.
Arm/Group Title Padsevonil (Period 1) (PK-PPS) Padsevonil (Period 2) (PK-PPS) Padsevonil and Erythromycin (Period 3b) (PK-PPS)
Arm/Group Description The study participants, of a single cohort, received Padsevonil during the Treatment Period 1 as follows: From Day 1 to Day 11: Padsevonil 100 mg bid on Day 1 to Day 4 Padsevonil 100 mg single dose on Day 5 1 week of wash-out (from evening of Day 5 to Day 11). Study participants formed the Pharmacokinetic-Per Protocol Set (PK-PPS). The study participants, of a single cohort, received Padsevonil during the Treatment Period 2 as follows: From Day 12 to Day 22: Padsevonil 100 mg bid on Day 12 to Day 15 Padsevonil 100 mg single dose on Day 16 1 week of wash-out (from evening of Day 16 to Day 22). Study participants formed the PK-PPS. The study participants, of a single cohort, received Padsevonil and Erythromycin during the second part of the Treatment Period 3b as follows: Padsevonil 100 mg bid and erythromycin 500 mg bid on Day 26 to Day 32 Padsevonil 100 mg single dose on Day 33 Erythromycin 500 mg bid on Day 33. Study participants formed the PK-PPS.
Measure Participants 28 28 26
Padsevonil
28.43
(58.0)
25.24
(59.7)
25.12
(56.1)
Metabolite 1
335.0
(50.2)
325.4
(40.8)
311.4
(51.7)
Metabolite 2
19390
(24.9)
18530
(20.7)
16470
(27.6)
21. Secondary Outcome
Title Cumulative Amount (Ae) of Padsevonil and Metabolites (1, 2, and 3) Excreted Into the Urine for Single Dose
Description Ae: The cumulative amount of padsevonil and its metabolites (1, 2, and 3) excreted into the urine for single dose. Ae was expressed in milligrams (mg).
Time Frame Urine samples were taken 0 to 12 hours post first dose of Padsevonil during each Treatment Period

Outcome Measure Data

Analysis Population Description
The Pharmacokinetic Per-Protocol Set (PK-PPS) was a subset of the FAS, consisting of those study participants who had no important protocol deviations affecting the PK parameters and for whom a sufficient number of samples were available to determine at least 1 PK parameter. As per the planned analysis, data was summarized by treatment periods.
Arm/Group Title Padsevonil (Period 1) (PK-PPS) Padsevonil (Period 2) (PK-PPS) Padsevonil and Erythromycin (Period 3b) (PK-PPS)
Arm/Group Description The study participants, of a single cohort, received Padsevonil during the Treatment Period 1 as follows: From Day 1 to Day 11: Padsevonil 100 mg bid on Day 1 to Day 4 Padsevonil 100 mg single dose on Day 5 1 week of wash-out (from evening of Day 5 to Day 11). Study participants formed the Pharmacokinetic-Per Protocol Set (PK-PPS). The study participants, of a single cohort, received Padsevonil during the Treatment Period 2 as follows: From Day 12 to Day 22: Padsevonil 100 mg bid on Day 12 to Day 15 Padsevonil 100 mg single dose on Day 16 1 week of wash-out (from evening of Day 16 to Day 22). Study participants formed the PK-PPS. The study participants, of a single cohort, received Padsevonil and Erythromycin during the second part of the Treatment Period 3b as follows: Padsevonil 100 mg bid and erythromycin 500 mg bid on Day 26 to Day 32 Padsevonil 100 mg single dose on Day 33 Erythromycin 500 mg bid on Day 33. Study participants formed the PK-PPS.
Measure Participants 28 28 27
Padsevonil
0.03914
(57.5)
0.04054
(75.0)
0.04987
(74.6)
Metabolite 1
0.2101
(43.2)
0.2333
(52.1)
0.2309
(45.8)
Metabolite 2
10.53
(42.5)
9.423
(45.5)
9.764
(53.1)
Metabolite 3
29.11
(39.3)
27.44
(42.3)
26.09
(40.6)
22. Secondary Outcome
Title Cumulative Amount (Ae) of Padsevonil and Metabolites (1, 2, and 3) Excreted Into the Urine for Multiple Doses
Description Ae: The cumulative amount of padsevonil and its metabolites (1, 2, and 3) excreted into the urine for multiple doses. Ae was expressed in milligrams (mg).
Time Frame Urine samples were taken 0 to 12 hours, 12 to 24 hours,and 24 to 48 hours post last PSL dose during Treatment Period 1 and 2; 0 to 12 hours, 12 to 24 hours, 24 to 48 hours, 48 to 72 hours, and 72 to 96 hours post last dose of PSL during Treatment Period 3

Outcome Measure Data

Analysis Population Description
The Pharmacokinetic Per-Protocol Set (PK-PPS) was a subset of the FAS, consisting of those study participants who had no important protocol deviations affecting the PK parameters and for whom a sufficient number of samples were available to determine at least 1 PK parameter. As per the planned analysis, data was summarized by treatment periods. Here, number of participants were included who were evaluable for the assessment.
Arm/Group Title Padsevonil (Period 1) (PK-PPS) Padsevonil (Period 2) (PK-PPS) Padsevonil and Erythromycin (Period 3b) (PK-PPS)
Arm/Group Description The study participants, of a single cohort, received Padsevonil during the Treatment Period 1 as follows: From Day 1 to Day 11: Padsevonil 100 mg bid on Day 1 to Day 4 Padsevonil 100 mg single dose on Day 5 1 week of wash-out (from evening of Day 5 to Day 11). Study participants formed the Pharmacokinetic-Per Protocol Set (PK-PPS). The study participants, of a single cohort, received Padsevonil during the Treatment Period 2 as follows: From Day 12 to Day 22: Padsevonil 100 mg bid on Day 12 to Day 15 Padsevonil 100 mg single dose on Day 16 1 week of wash-out (from evening of Day 16 to Day 22). Study participants formed the PK-PPS. The study participants, of a single cohort, received Padsevonil and Erythromycin during the second part of the Treatment Period 3b as follows: Padsevonil 100 mg bid and erythromycin 500 mg bid on Day 26 to Day 32 Padsevonil 100 mg single dose on Day 33 Erythromycin 500 mg bid on Day 33. Study participants formed the PK-PPS.
Measure Participants 28 28 26
Padsevonil
0.05825
(57.2)
0.05741
(58.6)
0.1274
(62.3)
Metabolite 1
0.6188
(45.3)
0.6657
(45.0)
0.8797
(46.8)
Metabolite 2
15.03
(45.8)
15.07
(46.9)
13.67
(41.4)
Metabolite 3
70.83
(30.7)
65.30
(34.0)
81.36
(30.7)
23. Secondary Outcome
Title Fraction (fe) of Padsevonil and Metabolites (1, 2, and 3) Excreted Into the Urine for Single Dose
Description fe: The fraction of padsevonil or metabolites (1, 2, and 3) excreted into the urine for single dose. fe was expressed in percentage (%).
Time Frame Urine samples were taken 0 to 12 hours post first dose of Padsevonil during each Treatment Period

Outcome Measure Data

Analysis Population Description
The Pharmacokinetic Per-Protocol Set (PK-PPS) was a subset of the FAS, consisting of those study participants who had no important protocol deviations affecting the PK parameters and for whom a sufficient number of samples were available to determine at least 1 PK parameter. As per the planned analysis, data was summarized by treatment periods.
Arm/Group Title Padsevonil (Period 1) (PK-PPS) Padsevonil (Period 2) (PK-PPS) Padsevonil and Erythromycin (Period 3b) (PK-PPS)
Arm/Group Description The study participants, of a single cohort, received Padsevonil during the Treatment Period 1 as follows: From Day 1 to Day 11: Padsevonil 100 mg bid on Day 1 to Day 4 Padsevonil 100 mg single dose on Day 5 1 week of wash-out (from evening of Day 5 to Day 11). Study participants formed the Pharmacokinetic-Per Protocol Set (PK-PPS). The study participants, of a single cohort, received Padsevonil during the Treatment Period 2 as follows: From Day 12 to Day 22: Padsevonil 100 mg bid on Day 12 to Day 15 Padsevonil 100 mg single dose on Day 16 1 week of wash-out (from evening of Day 16 to Day 22). Study participants formed the PK-PPS. The study participants, of a single cohort, received Padsevonil and Erythromycin during the second part of the Treatment Period 3b as follows: Padsevonil 100 mg bid and erythromycin 500 mg bid on Day 26 to Day 32 Padsevonil 100 mg single dose on Day 33 Erythromycin 500 mg bid on Day 33. Study participants formed the PK-PPS.
Measure Participants 28 28 27
Padsevonil
0.03914
(57.5)
0.04054
(75.0)
0.04987
(74.6)
Metabolite 1
0.2170
(43.2)
0.2410
(52.1)
0.2385
(45.8)
Metabolite 2
10.52
(42.5)
9.419
(45.5)
9.760
(53.1)
Metabolite 3
21.17
(39.3)
19.96
(42.3)
18.98
(40.6)
24. Secondary Outcome
Title Fraction (fe) of Padsevonil and Metabolites (1, 2, and 3) Excreted Into the Urine for Multiple Doses
Description fe: The fraction of padsevonil and its metabolites (1, 2, and 3) excreted into the urine for multiple doses. fe was expressed in percentage (%).
Time Frame Urine samples were taken 0 to 12 hours, 12 to 24 hours,and 24 to 48 hours post last PSL dose during Treatment Period 1 and 2; 0 to 12 hours, 12 to 24 hours, 24 to 48 hours, 48 to 72 hours, and 72 to 96 hours post last dose of PSL during Treatment Period 3

Outcome Measure Data

Analysis Population Description
The Pharmacokinetic Per-Protocol Set (PK-PPS) was a subset of the FAS, consisting of those study participants who had no important protocol deviations affecting the PK parameters and for whom a sufficient number of samples were available to determine at least 1 PK parameter. As per the planned analysis, data was summarized by treatment periods. Here, number of participants were included who were evaluable for the assessment.
Arm/Group Title Padsevonil (Period 1) (PK-PPS) Padsevonil (Period 2) (PK-PPS) Padsevonil and Erythromycin (Period 3b) (PK-PPS)
Arm/Group Description The study participants, of a single cohort, received Padsevonil during the Treatment Period 1 as follows: From Day 1 to Day 11: Padsevonil 100 mg bid on Day 1 to Day 4 Padsevonil 100 mg single dose on Day 5 1 week of wash-out (from evening of Day 5 to Day 11). Study participants formed the Pharmacokinetic-Per Protocol Set (PK-PPS). The study participants, of a single cohort, received Padsevonil during the Treatment Period 2 as follows: From Day 12 to Day 22: Padsevonil 100 mg bid on Day 12 to Day 15 Padsevonil 100 mg single dose on Day 16 1 week of wash-out (from evening of Day 16 to Day 22). Study participants formed the PK-PPS. The study participants, of a single cohort, received Padsevonil and Erythromycin during the second part of the Treatment Period 3b as follows: Padsevonil 100 mg bid and erythromycin 500 mg bid on Day 26 to Day 32 Padsevonil 100 mg single dose on Day 33 Erythromycin 500 mg bid on Day 33. Study participants formed the PK-PPS.
Measure Participants 28 28 26
Padsevonil
0.05825
(57.2)
0.05741
(58.6)
0.1274
(62.3)
Metabolite 1
0.6049
(45.6)
0.6700
(44.6)
0.8443
(45.3)
Metabolite 2
15.02
(45.8)
15.06
(46.9)
13.15
(37.9)
Metabolite 3
51.52
(30.7)
47.50
(34.0)
56.69
(38.0)
25. Secondary Outcome
Title Formation Clearance (CLform) of Padsevonil Metabolites (1, 2, and 3) in the Urine for Single Dose
Description CLform: The formation clearance of padsevonil metabolites (1, 2, and 3) in the urine for single dose. CLform was expressed in milliliters per hour (mL/hour).
Time Frame Urine samples were taken 0 to 12 hours post first dose of Padsevonil during each Treatment Period

Outcome Measure Data

Analysis Population Description
The Pharmacokinetic Per-Protocol Set (PK-PPS) was a subset of the FAS, consisting of those study participants who had no important protocol deviations affecting the PK parameters and for whom a sufficient number of samples were available to determine at least 1 PK parameter. As per the planned analysis, data was summarized by treatment periods.
Arm/Group Title Padsevonil (Period 1) (PK-PPS) Padsevonil (Period 2) (PK-PPS) Padsevonil and Erythromycin (Period 3b) (PK-PPS)
Arm/Group Description The study participants, of a single cohort, received Padsevonil during the Treatment Period 1 as follows: From Day 1 to Day 11: Padsevonil 100 mg bid on Day 1 to Day 4 Padsevonil 100 mg single dose on Day 5 1 week of wash-out (from evening of Day 5 to Day 11). Study participants formed the Pharmacokinetic-Per Protocol Set (PK-PPS). The study participants, of a single cohort, received Padsevonil during the Treatment Period 2 as follows: From Day 12 to Day 22: Padsevonil 100 mg bid on Day 12 to Day 15 Padsevonil 100 mg single dose on Day 16 1 week of wash-out (from evening of Day 16 to Day 22). Study participants formed the PK-PPS. The study participants, of a single cohort, received Padsevonil and Erythromycin during the second part of the Treatment Period 3b as follows: Padsevonil 100 mg bid and erythromycin 500 mg bid on Day 26 to Day 32 Padsevonil 100 mg single dose on Day 33 Erythromycin 500 mg bid on Day 33. Study participants formed the PK-PPS.
Measure Participants 28 28 27
Metabolite 1
151.9
(67.3)
153.4
(75.8)
92.59
(80.8)
Metabolite 2
7365
(80.2)
5994
(87.8)
3788
(107.5)
Metabolite 3
14820
(60.5)
12700
(59.9)
7367
(72.0)
26. Secondary Outcome
Title Formation Clearance (CLform) of Padsevonil Metabolites (1, 2, and 3) in the Urine for Multiple Doses
Description CLform: The formation clearance of padsevonil metabolites (1, 2, and 3) in the urine for multiple doses. CLform was expressed in milliliters per hour (mL/hour).
Time Frame Urine samples were taken 0 to 12 hours, 12 to 24 hours,and 24 to 48 hours post last PSL dose during Treatment Period 1 and 2; 0 to 12 hours, 12 to 24 hours, 24 to 48 hours, 48 to 72 hours, and 72 to 96 hours post last dose of PSL during Treatment Period 3

Outcome Measure Data

Analysis Population Description
The Pharmacokinetic Per-Protocol Set (PK-PPS) was a subset of the FAS, consisting of those study participants who had no important protocol deviations affecting the PK parameters and for whom a sufficient number of samples were available to determine at least 1 PK parameter. As per the planned analysis, data was summarized by treatment periods. Here, number of participants were included who were evaluable for the assessment.
Arm/Group Title Padsevonil (Period 1) (PK-PPS) Padsevonil (Period 2) (PK-PPS) Padsevonil and Erythromycin (Period 3b) (PK-PPS)
Arm/Group Description The study participants, of a single cohort, received Padsevonil during the Treatment Period 1 as follows: From Day 1 to Day 11: Padsevonil 100 mg bid on Day 1 to Day 4 Padsevonil 100 mg single dose on Day 5 1 week of wash-out (from evening of Day 5 to Day 11). Study participants formed the Pharmacokinetic-Per Protocol Set (PK-PPS). The study participants, of a single cohort, received Padsevonil during the Treatment Period 2 as follows: From Day 12 to Day 22: Padsevonil 100 mg bid on Day 12 to Day 15 Padsevonil 100 mg single dose on Day 16 1 week of wash-out (from evening of Day 16 to Day 22). Study participants formed the PK-PPS. The study participants, of a single cohort, received Padsevonil and Erythromycin during the second part of the Treatment Period 3b as follows: Padsevonil 100 mg bid and erythromycin 500 mg bid on Day 26 to Day 32 Padsevonil 100 mg single dose on Day 33 Erythromycin 500 mg bid on Day 33. Study participants formed the PK-PPS.
Measure Participants 28 28 26
Metabolite 1
295.3
(63.2)
294.6
(58.9)
166.4
(63.8)
Metabolite 2
7331
(80.5)
6622
(90.9)
2593
(93.9)
Metabolite 3
25150
(44.7)
20890
(48.1)
11170
(58.7)
27. Secondary Outcome
Title Percentage of Participants Experiencing Treatment-Emergent Serious Adverse Events (SAEs) During the Study
Description An 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 an 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.
Time Frame From beginning of the first Treatment Period (Day 1) to the Safety Follow-up Visit (up to 48 days )

Outcome Measure Data

Analysis Population Description
The Full Analysis Set (FAS) consisted of all study participants who have signed the Informed Consent form (ICF) and received investigational medicinal product (IMP). The analysis of this outcome measure was performed according to the treatment the participants actually received.
Arm/Group Title Padsevonil (Period 1+2) (FAS) Erythromycin (Period 3a) (FAS) Padsevonil and Erythromycin (Period 3b) (FAS) Erythromycin (Period 3c) (FAS)
Arm/Group Description Treatment Period 1 (Day 1 to Day 11): Padsevonil 100 mg bid on Day 1 to Day 4 Padsevonil 100 mg single dose on Day 5 1 week of wash-out (from evening of Day 5 to Day 11) Treatment Period 2 (Day 12 to 22): Padsevonil 100 mg bid on Day 12 to Day 15 Padsevonil 100 mg single dose on Day 16 1 week of wash-out (from evening of Day 16 to Day 22). Study participants formed the Full Analysis Set (FAS). Study participants received Erythromycin in Treatment Period 3a as follows: 500 mg bid on Day 23 to Day 25. Study participants formed the FAS. Study participants received Padsevonil and Erythromycin in Treatment Period 3b as follows: Padsevonil 100 mg bid and erythromycin 500 mg bid on Day 26 to Day 32 Padsevonil 100 mg single dose on Day 33 Erythromycin 500 mg bid on Day 33. Study participants formed the FAS. Study participants received Erythromycin in Treatment Period 3c as follows: 500 mg bid on Day 34 to Day 37. Study participants formed the FAS.
Measure Participants 28 27 27 26
Number [percentage of participants]
0
0%
0
NaN
0
NaN
0
NaN
28. Secondary Outcome
Title Percentage of Participants Experiencing Treatment-Emergent Non-serious Adverse Events (AEs) During the Study
Description Treatment-emergent Adverse Events (TEAEs) were defined as those events which started on or after the date of first dose of UP0057 IMP, or events in which severity worsened on or after the date of first dose of UP0057 study medication.
Time Frame From beginning of the first Treatment Period (Day 1) to the Safety Follow-up Visit (up to 48 days )

Outcome Measure Data

Analysis Population Description
The FAS consisted of all study participants who have signed the Informed Consent form ICF and received IMP. The analysis of this outcome measure was performed according to the treatment the participants actually received.
Arm/Group Title Padsevonil (Period 1+2) (FAS) Erythromycin (Period 3a) (FAS) Padsevonil and Erythromycin (Period 3b) (FAS) Erythromycin (Period 3c) (FAS)
Arm/Group Description Treatment Period 1 (Day 1 to Day 11): Padsevonil 100 mg bid on Day 1 to Day 4 Padsevonil 100 mg single dose on Day 5 1 week of wash-out (from evening of Day 5 to Day 11) Treatment Period 2 (Day 12 to 22): Padsevonil 100 mg bid on Day 12 to Day 15 Padsevonil 100 mg single dose on Day 16 1 week of wash-out (from evening of Day 16 to Day 22). Study participants formed the Full Analysis Set (FAS). Study participants received Erythromycin in Treatment Period 3a as follows: 500 mg bid on Day 23 to Day 25. Study participants formed the FAS. Study participants received Padsevonil and Erythromycin in Treatment Period 3b as follows: Padsevonil 100 mg bid and erythromycin 500 mg bid on Day 26 to Day 32 Padsevonil 100 mg single dose on Day 33 Erythromycin 500 mg bid on Day 33. Study participants formed the FAS. Study participants received Erythromycin in Treatment Period 3c as follows: 500 mg bid on Day 34 to Day 37. Study participants formed the FAS.
Measure Participants 28 27 27 26
Number [percentage of participants]
100
357.1%
11.1
NaN
96.3
NaN
19.2
NaN

Adverse Events

Time Frame From beginning of the first Treatment Period (Day 1) to the Safety Follow-up Visit (up to Day 48)
Adverse Event Reporting Description FAS consisted of all study participants who have signed the ICF and received the IMP. The analysis was performed according to the treatment the participants actually received.
Arm/Group Title Padsevonil (Period 1+2) (FAS) Erythromycin (Period 3a) (FAS) Padsevonil and Erythromycin (Period 3b) (FAS) Erythromycin (Period 3c) (FAS)
Arm/Group Description Treatment Period 1 (Day 1 to Day 11): Padsevonil 100 mg bid on Day 1 to Day 4 Padsevonil 100 mg single dose on Day 5 1 week of wash-out (from evening of Day 5 to Day 11) Treatment Period 2 (Day 12 to 22): Padsevonil 100 mg bid on Day 12 to Day 15 Padsevonil 100 mg single dose on Day 16 1 week of wash-out (from evening of Day 16 to Day 22). Study participants formed the Full Analysis Set (FAS). Study participants received Erythromycin in Treatment Period 3a as follows: 500 mg bid on Day 23 to Day 25. Study participants formed the FAS. Study participants received Padsevonil and Erythromycin in Treatment Period 3b as follows: Padsevonil 100 mg bid and erythromycin 500 mg bid on Day 26 to Day 32 Padsevonil 100 mg single dose on Day 33 Erythromycin 500 mg bid on Day 33. Study participants formed the FAS. Study participants received Erythromycin in Treatment Period 3c as follows: 500 mg bid on Day 34 to Day 37. Study participants formed the FAS.
All Cause Mortality
Padsevonil (Period 1+2) (FAS) Erythromycin (Period 3a) (FAS) Padsevonil and Erythromycin (Period 3b) (FAS) Erythromycin (Period 3c) (FAS)
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 0/28 (0%) 0/27 (0%) 0/27 (0%) 0/26 (0%)
Serious Adverse Events
Padsevonil (Period 1+2) (FAS) Erythromycin (Period 3a) (FAS) Padsevonil and Erythromycin (Period 3b) (FAS) Erythromycin (Period 3c) (FAS)
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 0/28 (0%) 0/27 (0%) 0/27 (0%) 0/26 (0%)
Other (Not Including Serious) Adverse Events
Padsevonil (Period 1+2) (FAS) Erythromycin (Period 3a) (FAS) Padsevonil and Erythromycin (Period 3b) (FAS) Erythromycin (Period 3c) (FAS)
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 28/28 (100%) 0/27 (0%) 25/27 (92.6%) 2/26 (7.7%)
General disorders
Medical device site reaction 5/28 (17.9%) 5 0/27 (0%) 0 7/27 (25.9%) 7 0/26 (0%) 0
Musculoskeletal and connective tissue disorders
Back pain 3/28 (10.7%) 3 0/27 (0%) 0 0/27 (0%) 0 0/26 (0%) 0
Nervous system disorders
Dizziness 18/28 (64.3%) 27 0/27 (0%) 0 8/27 (29.6%) 8 0/26 (0%) 0
Headache 5/28 (17.9%) 6 0/27 (0%) 0 0/27 (0%) 0 2/26 (7.7%) 2
Paraesthesia 2/28 (7.1%) 2 0/27 (0%) 0 0/27 (0%) 0 0/26 (0%) 0
Somnolence 28/28 (100%) 50 0/27 (0%) 0 25/27 (92.6%) 27 0/26 (0%) 0
Psychiatric disorders
Depressed mood 2/28 (7.1%) 2 0/27 (0%) 0 0/27 (0%) 0 0/26 (0%) 0
Euphoric mood 6/28 (21.4%) 6 0/27 (0%) 0 5/27 (18.5%) 5 0/26 (0%) 0
Insomnia 2/28 (7.1%) 3 0/27 (0%) 0 0/27 (0%) 0 0/26 (0%) 0
Skin and subcutaneous tissue disorders
Dry skin 2/28 (7.1%) 2 0/27 (0%) 0 0/27 (0%) 0 0/26 (0%) 0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.

Results Point of Contact

Name/Title UCB
Organization Cares
Phone +1844 599 ext 2273
Email UCBCares@ucb.com
Responsible Party:
UCB Biopharma S.P.R.L.
ClinicalTrials.gov Identifier:
NCT03480243
Other Study ID Numbers:
  • UP0057
  • 2017-004694-13
First Posted:
Mar 29, 2018
Last Update Posted:
Jul 12, 2021
Last Verified:
Jun 1, 2021