Safety, Tolerability, and Pharmacokinetics (PK) of Single and Multiple Ascending Oral Doses of XEN1101.

Healthy Volunteers Clinical Trial

Official title:

Phase 1, First-in-human, Double-blind, Placebo-controlled Study to Evaluate the Safety, Tolerability, and PK of Single and Multiple Ascending Oral Doses of XEN1101 and Preliminary Open-label Pharmacodynamic Assessment in Healthy Subjects Addendum: Phase 1, Randomised, Multi Part Study to Evaluate the Safety, Tolerability, Pharmacokinetics, Relative Bioavailability and Food Effect of Single and Multiple Ascending Doses of XEN1101 and Preliminary Drug-Drug Interaction Assessment With Itraconazole

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03340220
• Other study ID #: XPF-008-101a
• Secondary ID: 2017-003168-11C1
• Status: Completed
• Phase: Phase 1
• Start date: November 13, 2017
• Est. completion date: November 26, 2021

Study information

• Verified date: May 2023
• Source: Xenon Pharmaceuticals Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The XEN1101 Phase 1 clinical trial is a randomized, double-blind, placebo-controlled study that will evaluate the safety, tolerability and PK of both single ascending doses (SAD) and multiple ascending doses (MAD) of XEN1101 in healthy subjects. In addition to safety and PK data, the clinical trial has been designed to include a pharmacodynamic read-out by incorporating a pilot transcranial magnetic stimulation (TMS) sub-study. The TMS model sub-study is designed to demonstrate delivery of XEN1101 into the central nervous system and to observe a change in cortical excitability as measured by EEG and/or electromyographic (EMG) activity.

Part 3, 4 and 5: Phase 1, randomised, multi part study to evaluate the safety, tolerability, PK, relative bioavailability and food effect of single and multiple ascending doses of XEN1101 and Preliminary Drug-Drug Interaction Assessment with Itraconazole.

Description:

Part 1 will study safety, tolerability, PK of single ascending doses (SAD) of XPF-008 as well as the impact and variability of single ascending doses of XPF-008 on TMS.

Part 2 will study the safety, tolerability and PK of multiple ascending doses (MAD) of XPF-008

Part 3 will explore dose proportionality of XPF-010 and confirm dosing for subsequent cohorts, and the food effect and relative bioavailability of XPF-010 compared to XPF-008.

Part 4 will explore multiple dose PK.

Part 5 will explore the drug-drug interaction of XPF-010, when given with itraconazole.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 130
• Est. completion date: November 26, 2021
• Est. primary completion date: November 26, 2021
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 55 Years

Eligibility

Key Inclusion Criteria:

• Healthy male or females aged between 18 and 55 years inclusive with a body mass index (BMI) between 18.50 and 30.00 kg/m2

• Must agree to use effective methods of contraception, if applicable

• Able to swallow capsules

• Able to provide written, personally signed and dated informed consent form (ICF)

Key Exclusion Criteria:

• Any history of epileptic seizures

• Any current and relevant history of significant disease or disorder which, in the opinion of the investigator, may either put the subject at risk, affect clinical or laboratory results, or the subject's ability to participate in the study

• Answering "yes" to any of the questions within the Columbia Suicide Severity Rating Scale

• Mental incapacity or lingual barriers precluding adequate understanding, cooperation, and compliance with the study

• No prescription or over-the-counter (OTC) medications (except hormonal contraception), herbal or dietary supplements OTC medications 14 days prior to dosing to study end

• No smoking 60 days prior to dosing to study end

• No soft drugs 3 months prior to Screening and hard drugs 2 years prior to Screening

Related Conditions & MeSH terms

• Healthy Volunteers

Intervention

Drug:
• XPF-008
Capsule filled with XEN1101
• Microcrystalline Cellulose
Placebo capsule
• XPF-010
Capsule filled with XEN1101
• Itraconazole 400mg
Oral

Locations

Country	Name	City	State
United Kingdom	Richmond Pharmacology Ltd.	London

Sponsors (1)

Lead Sponsor	Collaborator
Xenon Pharmaceuticals Inc.

Country where clinical trial is conducted

United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Parts 1 & 2: Number of Participants with Adverse Events (AEs)	To assess AEs as a criteria of safety and tolerability	From screening (28 days prior to Day 1) through to 30 days post-final dose
Primary	Parts 1 & 2: Resting electrocardiogram (ECG)	To assess ECG as a criteria of safety and tolerability	At screening (28 days prior to Day 1) through to 7 days post-final dose
Primary	Parts 1 & 2: Vital signs	To assess vital signs as a criteria of safety and tolerability	At screening (28 days prior to Day 1) through to 7 days post-final dose
Primary	Part 3a: Maximum Observed Plasma Concentration (Cmax) of XEN1101	To characterize the PK profile of XEN1101 and M11 (a metabolite of XEN1101) in plasma of single ascending, oral doses of XPF-010	At screening (27 days prior to Day -1) through to 31 days post dose
Primary	Part 3a: Area under the plasma concentration-time curve (AUC) of XEN1101	To characterize the PK profile of XEN1101 and M11 (a metabolite of XEN1101) in plasma of single ascending, oral doses of XPF-010	At screening (27 days prior to Day -1) through to 31 days post dose
Primary	Part 3a: Frequency and severity of treatment-emergent adverse events (TEAEs), treatment-emergent serious adverse events (SAEs), and TEAEs leading to treatment discontinuations	To evaluate the safety and tolerability of XEN1101 (XPF-010)	At screening (27 days prior to Day -1) through to 31 days post dose
Primary	Part 3b: Maximum Observed Plasma Concentration (Cmax) of XEN1101	To assess the Food Effect on PK (Cmax) and the relative bioavailability/comparability (Cmax) of XEN1101 following single oral doses of XPF-010 (fed), XPF-008 (fed) and XPF-010 (fasted)	At screening (27 days prior to Day -1) through to 31 days post dose
Primary	Part 3b: Area under the plasma concentration-time curve (AUC) of XEN1101	To assess the Food Effect on PK (AUC0-240h) and the relative bioavailability/comparability (AUC0-240h) of XEN1101 following single oral doses of XPF-010 (fed), XPF-008 (fed) and XPF-010 (fasted)	At screening (27 days prior to Day -1) through to 31 days post dose
Primary	Part 3b: Frequency and severity of TEAEs, treatment-emergent SAEs, and TEAEs leading to treatment discontinuations	To evaluate the safety and tolerability of XEN1101	At screening (27 days prior to Day -1) through to 31 days post dose
Primary	Part 4: Maximum Observed Plasma Concentration (Cmax) of XEN1101	To characterize the PK profile of XEN1101 and M11 (metabolite of XEN1101) in plasma of multiple daily oral doses of XPF-010	At screening (27 days prior to Day -1) through to 51 days post dose
Primary	Part 4: Area under the plasma concentration-time curve (AUC) of XEN1101	To characterize the PK profile of XEN1101 and M11 (metabolite of XEN1101) in plasma of multiple daily oral doses of XPF-010	At screening (27 days prior to Day -1) through to 51 days post dose
Primary	Part 4: Frequency and severity of TEAEs, treatment-emergent SAEs, and TEAEs leading to treatment discontinuations	To evaluate the safety and tolerability of XEN1101 (XPF-010)	At screening (27 days prior to Day -1) through to 51 days post dose
Primary	Part 5: Maximum Observed Plasma Concentration (Cmax) of XEN1101	To assess the PK of XEN1101 (XPF-010) in the presence and absence of itraconazole	Day 10 and Day 11
Primary	Part 5: Area under the plasma concentration-time curve (AUC) of XEN1101	To assess the PK of XEN1101 (XPF-010) in the presence and absence of itraconazole	Day 10 and Day 11
Primary	Part 5: Frequency and severity of TEAEs, treatment-emergent SAEs, and TEAEs leading to treatment discontinuations	To evaluate the safety and tolerability of XEN1101 (XPF-010)	At screening (27 days prior to Day -1) through to 51 days post dose
Secondary	Parts 1 & 2: Maximum Observed Plasma Concentration (Cmax)	Cmax is the maximum observed plasma concentration in ng/mL	Day 1 predose through to 7 days post-final dose
Secondary	Parts 1 & 2: Time to the Maximum Observed Plasma Concentration (Tmax)	Tmax is the time in hours to reach Cmax following dosing	Day 1 predose through to 7 days post-final dose
Secondary	Parts 1 & 2: Terminal elimination half-life (t1/2)	The time in hours required for the plasma level of the study drug to decrease by one-half during the terminal elimination phase	Day 1 predose through to 7 days post-final dose
Secondary	Parts 1 & 2: Area Under the Plasma Concentration-Time Curve from Time Zero to the Time of the Last Quantifiable Plasma Concentration (AUC0-last)	The area under the plasma concentration-time curve [in ng.h/mL] from time zero to the time corresponding to the last quantifiable plasma concentration	Day 1 predose through to 7 days post-final dose
Secondary	Parts 3 to 5: Cardiac Safety	To evaluate the cardiovascular safety profile of XEN1101 (XPF-010), assessing potential ECG interval changes from baseline following dosing, in particular any effects on the QTc interval.	At screening (27 days prior to Day -1) through to 11 days post dose for Parts 3a and 3b and at screening (27days prior to Day -1) through to Day 21