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

NCT03340220 | Completed Phase 1 DMC

• 3 other identifiers: XPF-008-101a2017-003168-11C17030
• Study Type: interventional
• Target: 130
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Healthy Volunteers

Outcome Measures

Primary Outcomes (15)

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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 Outcomes (5)

• Parts 1 & 2: Maximum Observed Plasma Concentration (Cmax)

  Day 1 predose through to 7 days post-final dose

• Parts 1 & 2: Time to the Maximum Observed Plasma Concentration (Tmax)

  Day 1 predose through to 7 days post-final dose

• Parts 1 & 2: Terminal elimination half-life (t1/2)

  Day 1 predose through to 7 days post-final dose

• Parts 1 & 2: Area Under the Plasma Concentration-Time Curve from Time Zero to the Time of the Last Quantifiable Plasma Concentration (AUC0-last)

  Day 1 predose through to 7 days post-final dose

• Parts 3 to 5: Cardiac Safety

  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

Study Arms (5)

Drug: XEN1101 XPF-008 Formulation Oral

EXPERIMENTAL

XEN1101 XPF-008 Formulation Part 1 - Single ascending dose: Single oral dose for each cohort Part 2 - Multiple ascending dose: 7 days of single oral dose daily for each cohort

Drug: XPF-008

Placebo - Microcrystalline cellulose oral

PLACEBO COMPARATOR

Part 1- Single Ascending Dose: Single oral dose for each cohort Part 2 - Multiple Ascending Dose: 7 days of single oral dose daily for each cohort

Drug: Microcrystalline Cellulose

Drug: XEN1101 XPF-008 Formulation Oral Drug: XEN1101 XPF-010 Formulation Oral

EXPERIMENTAL

XEN1101 XPF-008 and XPF-010 Formulation Cross Over 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

Drug: XPF-010

Drug: XEN1101 XPF-010 Formulation Oral

EXPERIMENTAL

XEN1101 XPF-010 Formulation Oral Part 4 will explore multiple dose PK

Drug: XPF-010

Drug: XEN1101 XPF-010 Formulation Oral Drug: Itraconazole 400mg Oral

EXPERIMENTAL

XEN1101 XPF-010 Formulation + Itraconazole Part 5 will explore the drug-drug interaction of XPF-010, when given with itraconazole (400mg, single dose, oral solution, fasted)

Drug: Itraconazole 400mg

Interventions

XPF-008 DRUG

Capsule filled with XEN1101

Drug: XEN1101 XPF-008 Formulation Oral

Microcrystalline Cellulose DRUG

Placebo capsule

Placebo - Microcrystalline cellulose oral

XPF-010 DRUG

Capsule filled with XEN1101

Drug: XEN1101 XPF-008 Formulation Oral Drug: XEN1101 XPF-010 Formulation Oral; Drug: XEN1101 XPF-010 Formulation Oral

Itraconazole 400mg DRUG

Oral

Drug: XEN1101 XPF-010 Formulation Oral Drug: Itraconazole 400mg Oral

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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)

You may not qualify if:

• 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

Sponsors & Collaborators

• Xenon Pharmaceuticals Inc.: lead

Study Sites (1)

Richmond Pharmacology Ltd.

London, SE1 1YR, United Kingdom

Location

MeSH Terms

Interventions

microcrystalline cellulose; Itraconazole

Intervention Hierarchy (Ancestors)

Triazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Piperazines

Study Officials

• Gregory N Beatch, PhD

  Xenon Pharmaceuticals Inc.

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 31, 2017
• First Posted: November 13, 2017
• Study Start: November 13, 2017
• Primary Completion: November 26, 2021
• Study Completion: November 26, 2021
• Last Updated: May 11, 2023

Record last verified: 2023-05

Locations

GB (1)