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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Healthy Volunteers

Intervention / Treatment
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* Drug: XPF-008
* Drug: Microcrystalline Cellulose
* Drug: XPF-010
* Drug: Itraconazole 400mg


Participation Criteria
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Eligibility Criteria
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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

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

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Drug: XEN1101 XPF-008 Formulation Oral<br>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<br>* Capsule filled with XEN1101<br>|
| Placebo Comparator: Placebo - Microcrystalline cellulose oral<br>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<br>* Placebo capsule<br>|
| Experimental: Drug: XEN1101 XPF-008 Formulation Oral Drug: XEN1101 XPF-010 Formulation Oral<br>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<br>* Capsule filled with XEN1101<br>|
| Experimental: Drug: XEN1101 XPF-010 Formulation Oral<br>XEN1101 XPF-010 Formulation Oral Part 4 will explore multiple dose PK | Drug: XPF-010<br>* Capsule filled with XEN1101<br>|
| Experimental: Drug: XEN1101 XPF-010 Formulation Oral Drug: Itraconazole 400mg Oral<br>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<br>* Oral<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 |