Clinical trial NCT04039919
Conditions: Healthy Participants
Keywords: Ethanol Cannabidiol Padsevonil
Sponsor: UCB Biopharma S.P.R.L.
Start date: 2019-07-17; Completion date: 2020-05-22
Enrollment: 40 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

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

Detailed description:

Arms: arm 1: Subjects will be randomized to receive Padsevonil and Ethanol. arm 2: Subjects will be randomized to receive Padsevonil and Ethanol-Placebo. arm 3: Subjects will be randomized to receive Ethanol and Ethanol-Placebo. arm 4: Subjects will be randomized to receive Ethanol and Ethanol-Placebo. arm 5: Subjects will be randomized to receive Padsevonil and Cannabidiol. arm 6: Subjects will be randomized to receive Padsevonil-Placebo and Cannabidiol.
Interventions: intervention 1: Padsevonil intervention 2: Placebo (PSL)
Intervention descriptions: intervention 1: Padsevonil will be administered in predefined dosages. intervention 2: Placebo will be provided matching Padsevonil to maintain the blinding.

Protocol documents:
Prot_000.pdf: 
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A DOUBLE-BLIND, PLACEBO-CONTROLLED, RANDOMIZED, 
SINGLE-CENTER, CROSS-OVER STUDY TO INVESTIGATE 
THE PHARMACODYNAMIC, PHARMACOKINETIC, SAFETY, 
AND TOLERABILITY PROFILES OF PADSEVONIL IN 
HEALTHY STUDY PARTICIPANTS RECEIVING EITHER 
ETHANOL OR CANNABIDIOL 
PROTOCOL UP0071 AMENDMENT 1 
PHASE 1 
Short title: 
A pharmacodynamic, pharmacokinetic, safety, and tolerability study of padsevonil in healthy 
study participants receiving either ethanol or cannabidiol. 
Sponsor: 
UCB Biopharma SPRL 
Allée de la Recherche 60 
1070 Brussels 
BELGIUM 
Regulatory agency identifying number(s):  
Eudra CT Number: 
2019-000703-32 
Confidential Material 
Confidential 
This document is the property of UCB and may not – in full or in part – be passed on, 
reproduced, published, or otherwise used without the express permission of UCB. 
 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE 
Document History 
Document 
Date 
Type of amendment 
Amendment1 
25 Jul 2019 
Substantial 
Original Protocol 
13 May 2019 
Not applicable 
Amendment 1 (25 Jul 2019) 
Overall Rationale for the Amendment 
This protocol was originally written utilizing a new Standard Operating Procedure (SOP) that 
contains provisions to ensure compliance with the 2017 European Regulatory Guidance on Risk 
Mitigation in First-in-Human and Early Clinical Trials (EMEA/CHMP/SWP/28367/07 Rev. 1). 
That UCB SOP recommends use of the specific study stopping rules for the highest risk early 
phase studies that are recommended in the EU guidance, and these are reflected in the current 
protocol template in use for early phase studies at UCB. However, the UCB SOP does allow for 
those stopping rules to be adapted to match the known risk profile of the product as it passes 
from early phase to late phase development, provided that such adaptation is approved by the 
UCB product-specific Benefit/Risk Team. 
Unfortunately, in drawing up  these current protocols, the first 2 finalized protocols mistakenly 
included the default stopping rules in Protocol Section 7.1.2. These studies are being initiated, 
using these stringent criteria which are not appropriate for a late stage clinical pharmacology 
study of padsevonil, at lower doses or achieve exposure levels anticipated to be no higher, than 
those explored in previous studies. Padsevonil has been administered to over 
313 study participants to date, and the nature and pattern of its adverse effect profile is still 
evolving. In healthy volunteers, the few adverse events that have been severe in intensity have 
been transient, self-limiting, and reduced with repeated administration, with very few resulting in 
withdrawal of the individuals affected. Mitigation of more severe adverse events includes an 
extended titration and tapering of padsevonil dosing, which is known to improve tolerability.  
Accordingly, it is deemed appropriate to replace the current, overly stringent stopping criteria 
which were included in the protocol template specifically to address UCB first-in-man study, a 
first multiple-dose study, and a healthy volunteer study where exposures will exceed those 
previously studied, with criteria more in keeping with the current state of knowledge of the 
product and its stage of development, to ensure that the maximum benefit is derived from studies 
needed to explore its tolerability, pharmacokinetic, pharmacodynamic and interaction profiles 
without any impact on subjects safety & data integrity. 
 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 1.1.4, Objectives and 
endpoints 
Added smooth pursuit as a 
secondary objective 
This was inadvertently omitted 
from the original protocol.  
Section 1.3, Schedule of 
activities, Table 1-3 
Footnote a was clarified.  
Need to collect sample for 
clinical laboratory tests early 
enough for results to be 
available prior to dosing.  
Table 1-5 
Footnote o was clarified.  
Need for predose CBD PK 
sample.  
Table 1-7 
Hem/chem/urine moved from 
D1 ato D-1.  
Need to collect sample for 
clinical laboratory tests early 
enough for results to be 
available prior to dosing. 
Table 1-9 
Removed Hem/chem/urine from 
Day 1 
Safety lab were mistakenly 
duplicated in the Schedules of 
Assessments.  
Section 3, Objectives and 
endpoints, Table 3-1 
Added smooth pursuit as a 
secondary objective 
This was inadvertently omitted 
from the original protocol. 
Section 7.1.3 
Revised the study hold criteria 
See overall rationale for the 
amendment.  
 
 
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SERIOUS ADVERSE EVENT REPORTING 
Serious adverse event reporting (24h) 
Fax 
Europe and Rest of the World: +32 2 386 24 21 
Email 
Global: DS_ICT@ucb.com (for interventional clinical studies) 
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TABLE OF CONTENTS 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ...................................... 2 
SERIOUS ADVERSE EVENT REPORTING .......................................................................... 4 
1 
PROTOCOL SUMMARY ............................................................................................... 10 
1.1 Synopsis ........................................................................................................................... 10 
1.1.1 
Protocol title: ....................................................................................................... 10 
1.1.2 
Short title: ............................................................................................................ 10 
1.1.3 
Rationale: ............................................................................................................. 10 
1.1.4 
Objectives and endpoints ..................................................................................... 10 
1.1.5 
Overall design ...................................................................................................... 12 
1.1.5.1 
Part A ......................................................................................................... 12 
1.1.5.2 
Part B ......................................................................................................... 12 
1.1.6 
Number of participants ........................................................................................ 13 
1.1.7 
Treatment groups and duration ............................................................................ 13 
1.2 Schema ............................................................................................................................. 13 
1.3 Schedule of activities ....................................................................................................... 16 
1.3.1 
Part A ................................................................................................................... 16 
1.3.2 
Part B ................................................................................................................... 24 
2 
INTRODUCTION ........................................................................................................... 34 
2.1 Study rationale ................................................................................................................. 34 
2.2 Background ...................................................................................................................... 34 
2.3 Benefit/risk assessment .................................................................................................... 35 
3 
OBJECTIVES AND ENDPOINTS ................................................................................. 36 
4 
STUDY DESIGN ............................................................................................................. 38 
4.1 Overall design .................................................................................................................. 38 
4.1.1 
Part A ................................................................................................................... 38 
4.1.2 
Part B ................................................................................................................... 39 
4.2 Scientific rationale for study design................................................................................. 40 
4.2.1 
Part A ................................................................................................................... 40 
4.2.2 
Part B ................................................................................................................... 40 
4.3 Justification for dose ........................................................................................................ 40 
4.3.1 
Part A ................................................................................................................... 40 
4.3.2 
Part B ................................................................................................................... 41 
4.4 End of study definition ..................................................................................................... 41 
5 
STUDY POPULATION .................................................................................................. 41 
5.1 Inclusion criteria .............................................................................................................. 41 
5.2 Exclusion criteria ............................................................................................................. 42 
5.3 Lifestyle restrictions ......................................................................................................... 45 
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5.3.1 
Meals and dietary restrictions .............................................................................. 45 
5.3.2 
Caffeine, alcohol, and tobacco ............................................................................. 46 
5.3.3 
Activity ................................................................................................................ 46 
5.4 Screen failures .................................................................................................................. 46 
5.4.1 
Rescreening .......................................................................................................... 46 
6 
STUDY TREATMENTS ................................................................................................. 47 
6.1 Treatments administered .................................................................................................. 47 
6.2 Preparation, handling, storage, and accountability requirements .................................... 49 
6.2.1 
Drug accountability ............................................................................................. 49 
6.3 Measures to minimize bias: randomization and blinding ................................................ 49 
6.3.1 
Procedures for maintaining and breaking the treatment blind ............................. 51 
6.3.1.1 
Maintenance of treatment blind ................................................................. 51 
6.3.1.2 
Breaking the treatment blind in an emergency situation ........................... 51 
6.4 Treatment compliance ...................................................................................................... 51 
6.5 Concomitant medication(s)/treatment(s).......................................................................... 51 
6.5.1 
Permitted concomitant treatments (medications and therapies) .......................... 51 
6.5.2 
Prohibited concomitant treatments (medications and therapies) ......................... 52 
6.5.3 
Rescue medication ............................................................................................... 52 
6.6 Dose modification ............................................................................................................ 52 
6.7 Treatment after the end of the study ................................................................................ 52 
7 
DISCONTINUATION OF STUDY MEDICATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ........................................................................ 52 
7.1 Discontinuation of study medication ............................................................................... 52 
7.1.1 
Liver chemistry stopping criteria ......................................................................... 52 
7.1.2 
Temporary discontinuation .................................................................................. 53 
7.1.3 
Criteria for study hold due to adverse events ...................................................... 53 
7.2 Participant discontinuation/withdrawal from the study ................................................... 54 
7.3 Lost to follow up .............................................................................................................. 56 
8 
STUDY ASSESSMENTS AND PROCEDURES ........................................................... 56 
8.1 Efficacy assessments ........................................................................................................ 57 
8.2 Safety assessments ........................................................................................................... 57 
8.2.1 
Physical examination ........................................................................................... 57 
8.2.2 
Vital signs ............................................................................................................ 57 
8.2.3 
Electrocardiograms .............................................................................................. 57 
8.2.4 
Clinical safety laboratory assessments ................................................................ 58 
8.2.5 
Suicidal risk monitoring ...................................................................................... 58 
8.2.6 
Psychiatric and mental status ............................................................................... 59 
8.3 Adverse events ................................................................................................................. 59 
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8.3.1 
Time period and frequency for collecting AE and SAE information .................. 59 
8.3.2 
Method of detecting AEs and SAEs .................................................................... 60 
8.3.3 
Follow up of AEs and SAEs ................................................................................ 60 
8.3.4 
Regulatory reporting requirements for SAEs ...................................................... 60 
8.3.5 
Pregnancy ............................................................................................................ 60 
8.3.6 
Adverse events of special interest ........................................................................ 61 
8.4 Safety signal detection ..................................................................................................... 61 
8.5 Treatment of overdose ..................................................................................................... 61 
8.6 Pharmacokinetics ............................................................................................................. 62 
8.7 Pharmacodynamics .......................................................................................................... 63 
8.7.1 
VAS for alcohol intoxication ............................................................................... 63 
8.7.2 
VAS feeling (Bowdle) ......................................................................................... 63 
8.7.3 
VAS according to Bond-Lader ............................................................................ 63 
8.7.4 
Saccadic eye movements ..................................................................................... 63 
8.7.5 
Smooth pursuit eye movements ........................................................................... 64 
8.7.6 
Adaptive tracking ................................................................................................. 64 
8.7.7 
Body sway ........................................................................................................... 64 
8.8 Genetics ............................................................................................................................ 64 
8.9 Biomarkers ....................................................................................................................... 64 
9 
STATISTICAL CONSIDERATIONS ............................................................................. 64 
9.1 Definition of analysis sets ................................................................................................ 64 
9.2 General statistical considerations ..................................................................................... 65 
9.3 Planned efficacy/outcome analyses ................................................................................. 65 
9.4 Planned pharmacodynamic analyses ................................................................................ 65 
9.4.1 
Ethanol and PSL (Part A) .................................................................................... 65 
9.4.2 
Cannabidiol and PSL (Part B) ............................................................................. 65 
9.5 Planned pharmacokinetic analyses .................................................................................. 66 
9.5.1 
Ethanol interaction on PSL (Part A) .................................................................... 66 
9.5.2 
PSL interaction on ethanol (Part A) ..................................................................... 66 
9.5.3 
Cannabidiol interaction on PSL (Part B) ............................................................. 67 
9.5.4 
PSL interaction on CBD (Part B): ....................................................................... 67 
9.6 Planned safety analyses .................................................................................................... 67 
9.7 Handling of protocol deviations ....................................................................................... 67 
9.8 Handling of dropouts or missing data .............................................................................. 68 
9.9 Planned interim analysis and data monitoring ................................................................. 68 
9.10 Determination of sample size ........................................................................................... 68 
10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS... 69 
10.1 Appendix 1: Regulatory, ethical, and study oversight considerations ............................. 69 
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10.1.1 
Regulatory and eithical considerations ................................................................ 69 
10.1.2 
Financial disclosure ............................................................................................. 69 
10.1.3 
Informed consent process .................................................................................... 70 
10.1.4 
Data protection ..................................................................................................... 70 
10.1.5 
Committees structure ........................................................................................... 70 
10.1.6 
Data quality assurance ......................................................................................... 71 
10.1.6.1 
Case Report form completion .................................................................... 71 
10.1.6.2 
Apps ........................................................................................................... 71 
10.1.7 
Source documents ................................................................................................ 72 
10.1.8 
Study and site closure .......................................................................................... 72 
10.1.9 
Publication policy ................................................................................................ 72 
10.2 Appendix 2: Clinical Laboratory Tests ............................................................................ 73 
10.3 Appendix 3: Adverse events – definitions and procedures for recording, evaluating, 
follow up, and reporting ................................................................................................... 75 
10.3.1 
Definition of AE .................................................................................................. 75 
10.3.2 
Definition of SAE ................................................................................................ 76 
10.3.3 
Recording and follow up of AE and/or SAE ....................................................... 77 
10.4 Appendix 4: Contraceptive guidance and collection of pregnancy information ............. 80 
10.4.1 
Definitions ........................................................................................................... 80 
10.4.1.1 
Woman of childbearing potential .............................................................. 80 
10.4.2 
Contraception guidance ....................................................................................... 80 
10.4.2.1 
Male participants ....................................................................................... 80 
10.4.2.2 
Pregnancy testing ...................................................................................... 81 
10.4.2.3 
Collection of pregnancy information......................................................... 81 
10.5 Appendix 5: Genetics ....................................................................................................... 84 
10.6 Appendix 6: Liver safety – suggested actions and follow-up assessments ..................... 85 
10.7 Appendix 7: Medical device incidents – definition and procedures for recording, 
evaluating, follow-up, and reporting ................................................................................ 87 
10.8 Appendix 8: Rapid Alert Procedures ............................................................................... 88 
10.9 Appendix 9: Country-specific requirements .................................................................... 89 
10.10 
Appendix 10: Abbreviations and trademarks ........................................................ 90 
10.11 
Appendix 11: Protocol amendment history ........................................................... 93 
11 REFERENCES ................................................................................................................ 94 
SPONSOR DECLARATION .................................................................................................. 96 
 
LIST OF TABLES 
Table 1-1: 
Assessment schedule Part A: Screening & Treatment Periods 1 and 2 ........... 17 
Table 1-2: 
Assessment schedule Part A: Treatment Period 3 ........................................... 20 
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Table 1-3: 
Assessment schedule Part A: Treatment Periods 4 and 5 ................................ 21 
Table 1-4: 
Assessment schedule Part A: Treatment Period 6 and SFU Visit ................... 23 
Table 1-5: 
Assessment schedule Part B: Screening & Treatment Period 1 ...................... 25 
Table 1-6: 
Assessment schedule Part B: Treatment Period 2 ............................................ 27 
Table 1-7: 
Assessment schedule Part B: Treatment Period 3 ............................................ 29 
Table 1-8: 
Assessment schedule Part B: Treatment Period 4 and 5 .................................. 31 
Table 1-9: 
Assessment schedule Part B: Treatment Period 6 and SFU ............................ 33 
Table 3-1: 
Study objectives and endpoints ........................................................................ 37 
Table 6-1: 
Treatments administered .................................................................................. 48 
Table 8-1: 
Irrelevant time deviations for PK sampling ..................................................... 62 
Table 10-1: 
Highly Effective Contraceptive Methods ........................................................ 82 
Table 10-2: 
Phase I liver chemistry stopping criteria and follow-up assessments .............. 85 
 
LIST OF FIGURES 
Figure 1-1: 
Study schematic – Part A ................................................................................. 14 
Figure 1-2: 
Study schematic – Part B ................................................................................. 15 
Figure 7-1: 
Liver chemistry stopping algorithm ................................................................. 53 
 
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1 
PROTOCOL SUMMARY 
1.1 
Synopsis 
1.1.1 
Protocol title: 
A double-blind, placebo-controlled, randomized, single-center, cross-over study to investigate 
the pharmacodynamic (PD), pharmacokinetic (PK), safety, and tolerability profiles of padsevonil 
(PSL) in healthy study participants receiving either ethanol or cannabidiol (CBD). 
1.1.2 
Short title: 
A PD, PK, safety, and tolerability study of PSL in healthy study participants receiving either 
ethanol or CBD. 
1.1.3 
Rationale: 
This study aims to characterize the PD, PK, safety, and tolerability of steady-state PSL in healthy 
study participants receiving either ethanol or steady-state treatment of CBD. Drug-drug 
interactions that result in alterations in the PK of antiepileptic drugs (AEDs) can have a profound 
impact on tolerability, efficacy, and safety, and can potentially result in toxicity. It is therefore 
important to consider and estimate at an early stage the possible interactions that may occur with 
the concomitant use of PSL and other drugs. 
1.1.4 
Objectives and endpoints 
Objectives 
Endpoints 
Primary 
 Part A: To evaluate the PD interaction 
between steady-state treatment with PSL 
and ethanol 
 Smooth pursuit (%) to assess eye 
movement coordination and attention 
 Part B: To evaluate the PK interaction 
between steady-state treatment with PSL 
and CBD 
 Cmax,ss and AUCτ obtained from the 
plasma concentration-time profiles for 
PSL and CBD 
Secondary 
 Part A: To evaluate the PK interaction 
between steady-state treatment with PSL 
and ethanol 
 Ethanol dose infused over time 
 Cmax,ss and AUCτ obtained from the 
plasma concentration-time profiles for 
PSL 
 Part B: To evaluate the PK interaction 
between steady-state treatment with PSL 
and CBD 
 t1/2, and CLss/F obtained from the plasma 
concentration-time profiles for PSL and 
CBD 
 Parts A and B: To evaluate the PD 
interaction between steady-state treatment 
with PSL and ethanol or between 
steady-state treatment with PSL and CBD 
 Smooth pursuit (%) to assess eye 
movement coordination and attention 
(Part B only) 
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 Saccadic peak velocity (degrees/sec) to 
assess sedation 
 Adaptive tracking (%) to assess 
visuo-motor control and vigilance 
 Body Sway to assess postural stability 
 Parts A and B: To evaluate the safety and 
tolerability of PSL in study participants 
receiving concomitant ethanol or CBD 
 Adverse events (AEs), serious adverse 
events (SAEs), treatment-related AEs, and 
AEs leading to discontinuation of the 
study 
Other 
 Parts A and B: To evaluate the safety and 
tolerability of PSL in study participants 
receiving concomitant ethanol or CBD 
 Vital signs (pulse rate, respiratory rate, 
systolic blood pressure [SBP], and 
diastolic blood pressure [DBP]) 
 12-lead electrocardiogram (ECG) 
parameters  
 Physical examination findings 
 Clinical laboratory test results 
(hematology, clinical chemistry, and 
urinalysis) 
 Parts A and B: To evaluate the PD 
interaction between steady-state treatment 
with PSL and ethanol or steady-state 
treatment with PSL and CBD 
 Visual analogue scales (VAS) Bond & 
Lader to assess study participantive 
alertness, mood, and calmness 
 VAS feeling high, internal and external 
perception (Bowdle)  
 VAS for alcohol intoxication to assess 
study participantive effects of ethanol 
(Part A only) 
 Part B: To evaluate the PK interaction 
between steady-state treatment with PSL 
and CBD 
 tmax obtained from the plasma 
concentration-time profiles for PSL and 
CBD  
 Cmax,ss, AUCτ, t1/2, tmax, and 
metabolite/parent (based on Cmax,ss and 
AUCτ) obtained from the plasma 
concentration-time profiles for PSL 
metabolites and CBD active metabolite 
 Part A and B: To collect and store blood 
for potential ADME genotype (if needed) 
 Possible ADME genotyping for drug 
metabolizing enzymes (depending on the 
outcome of PSL (and metabolite) PK 
analyses, if needed 
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 Part A and B: To collect urine samples for 
additional PK analyses depending on the 
outcome of PSL (and metabolite) PK 
analyses, if needed 
 Urine sample PK analysis 
1.1.5 
Overall design 
This is a Phase 1, double-blind, randomized, placebo-controlled, single-center, cross-over study 
to evaluate the PK, PD, safety, and tolerability of steady state treatment of PSL in healthy study 
participants receiving either ethanol (Part A) or steady-state treatment of CBD (Part B). Study 
participants that complete Part A of the study are not eligible to complete Part B; similarly, study 
participants that complete Part B are not eligible to complete Part A. 
1.1.5.1 
Part A 
Treatment Periods 1 and 2, and 4 and 5 are 2-way cross-over, placebo-controlled, 
ethanol-clamping periods with a washout of at least 2 days between Treatment Periods 2 and 3; 
PSL is not administered in Treatment Periods 1 and 2. Treatment Period 3 is an open-label PSL 
up-titration period toward a maintenance level of 200mg BID, and is immediately followed by 
Treatment Period 4 and Treatment Period 5. Treatment Period 6 is the PSL tapering open-label 
period. 
During each cross-over period, the study participant will check into the clinic the evening prior 
to the day of administration of ethanol/dummy infusion and PSL (Day -1). On Day 1 of 
Treatment Periods 1, 2, 4 and 5, continuous infusion of ethanol or dummy infusion will begin 
with a 30 minute loading phase and will continue for 5 hours. On Day 1 of Treatment Periods 4 
and 5, PSL will be administered right after the end of the loading phase. 
During the first 10 minutes, the infusion will be accompanied by an infusion of 5% glucose via 
the same line in order to mask the sensation at the beginning of the ethanol infusion. The ethanol 
infusion rate is initially based on weight, height, age, and sex. The infusion rate is determined 
based on the Watson estimate of body water (Watson et al, 1980). Subsequently, the infusion rate 
will be adjusted based on breath ethanol measurements to maintain breath ethanol levels (and by 
extension, blood ethanol levels) of 0.6g/L. Following administration of PSL, the study 
participant will be observed for approximately 24 hours. 
1.1.5.2 
Part B 
Treatment Period 1 of Part B will be conducted in a sentinel cohort of healthy study participants 
in order to evaluate CBD safety and PK exposure under a single dose of CBD 10mg/kg (fasted 
conditions). The results of the PK analysis will be compared to published PK data of CBD (dose 
of 750mg in fasted conditions) obtained in similar conditions with Epidiolex® (Taylor et al, 
2018). The decision to continue on with the rest of Part B or terminate the study following the 
first CBD dose in Treatment Period 1 of Part B will be made pending the outcome of the analysis 
of CBD safety and exposure. A difference between the PK results in the present study and the 
literature findings requiring a >2-fold dose adjustment will be considered as not manageable and 
would result in termination of the study. If a dose adjustement ≤2-fold is needed, then the study 
will proceed with the second dose of CBD of Treatment Period 1 in Part B. If the observed CBD 
exposure matches the data from the literature, then study will proceed directly to Treatment 
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Period 2 of Part B (no second dosing of CBD will be required). Treatment Period 2 cannot 
commence until the results from Treatment Period 1 are analyzed. 
A washout of at least 6 days will occur between Treatment Period 1 and Treatment Period 2. 
Treatment Period 2 will include 7 days of treatment with open-label PSL treatment. Treatment 
Period 3 starts after a washout of minimally 6 days for all study participants, and includes an 
ambulatory open-label CBD up titration of 16 days toward a maintenance level of 10mg/kg BID. 
Treatment Periods 4 and 5 are 2-way cross-over, double-blind and placebo-controlled periods 
with PSL up titrated to a maintenance level of 200mg BID through Day 5 and subsequent down 
titration until Day 8. A maintenance dose of 10mg/kg BID CBD will occur in-house between 
Treatment Periods 4 and 5. Cannabidiol down titration starts in Treatment Period 6. 
1.1.6 
Number of participants 
Based on the study PK and PD objectives, the total planned number of healthy study participants 
will be 44, including 22 evaluable participants for Part A and 22 evaluable participants for 
Part B. Drop outs will be replaced at the discretion of the Investigator and Sponsor. A total of 
16 evaluable study participants are needed to complete Treatment Period 1 of Part B. 
1.1.7 
Treatment groups and duration 
The maximum total duration is 54 days for Part A and 116 days for Part B (including Screening, 
the Treatment Period, and Follow-up) for each participant. The total duration of PSL exposure is 
10 days in Part A and 21 days in Part B. 
1.2 
Schema 
A detailed schematic diagram of the study is provided in Figure 1-1. 
 
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Figure 1-1: Study schematic – Part A 
 
BID=twice daily; CBD=cannibidiol; D=day; FU=Follow-up Period; PBO=placebo; PSL=padsevonil; W=week 
Note: Follow up will occur between 7 to 10 days after the final dose of PSL. 
Note: A WO of at least 2 days will occur between Treatment Period 2 and Treatment Period 3. 
 
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Figure 1-2: Study schematic – Part B 
 
Note: Follow up will occur between 7 to 10 days after the final dose of CBD. 
Note: A WO of at least 6 days will occur following Treatment Period 1 and Treatment Period 2. 
BID=twice daily; CBD=cannabidiol; D=day; FU=Follow-up Period; PBO=placebo for PSL; PSL=padsevonil; SD=single dose; W=week 
 
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1.3 
Schedule of activities 
1.3.1 
Part A 
For Part A, the schedule of activities is provided in Table 1-1 for Screening and Treatment 
Periods 1 and 2, in Table 1-2 for Treatment Period 3, in Table 1-3 for Treatment Periods 4 and 5, 
and in Table 1-4 for Treatment Period 6 and the SFU Visit. 
 
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Table 1-1: 
Assessment schedule Part A: Screening & Treatment Periods 1 and 2 
Study Period 
Screening 
 
Treatment Period 1 and 2 
Study day 
-28 to -2 
D-1 a 
D1 
D2 
Time related to morning IMP 
administration 
 
 
Pre-ethanol  
dose 
-30 
m 
0 
h 
30 
m 
1 
h 
2 
h 
2.5 
h 
3 
h 
4 
h 
5 
h 
6 
h 
8 
h 
10 
h 
24 h 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Previous/concomitant med 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Psychiatric/mental status 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination b 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Body weight and height c 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine drug screen/breath alcohol 
test d 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test e 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
FSH test f 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hem/chem/urine/ serol. 
X g h 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
C-SSRS i 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X j 
Vital signs (BP, HR, RR, T) k 
X 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
Triplicate 12-lead ECG 
X 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
VAS alcohol intoxication 
X l 
 
X 
 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
NeuroCart m 
X l 
 
X 
 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
Arrival at the clinic 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine sampling (blank aliquot) 
 
 
X n 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Table 1-1: 
Assessment schedule Part A: Screening & Treatment Periods 1 and 2 
Study Period 
Screening 
 
Treatment Period 1 and 2 
Study day 
-28 to -2 
D-1 a 
D1 
D2 
Time related to morning IMP 
administration 
 
 
Pre-ethanol  
dose 
-30 
m 
0 
h 
30 
m 
1 
h 
2 
h 
2.5 
h 
3 
h 
4 
h 
5 
h 
6 
h 
8 
h 
10 
h 
24 h 
Sample collection for exploratory 
genotype analysis 
 
 
X n 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ethanol breath sampling o 
 
 
X 
 
Ethanol/placebo infusion p 
 
 
 
X 
 
 
 
 
Discharge 
 
 
 
 
 
 
 
X j 
AE=adverse event; BP=blood pressure; C-SSRS=Columbia-Suicide Severity Rating Scale; D=Day; ECG=electrocardiogram; FSH=follicle stimulating hormone; 
h=hours; HBsAg=hepatitis B surface antigen; HCV-Ab=hepatitis C antibody; HIV-1/2Ab=human immunodeficiency virus-1/2 antibody; HR=heart rate; 
m=minutes; PK=pharmacokinetic; PSL=Padsevonil; RR=respiratory rate; T=body temperature; VAS=Visual Analog Scale 
a Refers to D-1 (Admission) prior to Part A Treatment Period 1 only. 
b A complete physical examination will be conducted at Part A Screening. A brief physical examination will be conducted at all other visits, including at 
discharge prior to the release of study participants. 
c Height measured only at Screening. Body weight will be measured at Part A Screening and predose in Part A Treatment Period 1 and 2. 
d All study participants will have a urine drug screen/breath alcohol test at admission. For study participants who are discharged between Treatment Periods, a 
urine drug screen/breath alcohol test will be performed at re-admission at the discretion of the PI. 
e For women of childbearing potential: A serum beta-HCG pregnancy test will be performed at Screening and urine beta HCG will be performed either on the 
first day of each treatment period or the day before the first day of each Treatment Period at discretion of Investigator. In either case, the results must be 
negative prior to dosing study participants. 
f Female study participants of non-childbearing potential to confirm postmenopausal status. 
g Virus serology (HIV-1/2Ab, HBsAg, and HCV-Ab) only at Screening. 
h Fasted conditions only at Screening. 
i At the Screening Visit, “Baseline/Screening” version of the C-SSRS will be completed. At all other visits, “Since Last Visit” version of the C-SSRS will be 
completed. 
j In Part A Treatment Period 2 only. 
k Vital signs will be taken in a supine/standing position at Screening, and in a supine position at all other assessments.  
l PD training session for all study participants. Training session will be performed at the Screening visit or during a separate visit. Baseline PD assessment will 
be collected as a duplicate at D1 predose. Final Baseline score will be averaged (from duplicate values). 
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m NeuroCart assessments in Part A consist of the following tests: Body Sway, VAS mood & alertness (Bond & Lader), VAS feeling high, internal- and external 
perception (Bowdle), SEM, Adaptive tracking, and Smooth Pursuit Eye Movements. NeuroCart assessments are taken twice at least 30 minutes prior to dosing 
and singlicate postdose at 30 minutes, 1, 2, 3, 4, 5, 6, 8, and 10 hours. 
n Part A Treatment Period 1 only prior to ethanol dosing.  
o During the ethanol/dummy infusion, the infusion rate will be adjusted based on ethanol breath sampling.  
p Continuous infusion will begin with a 30 minute loading phase (prior to 0 hours) and will continue for 5 hours. 
 
 
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Table 1-2: 
Assessment schedule Part A: Treatment Period 3 
Study Period 
Treatment Period 3 
Study day 
D -1a 
D1 
D2 
D3 
D4 
Arrival at the clinic  
X 
 
 
 
 
Previous/concomitant med  
X 
X 
X 
X 
X 
Urine drug screen/breath alcohol test b  
X 
 
 
 
 
Pregnancy test c 
X 
 
 
 
 
Adverse events 
X 
X 
X 
X 
X 
Psychiatric/mental status  
 
X 
X 
X 
X 
Hem/chem/urine e 
X 
 
 
 
 
C-SSRS d, e 
 
X 
 
 
 
Brief physical examination  
 
X e 
X 
X 
X 
Supine vital signs (BP, RR, HR, T) f 
 
X 
 
 
X 
Triplicate 12-lead ECG  f 
 
X 
 
 
X 
PSL administration g 
 
X 
X 
X 
X 
PSL trough PK sampling e 
 
X 
X 
X 
X 
AE=adverse event; BID=twice daily; BP=blood pressure; C-SSRS=Columbia-Suicide Severity Rating Scale; D=Day; ECG=electrocardiogram; HR=heart 
rate; PK=pharmacokinetic; PSL=Padsevonil; T=body temperature; RR=respiratory rate; VAS=Visual Analog Scale 
a A washout period of at least 2 days will occur between Part A Treatment Period 2 and Part A Treatment Period 3. Study participants will be re-admitted in 
Part A Treatment Period 3. 
b Performed at the discretion of the PI. 
c For women of childbearing potential: Urine beta HCG will be performed either on the first day of the treatment period or the day before the first day of the 
Treatment Period at discretion of Investigator. The results must be negative prior to dosing study participants. 
d “Since Last Visit” version of the C-SSRS will be completed. 
e Prior to IMP morning administration. 
f Prior to and 2.5 hours after morning IMP administration (0 hours). 
g D1: PSL 100mg BID; D2: PSL 200mg BID; D3: PSL 200mg BID; D4: PSL 200mg BID. 
 
 
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Table 1-3: 
Assessment schedule Part A: Treatment Periods 4 and 5 
Study Period 
Treatment Period 4 and 5 
Study day 
D5 / D7 
D6/ 
D8 
Time related to 
Padsevonil/placebo 
administration 
Pre-
etha
nold
ose 
-30 
m 
0 
h 
15 
m 
30 
m 
1 
h 
1.5 
h 
2 
h 
2.5 
h 
3 
h 
4 
h 
5 
h 
6 
h 
8 
h 
10 
h 
12 
h 
24 
h 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Previous/concomitant med 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hem/chem/urine 
X a 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C-SSRS b 
X a 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Psychiatric/mental status  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Brief physical examination 
X a 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Body weight 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Supine vital signs (BP, HR, 
RR, T)  
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
Triplicate 12-lead ECG 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
Ethanol breath sampling c 
X 
 
 
Ethanol/placebo infusion d 
 
X 
 
 
 
 
 
PSL administration e 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
PSL PK trough sampling f 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
Start/stop urine collection  
 
 
X 
 
VAS alcohol intoxication 
X 
 
 
 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
 
 
Neurocart g 
X 
 
 
 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
 
 
AE=adverse event; BP=blood pressure; C-SSRS=Columbia-Suicide Severity Rating Scale; D=Day; ECG=electrocardiogram; h=hours; HR=heart rate; 
m=minutes; PK=pharmacokinetic; PSL=Padsevonil; T=body temperature; RR=respiratory rate; VAS=Visual Analog Scale 
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a On Day 5 in Part A Treatment Period 4. Hem/Chem/urine safety lab: to be collected the day before dosing (P3D4).  
b “Since Last Visit” version of the C-SSRS will be completed. 
c During the ethanol/placebo infusion, the infusion rate will be adjusted based on ethanol breath sampling. 
d Continuous infusion will begin with a 30 minute loading phase and will continue for 5 hours. To avoid local pain, an additional glucose 5% solution will be 
infused in parallel for approximately 10 minutes at the start of the ethanol/dummy infusion. 
e D5: PSL 200mg BID; D6: PSL 200mg BID; D7: PSL 200mg AM and PSL 100mg PM; D8: PSL 100mg BID 
f Prior to morning IMP administration (0 hours). 
g NeuroCart assessments in Part A consist of the following tests: Body Sway, VAS mood & alertness (Bond & Lader), VAS feeling high, internal- and external 
perception (Bowdle), SEM, Adaptive tracking, and Smooth Pursuit Eye Movements. NeuroCarts assessments are taken twice at least 30 minutes prior to dosing 
and singlicate postdose at 30 minutes, 1, 2, 3, 4, 5, 6, 8, and 10 hours. 
 
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Table 1-4: 
Assessment schedule Part A: Treatment Period 6 and SFU Visit 
Study Period 
Treatment Period 6  
SFU Visit a 
Study day 
D9 
D10 
 
PSL administration b 
X 
 
 
Adverse events 
X 
X 
X 
Previous/concomitant med 
X 
X 
X 
Psychiatric and mental status 
X 
X 
X 
Supine vital signs (BP, RR, HR, T) c 
 
X 
X 
Triplicate 12-lead ECG d 
 
X 
 
C-SSRS e 
 
X 
X 
Physical examination d 
 
X 
X 
Hem/chem/urine  
 
X 
X 
Discharge from the clinic f 
 
X 
 
Pregnancy test g 
 
X  
 
AE=adverse event; BID=twice daily; BP=blood pressure; C-SSRS=Columbia-Suicide Severity Rating Scale; D=Day; ECG=electrocardiogram; HR=heart rate; 
PK=pharmacokinetic; PSL=Padsevonil; SFU=Safety Follow-up; T=body temperature; RR=respiratory rate; VAS=Visual Analog Scale 
a Study participants will return for a SFU Visit between 7 to 10 days after the final dose of PSL in Part A. 
b D9: PSL 100mg BID 
d Brief physical exams will be conducted during Part A Treatment Period 6. A full physical exam will be conducted at the SFU Visit. 
d Prior to and 2.5 hours after morning IMP administration (0 hours). 
e “Since Last Visit” version of the C-SSRS will be completed. 
f Study participants will be discharged in the morning on Day 11 following the completion of all assessments. 
g For women of childbearing potential: Urine beta HCG will be performed. 
 
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1.3.2 
Part B 
For Part B, the schedule of activities is provided in Table 1-5 for Treatment Period 1, Table 1-6 
for Treatment Period 2, Table 1-7 for Treatment Period 3, Table 1-8 for Treatment Periods 4 and 
5, and Table 1-9 for Treatment Period 6 and the SFU Visit. 
 
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Table 1-5: 
Assessment schedule Part B: Screening & Treatment Period 1 
Study Period 
Screening 
 
Treatment Period 1 a 
Study day 
-28 to -2 
D-1 b 
D1/D15 (Optional) c 
D2/D16 (Optional) d 
Informed consent 
X 
 
 
 
Medical history 
X 
X 
 
 
Previous/concomitant med 
X 
X 
X 
X 
Adverse events 
X 
X 
X 
X 
Psychiatric/mental status  
X 
 
X 
X 
Physical examination e 
X 
 
X 
X 
Body weight and height  
X 
 
 
 
Urine drug screen/breath 
alcohol test f 
X 
X 
 
 
Pregnancy test g 
X 
X 
 
 
FSH test h 
X 
 
 
 
Hem/chem/urine/ serol. i 
X  
X 
 
X 
C-SSRS j 
X 
 
X 
X 
Vital signs (BP, HR, RR, T) k 
X 
 
X 
X 
Triplicate 12-lead ECG 
X 
 
X 
X 
NeuroCart l 
X m 
 
X 
X 
Arrival at the clinic 
 
X 
 
 
CBD administration n 
 
 
X 
X 
CBD PK sampling o 
 
 
X 
X 
Discharge 
 
 
 
X 
AE=adverse event; BP=blood pressure; C-SSRS=Columbia-Suicide Severity Rating Scale; D=Day; ECG=electrocardiogram; FSH=follicle stimulating 
hormone; h=hours; HBsAg=hepatitis B surface antigen; HCV-Ab=hepatitis C antibody; HIV-1/2Ab=human immunodeficiency virus-1/2 antibody; 
HR=heart rate; m=minutes; PK=pharmacokinetic; PSL=Padsevonil; RR=respiratory rate; SD=single dose; T=body temperature; VAS=Visual Analog Scale 
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a Assessments will be taken under fasted conditions at Screening, Day 1, and optional Day 15 only. 
b Refers to D-1 (Admission) prior to Part B Treatment Period 1. 
c An optional second dose of CBD may be administered on Day 15 after evaluation of PK/safety data at the discretion of the Sponsor. 
d A washout of at least 6 days will occur between Treatment Period 1 and Treatment Period 2. 
e A complete physical examination will be conducted at Screening. A brief physical examination will be conducted at all other visits, including at discharge prior 
to the release of study participants. 
f All study participants will have a urine drug screen/breath alcohol test at admission. For study participants who are discharged between treatment periods, a 
urine drug screen/breath alcohol test will be performed at re-admission at the discretion of the PI. 
g For women of childbearing potential: A serum beta-HCG pregnancy test will be performed at Screening and urine beta HCG will be performed either on the 
first day of each treatment period or the day before the first day of each treatment period at discretion of Investigator. In either case, the results must be 
negative prior to dosing study participants. 
h Female study participants of non-childbearing potential to confirm postmenopausal status. 
i Virus serology (HIV-1/2Ab, HBsAg, and HCV-Ab) only at Screening. 
j At the Screening Visit, “Baseline/Screening” version of the C-SSRS will be completed. At all other visits, “Since Last Visit” version of the C-SSRS will be 
completed. 
k Vital signs will be taken in a supine/standing position at Screening, and in a supine position at all other assessments. 
l NeuroCart assessments in Part B consist of the following tests: Body Sway, VAS mood & alertness (Bond & Lader), VAS feeling high, internal- and external 
perception (Bowdle), SEM, and Smooth Pursuit Eye Movements. 
m PD training session for all study participants. Training session will be performed at Screening or during a separate visit. Baseline PD assessment will be 
collected as a duplicate at D1 predose. Final Baseline score will be averaged (from duplicate values). 
n D1: CBD 10mg/kg SD; D15 (optional): CBD dose to be defined (within 5 and 20mg/kg SD) 
o CBD PK sampling will occur at 0, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8,12 and 24 hours postdose. 
 
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Table 1-6: 
Assessment schedule Part B: Treatment Period 2 
Study Period 
Treatment Period 2 a b 
Study day 
D -1 
D1 
D2 
D3 
D4 
D5 
D6 
D7/D8  
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
Psychiatric and mental status 
 
X 
X 
X 
X 
X 
X 
X 
Previous/concomitant med 
X 
X 
X 
X 
X 
X 
X 
X 
Arrival at clinic 
X 
 
 
 
 
 
 
 
Urine drug screen/ breath alcohol test \ 
X 
 
 
 
 
 
 
 
Urine sampling (blank aliquot) c 
X 
 
 
 
 
 
 
 
Pregnancy test d 
X 
 
 
 
 
 
 
 
Hem/chem/urine c 
X 
X 
 
 
X 
 
 
X 
Neurocart 
 
 
 
 
 
 
 
 
C-SSRS e 
 
X 
 
 
 
 
 
X f  
Brief physical examination  
 
X  
 
 
X  
 
 
X f 
Supine vital signs (BP, RR, HR, T) g 
 
X 
 
 
X 
X 
X 
X f 
Triplicate 12-lead ECG g 
 
X  
 
 
X  
X 
X  
X f 
PSL administration h 
 
X 
X 
X 
X 
X 
X 
X 
PSL PK trough sampling c i 
 
X 
X 
X 
X 
X 
X 
X 
NeuroCart j 
X  
 
 
 
 
X 
 
 
Urine sampling (blank aliquot) c 
X 
 
 
 
 
 
 
 
Sample collection for exploratory 
genotype analysis c 
X 
 
 
 
 
 
 
 
Start/stop urine collection 
 
 
 
 
 
X k 
 
 
Discharge 
 
 
 
 
 
 
 
X f 
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Table 1-6: 
Assessment schedule Part B: Treatment Period 2 
Study Period 
Treatment Period 2 a b 
Study day 
D -1 
D1 
D2 
D3 
D4 
D5 
D6 
D7/D8  
AE=adverse event; BID=twice daily; BP=blood pressure; C-SSRS=Columbia-Suicide Severity Rating Scale; D=Day; ECG=electrocardiogram; h=hour; 
HR=heart rate; PK=pharmacokinetic; PSL=Padsevonil; RR=respiratory rate; T=body temperature; SEM=Saccadic Eye Movements; VAS=Visual Analog 
Scale 
a For study participants that begin Part B in Treatment Period 2, Screening assessments will be performed according the Screening assessments described in 
Table 1-5. 
b A washout of at least 6 days will occur at the end of Treatment Period 2 prior to Treatment Period 3 in Part B. 
c Prior to IMP administration. 
d For women of childbearing potential: A urine beta HCG will be performed either on the first day of the treatment period or the day before the first day of the 
treatment period at discretion of Investigator. The result must be negative prior to dosing study participants. 
e “Since Last Visit” version of the C-SSRS will be completed. 
f In Treatment Period 2, on Day 9 only. 
g Prior to and 2.5 hours after morning IMP administration. 
h D1: PSL 100mg BID; D2: PSL 200mg BID; D3: PSL 200mg BID; D4: PSL 200mg BID; D5: PSL 200mg AM; D5: PSL 100mg PM; D6: PSL 100mg BID; 
D7: PSL 100mg BID 
i Blood samples for measurement of plasma concentration of PSL will be obtained at the following times: predose (within 5 minutes of dosing), and at Day 5 
(PK day) postdose at 0.25h, 0.5h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, and 12h postdose. 
j NeuroCart assessments in Part B consist of the following tests: Body Sway, VAS mood & alertness (Bond & Lader), VAS feeling high, internal- and external 
perception (Bowdle), SEM, and Smooth Pursuit Eye Movements. NeuroCarts assessments are taken twice at least 30 minutes prior to dosing and singlicate 
postdose at 30 minutes, 1, 2, 3, 4, 5, 6, 8, and 10 hours. 
k Urine collection for additional PK analysis will be collected for 12-hours post-morning dose on Day 5. 
 
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Table 1-7: 
Assessment schedule Part B: Treatment Period 3 
Study Period 
 
Treatment Period 3 a 
Study day 
D-1 
D1 
D2 
D3 
D4 
D5 
D6 
D7 
D8 
D9 
D10 
D11 
D12 
D13 
D14 
D15 
D16 
Previous/concomitant 
meds c 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Psychiatric and 
mental status 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 
X 
Urine drug 
screen/breath alcohol 
screen b c 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 
X 
Pregnancy test d 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 
X 
Brief physical 
examination c 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 
 
Hem/chem/urine c 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
Supine Vital signs 
(BP, RR, HR, T) e 
 
X 
 
 
X 
 
 
X 
 
 
X  
 
 
 
 
 
 
Triplicate 12-lead 
ECG e 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 
 
C-SSRS f 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CBD administration g 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CBD PK trough 
sampling c 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 
X 
NeuroCart h 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Arrival at the clinic 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 
X 
AE=adverse event; BID=twice daily; BP=blood pressure; CBD=cannabidiol; C-SSRS=Columbia-Suicide Severity Rating Scale; D=Day; 
ECG=electrocardiogram; h=hour; HR=heart rate; PK=pharmacokinetic; PSL=Padsevonil; RR=respiratory rate; SEM=Saccadic Eye Movements; T=body 
temperature; VAS=Visual Analog Scale; W=Week 
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a A washout of at least 6 days will occur prior to the start of Treatment Period 3. 
b Performed at the discretion of the PI. 
c Prior to morning CBD administration. 
d Urine beta HCG will be collected either on the first day of the treatment period or the day before the first day of the treatment period at discretion of 
Investigator. In either case, the result must be negative prior to dosing study participants. 
e Prior to and 2.5 hours after morning CBD administration. 
f “Since Last Visit” version of the C-SSRS will be completed. 
g Days 1 to 3: CBD 2.5mg/kg BID; Days 4 to 6: CBD 5mg/kg BID; Days 7 to 9: CBD 7.5mg/kg BID; Days 10 to 16: CBD 10mg/kg BID (doses to be confirmed 
from CBD PK exposure in Treatment Period 1). 
h NeuroCart assessments in Part B consist of the following tests: Body Sway, VAS mood & alertness (Bond & Lader), VAS feeling high, internal- and external 
perception (Bowdle), SEM, and Smooth Pursuit Eye Movements. NeuroCarts assessments are taken twice at least 30 minutes prior to dosing and singlicate 
postdose at 30 minutes, 1, 2, 3, 4, 5, 6, 8, and 10 hours. 
 
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Table 1-8: 
Assessment schedule Part B: Treatment Period 4 and 5 
Study Period 
Treatment Periods 4 & 5 
Study day 
D1 
D2 
D3 
D4 
D5 
D6 
D7 
Previous/concomitant med a 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
Psychiatric and mental status 
X 
X 
X 
X 
X 
X 
X 
Brief physical examination a 
X  
X 
X 
X 
X 
X 
X 
Supine vital signs (BP, RR, HR, T) 
b 
X 
X 
X 
X 
X 
X 
X 
CBD 10 mg/kg BID c 
X 
X 
X 
X 
X 
X 
X 
PSL/placebo administration d 
X 
X 
X 
X 
X 
X 
X 
CBD PK trough sampling e 
X 
X 
X 
X 
X 
X 
X 
PSL PK trough sampling f 
X 
X 
X 
X 
X 
X 
X 
Triplicate 12-lead ECG b 
X 
 
 
X 
X 
X 
X 
C-SSRS g 
X 
 
 
 
 
 
X 
NeuroCart h 
X 
 
 
 
X 
 
 
Start/stop urine collection i 
 
 
 
 
X 
 
 
Hem/chem/urine a 
 
 
 
 
 
 
X 
AE=adverse event; BID=twice daily; BP=blood pressure; CBD=cannabidiol; C-SSRS=Columbia-Suicide Severity Rating Scale; D=Day; 
ECG=electrocardiogram; h=hour; HR=heart rate; PK=pharmacokinetic; PSL=Padsevonil; RR=respiratory rate; SEM=Saccadic Eye Movements; T=body 
temperature; VAS=Visual Analog Scale 
Note: A washout of at least 4 days will occur between Treatment Periods 4 and 5 for PSL. 
a Prior to PSL/placebo/CBD administration. 
b Prior to and 2.5 hours after IMP administration. 
c CBD maintenance 10mg/kg BID (dose to be confirmed from CBD PK exposure in Treatment Period 1) between Treatment Period 4 and Treatment Period 5 for 
4 Days (study participants in house). 
d D1: PSL 100mg BID; D2: PSL 200mg BID; D3: PSL 200mg BID; D4: PSL 200mg BID; D5: PSL 200mg AM; D5: PSL 100mg PM; D6: PSL 100mg BID; 
D7: PSL 100mg BID. 
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f Blood samples for measurement of plasma concentration of PSL and CBD will be obtained at the following times: predose (within 5 minutes of dosing), and at 
Day 5 (PK day) postdose at 0.25h, 0.5h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, and 12h postdose. 
g “Since Last Visit” version of the C-SSRS will be completed. 
h NeuroCart assessments in Part B consist of the following tests: Body Sway, VAS mood & alertness (Bond & Lader), VAS feeling high, internal- and external 
perception (Bowdle), SEM, and Smooth Pursuit Eye Movements. NeuroCarts assessments are taken twice at least 30 minutes prior to dosing and singlicate 
postdose at 30 minutes, 1, 2, 3, 4, 5, 6, 8, and 10 hours. 
i Urine samples for additional PK analysis will be collected 12-hours postdose on Day 5. 
 
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Table 1-9: 
Assessment schedule Part B: Treatment Period 6 and SFU 
Study Period 
Treatment Period 6 
SFU Visit a 
Study day 
D1 
D2 
D3 
D4 
D5 
D6/D7 
 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
Previous/concomitant meds 
X 
X 
X 
X 
X 
X 
X 
Hem/chem/urine b 
 
 
 
 
 
X 
X 
Supine vital signs (BP, RR, HR, T) 
c  
X 
 
X 
 
 
X d 
X 
Psychiatric and mental status 
X 
 
X 
 
 
X 
X 
Triplicate 12-lead ECG c 
X 
 
X 
 
 
X d 
X 
C-SSRS e 
X 
 
 
 
 
X d 
X 
CBD administration f 
X 
X 
X 
X 
X 
X 
 
CBD PK trough sampling b 
X 
 
X 
 
 
X 
X 
Physical examination g 
X 
 
X 
 
 
X d 
X 
Pregnancy test 
 
 
 
 
 
X h 
 
Discharge 
X 
 
 
 
 
X d 
 
AE=adverse event; BID=twice daily; BP=blood pressure; CBD=cannabidiol; C-SSRS=Columbia-Suicide Severity Rating Scale; D=Day; 
ECG=electrocardiogram; h=hour; HR=heart rate; PK=pharmacokinetic; PSL=Padsevonil; RR=respiratory rate; SAE=serious adverse event; T=body 
temperature; VAS=Visual Analog Scale; W=Week 
a Study participants will return for a SFU Visit between 7 to 10 days after the final dose of CBD in Part B. 
b Prior to CBD administration. 
c Prior to and 2.5 hours after morning IMP administration. 
d Study participants will be discharged in the morning on Day 7 following the completion of all assessments. 
e “Since Last Visit” version of the C-SSRS will be completed. 
f Days 1 to 2: CBD 7.5mg/kg BID; Days 3 to 4: CBD 5mg/kg BID; Days 5 to 6: CBD 2.5mg/kg BID (doses to be confirmed from CBD PK exposure in 
Treatment Period 1). 
gBrief physical exams will be conducted during Part B Treatment Period 6. A full physical exam will be conducted at the SFU Visit. 
h For women of childbearing potential: Urine beta HCG will be performed. 
 
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2 
INTRODUCTION 
2.1 
Study rationale 
Padsevonil is a novel chemical entity with selective affinity for both presynaptic vesicle protein 2 
isoforms and postsynaptic cBZR sites on the GABAA receptor that has shown compelling, 
broad-range efficacy in several preclinical models of epilepsy conducted by UCB. Padsevonil is 
cleared via metabolism involving the CYP pathway; the formation of the 2 major metabolites, 
, is 
mainly mediated by CYP3A4, with potential involvement of CYP2C19. Drug-drug interactions 
that result in alterations in the PK of AEDs can have a profound impact on tolerability, efficacy, 
and safety, and can potentially result in toxicity. It is therefore important to consider and estimate 
at an early stage the possible interactions that may occur with the concomitant use of PSL and 
other drugs. 
UP0071 is designed to characterize the PK/PD of steady-state PSL in healthy study participants 
receiving either ethanol or steady-state treatment of CBD. Considering the central nervous system 
(CNS) effect of ethanol, PD interaction between PSL and ethanol is plausible. However, it is 
difficult to predict the potential impact of the combination. Cannabidiol is a major chemical of 
marijuana that does not possess psychoactive properties. There seems to be a growing body of 
basic pharmacologic data suggesting there may be a role for CBD, especially in the treatment of 
refractory epilepsy. As PSL and CBD share the same P450 CYP pathway and aim to treat the 
same patient population, a clinical study investigating the potential PD and PK interaction is 
useful. 
2.2 
Background 
More than 50 million people worldwide suffer from epilepsy (World Health Organization, 2018). 
An imbalance between excitatory and inhibitory neurotransmission is widely recognized as a key 
factor leading to epilepsy. Consequently, drugs currently used in the treatment of epilepsy aim to 
restore this balance. In fact, most of the current AEDs modulate neuronal transmission by either 
blocking voltage-gated sodium channels or acting on inhibitory/excitatory receptors located at the 
postsynaptic level. 
The GABAA receptor mediates the bulk of inhibitory neurotransmissions in the brain. Allosteric 
modulation of inhibitory GABAA receptors by the cBZR site offers robust protection against 
seizures (Riss et al, 2008). However, their clinical use as AEDs is limited due to an unfavourable 
side effect profile (eg, drowsiness, ataxia, amnesia, paradoxical aggression), as well as the 
development of tolerance to anticonvulsant effects. 
Compounds binding to SV2A proteins on synaptic vesicles are characterized by broad-spectrum 
efficacy against both generalized and partial seizures in preclinical models, and this protective 
activity strongly correlates with their binding affinity (Kaminski et al, 2008). The function of 
SV2B and SV2C subtypes is not well established, but they share a high degree of sequence 
homology to SV2A and localization within synaptic vesicles (Wan et al, 2010; 
Janz and Südhof, 1999). Levetiracetam (LEV), exemplifying a SV2A-related mechanism of 
action, displays prominent clinical efficacy in patients with different forms of epilepsy 
(Klitgaard and Verdru, 2007). 
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Compounds with dual activity at SV2A and GABAA receptors are expected to have superior 
efficacy to those drugs working through only 1 of these mechanisms. Preclinical data in animal 
models of epilepsy support this assumption with compelling synergistic interaction observed 
between LEV and AEDs with GABAergic mechanisms of action (Kaminski et al, 2009). This 
synergistic interaction was particularly pronounced when combinations of LEV and 
benzodiazepines were tested and a significant increase in anticonvulsant potency of these drugs 
was observed associated with a higher therapeutic index. 
Padsevonil is a novel chemical entity with selective affinity for both presynaptic SV2 proteins and 
postsynaptic cBZR sites on the GABAA receptor. At presynaptic sites, PSL binds with high 
affinity to all 3 subtypes of the SV2 protein (ie, SV2A, SV2B, and SV2C), and with moderate 
affinity to postsynaptic cBZR sites. Pharmacological results obtained in rodent models of either 
partial or generalized seizures in humans show that PSL provides potent and efficacious seizure 
suppression, suggesting a broad spectrum profile. Furthermore, PSL revealed potent and 
efficacious seizure suppression in models of drug-refractory epilepsy, suggesting superior 
efficacy against seizures refractory to currently used AEDs. Specifically, in the rat amygdala 
kindling model, a model of refractory focal epilepsy, PSL was the only compound that produced 
seizure freedom at doses that can be administered in humans. Valproate, brivaracetam, 
clonazepam, diazepam, and phenobarbital only produced seizure freedom at plasma exposures 
that exceeded the maximum human exposures multiple times over. Padsevonil is not associated 
with loss of anticonvulsant efficacy after repeated administration in mice, suggesting reduced 
potential for the development of tolerance. Because of its unique properties, PSL is currently 
being proposed as adjunctive treatment for non-drug-resistant focal seizures in patients with 
epilepsy. 
2.3 
Benefit/risk assessment 
Overall, the clinical pharmacology and clinical studies in drug-resistant epilepsy demonstrated the 
AE profile of PSL is generally consistent with the pharmacological activity of the product, and as 
expected in the context of early dose-escalation studies in healthy study participants and patients 
with epilepsy. The safety findings to date suggest that the AEs experienced by study participants 
receiving single and repeated doses of PSL are limited principally to CNS effects. The AEs tend 
to be dose-related in frequency and intensity, self-limiting, and tend to decrease in intensity over 
the first few days of dosing. 
Reported acute psychiatric SAEs are consistent with adverse effects of other AEDs, including 
SV2A ligands. Events were transient, acute, and required admission to psychiatric care and 
medical treatment. The events in healthy study participants (n=2) occurred early after initiation or 
cessation of PSL which was done without titration or tapering. The psychotic effect in an epilepsy 
study participant (study EP0069) emerged after dramatic improvement in seizure control and 
electroencephalogram (EEG) activity a few weeks after the start of PSL, suggesting a “forced 
normalization” (Clemens, 2005, Loganathan et al, 2015). Dose reduction of PSL and medical 
treatment resulted in complete resolution of psychosis within days, as the treatment with PSL 
continued. The occurrence of acute psychiatric SAEs in these 3 study participants administered 
PSL highlights the need to consider the possibility of significant psychiatric adverse effects and to 
maintain a vigilance for such effects. The mitigation plan for acute psychiatric effects involves 
gradual titration and taper, which are known to improve tolerability of antiepileptic drugs and 
monitoring for psychiatric and mental status changes. 
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Despite the occurrence of several electrocardiogram (ECG) findings (including different types of 
ectopy) both in healthy study participants and study participants with epilepsy, an independent 
expert cardiologist reviewed data from Phase 1 and Phase 2 and determined that none of these 
findings were assessed as being likely to be related to PSL. No clinically significant 
echocardiographic findings (only minor/trace or Grade 1 findings) have been observed in studies 
EP0069 and EP0073 and all echocardiograms were assessed as normal. There are currently no 
data to suggest that the drug has an adverse effect on cardiovascular function other than a minimal 
lowering effect on blood pressure. The degrees of reduction seen in both systolic blood pressure 
(SBP) and diastolic blood pressure (DBP) are consistent with the GABAA-targeted mechanism of 
action of PSL and do not appear likely to have a clinically significant effect in therapeutic use. As 
a precaution, and in view of the nonclinical histopathological (microscopic) cardiac findings, 
echocardiogram screening of study participants at Baseline and ongoing echocardiogram 
monitoring during treatment and posttreatment have been implemented in the studies that have a 
>3 week treatment duration. To date, no clinically significant echocardiogram findings (only 
minor/trace or Grade 1 findings) have been observed. 
More detailed information about the known and expected benefits and risks and reasonably 
expected adverse events of PSL may be found in the Investigator’s Brochure (IB). The current IB 
reflects the safety profile of PSL as it is known and may change with the accumulation of 
additional data. 
The healthy study participants included in this study will receive no medical benefit from 
participation. The risks from taking part in the study will be minimized through the selection of 
appropriate dose levels, selection of appropriate study participants defined by the 
inclusion/exclusion criteria, and safety monitoring. 
3 
OBJECTIVES AND ENDPOINTS 
The objectives and corresponding endpoints for this study are presented in Table 3-1. 
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Table 3-1: 
Study objectives and endpoints 
Objectives 
Endpoints 
Primary 
 Part A: To evaluate the PD interaction 
between steady-state treatment with PSL 
and ethanol  
 Smooth pursuit (%) to assess eye 
movement coordination and attention 
 Part B: To evaluate the PK interaction 
between steady-state treatment with PSL 
and CBD 
 Cmax,ss and AUCτ obtained from the plasma 
concentration-time profiles for PSL and 
CBD 
Secondary 
 Part A: To evaluate the PK interaction 
between steady-state treatment with PSL 
and ethanol  
 Ethanol dose infused over time  
 Cmax,ss and AUCτ obtained from the plasma 
concentration-time profiles for PSL 
 Part B: To evaluate the PK interaction 
between steady-state treatment with PSL 
and CBD 
 t1/2, and CLss/F obtained from the plasma 
concentration-time profiles for PSL and 
CBD  
 Parts A and B: To evaluate the PD 
interaction between steady-state treatment 
with PSL and ethanol or between 
steady-state treatment with PSL and CBD 
 Smooth pursuit (%) to assess eye 
movement coordination and attention (Part 
B only) 
 Saccadic peak velocity (degrees/sec) to 
assess sedation 
 Adaptive tracking (%) to assess 
visuo-motor control and vigilance 
 Body Sway to assess postural stability 
 Parts A and B: To evaluate the safety and 
tolerability of PSL in study participants 
receiving concomitant ethanol or CBD 
 Adverse events (AEs), serious adverse 
events (SAEs), treatment-related AEs, and 
AEs leading to discontinuation of the 
study 
Other 
 Parts A and B: To evaluate the safety and 
tolerability of PSL in study participants 
receiving concomitant ethanol or CBD 
 Vital signs (pulse rate, respiratory rate, 
systolic blood pressure [SBP], and 
diastolic blood pressure [DBP]) 
 12-lead electrocardiogram (ECG) 
parameters  
 Physical examination findings 
 Clinical laboratory test results 
(hematology, clinical chemistry, and 
urinalysis) 
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 Parts A and B: To evaluate the PD 
interaction between steady-state treatment 
with PSL and ethanol or steady-state 
treatment with PSL and CBD 
 Visual analogue scales (VAS) Bond & 
Lader to assess study participantive 
alertness, mood, and calmness 
 VAS feeling high, internal and external 
perception (Bowdle) 
 VAS for alcohol intoxication to assess 
study participantive effects of ethanol 
(Part A only) 
 Part B: To evaluate the PK interaction 
between steady-state treatment with PSL 
and CBD 
 tmax obtained from the plasma 
concentration-time profiles for PSL and 
CBD 
 Cmax,ss, AUCτ, t1/2, tmax, and 
metabolite/parent (based on Cmax,ss and 
AUCτ) obtained from the plasma 
concentration-time profiles for PSL 
metabolites and CBD active metabolite 
 Part A and B: To collect and store blood 
for potential ADME genotype (if needed) 
 Possible ADME genotyping for drug 
metabolizing enzymes (depending on the 
outcome of PSL (and metabolite) PK 
analyses, if needed 
 Part A and B: To collect urine samples for 
additional PK analyses depending on the 
outcome of PSL (and metabolite) PK 
analyses, if needed 
 Urine sample PK analysis 
4 
STUDY DESIGN 
4.1 
Overall design 
This is a Phase 1, double-blind, randomized, placebo-controlled, single-center, cross-over study to 
evaluate the PK, PD, safety, and tolerability of steady state treatment of PSL in healthy study 
participants receiving either ethanol (Part A) or steady-state treatment of CBD (Part B). The study 
design is shown in Figure 1-1. 
A study participant who provides written informed consent will be screened within 28 days before 
the first Treatment Period in Part A or Part B. Study participants that complete Part A of the study 
are not eligible to complete Part B; similarly, study participants that complete Part B are not 
eligible to complete Part A. 
4.1.1 
Part A 
Treatment Periods 1 and 2, and 4 and 5 are 2-way cross-over, placebo-controlled, 
ethanol-clamping periods with a washout of at least 2 days between Treatment Periods 2 and 3; 
PSL is not administered in Treatment Periods 1 and 2. Treatment Period 3 is an open-label PSL 
up titration period toward a maintenance level of 200mg BID, and is immediately followed by 
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Treatment Period 4 and Treatment Period 5. Treatment Period 6 is the PSL tapering open-label 
period. See Section 1.3.1 for the schedule of activites for Part A. 
During each cross-over period, the study participant will check into the clinic the evening prior to 
the day of administration of ethanol/dummy infusion and PSL (Day -1). On Day 1 of Treatment 
Periods 1, 2, 4 and 5, a continuous infusion of ethanol or dummy infusion will begin with a 
30 minute loading phase and will continue for 5 hours. On Day 1 of Treatment Periods 4 and 5, 
PSL will be administered immediately after the end of the loading phase. 
During the first 10 minutes, the infusion will be accompanied by an infusion of 5% glucose via 
the same line in order to mask the sensation at the beginning of the ethanol infusion. The ethanol 
infusion rate is initially based on weight, height, age, and sex. The infusion rate is determined 
based on the Watson estimate of body water (Watson et al, 1980). Subsequently, the infusion rate 
will be adjusted based on breath ethanol measurements to maintain breath ethanol levels (and by 
extension, blood ethanol levels) of 0.6g/L. Following administration of PSL, the study participant 
will be observed for approximately 24 hours. 
4.1.2 
Part B 
Treatment Period 1 of Part B will be conducted in a sentinel cohort of healthy study participants 
in order to evaluate CBD safety and PK exposure under a single dose of CBD 10mg/kg (fasted 
conditions). The results of the PK analysis will be compared to published PK data of CBD (dose 
of 750mg in fasted conditions) obtained in similar conditions with Epidiolex® (Taylor et al, 2018). 
The decision to continue on with the rest of Part B or terminate the study following the first CBD 
dose in Treatment Period 1 of Part B will be made pending the outcome of the analysis of CBD 
safety and exposure. A difference between the PK results in the present study and the literature 
findings requiring a >2-fold dose adjustment will be considered as not manageable and would 
result in termination of the study. If a dose adjustement ≤2-fold is needed, then the study will 
proceed with the second dose of CBD of Treatment Period 1 in Part B. If the observed CBD 
exposure matches the data from the literature, then study will proceed directly to Treatment 
Period 2 of Part B (no second dosing of CBD will be required). Treatment Period 2 cannot 
commence until the results from Treatment Period 1 are analyzed. 
A washout of at least 6 days will occur between Treatment Period 1 and Treatment Period 2. 
Treatment Period 2 will include 7 days of treatment with open-label PSL treatment. Treatment 
Period 3 starts after a washout of minimally 6 days for all study participants, and includes an 
ambulatory open-label CBD up titration of 16 days toward a maintenance level of 10mg/kg BID. 
Treatment Periods 4 and 5 are 2-way cross-over, double-blind and placebo-controlled periods 
with PSL up titrated to a maintenance level of 200mg BID through Day 5 and subsequent down 
titration until Day 8. A maintenance dose of 10mg/kg BID CBD will occur in-house between 
Treatment Periods 4 and 5. Cannabidiol down titration starts in Treatment Period 6. 
Study participants will be discharged at the end of Treatment Period 6 and return for a SFU Visit 
7 to 10 days after the final dose of CBD. See Section 1.3.2 for the schedule of activities for 
Part B. 
 
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4.2 
Scientific rationale for study design 
4.2.1 
Part A 
Considering the CNS effect of ethanol, a PD interaction between PSL and ethanol is plausible. 
Nonetheless, it is difficult to predict the potential impact of the combination. However, knowing 
the elimination pathways of both PSL (mainly CYP3A4) and ethanol (CYP2E1, alcohol 
dehydrogenase) as well as their perpetrator profiles, it is unlikely that a PK interaction between 
PSL and ethanol will occur. 
The interaction between ethanol and PSL will be assessed under PSL at steady state. This is 
deemed to be more clinically relevant and should reduce the risk of having serious AEs when 
combined with ethanol. Indeed, healthy study participants have demonstrated better tolerability 
to PSL after 2 to 3 days of repeated dosing. A study in patients with epilepsy is not possible as 
most common AEDs have recommendations in their label regarding avoiding alcohol intake. 
4.2.2 
Part B 
Cannabidiol is a major chemical of marijuana that does not possess psychoactive properties. 
There seems to be a growing body of data suggesting there may be a role for CBD, especially in 
the treatment of refractory epilepsy (Devinsky et al, 2017; Devinsky et al, 2018). Cannabidiol is 
well tolerated in humans, with doses up to 600mg not resulting in psychotic symptoms (Taylor et 
al, 2018). Following single doses in humans, the half-life of CBD when taken orally is about 1 to 
2 days (Devinsky et al, 2014). In vitro studies have shown that CBD is a potent inhibitor of 
multiple CYP isozymes, including CYP2C19 and CYP3A4 (Zhornitsky and Potvin, 2012). As 
PSL and CBD share some of the same enzymatic pathways and aim to treat epilepsy populations, 
a clinical study investigating the potential PD and PK interactions would be useful. 
Padsevonil will be up titrated to a maintenance dose of 200mg BID (1 of the clinical doses 
administered in the global studies). Assessments will take place after 4 days of dosing to allow 
for maximum CYP2C19 inhibition. The PK of CBD will be evaluated in a sentinel cohort of at 
least 16 healthy study participants in Part B to assess the safety and exposure of CBD 
formulations prior to PSL dosing. 
4.3 
Justification for dose 
The dosages of PSL for this study will be 100mg, 100mg BID, and 200mg BID. These are 
several of the doses being evaluated in the late phase development program and, while lower 
than the maximum tolerated dose (MTD; 400mg BID), are considered adequate for the purposes 
of this study while not exposing healthy study participants to the MTD. 
4.3.1 
Part A 
Study participants will receive ethanol by infusion. The rate is initially based on weight, height, 
age, and sex. The infusion rate is determined based on the Watson estimate of body water with 
an average of approximately 60g ethanol/hour for the first 5 minutes and 45g ethanol/hour during 
the second 5 minutes in healthy male Caucasians. Subsequently, the infusion rate will be 
adjusted based on breath ethanol measurements to maintain breath ethanol levels (and by 
extension, blood ethanol levels) of 0.6g/L. 
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4.3.2 
Part B 
Study participants will take GMP Cannabidiol according to reference material. Cannabidiol will 
be provided as an oily solution (similar to Epidiolex®). The first single dose of CBD will be 
10mg/kg given in fasted conditions (Treatment Period 1). This dose level is a recommended dose 
for Epidiolex® for the treatment of seizure associated with Lennox-Gastaut syndrome or Dravet 
syndrome (Devinsky et al, 2017; Devinsky et al, 2018). Following analysis of safety and PK 
data, this dose may be adjusted (within 2-fold) to match published exposure data obtained with 
Epidiolex®. 
4.4 
End of study definition 
A study participant is considered to have completed the study if he/she has completed all phases 
of the study including the last scheduled procedure shown in the Schedule of Activities (see 
Section 1.3). 
The end of the study is defined as the date of last scheduled procedure shown in the Schedule of 
Activities for the last participant in the study. 
5 
STUDY POPULATION 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
5.1 
Inclusion criteria 
Participants are eligible to be included in the study only if all of the following criteria apply at 
Screening: 
Age 
1. Participant must be 18 to 55 years of age inclusive, at the time of signing the informed 
consent. 
Type of participant and disease characteristics 
2. Participants who are overtly healthy as determined by medical evaluation including medical 
history, physical examination, laboratory tests, and cardiac monitoring. 
Note: Study participant has clinical laboratory test results within the local reference ranges or 
values that are considered as not clinically relevant by the investigator and approved by the 
UCB Study Physician. Lab parameters outside the reference ranges can be retested and if the 
retest result is within the reference range or considered as clinically not relevant the study 
participant will be allowed in the study 
3. Participant must have previous experience with alcohol consumption and, therefore, must be 
familiar with the effects and able to tolerate social amounts of alcohol. 
Weight 
4. Participant has a body weight of at least 50kg (males) or 45kg (females) and body mass index 
(BMI) within the range 18 to 30kg/m2 (inclusive). 
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Sex 
5. Participants are male or female: 
 A male participant must agree to use contraception as detailed in Appendix 4 
(Section 10.4) of this protocol during the treatment period and for at least 7 days after the 
last dose of study treatment and refrain from donating sperm during this period until 
90 days after the last dose of study treatment. 
 A female participant is eligible to participate if she is not pregnant (see Appendix 4; 
Section 10.4), not breastfeeding, and at least 1 of the following conditions applies: 
◦ 
Not a woman of childbearing potential (WOCBP) as defined in Appendix 4 
(Section 10.4) 
OR 
A WOCBP who agrees to follow the contraceptive guidance in Appendix 4 
(Section 10.4) during the Treatment Period and for at least 90 days after the last dose 
of study treatment. 
Informed consent 
6. Participant must be capable of giving signed informed consent as described in Appendix 1 
(Section 10.1), which includes compliance with the requirements and restrictions listed in the 
informed consent form (ICF). 
7. Participant must be considered reliable and capable of adhering to the protocol, according to 
the judgment of the Investigator, and is capable of communicating satisfactorily with the 
Investigator. 
5.2 
Exclusion criteria 
Participants are excluded from the study if any of the following criteria apply: 
Medical conditions 
1. Participant has any medical or psychiatric condition that, in the opinion of the Investigator, 
could jeopardize or would compromise the study participant’s ability to participate in this 
study, such as a history of schizophrenia, or other psychotic disorder, bipolar disorder, or 
severe unipolar depression. The presence of potential psychiatric exclusion criteria will be 
determined based on the psychiatric history collected at the Screening Visit. 
2. Participant has history or presence of cardiovascular, respiratory, hepatic, renal, 
gastrointestinal, endocrinological, hematological, or neurological disorders capable of 
significantly altering the absorption, metabolism, or elimination of drugs; constituting a risk 
when taking the study intervention; or interfering with the interpretation of data. 
3. Participant has a history of chronic alcohol or drug abuse within the previous 6 months or the 
presence of drug or alcohol dependency at Screening or Day -1 or tests positive for alcohol 
and/or drugs at Screening or Day -1. In case a false positive is suspected, the alcohol or drug 
test may be repeated once. 
For the purposes of this study, history of chronic alcohol abuse is defined as an average 
weekly intake of more than 21 units or an average daily intake of more than 3 units (males), 
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or defined as an average weekly intake of more than 14 units or an average daily intake of 
more than 2 units (females). One unit is equivalent to a half-pint (220mL) of beer or 
1 measure (25mL) of spirits or 1 glass (125mL) of wine. 
4. Participant has a positive prestudy drug screen (to include at minimum: amphetamines, 
barbiturates, cocaine, opiates, cannabinoids and benzodiazepines). 
Note: A participant with a positive finding on the drug screen may still be enrolled at the 
discretion of the Investigator if a plausible clinical explanation exists (eg, prior or 
concomitant medication use). 
5. Participant has a known hypersensitivity to any components of the study medication or 
comparative drugs (and/or an investigational device) as stated in this protocol. 
6. Participant has abnormal blood pressure. 
Note: This includes both the routine and orthostatic hypotension BP assessments. For routine 
BP, participants must have blood pressure and PR within normal range in the supine position 
after 5 minutes rest (SBP: 90mmHg to 145mmHg; DBP: 40mmHg to 95mmHg; PR: 40bpm 
to 100bpm).  
Any values marginally (ie, no more than 5mmHg) outside the normal range but considered 
not clinically significant by the Investigator would be allowed. In case of an out of range 
result, 1 repeat will be allowed. If the readings are out of range again, the study participant 
will not be included. 
7. Participant has a lifetime history of suicide attempt (including an actual attempt, interrupted 
attempt, or aborted attempt), or has had suicidal ideation in the past 6 months as indicated by 
a positive response (“Yes”) to either Question 4 or Question 5 of the “Screening/Baseline” 
version of the C-SSRS at Screening. 
8. Participant has a history of unexplained syncope or a family history of sudden death due to 
long QT syndrome. 
9. Participant has lymphoma, leukemia, or any malignancy within the past 5 years except for 
basal cell or squamous epithelial carcinomas of the skin that have been resected with no 
evidence of metastatic disease for 3 years. 
Prior/concomitant therapy 
10. Participant has past or intended use of over-the-counter or prescription medication including 
herbal medications within 2 weeks or 5 half-lives prior to dosing. Specific medications listed 
in Section 6.5.1 may be allowed. 
11. Participant has used hepatic enzyme-inducing drugs (eg, glucocorticoids, phenobarbital, 
isoniazid, phenytoin, rifampicin etc.) within 2 months prior to dosing. In case of uncertainty, 
the Medical Monitor should be consulted. 
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Prior/concurrent clinical study experience 
12. Participant has previously received PSL in this or any another study. 
13. Participant has participated in another study of an IMP (and/or an investigational device) 
within the previous 30 days of Screening or 5 half-lives whichever is longer or is currently 
participating in another study of an IMP (and/or an investigational device). 
Diagnostic assessments 
14. Participant has alanine transaminase (ALT), aspartate aminotransferase (AST), or alkaline 
phosphatase (ALP) >1.0x upper limit of normal (ULN). 
For randomized study participants with a Baseline result >ULN for ALT, AST, ALP, or total 
bilirubin, a Baseline diagnosis and/or the cause of any clinically meaningful elevation must 
be understood and recorded in the electronic Case Report form (eCRF). 
If study participant has >ULN ALT, AST, or ALP that does not meet the exclusion limit at 
Screening, repeat the tests, if possible, prior to dosing to ensure there is no further ongoing 
clinically relevant increase. In case of a clinically relevant increase, inclusion of the study 
participant must be discussed with the Medical Monitor. 
Tests that result in ALT, AST, or ALP up to 25% above the exclusion limit may be repeated 
once for confirmation. This includes re-screening. 
15. Participant has bilirubin >1.0xULN (isolated bilirubin >1.0xULN is acceptable if bilirubin is 
fractionated and direct bilirubin <35%). 
16. Participant has current or chronic history of liver disease or known hepatic or biliary 
abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones). 
17. Participant has any clinically relevant ECG finding at the Screening Visit or at Baseline. 
Study participant has an abnormality in the 12-lead ECG that, in the opinion of the 
Investigator, increases the risks associated with participating in the study. In addition, any 
study participant with any of the following findings will be excluded: (a) QT interval 
corrected for heart rate using Bazett’s formula (QTcB) or Fridericia’s formula (QTcF) 
>450ms in participants in 2 of 3 ECG recordings; (b) other conduction abnormalities (defined 
as PR interval ≥220ms); (c) irregular rhythms other than sinus arrhythmia or occasional, rare 
supraventricular or rare ventricular ectopic beats. In case of an out of range result, 1 repeat 
will be allowed. If out of range again, the study participant cannot be included. 
NOTE A: The QTc is the QT interval corrected for heart rate according to Bazett’s formula 
(QTcB), Fridericia’s formula (QTcF), and/or another method. It is either machine-read or 
manually over-read. 
NOTE B: The specific formula used to determine eligibility and discontinuation for an 
individual participant should be determined prior to initiation of the study. In other words, 
several different formulas cannot be used to calculate the QTc for an individual participant 
and then the lowest QTc value used to include or discontinue the participant. 
18. Participant has other clinical laboratory test results outside the local reference ranges that are 
considered as clinically significant by the Investigator. In the case of uncertainty, lab 
parameters outside the reference ranges can be retested once. If lab parameters outside the 
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reference range are considered as clinically insignificant, the study participant may be 
allowed in the study, but such inclusions should be agreed with the UCB Study Physician. 
19. Participant has the presence of hepatitis B surface antigen (HBsAg) at Screening. 
20. Participant has a positive hepatitis C antibody test result at Screening.  NOTE: Participants 
with positive Hepatitis C antibody due to prior resolved disease can be enrolled if a 
confirmatory negative Hepatitis C ribonucleic acid (RNA) test is obtained 
21. Participant has a positive human immunodeficiency virus (HIV) antibody test at Screening. 
Other exclusions 
22. Participant has made a blood or plasma donation or has had a comparable blood loss 
(>450mL) within the last 90 days prior to the Screening Visit. Blood donation during the 
study is not permitted. 
23. Participant has a consumption of more than 600mg of caffeine/day (200mL of coffee 
contains approximately 100mg of caffeine, 200mL of black tea approximately 30mg, and 
200mL of cola approximately 20mg). 
24. Participant smokes more than 5 cigarettes per day (or equivalent) or has done so within 
6 months prior to the Screening Visit. Smoking within 48 hours prior to CNS assessments is 
prohibited. 
25. Participant ingests grapefruit, passion fruit, or pawpaw (as beverage, fruit, or supplements) 
within 72 hours before each administration of IMP. If this is the case at the start of the study, 
study participants may be rescreened. 
26. Female participants tests positive for pregnancy, plans to get pregnant during the 
participation in the study, or who is breastfeeding. 
27. Study participant has a diet that deviates notably from the “normal” amounts of protein, 
carbohydrate, and fat, as judged by the Investigator. 
28. Study participant has undergone sudden and/or extreme changes in exercise levels for 
2 weeks prior to Screening Visit. 
5.3 
Lifestyle restrictions 
5.3.1 
Meals and dietary restrictions 
 Study participants will complete a light meal approximately 30 minutes prior to each 
morning dose of CBD/PSL administration and will complete a standard meal approximately 
30 minutes prior to the evening dose. On days when PK assessments will be taken, study 
participants will complete a similar meal between periods. 
 Study participants will complete assessments on the morning of Day 1 and Day 15 of 
Treatment Period 1 (Part B) and at Screening under fasting conditions. 
 Study participants should keep their usual diet (besides the restrictions for the study) 
necessary for the maintenance of good health; excessive food consumption should be 
avoided. 
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 Padsevonil will be administered orally with 8oz (240mL) of water. Between 1 hour predose 
and 2 hours postdose, the total intake of beverages should be limited to 100mL. Water will be 
available ad libitum except for between 1 hour before and 2 hours after dosing. 
 Study participants should refrain from consumption of grapefruit, starfruit, and pawpaw (as 
beverage, fruit or supplements) from 3 days before the start of study treatment until after the 
final dose. 
5.3.2 
Caffeine, alcohol, and tobacco 
 During each dosing session, participants will abstain from ingesting caffeine- or 
xanthine-containing products (eg, coffee, tea, cola drinks, and chocolate) for 48 hours before 
the start of dosing until after collection of the final PK and/or PD sample. 
 During each dosing session, participants will abstain from alcohol for 24 hours before the 
start of dosing until after collection of the final PK and/or PD sample. 
 Participants who use tobacco products will be instructed that use of nicotine-containing 
products (including nicotine patches) will not be permitted while they are in the clinical unit. 
5.3.3 
Activity 
 Participants will abstain from strenuous exercise from 3 days prior to visit and during the 
study. Participants may participate in light recreational activities during the study 
(eg, watching television, reading, and playing table tennis). 
5.4 
Screen failures 
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently entered in the study. A minimal set of screen failure information is required to 
ensure transparent reporting of screen failure participants to meet the Consolidated Standards of 
Reporting Trials (CONSORT) publishing requirements and to respond to queries from regulatory 
authorities. Minimal information includes demography, screen failure details, eligibility criteria, 
and any SAE. 
5.4.1 
Rescreening 
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened. Study participants may be rescreened under conditions such as the following: 
 Study participant ingests grapefruit (as beverage, fruit, or supplements) within 72 hours 
before each administration of IMP. 
 Study participant has a suspected false positive drug test. 
 Study participant has a non-clinically significant vital signs measurement. 
 If a study participant does meets the exclusion criteria at Screening or on Day -1 due to an 
out-of-range laboratory result or a minor illness, he/she can be rescreened once at the 
discretion of the Investigator. Provided all inclusion criteria are met at the second Screening, 
the study participant can be included. 
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Study participants may be included if the repeat values for the laboratory screening criteria are 
within normal ranges and/or if repeat values show normalization of the out-of-range safety 
laboratory values, and/or after the study participant makes a complete recovery from the mild or 
moderate illness and if all other screening criteria are met. 
Tests that result in ALT, AST, or ALP up to 25% above the exclusion limit may be repeated 
once for confirmation. This includes re-screening. 
Rescreened participants will be assigned a new participant number. 
6 
STUDY TREATMENTS 
Study treatment is defined as any investigational treatment(s), marketed product(s), placebo, or 
medical device(s) intended to be administered to a study participant according to the study 
protocol. 
6.1 
Treatments administered 
A summary of the treatments administered is provided in Table 6-1. Further Guidance or 
information are provided in the IMP Handling Manual. 
 
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Table 6-1: 
Treatments administered 
Study Treatment 
Name: 
PSL 
Placebo (for 
PSL) 
Ethanol 
Placebo (for ethanol) 
infusion 
CBD 
Dosage formulation: 
Tablets 
Matching PBO 
tablets 
IV infusion 
IV infusion 
Solution/suspension 
Unit dose 
strength(s)/Dosage 
level(s): 
100mg, 
100mg BID, 
200mg BID 
Matching PBO 
tablets 
Alcohol 10% in Glucose 
5%; Adjusted to maintain 
breath ethanol levels of 
0.6g/L 
Glucose 5%; 
275mmol/L in bag of 
500mL 
Up to 10mg/kg BID a 
Route of 
Administration 
Oral 
Oral 
Infusion 
Infusion 
Oral 
Dosing instructions: 
Dosing instructions are provided in the “UP0071 IMP Handling Manual” (IP Instruction for Handling). 
Packaging and 
Labeling 
PSL and matching PBO tablets are 
manufactured, packaged, and 
labeled according to Good 
Manufacturing Practice guidelines 
and applicable laws or regulations. 
Ethanol and matching PBO are manufactured, 
packaged, and labeled according to Good 
Manufacturing Practice guidelines and applicable 
laws or regulations. 
CBD is manufactured, 
packaged, and labeled 
according to Good 
Manufacturing Practice 
guidelines and 
applicable laws or 
regulations. 
Manufacturer 
UCB 
UCB 
LUMC 
LUMC 
EchoPharma 
BID=twice per day; CBD=cannabidiol; h=hours; IP=investigational product; PBO=placebo; PK=pharmacokinetic. PSL=padsevonil; SmPC=Summary of 
Product Characteristics 
a Doses to be confirmed from CBD PK exposure in Part B, Treatment Period 1. 
 
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6.2 
Preparation, handling, storage, and accountability requirements 
The Investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study treatment received and any discrepancies are reported and 
resolved before use of the study treatment. 
Only participants enrolled in the study may receive study treatment and only authorized site staff 
may supply or administer study treatment. All study treatments must be stored in a secure, 
environmentally controlled, and monitored (manual or automated) area in accordance with the 
labeled storage conditions with access limited to the Investigator and authorized site staff. 
The Investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study treatment accountability, reconciliation, and record maintenance 
(ie, receipt, reconciliation, and final disposition records). 
In case an out-of-range temperature is noted, it must be immediately reported as per instructions 
contained in the IMP Handling Manual. 
Further guidance and information for the final disposition of unused study treatment are provided 
in the “UP0071 IMP Handling Manual” (IP Instruction for Handling). 
6.2.1 
Drug accountability 
A Drug Accountability form will be used to record study medication dispensing and return 
information on a by-participant basis and will serve as source documentation during the course 
of the study. Details of any study medication lost, damaged (due to breakage or wastage), not 
used, partially used, disposed of at the study site, or returned to the Sponsor or designee must 
also be recorded on the appropriate forms. All supplies and pharmacy documentation must be 
made available throughout the study for UCB (or designee) to review. 
The Investigator (or designee) is responsible for retaining all used, unused, and partially used 
containers of study medication until returned or destroyed. 
The Investigator may assign some of the Investigator’s duties for drug accountability at the study 
site to an appropriate pharmacist/designee. 
The Investigator must ensure that the study medication is used only in accordance with the 
protocol. 
Periodically, and/or after completion of the clinical phase of the study, all used (including empty 
containers)/partially used, unused, damaged, and/or expired study medication must be reconciled 
and either destroyed at the site according to local laws, regulations, and UCB SOPs or returned 
to UCB (or designee). Investigational medicinal product intended for the study cannot be used 
for any other purpose than that described in this protocol. 
6.3 
Measures to minimize bias: randomization and blinding 
A contract research organization (CRO; ie, ICON) randomization biostatistician will create the 
program to generate the randomization code and code break envelopes for each study part. The 
randomization biostatistician will be independent of the study. A dummy randomization schedule 
will be prepared by the randomization biostatistician (for Part A: cross-over 2x2 scheme with 
4 treatment sequences; for Part B: cross-over 2x2 scheme with 2 treatment sequences) and 
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reviewed by the Clinical Study Biostatistician in order to ensure that the code meets the study 
requirements. 
After finalization of the dummy code, the randomization program will be run with a different 
seed number to create the final randomization list; the final list will be generated in a secure 
environment and will be reviewed by a quality control randomization biostatistician, also 
independent of the study. These randomization lists (list of Part A and list of Part B) will be 
retained by ICON until the end of the study (ie, until after database lock). The treatment 
assignment will be random. 
Copies of the randomization lists will be sent before the start of the study in a secure fashion 
directly from the contracted CRO to: 
 Sponsor Patient Safety staff for SAE reporting (sealed envelope) 
 Bioanalytical staff (to identify samples to be measured) 
 Unblinded member of pharmacy involved in IMP preparation and dispensing or site 
quality/safety insurance 
 Independent Biostatistician/Early Statistical Programmer 
In addition, staff involved in the analysis of unblinded PK data, such as a representative from the 
UCB Clinical Pharmacology/Modeling and Simulation team and an unblinded monitor, will have 
access to the unblinded data during the study. 
After eligibility of a participant has been confirmed, the study participants may be included and 
assigned to a subject number from 1 to 22 in Part A. Replacement study participants will be 
numbered +100 (eg, Study participant 5 will have Study participant 105 as replacement). 
Similarly, for Part B, eligible study participant may be included and assigned a study participant 
number from 1001 to 1022. Replacement subjects will be numbered +100, e.g. Study 
participant 1005 will have Study participant 1105 as replacement. 
In Part A and Part B, each study participant (screen failure and eligible) will receive a unique 
5 digit UCB number assigned at Screening from a range of numbers supplied by UCB Clinical 
Data Operations, Technology, and Standards, which will serve as the UCB study participant 
identifier throughout the study. 
Study participants that complete Part A of the study are not eligible to complete Part B; 
similarly, study participants that complete Part B are not eligible to complete Part A. 
Once the Investigator determines that the study participant is eligible for the study, and before 
IMP administration, a central person in charge of issuing the randomization numbers will 
manually allocate a randomization number to the study participant (1 for each study part) and 
communicate the randomization assignment to the unblinded site pharmacist. Each specific 
randomization number will be linked to the treatment allocation on the randomization schedule, 
which will be dispensed by the unblinded site pharmacist. The randomization numbers will also 
be recorded in the eCRF. 
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6.3.1 
Procedures for maintaining and breaking the treatment blind 
6.3.1.1 
Maintenance of treatment blind 
All participant treatment details (treatments, Treatment Period, and treatment sequences) will be 
allocated and maintained through the use of randomization lists and emergency envelopes (or 
equivalent). The investigator and all study site personel will be blinded to treatment assignments 
during the study. 
6.3.1.1.1 
Ethanol and matching placebo 
To maintain blinding with respect to ethanol (ethanol 10% w/v solution in 5% glucose) and 
ethanol placebo (5% glucose), an individual who is not a member of the study team (has no 
responsibilities for study participant assessments) will obtain breath ethanol concentrations and 
adjust the infusion rate accordingly. For study participants randomized to ethanol, the infusion 
assistant will use actual breath ethanol concentration measurements to adjust the infusion rate 
according to an algorithm. For study participants randomized to placebo, the infusion assistant 
will use sham breath ethanol concentrations prepared prior to the study to make sham 
adjustments to the infusion rate. 
6.3.1.1.2 
PSL and matching placebo 
A site pharmacist who is not a member of the study team (has no responsibilities for study 
participant assessments) will prepare PSL or PSL placebo treatment from bulk supplies in 
accordance with the randomization schedule supplied by the ICON unblinded Statistician. 
6.3.1.2 
Breaking the treatment blind in an emergency situation 
An emergency envelope (or equivalent) containing the randomization code will be printed for 
each participant in a double-blind study and must not be broken, except for emergency situations. 
The CPM must be informed immediately when a code is broken, but should remain blinded to 
specific treatment information. Any unblinding of the study medication performed by the 
Investigator must be recorded in the source documents and on the Study Termination eCRF 
page. 
6.4 
Treatment compliance 
Study participant compliance will be ensured by the administration of IMP by designated site 
personnel. Drug accountability must be recorded on the Drug Accountability form. 
6.5 
Concomitant medication(s)/treatment(s) 
6.5.1 
Permitted concomitant treatments (medications and therapies) 
The following concomitant medications are permitted during the study: 
 Paracetamol for the treatment of mild symptoms (eg, headache or other pain), given at most 
every 6h to 8h, not exceeding 2g/day, and with a total of no more than 5g over 7 days 
 Inhaled corticosteroids for seasonal rhinitis 
 Oral contraceptives not exceeding 30μg ethinyl estradiol or postmenopausal hormone 
replacement therapy or implants, patches, or IUDs/IUSs delivering progesterone (for female 
study participants 
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6.5.2 
Prohibited concomitant treatments (medications and therapies) 
The following concomitant medications are prohibited during the study: 
 With the exception of permitted concomitant treatments listed in Section 6.5.1, all 
prescription or nonprescription medicines are prohibited within 2 weeks or 5 half-lives 
whichever is longer of the respective drug prior to first administration of IMP and during the 
clinical part of the study unless required to treat an AE. This includes all OTC remedies, 
vitamins, and herbal and dietary supplements (including St. John’s Wort). 
 Hepatic enzyme-inducing drugs (eg, glucocorticoids, phenobarbital, isoniazid, phenytoin, 
rifampicin etc.) should not be used within 2 months prior to dosing. In case of 
uncertainty, the Medical Monitor should be consulted. 
 Drugs of unknown half-lives are prohibited within 2 weeks before administration of IMP and 
during the clinical part of the study, unless required to treat an AE. 
If a study participant needs or takes any prohibited medication, the Investigator will (where 
possible) discuss with the Sponsor Study Physician and a decision will be made whether the 
study participant can continue in the study or must be withdrawn. 
6.5.3 
Rescue medication 
Not applicable. 
6.6 
Dose modification 
Dose modifications, in accordance with the Investigator and/or Sponsor, are permitted during the 
study for PSL and cannabidiol for an individual study participant. During the ethanol/placebo 
infusion, the infusion rate will be adjusted based on ethanol breath sampling. 
6.7 
Treatment after the end of the study 
There are no plans for participant treatment after the end of the study. 
7 
DISCONTINUATION OF STUDY MEDICATION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
7.1 
Discontinuation of study medication 
Study medication will be stopped if the study participant develops a medical condition (or 
laboratory abnormality or ECG change) that, in the opinion of the Investigator, compromises the 
study participant’s ability to participate or compromises the study participant’s safety. 
In all cases the study participant should be followed until the condition has resolved as agreed by 
the Investigator and the UCB Study Physician. If a participant discontinues study medication, no 
restart will be allowed. 
7.1.1 
Liver chemistry stopping criteria 
Discontinuation of study treatment for abnormal liver function should be considered by the 
Investigator when a participant meets 1 of the conditions outlined in Figure 7-1 or if the 
Investigator believes that it is in best interest of the participant. 
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Study medication will be discontinued immediately and permanently for a participant if liver 
chemistry stopping criteria are met. 
Figure 7-1: Liver chemistry stopping algorithm 
 
ALT=alanine aminotransferase; INR=international normalized ratio; SAE=serious adverse event; ULN=upper limit 
of normal. 
Specific assessments and follow-up actions for potential drug-induced liver injury are provided 
in Appendix 6 (Section 10.6). 
7.1.2 
Temporary discontinuation 
If a participant discontinues study medication, no restart will be allowed. 
7.1.3 
Criteria for study hold due to adverse events 
In recognition of the advanced status of the development program for PSL, the following 
hold/stopping rules will apply to this study. 
In the event that either or both of the following criteria are met a safety review will be 
immediately initiated: 
 The occurrence of a serious, unexpectedadverse reaction (ie, an SAE considered at least 
possibly related to the study medication) in 2 study participants, where those serious adverse 
reactions occur in the same body system. 
 The occurrence of a severe nonserious adverse reaction (ie, severe nonserious AEs 
considered at least possibly related to the study medication) in 3 study participants, where 
those severe adverse reactions: 
 Occur in the same body system, and 
Refer to the Liver Safety Required Actions and Follow up Assessments section in Appendix 6. 
Report as an SAE if possible Hy’s Law case: AST/ALT ≥3xULN and Bilirubin ≥2xULN 
(>35% direct) or INR>1.5, if measured 
(Note: INR value not applicable to patients on anticoagulants) 
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 Lead to withdrawal of the affected participant 
The safety review will be conducted by an internal, study-specific Safety Monitoring Committee 
comprising comprised of the Investigator and appropriate members of the UCB Study Team 
(such as Study Physician, Safety Physician, Clinical Project Manager, and Clinical 
Pharmacologist), as quickly as possible, to review the available data and determine whether it is 
appropriate to continue dosing at the next scheduled dosing point. This will take the form of a 
risk/benefit evaluation from the perspective of the individual study participants. In making this 
evaluation, account will be taken of the potential risks of sudden discontinuation of study 
medication, particularly in participants who may be taking higher dose levels, and whether or not 
a taper off tapering period, and its duration / speed, should be undertaken. 
If the Safety Monitoring Committee cannot be convened before the next scheduled dosing point, 
the Investigator will make an independent evaluation as to whether it is appropriate to continue 
dosing pending the review.   
The Safety Monitoring Committee will also decide whether it is appropriate to continue the study 
with or without dose adaptations, additional safety assessments, or other changes in design. If 
such changes are deemed necessary to protect the wellbeing of participants, further dosing in the 
study will be suspended while a substantial amendment is submitted to the Country(ies) Health 
Authority and Research Ethics Committee(s) and the study will not restart until that amendment 
has been approved. 
Detailed procedures for reporting SAEs and other safety events which may meet study 
hold/stopping criteria are provided in Appendix 3 (Section 10.3). 
7.2 
Participant discontinuation/withdrawal from the study 
Study participants are free to withdraw from the study at any time, without prejudice to their 
continued care. 
A study participant may withdraw from the study at any time at his/her own request, or may be 
withdrawn at any time at the discretion of the Investigator for safety, behavioral, compliance, or 
administrative reasons. 
If the study participant withdraws consent for disclosure of future information, the Sponsor may 
retain and continue to use any data collected before such a withdrawal of consent. 
If a study participant withdraws from the study, he/she may request destruction of any samples 
taken and not tested, and the Investigator must document this in the site study records. 
See the Schedule of Activities for data to be collected at the time of study discontinuation and 
follow up and for any further evaluations that need to be completed. 
Study participants should be withdrawn from the study if any of the following events occur: 
1. The study participant develops a clinically relevant medical condition (physical or 
psychiatric) that, in the opinion of the Investigator, jeopardizes or compromises the study 
participant’s ability to participate in the study or makes it unsafe to continue. 
2. Study participant is noncompliant with the study procedures or medications in the opinion of 
the Investigator. 
3. Study participant takes prohibited concomitant medications as defined in this protocol. 
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4. Study participant withdraws his/her consent. 
5. There is confirmation of a pregnancy during the study, as evidenced by a positive pregnancy 
test. 
6. The Sponsor or a regulatory agency requests withdrawal of the participant. 
7. Study participant has changes in the ECG that are regarded as clinically significant and/or 
that worsen over time. An ECG shows an absolute confirmed value for QTcB or QTcF 
≥500ms or ≥60ms above Baseline. 
8. Study participant develops second- or third-degree atrioventricular block or another clinically 
relevant change in ECG as determined by the Investigator. 
9. Study participant has active suicidal ideation without a specific plan as indicated by a 
positive response ("Yes") to Question 4 of the "Since Last Visit" version of the C-SSRS. The 
study participant should be referred immediately to a mental healthcare professional and may 
be withdrawn from the study based upon the Investigator's judgment of the benefit/risk ratio 
of continuing the study participant in the study on PSL. 
 Study participant has active suicidal ideation with a specific plan as indicated by a 
positive response ("Yes") to Question 5 of the "Since Last Visit" version of the C-SSRS. 
The study participant should be referred immediately to a mental healthcare professional 
and must be withdrawn from the study. 
10. Study participant is suspected of having a serious multiorgan hypersensitivity reaction. 
Serious suspected multiorgan hypersensitivity cases may be identified and reported to the 
Sponsor by the Investigator using the following algorithm: 
 An AE or laboratory value (as defined below) suggestive of internal organ involvement 
including but not limited to hepatitis, nephritis, pneumonitis, carditis, colitis, encephalitis, 
pancreatitis, myositis, arthritis, or hematologic system involvement combined with at 
least 1 of the following: fever, rash, lymphadenopathy, or eosinophilia. 
 Treatment-emergent abnormal laboratory value criteria suggestive of internal organ 
involvement or eosinophilia: 
 Eosinophils percentage ≥10% 
 Eosinophils absolute ≥0.5G/L 
 Neutrophils absolute <1.5G/L 
 Platelets absolute ≤100G/L 
Withdrawn particpants should follow the taper schedule if possible unless faster discontinuation 
is considered necessary in the medical judgement of the Investigator. Investigators should 
attempt to obtain information on study participants in the case of withdrawal. 
For study participants considered as lost to follow up, the Investigator should make an effort (at 
least 1 phone call and 1 written message to the study participant), and document his/her effort 
(date and summary of the phone call and copy of the written message in the source documents), 
to complete the final evaluation. All results of these evaluations and observations, together with a 
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narrative description of the reason(s) for removing the study participant, must be recorded in the 
source documents. The eCRF must document the primary reason for withdrawal. 
Investigators should contact the Medical Monitor, whenever possible, to discuss the withdrawal 
of a study participant in advance. 
Study particpants withdrawn will be replaced at the discretion of the Investigator and Sponsor. 
7.3 
Lost to follow up 
A study participant will be considered lost to follow up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit: 
 The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the study participant wishes to and/or should continue 
in the study. 
 Before a study participant is deemed lost to follow up, the Investigator or designee must 
make every effort to regain contact with the study participant (at least 1 phone call and 
1 written message to the study participant), and document his/her effort (date and summary 
of the phone call and copy of the written message in the source documents), to complete the 
final evaluation. All results of these evaluations and observations, together with a narrative 
description of the reason(s) for removing the study participant, must be recorded in the 
source documents. The eCRF must document the primary reason for withdrawal. 
Should the study participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study with a primary reason of lost to follow up documented in the eCRF. 
8 
STUDY ASSESSMENTS AND PROCEDURES 
Study procedures and their timing are summarized in the Schedule of Activities (Section 1.3). 
Protocol waivers or exemptions are not allowed. 
Immediate safety concerns should be discussed with the Sponsor immediately upon occurrence 
or awareness to determine if the participant should continue or discontinue study treatment. 
Adherence to the study design requirements, including those specified in the Schedule of 
Activities (Section 1.3), is essential and required for study conduct. 
All screening evaluations must be completed and reviewed to confirm that potential study 
participants meet all eligibility criteria. The Investigator will maintain a screening log to record 
details of all study participants screened and to confirm eligibility or record reasons for screening 
failure, as applicable. 
The maximum amount of blood collected from each study participant over the duration of the 
study, including any extra assessments that may be required, will not exceed 500mL per study 
participant. Repeat or unscheduled samples may be taken for safety reasons or for technical 
issues with the samples. 
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8.1 
Efficacy assessments 
Not applicable. 
8.2 
Safety assessments 
The safety and tolerability of repeated doses of PSL when co-administered with single dose of 
ethanol or in the setting of stable concomitant therapy with CBD will be monitored by evaluation 
of AEs, vital signs (pulse rate, body temperature, respiratory rate, SBP, and DBP), 12-lead ECG 
parameters, psychiatric and mental status findings, physical examination findings, clinical 
laboratory test results, and suicidal risk monitoring. Planned time points for all safety 
assessments are provided in the Schedule of Activities (Section 1.3). 
8.2.1 
Physical examination 
Physical examinations will be performed at Screening at the time points specified in Section 1.3. 
A complete physical examination will be performed at Screening and will include, at a 
minimum, general appearance; ear, nose, and throat; eyes, hair, and skin; assessments of the 
Cardiovascular, Respiratory, Gastrointestinal, Neurological, Musculoskeletal, and Hepatic 
systems; and mental status. Height and weight will also be measured and recorded. 
A brief physical examination will be performed at the time points specified in Section 1.3. A 
brief physical examination will include, at a minimum, assessments of general appearance, skin, 
lungs, cardiovascular system, and mental status. 
Investigators should pay special attention to clinical signs related to previous serious illnesses. 
Clinically relevant findings or worsening of previous findings will be recorded as AEs. 
8.2.2 
Vital signs 
Body temperature, pulse rate, respiratory rate, and blood pressure will be assessed as outlined in 
the Schedule of Activities (see Section 1.3). 
Temperature may be measured by either oral or aural route at the discretion of the site, but must 
be performed using the same method in any individual participant on all occasions. 
Blood pressure measurements will be performed in both supine and standing positions for 
orthostatic measurement at Screening (supine BP after the participant has been lying down for 
5 minutes, then standing BP after 1 minute and 3 minutes), and in a supine position for routine 
blood pressure measurements at all assessments. Blood pressure and pulse measurements will be 
assessed with a completely automated device. Manual techniques will be used only if an 
automated device is not available. 
Blood pressure and pulse measurements should be preceded by at least 5 minutes of rest for the 
participant in a quiet setting without distractions (eg, television, cell phones). 
Vital signs (to be taken before blood collection for laboratory tests) will consist of 1 pulse and 
1 blood pressure measurement. 
8.2.3 
Electrocardiograms 
Triplicate 12-lead ECG will be obtained as outlined in the Schedule of Activities (see 
Section 1.3) using an ECG machine that automatically calculates the heart rate and measures PR, 
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QRS, QT, and QTc intervals. Refer to Section 7 for QTc withdrawal criteria and any additional 
QTc readings that may be necessary. 
All ECG recordings should be taken with the study participant resting in the supine position for 
at least for ≥5 minutes before the recording. 
At each time point at which triplicate ECG are required, 3 individual ECG tracings should be 
obtained as closely as possible in succession, but no more than 2 minutes apart. The full set of 
triplicates should be completed in less than 4 minutes. 
8.2.4 
Clinical safety laboratory assessments 
See Appendix 2 (Section 10.2) for the list of clinical laboratory tests to be performed and to the 
Schedule of Activities for the timing and frequency. 
The Investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the eCRF. The 
laboratory reports must be filed with the source documents. Clinically significant abnormal 
laboratory findings are laboratory findings that change considerably or their frequency or 
intensity increases more than expected as compared to the clinical profile known to the 
Investigator from the study participant’s history or Screening Period. 
All laboratory tests with values considered clinically significantly abnormal during participation 
in the study or at the Follow-up Visit of study medication should be repeated until the values 
return to normal or Baseline or are no longer considered clinically significant by the Investigator 
or medical monitor. 
If such values do not return to normal or Baseline within a period of time judged reasonable by 
the Investigator, the etiology should be identified and the Sponsor notified. 
All protocol-required laboratory assessments, as defined in Appendix 2 (Section 10.2), must be 
conducted in accordance with the laboratory manual or equivalent document and the Schedule of 
Activities. 
If laboratory values from nonprotocol specified laboratory assessments performed at the 
institution’s local laboratory require a change in participant management or are considered 
clinically significant by the Investigator (eg, SAE or AE or dose modification), then the results 
must be recorded in the eCRF. 
8.2.5 
Suicidal risk monitoring 
Padsevonil is considered to be an AED. Suicidal ideation and behavior have been reported in 
patients treated with antiepileptic agents in several indications. A meta-analysis of randomized 
placebo-controlled studies of AEDs has also shown a small increased risk of suicidal ideation 
and behavior. The mechanism of this risk is not known and the available data do not exclude the 
possibility of an increased risk for PSL. 
Suicidality will be assessed by trained study personnel using the C-SSRS (Columbia Univerity 
Medical Center, 2008). This scale will be used for screening as well as to assess suicidal ideation 
and behavior that may occur during the study. At the Screening Visit, “Baseline/Screening” 
version of the C-SSRS will be completed. At all other visits, “Since Last Visit” version of the 
C-SSRS will be completed as indicated on the Schedule of Activities (Section 1.3). 
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Participants being treated with PSL should be monitored appropriately and observed closely for 
suicidal ideation and behavior or any other unusual changes in behavior. Families and caregivers 
of participants being treated with PSL should be instructed to monitor participants for the 
emergence of unusual changes in behavior, as well as the emergence of suicidal ideation and 
behavior, and to report such symptoms immediately to the study Investigator. Consideration 
should be given to discontinuing PSL in participants who experience signs of suicidal ideation or 
behavior. 
8.2.6 
Psychiatric and mental status 
Psychiatric and mental status will be assessed at Baseline and scheduled visits as specified in 
Section 1.3. 
The psychiatric and mental status of participating subjects will be closely monitored. Assessment 
of specific domains of psychiatric and cognitive symptoms will be performed by a staff member 
trained in the identification of psychiatric symptoms. The parameters that will be evaluated are 
Psychiatric symptoms, mental impairment and behavioral problem (as orientation, attention, 
memory, mood, calculus, behavior, and thinking or feeling). These parameters will be assessed 
as normal or abnormal and then determined whether clinically significant. If present and 
abnormal, psychiatric symptoms, mental impairment, and behavioral problems will be assessed 
as to whether they are clinically significant. 
8.3 
Adverse events 
The definitions of an AE or SAE can be found in Appendix 3 (Section 10.3). 
Adverse events will be reported by the participant (or, when appropriate, by a caregiver, 
surrogate, or the participant's legally authorized representative). 
The Investigator and any designees are responsible for detecting, documenting, and recording 
events that meet the definition of an AE or SAE and remain responsible for following up AEs 
that are serious, considered related to the study treatment or study procedures, or that caused the 
participant to discontinue PSL or UP0071 (see Section 7). 
8.3.1 
Time period and frequency for collecting AE and SAE information 
All AEs and SAEs will be collected from the signing of the ICF and at the time points specified 
in the Schedule of Activities (Section 1.3). 
Medical occurrences that begin before the start of study treatment but after obtaining informed 
consent will be recorded on the Medical History/Current Medical Conditions section of the 
eCRF, not the AE section. 
All SAEs will be recorded and reported to the Sponsor or designee within 24 hours, as indicated 
in Appendix 4. The Investigator will submit any updated SAE data to the Sponsor within 
24 hours of it being available. 
The Investigator is specifically requested to collect and report to UCB (or its representative) any 
SAEs (even if the Investigator is certain that they are in no way associated with the study 
medication), up to 30 days from the end of the study for each participant, and to also inform 
participants of the need to inform the Investigator of any SAE within this period. Serious AEs 
that the Investigator thinks may be associated with the study medication must be reported to 
UCB regardless of the time between the event and the end of the study. 
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The method of recording, evaluating, and assessing causality of AE and SAE and the procedures 
for completing and transmitting SAE reports are provided in Appendix 3 (Section 1.3). 
8.3.2 
Method of detecting AEs and SAEs 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
nonleading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences. 
8.3.3 
Follow up of AEs and SAEs 
After the initial AE/SAE report, the Investigator is required to proactively follow each study 
participant at subsequent visits/contacts. All SAEs and nonserious AEs of special interest (as 
defined in Section 8.3.6), will be followed until resolution, stabilization, the Investigator 
determines that it is no longer clinically significant, the event is otherwise explained, or the 
participant is lost to follow up (as defined in Section 7.3). Further information on follow-up 
procedures is given in Appendix 3 (Section 10.3). 
8.3.4 
Regulatory reporting requirements for SAEs 
Prompt notification by the Investigator to the Sponsor of a SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of study participants and the safety of a 
study treatment under clinical investigation are met. 
The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study treatment under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements relating to safety reporting to 
the regulatory authority, Institutional Review Boards (IRB)/Independent Ethics Committees 
(IEC), and Investigators. 
Investigator safety reports must be prepared for suspected unexpected serious adverse reactions 
(SUSAR) according to local regulatory requirements and Sponsor policy and forwarded to 
Investigators as necessary. 
An Investigator who receives an Investigator safety report describing a SAE or other specific 
safety information (eg, summary or listing of SAEs) from the Sponsor will review and then file it 
along with the Investigator’s Brochure and will notify the IRB/IEC, if appropriate according to 
local requirements. 
8.3.5 
Pregnancy 
Details of all pregnancies in female study participants and, if indicated, female partners of male 
study participants will be collected after the start of study treatment and until 30 days after the 
birth for any significant medical issues. In certain circumstances, UCB may request that follow 
up is continued for a period longer than 30 days. If the study participant is lost to follow up 
and/or refuses to give information, written documentation of attempts to contact the study 
participant needs to be provided by the Investigator and filed at the site. UCB’s PS department is 
the primary contact for any questions related to the data collection for the pregnancy, eventual 
birth, and follow up. 
If a pregnancy is reported, the Investigator must immediately inform the Sponsor within 24 hours 
of learning of the pregnancy and should follow the procedures outlined in Appendix 4 
Section 10.4). 
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The study participant should be withdrawn from the study as soon as pregnancy is known (by 
positive pregnancy test), and the following should be completed: 
 The study participant should return for an early discontinuation visit. 
 The study participant should immediately stop the intake of the study medication or be 
down-titrated as instructed at the early discontinuation visit. 
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs. 
8.3.6 
Adverse events of special interest 
An AE of special interest is any AE that a regulatory authority has mandated be reported on an 
expedited basis, regardless of the seriousness, expectedness, or relatedness of the AE to the 
administration of a UCB product/compound. No AEs of special interest have been identified for 
PSL to date, with the exception of potential Hy’s Law as described below. 
Potential Hy’s Law, defined as ≥3xULN  ALT or AST with coexisting ≥2xULN total bilirubin in 
the absence of ≥2xULN ALP, with no alternative explanation for the biochemical abnormality, 
must ALWAYS be reported to UCB as an AE of special interest (ie, without waiting for any 
additional etiologic investigations to have been concluded). Follow-up information should then 
be reported if an alternative etiology is identified during investigation and monitoring of the 
study participant. 
8.4 
Safety signal detection 
Selected data from this study will be reviewed periodically to detect as early as possible any 
safety concern(s) related to the study medication so that Investigators, clinical study participants, 
regulatory authorities, and IRBs/IECs will be informed appropriately and as early as possible. 
The Study Physician or medically qualified designee/equivalent will conduct an ongoing review 
of SAEs and perform ongoing SAE reconciliations in collaboration with the Patient Safety 
representative. 
As appropriate for the stage of development and accumulated experience with the study 
medication, medically qualified personnel at UCB may identify additional safety measures 
(eg, AEs, vital signs, laboratory or ECG results) for which data will be periodically reviewed 
during the course of the study. 
8.5 
Treatment of overdose 
For this study, any dose of treatments (PSL, ethanol, and CBD) greater than that prescribed in 
the protocol will be considered an overdose. Overdose events are only considered AEs or SAEs 
if there are associated clinical signs and/or symptoms or if the act of taking the excess study 
medication itself is an AE or SAE (eg, suicide attempt). 
UCB does not recommend specific treatment for an overdose. Padsevonil will not be 
self-administered by the study participant. 
In the event of an overdose, the Investigator should: 
1. Contact the Sponsor Medical Monitor immediately. 
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2. Closely monitor the participant for any AE/SAE and laboratory abnormalities until study 
treatment can no longer be detected systemically (at least 3 days). 
3. Obtain a plasma sample for PK analysis within 3 days from the date of the last dose of study 
treatment if requested by the Medical Monitor (determined on a case-by-case basis). 
4. Document the quantity of the excess dose as well as the duration of the overdose in the 
eCRF. 
Decisions regarding dose interruptions or modifications will be made by the Investigator in 
consultation with the Medical Monitor based on the clinical evaluation of the participant. 
8.6 
Pharmacokinetics 
Whole blood samples will be collected for measurement of plasma concentrations of PSL, its 
metabolite, CBD and its active metabolite, as specified in the Schedule of Activities 
(Section 1.3). Urine samples will be collected for measurement of urine concentrations of PSL 
and/or metabolites depending on the outcome of PSL (and metabolite) PK analyses. The actual 
date and time (24-hour clock time) of each sample will be recorded. 
Drug concentration information that may unblind the study will not be reported to investigative 
sites or blinded personnel until the study has been unblinded. 
Ethanol breath sampling will be performed during ethanol/placebo infusion as specified in the 
Schedule of Activities (Section 1.3). 
Any changes in the timing or addition of time points for any planned study assessments must be 
documented and approved by the relevant study team member and then archived in the Sponsor 
and site study files, but will not constitute a protocol amendment. The IRB/IEC will be informed 
of any safety issues that require alteration of the safety monitoring scheme or amendment of the 
ICF. 
Instructions and additional details regarding PK sampling are provided in the Laboratory Manual 
(or equivalent document). 
The maximum deviations from scheduled sampling times considered irrelevant for PK are 
defined in Table 8‒1. 
Table 8-1: 
Irrelevant time deviations for PK sampling 
PK blood sampling times 
Deviation from scheduled time considered irrelevant 
0 hours (predose) 
Within 60 minutes  
0.25 to 1.5 hours 
2 minutes 
2 to 8 hours 
5 minutes 
12 hours 
15 minutes 
24 to 48 hours 
60 minutes 
PK=pharmacokinetic 
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8.7 
Pharmacodynamics 
All study participants will undergo at least 1 PD training session at Screening or during a 
separate visit for each PD assessment in order to be familiar with the test. Baseline PD 
assessment will be collected as a duplicate at Day 1 predose. The PD training sessions will be 
conducted according to the standard operating procedures at the site. 
8.7.1 
VAS for alcohol intoxication 
The specific study participantive effects of alcohol will be assessed by VAS alcohol effects, 
asking the study participant to indicate the size of the alcohol effect. The scale consists of a 10cm 
line anchored on the left end by “sober” and on the right end by “drunk.” Study participants mark 
a point on the line that best represents their subjective state corresponding to the condition tested. 
The result is a distance calculated from the mark on the line. 
8.7.2 
VAS feeling (Bowdle) 
The Bowdle VAS (B-VAS) evaluates psychedelic effects. These could cluster into 2 distinct total 
sum scores “internal perception” (reflects inner feelings that do not correspond with reality, 
including mistrustful feelings) and “external perception” (reflects a misperception of an external 
stimulus or a change in the awareness of the study participant's surroundings). From the B-VAS, 
composite scores of “internal perception” (5 items) and “external perception” (6 items) will be 
calculated as described in Zuurmann et al, 2008. In addition, all 13 items could be analyzed also 
separately. 
8.7.3 
VAS according to Bond-Lader 
The study participantive VASs for this study are the Bond and Lader of Mood and Alertness 
Scales (Bond and Lader, 1974). This VAS scale consists of 16 bipolar self-rating 100mm long 
lines between 2 opposite adjectives. The study participant will indicate on the line how she/he is 
feeling at the evaluation time. The response is scored by measuring the distance in mm between 
the left end of the line and the study participant’s mark. This questionnaire derives 3 factors that 
assess change in self-rated alertness, self-rated calmness, and self-rated contentment. A 
computerized version of this test will be used, with the participant using the computer mouse. 
8.7.4 
Saccadic eye movements 
Saccadic peak velocity is one of the most sensitive parameters for sedation. The use of a 
computer for measurement of SEM was originally described by Baloh et al, 1975. Recording of 
eye movements will be performed in a quiet room with ambient illumination. Recording and 
analysis of SEMs will be conducted with a microcomputer-based system for sampling and 
analysis of eye movements. A camera-based eye-tracking system will be used for monitoring eye 
movements towards target signals. Head movements will be restrained using a fixed head 
support. Saccadic eye movements will be recorded for stimulus amplitudes of approximately 
15 degrees to either side. Sixteen saccades will be recorded with interstimulus intervals varying 
randomly. Average values of latency (reaction time), saccadic peak velocity of all correct 
saccades, and inaccuracy of all saccades will be used as parameters. Saccadic inaccuracy will be 
calculated as the absolute value of the difference between the stimulus angle and the 
corresponding saccade, expressed as a percentage of the stimulus angle. Saccadic eyes 
movements are specific measures of alertness and sedation. Peak velocity decreases and latency 
increases with sedation. 
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8.7.5 
Smooth pursuit eye movements 
For smooth pursuit eye movements, the target will move sinusoidally at frequencies ranging 
from 0.3 to 1.1Hz, by steps of 0.1Hz. The amplitude of target displacement corresponds to 
22.5°eyeball rotation to both sides. Four cycles will be recorded for each stimulus frequency. 
The time during which the eyes are in smooth pursuit of the target will be calculated for each 
frequency and expressed as a percentage of stimulus duration. The average percentage of smooth 
pursuit for all stimulus frequencies will be used as a parameter. This parameter can be used as an 
accurate biomarker for oculomotor function and attention (Lehtinen et al, 1982). The method has 
been validated at the CHDR by Van Steveninck et al (Van Steveninck et al, 1993; Van 
Steveninck et al, 1989) based on the work of Bittencourt et al (Bittencourt et al, 1983) and the 
original description of Baloh et al (Baloh et al, 1975). 
8.7.6 
Adaptive tracking 
The adaptive tracking test will be performed as originally described by Borland and Nicholson 
(Borland and Nicholson, 1984), using customized equipment and software. Adaptive tracking is 
a pursuit tracking task that has proved to be useful for measurement of CNS effects of alcohol, 
various psychoactive drugs and sleep deprivation (Van Steveninck et al, 1999; Van Steveninck et 
al, 1991). Each test will be preceded by a run-in period. Performance will be scored after a fixed 
period of 3.5 minutes and reflected visuo-motor control and vigilance. The average performance 
scores will be used in the analysis. 
8.7.7 
Body sway 
Body sway will be measured by CHCR NeuroCart. Body Sway test measures the study 
participant’s body movements in a single direction. Study participants will be asked to stand 
erect and motionless with their eyes closed. The amplitude and direction of any Body Sway will 
be recorded for 1 minute. 
8.8 
Genetics 
Archive blood samples for genotyping of drug metabolizing enzymes will be collected as 
specified in the Schedule of Activities (Section 1.3). 
8.9 
Biomarkers 
Biomarkers are not evaluated in this study. 
9 
STATISTICAL CONSIDERATIONS 
A description of statistical methods follows and will be described in more detail in the Statistical 
Analysis Plan (SAP). 
9.1 
Definition of analysis sets 
The following are the defined analysis sets: 
 Enrolled Set (ES): All study participants who have signed the informed consent. 
 Randomized Set (RS): All enrolled study participants who were randomized will be included 
in the RS. 
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 Full analysis Set (FAS): All randomized study participants who received IMP according to 
the treatment the study participants actually received. 
 Pharmacokinetic Per Protocol Set (PK-PPS): PK-PPS is 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 are available to determine at least 
1 PK parameter. 
 Pharmacodynamic Per Protocol Set (PD-PPS): PD-PPS is a subset of the FAS, consisting of 
those study participants who had no important protocol deviations affecting the PD 
parameters and for whom a sufficient number of PD assessments are available to determine 
at least 1 PD parameter. 
9.2 
General statistical considerations 
All analyses will be performed using SAS® Version 9.4 or later (SAS Institute, Cary, NC, USA). 
For continuous variables, summary statistics will include number of study participants, mean, 
median, standard deviation, minimum, and maximum. Categorical endpoints will be summarized 
using number of study participants, frequency, and percentages. Missing data will not be 
imputed. 
If not otherwise stated, Baseline will be the last assessment prior to dosing. Measurement of 
specific Baseline values will be described in the SAP. 
9.3 
Planned efficacy/outcome analyses 
As efficacy was not evaluated in this study, there will be no primary efficacy endpoint. 
9.4 
Planned pharmacodynamic analyses 
All PD parameters (raw values, change from Baseline, and percentage change from Baseline) 
and variables will be listed and summarized by study part and treatment with mean, median, 
standard deviation (SD), minimum and maximum for the PD-PPS. 
9.4.1 
Ethanol and PSL (Part A) 
The similarity of the PD parameters between treatments with ethanol and without ethanol 
(ethanol placebo alone, ethanol alone, PSL with ethanol placebo, PSL with ethanol) will be 
analysed separately by a mixed model of analysis of variance (ANOVA) with treatment, 
sequence, period, time, and treatment by time as fixed effects; with subject, subject by treatment, 
and subject by time as random effect; and with the (average) Baseline value as covariate. The 
primary comparison is PSL with ethanol vs PSL alone. The other comparisons will be: PSL 
alone vs ethanol placebo, ethanol alone vs ethanol placebo alone, and PSL with ethanol vs 
ethanol alone. Different contrasts (with estimate difference and 95% confidence interval [CI]) 
from ANOVA will be defined for each of these comparisons. 
9.4.2 
Cannabidiol and PSL (Part B) 
The similarity of the PD parameters between treatment with CBD and without CBD will be 
analysed by a mixed model ANOVA with treatment, sequence, period, time, and treatment by 
time as fixed effects; with study participant, study participant by treatment, and study participant  
by time as random effect; and with the (average) Baseline value as covariate. Estimated 
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differences with 95% CI will be provided. The primary comparison is PSL with CBD vs PSL 
alone (from Part B Treatment Period 2). The other comparisons will be: PSL with CBD vs CBD 
alone. 
9.5 
Planned pharmacokinetic analyses 
Pharmacokinetic parameters of PSL (and metabolites 
) 
and CBD (and metabolite [7-hydroxy-CBD]) (Cmax,ss, tmax, AUCτ, t½, CLss/F) will be estimated 
using noncompartmental analysis (NCA) with Pharsight Phoenix® WinNonlin® v6.3 (or higher) 
software. 
Pharmacokinetic analyses will be performed using the PK-PPS set.The individual plasma 
concentration of PSL and metabolites, CBD and metabolites and PK parameters of CBD, PSL 
and metabolites will be summarized by treatment group using descriptive statistics (number of 
observations [n], geometric mean, lower and upper 95% CI, geometric coefficient of variation 
[CV], arithmetic mean, SD and CV, median, and minimum and maximum value) and graphical 
displays. 
For the calculation of descriptive statistics, a plasma concentration below the lower limit of 
quantification (LLOQ) will be substituted by LLOQ/2. Mean, SD, and CV will be calculated 
only if at least two-thirds of the individual measurements are above or equal to LLOQ. Minimum 
will be reported if all measurements are above or equal to LLOQ. Individual concentration time 
profiles will be displayed graphically on a linear scale and semilogarithmic scale. Geometric 
mean profiles with lower and upper limit of the 95% CI for the linear scale and without limits for 
the semilogarithmic scale will be displayed. 
9.5.1 
Ethanol interaction on PSL (Part A) 
Effects of ethanol on log-transformed PK parameters (Cmax,ss, AUCτ) of PSL and its metabolites 
will be analysed with a mixed model of variance for a 2x2 cross-over with fixed factors of 
treatment, sequence, period and random factor study participant within sequence. Estimation of 
geometric ratio of PK parameters between the 2 treatments (ethanol+PSL vs ethanol 
placebo+PSL) with their 90% CI will be provided. 
Lack of ethanol effect on PSL will be concluded if the 90% CI of the ratio between ethanol+PSL 
and ethanol placebo+PSL of the least squares means for the log transformed AUCτ, and Cmax,ss is 
within the conventional acceptance range of 80% to 125%. 
9.5.2 
PSL interaction on ethanol (Part A) 
Individual breath ethanol concentration-time data will be listed by study participant and 
treatment and will be summarized by treatment (ethanol+PSL and ethanol) presenting the 
number of observations, geometric mean, lower and upper limit of the 95% CI for the geometric 
mean, geoCV(%), arithmetic mean, SD, median, minimum, and maximum. 
The individual metabolizing capacity will be characterized by calculating the total ethanol dose, 
ie, the total amount of ethanol infused during each of the treatments. 
Total ethanol dose will be analyzed by mixed model ANOVA with treatment, sequence, and 
period as fixed factors, and study participant within sequence as a random factor to assess 
potential differences of metabolizing capacity between treatments (with and without PSL). The 
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ratio of the least squares means in ethanol dose between treatment with PSL and treatment 
without PSL, and its 90% CI will be calculated. 
9.5.3 
Cannabidiol interaction on PSL (Part B) 
Effects of CBD on log-transformed PK parameters (Cmax,ss, AUCτ) of PSL and its metabolites 
will be analysed with a mixed model of variance for a 2x2 cross-over with fixed factors of 
treatment, sequence, period and random factor study participant within sequence. Estimation of 
geometric ratio of PK parameters between the 2 treatments (CBD+PSL vs PSL) with their 90% 
CI will be provided. The PK of PSL without CBD is obtained in Part B Treatment Period 2. 
9.5.4 
PSL interaction on CBD (Part B): 
Effects of PSL on log-transformed PK parameters (Cmax,ss, AUCτ) of CBD and its metabolites 
will be analysed with a mixed model of variance for a 2x2 cross-over with fixed factors of 
treatment, sequence, period and random factor study participant within sequence. Estimation of 
geometric ratio of PK parameters between the 2 treatments (PSL+CBD vs PSL placebo+CBD) 
with their 90% CI will be provided. 
9.6 
Planned safety analyses 
All safety analyses will be performed using the FAS. All safety variables will be listed and 
summarized by each study part and treatment. 
All AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA®) and 
characterized as pretreatment and treatment-emergent according to the intake of the IMP. All AE 
data will be listed by study participant number, visit, treatment and time. The listings will include 
the following data pertaining to the AEs: start and end dates with relative days to study 
medication administration, duration, intensity, seriousness, relationship to study medication, 
action taken, and final outcome. 
The occurrence and incidence of TEAEs will be summarized by study part according to the 
intake of PSL (pretreatment or treatment-emergent) and by intensity or relationship to PSL, CBD 
and ethanol. 
Safety laboratory measurements, vital signs and 12-lead ECGs parameters will be tabulated by 
study part and treatment using descriptive statistics. Laboratory values outside the reference 
range will be flagged in the listings. Any PDILI events will be listed. 
Assessment of suicidality will be listed. 
Physical examinations abnormalities and psychological and mental status abnormalities will be 
listed. 
9.7 
Handling of protocol deviations 
Important protocol deviations are deviations from the protocol which potentially could have a 
meaningful impact on study conduct or on the primary PK or PD outcome for an individual study 
participant. Furthermore, study participants will be excluded from FAS only when there is 
documented evidence that they received no treatment. The criteria for identifying important 
protocol deviations and the classification of important protocol deviations will be defined within 
the relevant protocol deviation specification document, which is part of the study Data Cleaning 
Plan. To the extent feasible, rules for identifying protocol deviations will be defined without 
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review of the data and without consideration of the frequency of occurrence of such deviations. 
Whenever possible, criteria for identifying important protocol deviations will be implemented 
algorithmically to ensure consistency in the classification of important protocol deviations across 
all study participants. 
Important protocol deviations will be reviewed as part of an ongoing blinded data cleaning 
process prior to database lock to confirm exclusion from analysis sets. 
9.8 
Handling of dropouts or missing data 
The methods for handling dropouts will be described in the SAP. Data of study participants 
prematurely terminating the study will be used to the maximum possible extent. No procedures 
for replacing missing data are intended. If a Baseline value is missing or not reliable, the last 
value before administration of study medication will serve as Baseline. 
9.9 
Planned interim analysis and data monitoring 
No interim analysis or data monitoring are planned in this study. 
9.10 
Determination of sample size 
Based on the study PK and PD objectives, the total planned number of healthy study participants 
will be 44, including 22 evaluable participants for Part A and 22 evaluable participants for 
Part B. 
For Part A, the sample size is based on pragmatic considerations and the ability to detect an 
ethanol effect on PD assessments (CNS variable). A sample size of 22 evaluable study 
participants provides 80% power to detect an ethanol effect in a difference in means of 
3.96 (% points) for the smooth pursuit test, which is the most sensitive CNS variable to ethanol 
effects, assuming a SD of difference of 6.0 (% points) based on previous ethanol clamp 
interaction studies and using a paired t-test 2-sided with a 0.05 significance level. This sample 
size is also valid for the CBD effect assessment (Part B). 
For Part B, a sample size of 22 evaluable study participants is needed to assess the PK interaction 
between PSL and CBD, and to estimate the mean PSL AUCτ ratio of with/without CBD of 
1.5 with a half-width of the CI of 0.3. This sample size has been evaluated with a conditional 
probability of 90%, assuming an inter-participant coefficient of variation of 45% of PSL AUCτ 
(observed in study UP0057), correlation of 0.5, 2-sided and α = 0.05. A sufficient number of 
healthy study participants (up to 20) will be selected to have 16 completed study participants. 
Regarding the assessment of the single dose formulation of CBD (under fasted conditions) in 
Part B (study formulation vs Epidiolex formulation from literature data), 16 healthy study 
participants are required to assess the similarity of the 2 formulations (equivalence range of 50 to 
200% based on the high variability of CBD) with a 80% power and assuming an expected 
geometric mean ratio of AUC and Cmax between 0.8 and 1.3, and inter-participant CV of 80% 
(based on CBD literature) and correlation of 0.5. 
Sample size computations were performed using SAS version 9.4 (Proc Power). 
Drop outs will be replaced at the discretion of the Investigator and Sponsor. 
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10 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
10.1 
Appendix 1: Regulatory, ethical, and study oversight 
considerations 
10.1.1 
Regulatory and eithical considerations 
The study will be conducted under the auspices of an IRB/IEC, as defined in local regulations, 
ICH-GCP, and in accordance with the ethical principles that have their origin in the Declaration 
of Helsinki. 
The Investigator/UCB will ensure that an appropriately constituted IRB/IEC that complies with 
the requirements of the current ICH-GCP version or applicable country-specific regulations will 
be responsible for the initial and continuing review and approval of the clinical study. Prior to 
initiation of the study, the Investigator/UCB will forward copies of the protocol, Informed 
Consent form, Investigator’s Brochure, Investigator’s curriculum vitae (if applicable), 
advertisement (if applicable), and all other participant-related documents to be used for the study 
to the IRB/IEC for its review and approval. 
Before initiating a study, the Investigator will have written and dated full approval from the 
responsible IRB/IEC for the protocol. 
The Investigator will also promptly report to the IRB/IEC all changes in the study, all 
unanticipated problems involving risks to participants or others, and any protocol deviations, to 
eliminate immediate hazards to participants. 
The Investigator will not make any changes in the study or study conduct without IRB/IEC 
approval, except where necessary to eliminate apparent immediate hazards to the participants. 
For minor changes to a previously approved protocol during the period covered by the original 
approval, it may be possible for the Investigator to obtain an expedited review by the IRB/IEC as 
allowed. 
As part of the IRB/IEC requirements for continuing review of approved studies, the Investigator 
will be responsible for submitting periodic progress reports to the IRB/IEC (based on IRB/IEC 
requirements), at intervals appropriate to the degree of participant risk involved, but no less than 
once per year. The Investigator should provide a final report to the IRB/IEC following study 
completion. 
UCB (or its representative) will communicate safety information to the appropriate regulatory 
authorities and all active Investigators in accordance with applicable regulatory requirements. 
The appropriate IRB/IEC will also be informed by the Investigator or the sponsor, as specified 
by the applicable regulatory requirements in each concerned country. Where applicable, 
Investigators are to provide the sponsor (or its representative) with evidence of such IRB/IEC 
notification. 
10.1.2 
Financial disclosure 
Insurance coverage will be handled according to local requirements. 
Finance and insurance are addressed in the Investigator and/or CRO agreements, as applicable. 
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10.1.3 
Informed consent process 
Participant’s informed consent must be obtained and documented in accordance with local 
regulations, ICH-GCP requirements, and the ethical principles that have their origin in the 
principles of the Declaration of Helsinki. 
Prior to obtaining informed consent, information should be given in a language and at a level of 
complexity understandable to the participant in both oral and written form by the Investigator (or 
designee). Each participant will have the opportunity to discuss the study and its alternatives 
with the Investigator. 
Prior to participation in the study, the ICF should be signed and personally dated by the 
participant, or his/her legal representative, and by the person who conducted the informed 
consent discussion (Investigator or designee). The participant or his/her legal representative must 
receive a copy of the signed and dated ICF. As part of the consent process, each participant must 
consent to direct access to his/her medical records for study-related monitoring, auditing, 
IRB/IEC review, and regulatory inspection. 
If the ICF is amended during the study, the Investigator (or the sponsor, if applicable) must 
follow all applicable regulatory requirements pertaining to the approval of the amended ICF by 
the IRB/IEC and use of the amended form. 
The participant may withdraw his/her consent to participate in the study at any time. A 
participant is considered as enrolled in the study when he/she has signed the ICF. An eCRF must 
not be started, nor may any study specific procedure be performed for a given participant, 
without having obtained his/her written consent to participate in the study. 
10.1.4 
Data protection 
UCB staff (or designee) will affirm and uphold the participant’s confidentiality. Throughout this 
study, all data forwarded to UCB (or designee) will be identified only by the study participant 
number assigned prior to dosing. 
The Investigator agrees that representatives of UCB, its designee, representatives of the relevant 
IRB/IEC, or representatives of regulatory authorities will be allowed to review that portion of the 
participant’s primary medical records that directly concerns this study (including, but not limited 
to, laboratory test result reports, ECG reports, admission/discharge summaries for hospital 
admissions occurring during a participant’s study participation, and autopsy reports for deaths 
occurring during the study). 
The participant must be informed that his/her personal study-related data will be used by the 
sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant. 
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
10.1.5 
Committees structure 
Not applicable. 
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10.1.6 
Data quality assurance 
All participant data relating to the study will be recorded on printed or eCRF unless transmitted 
to the sponsor or designee electronically (eg, laboratory data). The Investigator is responsible for 
verifying that data entries are accurate and correct by physically or electronically signing the 
eCRF. 
The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF. 
The Investigator must permit study-related monitoring, audits, IRB/IEC review, and regulatory 
agency inspections and provide direct access to source data documents. 
The sponsor or designee is responsible for the data management of this study including quality 
checking of the data. 
Study monitors will perform ongoing source data verification to confirm that data entered into 
the eCRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of participants are being protected; and that the study is 
being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements. 
All essential documents are to be retained by the Investigator until at least 2 years after the last 
approval of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region, or at least 2 years have elapsed since the 
formal discontinuation of clinical development of the study medication/investigational device. 
These documents should be retained for a longer period, however, if required by the applicable 
regulatory requirement(s) or by an agreement with UCB (CPMP/ICH/135/95, 2002 
[Section 4.9.5]). The Investigator will contact UCB for authorization prior to the destruction of 
any study records or in the event of accidental loss or destruction of any study records. The 
Investigator will also notify UCB should he/she relocate or move the study-related files to a 
location other than that specified in the sponsor’s trial master file. 
10.1.6.1 
Case Report form completion 
The Investigator is responsible for prompt reporting of accurate, complete, and legible data in the 
eCRFs and in all required reports. 
Any change or correction to the eCRF after saving must be accompanied by a reason for the 
change. 
Corrections made after the Investigator’s review and approval (by means of a 
password/electronic signature) will be reapproved by the Investigator. 
The Investigator should maintain a list of personnel authorized to enter data into the eCRF. 
Detailed instructions will be provided in the eCRF Completion Guidelines. 
10.1.6.2 
Apps 
Not applicable. 
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10.1.7 
Source documents 
All source documents must be accurate, clear, unambiguous, permanent, and capable of being 
audited. They should be made using some permanent form of recording (ink, typing, printing, 
optical disc). They should not be obscured by correction fluid or have temporary attachments 
(such as removable self-stick notes). 
Source documents are original records in which raw data are first recorded. These may include 
clinic records, charts, laboratory results, printouts, pharmacy records, ECG or other printouts, or 
completed scales, for example. Source documents should be kept in a secure, limited access area. 
Source documents that are computer generated and stored electronically must be printed for 
review by the monitor (eg, ECG reports). Once printed, these copies should be signed and dated 
by the Investigator and become a permanent part of the participant’s source documents. The 
Investigator will facilitate the process for enabling the monitor to compare the content of the 
printout and the data stored in the computer to ensure all data are consistent. 
Electronic data records, such as Holter monitor records or electroencephalogram records, must 
be saved and stored as instructed by UCB (or designee). 
10.1.8 
Study and site closure 
The sponsor designee reserves the right to close the study site or terminate the study at any time 
for any reason at the sole discretion of the sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed. 
The Investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or Investigator may include but are 
not limited to: 
 Failure of the Investigator to comply with the protocol, the requirements of the IRB/IEC or 
local health authorities, the Sponsor's procedures, or GCP guidelines 
 Inadequate recruitment of participants by the Investigator 
 Discontinuation of further study medication development 
10.1.9 
Publication policy 
The results of this study may be published or presented at scientific meetings. If this is foreseen, 
the Investigator agrees to submit all manuscripts or abstracts to the sponsor before submission. 
This allows the sponsor to protect proprietary information and to provide comments. 
The sponsor will comply with the requirements for publication of study results. In accordance 
with standard editorial and ethical practice, the sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a 
coordinating Investigator will be designated by mutual agreement. 
Authorship will be determined by mutual agreement and in line with International Committee of 
Medical Journal Editors authorship requirements. 
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10.2 
Appendix 2: Clinical Laboratory Tests 
 The tests detailed in the table below will be performed by a local laboratory. 
 Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5.1 and Section 5.2 of the protocol. 
 Additional tests may be performed at any time during the study as determined necessary by 
the Investigator or required by local regulations. 
Protocol-Required Safety Laboratory Assessments 
Laboratory 
Assessments 
Parameters 
Hematology1 
Platelet Count  
RBC Indices: 
MCV 
MCH 
%Reticulocytes 
WBC Count with 
Differential: 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
RBC Count 
Hemoglobin 
Hematocrit 
Clinical 
Chemistry1,2 
Blood Urea 
Nitrogen 
(BUN) 
Potassium 
Aspartate Aminotransferase 
(AST)/Serum Glutamic-
Oxaloacetic Transaminase 
(SGOT) 
Total and direct 
bilirubin (direct 
is only measured 
if total >1xULN) 
 
Creatinine 
Sodium 
Alanine Aminotransferase 
 (ALT)/Serum Glutamic-
Pyruvic Transaminase 
(SGPT) 
Total Protein 
 
Glucose 
(fasting at 
Screening)  
Calcium 
Alkaline phosphatase 
 
Routine 
Urinalysis1 
 Specific gravity, pH, glucose, protein, blood, ketones, bilirubin, 
urobilinogen, nitrite, leukocyte  by dipstick  
If protein or blood or leukocytes are abnormal (positive), a microscopic 
examination of the sediment will be performed. 
Other 
Screening 
Tests 
 Follicle-stimulating hormone (at Screening only to confirm postmenopausal 
status in female study participants 
 Urine drug screen (to include at minimum: amphetamines, barbiturates, 
cocaine, opiates, cannabinoids and benzodiazepines) 
 Breath alcohol test 
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Laboratory 
Assessments 
Parameters 
 Pregnacy test: Urine or serum beta human chorionic gonadotropin (hCG) 
test (as needed for women of childbearing potential; serum hCG test used at 
Screening only) 
 Serology (HIV 1 and 2 Ab, HBsAg, HCV-Ab)  
1 Hematology, clinical chemistry, and urinalysis asssessments will be performed under fasting conditions at 
Screening and non-fasting conditions at all other assessments.  
2 Details of liver chemistry stopping criteria and required actions and follow-up assessments after liver stopping or 
monitoring event are given in Section 7.1.1 and Section 10.6. All events of ALT 3 × UL) and bilirubin 2 × 
ULN (>35% direct bilirubin) or ALT 3 × ULN and international normalized ratio (INR) >1.5, if INR measured, 
may indicate severe liver injury (possible Hy’s Law) and must be reported as an SAE (excluding studies of hepatic 
impairment or cirrhosis). 
Investigators must document their review of each laboratory safety report. 
Laboratory/analyte results that could unblind the study will not be reported to investigative sites 
or other blinded personnel until the study has been unblinded. 
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10.3 
Appendix 3: Adverse events – definitions and procedures for 
recording, evaluating, follow up, and reporting 
10.3.1 
Definition of AE 
AE Definition 
 An AE is any untoward medical occurrence in a patient or clinical study participant, 
temporally associated with the use of study medication, whether or not considered related 
to the study medication. 
 NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of study medication. 
 
Events Meeting the AE Definition 
 Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from Baseline, considered clinically significant in the medical 
and scientific judgment of the Investigator (ie, not related to progression of underlying 
disease). 
 Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
 New conditions detected or diagnosed after study medication administration even though it 
may have been present before the start of the study. 
 Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
 Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
medication or a concomitant medication. Overdose per se will not be reported as an 
AE/SAE unless it is an intentional overdose taken with possible suicidal/self-harming 
intent. Such overdoses should be reported regardless of sequelae. 
 
Events NOT Meeting the AE Definition  
 Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
Investigator to be more severe than expected for the participant’s condition. 
 The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the study participant’s 
condition. 
 Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE. 
 Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
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 Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen. 
10.3.2 
Definition of SAE 
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions 
are met (eg, hospitalization for signs/symptoms of the disease under study, death due to 
progression of disease). 
A SAE is defined as any untoward medical occurrence that, at any dose: 
a. Results in death 
b. Is life-threatening 
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, which 
hypothetically might have caused death, if it were more severe. 
c. 
Requires inpatient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the participant has been detained (usually involving at 
least an overnight stay) at the hospital or emergency ward for observation and/or treatment that 
would not have been appropriate in the physician’s office or outpatient setting. Complications 
that occur during hospitalization are AEs. If a complication prolongs hospitalization or fulfills 
any other serious criteria, the event is serious. When in doubt as to whether “hospitalization” 
occurred or was necessary, the AE should be considered serious. 
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
Baseline is not considered an AE. 
d. Results in persistent disability/incapacity 
 The term disability means a substantial disruption of a person’s ability to conduct normal 
life functions. 
 This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and 
accidental trauma (eg, sprained ankle) which may interfere with or prevent everyday life 
functions but do not constitute a substantial disruption. 
e. 
Is a congenital anomaly/birth defect 
f. 
Important medical events: 
 Medical or scientific judgment should be exercised in deciding whether SAE reporting is 
appropriate in other situations such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize the 
participant or may require medical or surgical intervention to prevent 1 of the other 
outcomes listed in the above definition. These events should usually be considered serious. 
Examples of such events include, but are not limited to, potential Hy’s law, invasive or 
malignant cancers, intensive treatment in an emergency room or at home for allergic 
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bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization, or 
development of drug dependency or drug abuse. 
10.3.3 
Recording and follow up of AE and/or SAE 
AE and SAE Recording 
 When an AE/SAE occurs, it is the responsibility of the Investigator to review all 
documentation (eg, hospital progress notes, laboratory reports, and diagnostics reports) 
related to the event. 
 The Investigator will then record all relevant AE/SAE information in the eCRF. 
 It is not acceptable for the Investigator to send photocopies of the participant’s medical 
records to UCB in lieu of completion of the UCB AE/SAE eCRF page. 
 There may be instances when copies of medical records for certain cases are requested by 
UCB. In this case, all participant identifiers, with the exception of the participant number, 
will be redacted on the copies of the medical records before submission to UCB. 
 The Investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE. 
Assessment of Intensity 
The Investigator will make an assessment of intensity for each AE and SAE reported during 
the study and assign it to 1 of the following categories: 
 Mild: An event that is easily tolerated by the participant, causing minimal discomfort and 
not interfering with everyday activities. 
 Moderate: An event that causes sufficient discomfort and interferes with normal everyday 
activities. 
 Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with a SAE. Severe is a category utilized for rating the 
intensity of an event; and both AEs and SAEs can be assessed as severe. 
 An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, NOT when it is rated as severe (eg, a severe AE may 
be either serious or not serious, depending on whether these criteria are also met). 
The National Cancer Institute Common Terminology Criteria for Adverse Events 
(NCI-CTCAE) should be used as a supportive standardization instrument to evaluate AEs and 
SAEs but the final intensity grading by the Investigator must be mild, moderate, or severe. 
 
Assessment of Causality 
 The Investigator is obligated to assess the relationship between study medication and each 
occurrence of each AE/SAE. 
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 A "reasonable possibility" of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out. 
 The Investigator will use clinical judgment to determine the relationship. 
 Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study medication administration 
will be considered and investigated. 
 The Investigator will also consult the Investigator’s Brochure (IB) and/or Product 
Information, for marketed products, in his/her assessment. 
 For each AE/SAE, the Investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality. 
 There may be situations in which an SAE has occurred and the Investigator has minimal 
information to include in the initial report to UCB. However, it is very important that the 
Investigator always make an assessment of causality for every event before the initial 
transmission of the SAE data to UCB. 
 The Investigator may change his/her opinion of causality in light of follow-up information 
and send a SAE follow-up report with the updated causality assessment. 
 The causality assessment is 1 of the criteria used when determining regulatory reporting 
requirements. 
 
Follow up of AEs and SAEs 
 The Investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by UCB to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals. 
 An AE should be followed until it has resolved, has a stable sequelae, the Investigator 
determines that it is no longer clinically significant, or the participant is lost to follow up. 
This follow-up requirement applies to AEs, SAEs, and AEs of special interest. 
 If a participant dies during participation in the study or during a recognized follow-up 
period, the Investigator will provide UCB with a copy of any postmortem findings 
including histopathology. 
 New or updated information will be recorded in the originally completed eCRF. 
 The Investigator will submit any updated SAE data to UCB within 24 hours of receipt of 
the information. 
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Reporting of SAEs 
SAE Reporting to UCB via an Electronic Data Collection Tool 
 The primary mechanism for reporting an SAE to UCB will be the electronic data collection 
tool. 
 If the electronic system is unavailable for more than 24 hours, then the site will use the 
paper SAE data collection tool (see next section). 
 The site will enter the SAE data into the electronic system as soon as it becomes available. 
 After the study is completed at a given site, the electronic data collection tool will be taken 
off-line to prevent the entry of new data or changes to existing data. 
 If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the electronic data collection tool has been taken off-
line, then the site can report this information on a paper SAE form (see next section) or to 
the UCB Study Physician by telephone. 
 Contacts for SAE reporting can be found in SERIOUS ADVERSE EVENT REPORTING. 
 
SAE Reporting to UCB via Paper CRF 
 Facsimile transmission of the SAE paper CRF is the preferred method to transmit this 
information to the UCB Study Physician. 
 In rare circumstances and in the absence of facsimile equipment, notification by telephone 
is acceptable with a copy of the SAE data collection tool sent by overnight mail or courier 
service. 
 Initial notification via telephone does not replace the need for the Investigator to complete 
and sign the SAE CRF pages within the designated reporting time frames. 
 Contacts for SAE reporting can be found in SERIOUS ADVERSE EVENT REPORTING. 
 
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10.4 
Appendix 4: Contraceptive guidance and collection of 
pregnancy information 
10.4.1 
Definitions 
10.4.1.1 
Woman of childbearing potential 
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile (see below). 
Women in the following categories are not considered WOCBP: 
1. Premenarchal 
2. Premenopausal female with 1 of the following: 
 Documented hysterectomy 
 Documented bilateral salpingectomy 
 Documented bilateral oophorectomy 
Note: Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview. 
3. Postmenopausal female 
 A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal 
range may be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy (HRT). However, in the absence of 
12 months of amenorrhea, a single FSH measurement is insufficient. 
 Females on HRT and whose menopausal status is in doubt will be required to use 1 of the 
nonestrogen hormonal highly effective contraception methods if they wish to continue 
their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation 
of postmenopausal status before study enrollment. 
10.4.2 
Contraception guidance 
10.4.2.1 
Male participants 
Male participants with female partners of childbearing potential are eligible to participate if they 
agree to ONE of the following during the treatment period and for at least 7 days after the last 
dose of study treatment as described in Section 5.1: 
 Are abstinent from penile-vaginal intercourse as their usual and preferred lifestyle (abstinent 
on a long term and persistent basis) and agree to remain abstinent. 
 Agree to use a male condom plus partner use of a contraceptive method with a failure rate of 
<1% per year as described in Table 10-1 when having penile-vaginal intercourse with a 
woman of childbearing potential who is not currently pregnant. 
In addition male participants must refrain from donating sperm for the duration of the study and 
for 90 days after the final dose of study medication. 
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Male participants with a pregnant or breastfeeding partner must agree to remain abstinent from 
penile-vaginal intercourse or use a male condom during each episode of penile penetration 
during the protocol-defined time frame and for 7 days after the final dose of study medication. 
10.4.2.2 
Pregnancy testing 
 WOCBP should only be included after a confirmed menstrual period and a negative highly 
sensitive serum pregnancy test. 
 Pregnancy testing will be performed whenever a menstrual cycle is missed or when 
pregnancy is otherwise suspected 
 Urine beta HCG pregnancy testing, with a sensitivity of 10mIU/mL will be performed 
according to the schedule of activities (Section 1.3). 
10.4.2.3 
Collection of pregnancy information 
10.4.2.3.1 
Female participants 
Female participants of childbearing potential are eligible to participate if they agree to 
consistently and correctly use a highly effective method of contraception as described in 
Table 10-1. 
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Table 10-1: Highly Effective Contraceptive Methods 
Highly Effective Contraceptive Methods That Are User Dependent a, b 
Failure rate of <1% per year when used consistently and correctly. 
Combined (estrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulation 
 Oral 
 Intravaginal 
 Transdermal 
Progestogen only hormonal contraception associated with inhibition of ovulation 
 Oral 
 Injectable 
Highly Effective Methods That Are User Independent b 
Implantable progestogen only hormonal contraception associated with inhibition of ovulation 
 Intrauterine device (IUD) 
 Intrauterine hormone-releasing system (IUS) 
 Bilateral tubal occlusion 
Vasectomized partner 
A vasectomized partner is a highly effective contraception method provided that the partner is 
the sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. If 
not, an additional highly effective method of contraception should be used. 
Sexual abstinence 
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study medication. 
The reliability of sexual abstinence needs to be evaluated in relation to the duration of the 
study and the preferred and usual lifestyle of the participant. 
a Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent 
with local regulations regarding the use of contraceptive methods for participants participating in clinical studies. 
b Hormonal contraception may be susceptible to interaction with the study medication, which may reduce the 
efficacy of the contraceptive method. In this case, an appropriate barrier method of contraception should be 
utilized during the treatment period and for at least least 90 days after the final dose of study treatment. 
10.4.2.3.2 
Male participants with partners who become pregnant 
 The Investigator will attempt to collect pregnancy information on any male participant’s 
female partner who becomes pregnant while the male participant is in this study. 
 After obtaining the necessary signed informed consent from the pregnant female partner 
directly, the Investigator will record pregnancy information on the appropriate form and 
submit it to the sponsor within 24 hours of learning of the partner’s pregnancy. The female 
partner will also be followed to determine the outcome of the pregnancy. Information on the 
status of the mother and child will be forwarded to the sponsor. Generally, the follow up will 
be at least 12 months after the delivery date. Any termination of the pregnancy will be 
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reported regardless of fetal status (presence or absence of anomalies) or indication for the 
procedure. 
10.4.2.3.3 
Female participants who become pregnant 
 The Investigator will collect pregnancy information on any female participant who becomes 
pregnant while participating in this study. Information will be recorded on the appropriate 
form and submitted to the Sponsor within 24 hours of learning of a participant's pregnancy. 
The participant will be followed to determine the outcome of the pregnancy. The Investigator 
will collect follow up information on the participant and the neonate and the information will 
be forwarded to the Sponsor. Generally, the follow up will be at least 12 months after the 
delivery date. Any termination of pregnancy will be reported, regardless of fetal status 
(presence or absence of anomalies) or indication for the procedure. 
 While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or 
elective termination of a pregnancy will be reported as an AE or SAE. A spontaneous 
abortion is always considered to be an SAE and will be reported as such. Any poststudy 
pregnancy related SAE considered reasonably related to the study medication by the 
Investigator will be reported to the sponsor as described in Section 8.3.5. While the 
Investigator is not obligated to actively seek this information in former study participants, he 
or she may learn of an SAE through spontaneous reporting. 
 Any female participant who becomes pregnant while participating in the study will be 
withdrawn from the study. 
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10.5 
Appendix 5: Genetics 
Genetics are not evaluated in this study; however, a DNA sample will be taken for future 
exploratory purposes to caracterize outlier PK profile (CYP ADME purpose). 
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10.6 
Appendix 6: Liver safety – suggested actions and follow-up 
assessments 
Participants with potential drug-induced liver injury must be assessed to determine if study 
medication must be discontinued. In addition, all concomitant medications and herbal 
supplements that are not medically necessary should also be discontinued. 
Investigators should attempt to obtain information on study participants in the case of study 
medication disconintuation to complete the final evaluation. 
Study participants with potential drug-induced liver injury should not be withdrawn from the 
study until investigation and monitoring are complete. All results of these evaluations and 
observations, as well as the reason(s) for study medication discontinuation and/or participant 
withdrawal (if applicable), must be recorded in the source documents. The eCRF must document 
the primary reason for discontinuation of study medication. 
A specific monitoring plan must be agreed between the UCB study physician and the 
Investigator for study participants who have ALT >5xULN. The monitoring plan should include 
any necessary follow-up assessments (until resolution of the abnormal lab values). 
Phase 1 liver chemistry stopping criteria are designed to assure participant safety and to evaluate 
liver event etiology (Table 10-2). 
Table 10-2: Phase I liver chemistry stopping criteria and follow-up 
assessments 
Liver Chemistry Stopping Criteria – Liver Stopping Event 
ALT-absolute 
ALT≥3xULN 
If ALT ≥3xULN AND bilirubin 2xULN (>35% direct bilirubin) OR international 
normalized ratio (INR) >1.5, report as a serious adverse event (SAE).a,b 
See additional actions and follow-up assessments listed below 
Suggested Actions and Follow up Assessments 
Actions 
Follow Up Assessments 
 Report the event to the UCB within 24 hours 
 Complete the liver event eCRF, and complete a 
SAE data collection tool if the event also met 
the criteria for an SAE.b 
 Perform liver chemistry follow-up assessments. 
 Monitor the participant until liver chemistry 
test abnormalities resolve, stabilize, or return to 
Baseline (see MONITORING). 
MONITORING: 
If ALT 3xULN AND bilirubin 2xULN or INR 
>1.5: 
 Viral hepatitis serologyc 
 Obtain INR and recheck with each 
liver chemistry assessment until the 
transaminases values show 
downward trend 
 Serum creatine phosphokinase 
(CPK) and lactate dehydrogenase 
(LDH) 
 Fractionate bilirubin, if total 
bilirubin  2xULN 
 Obtain complete blood count with 
differential to assess eosinophilia 
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 Repeat liver chemistry tests (include ALT, 
aspartate transaminase [AST], alkaline 
phosphatase, bilirubin) and perform liver event 
follow-up assessments within 24 hours. 
 Monitor participant twice weekly until liver 
chemistry test abnormalities resolve, stabilize, 
or return to Baseline. 
 A specialist or hepatology consultation is 
recommended. 
If ALT ≥3xULN AND bilirubin <2xULN and INR 
≤1.5: 
 Repeat liver chemistry tests (include ALT, 
AST, alkaline phosphatase, bilirubin) and 
perform liver chemistry follow-up assessments 
within 24 to 72 hours. 
 Monitor participants weekly until liver 
chemistry abnormalities resolve, stabilize, or 
return to Baseline. 
 Record the appearance or worsening 
of clinical symptoms of liver injury, 
or hypersensitivity, on the AE eCRF 
 Record use of concomitant 
medications (including 
acetaminophen, herbal remedies, and 
other over-the-counter medications) 
on the concomitant medications 
eCRF. 
 Record alcohol use on the liver event 
alcohol intake eCRF. 
If ALT ≥3xULN AND bilirubin 
2xULN or INR >1.5: 
 Anti-nuclear antibody, anti-smooth 
muscle antibody, Type 1 anti-liver 
kidney microsomal antibodies, and 
quantitative total IgG or gamma 
globulins. 
 Serum acetaminophen adduct high 
performance liquid chromatography 
(HPLC) assay (quantifies potential 
acetaminophen contribution to liver 
injury in participants with definite or 
likely acetaminophen use in the 
preceding week.) NOTE: Not 
required in China. 
 Liver imaging (ultrasound, magnetic 
resonance, or computerized 
tomography) and/or liver biopsy to 
evaluate liver disease; complete liver 
imaging and/or liver biopsy CRFs. 
a Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation testing is 
unavailable, record the absence/presence of detectable urinary bilirubin on dipstick, which is indicative of direct 
bilirubin elevations suggesting liver injury. 
b All events of ALT ≥3xULN and bilirubin ≥2xULN (>35% direct bilirubin) or ALT ≥3xULN and INR >1.5 may 
indicate severe liver injury (possible ‘Hy’s Law’) and must be reported as an SAE (excluding studies of hepatic 
impairment or cirrhosis). The INR measurement is not required and the stated threshold value will not apply to 
participants receiving anticoagulants. 
c Hepatitis A immunoglobulin M (IgM) antibody; HBsAg and HBcAb; hepatitis C RNA; cytomegalovirus IgM 
antibody; Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, heterophile antibody or monospot 
testing); and hepatitis E IgM antibody. 
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10.7 
Appendix 7: Medical device incidents – definition and 
procedures for recording, evaluating, follow-up, and reporting 
Not applicable. 
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10.8 
Appendix 8: Rapid Alert Procedures 
Not applicable. 
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10.9 
Appendix 9: Country-specific requirements 
Not applicable. 
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10.10 
Appendix 10: Abbreviations and trademarks 
ADE 
adverse device effect 
AE 
adverse event 
AED 
antiepileptic drug 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANOVA 
analysis of variance 
app 
application 
ASADE 
anticipated serious adverse device effect 
AST 
aspartate aminotransferase 
BMI 
body mass index 
BZDs 
benzodiazepines 
cBZR 
central benzodiazepine receptor 
CBD 
cannabidiol 
CDMS 
clinical data management system 
CNS 
central nervous system 
CI 
confidence interval 
CPM 
Clinical Project Manager 
CPMP 
Committee for Proprietary Medicinal Products 
CRO 
contract research organization 
CV 
coefficient of variation 
DBP 
diastolic blood pressure 
DMC 
Data Monitoring Committee 
ECG 
electrocardiogram 
eCRF 
electronic Case Report form 
EDC 
electronic data capture 
EEG 
electroencephalogram 
EMA/EMEA 
European Medicines Agency 
ES 
Enrolled Set 
EudraCT 
European Union Drug Regulating Authorities Clinical Trials 
FAS 
Full analysis Set 
FDA 
Food and Drug Administration 
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GABAA 
gamma-aminobutyric acid type A 
GCP 
Good Clinical Practice 
HBsAg 
hepatitis B surface antigen 
HCV-Ab 
hepatitis C antibody 
HIV 
human immunodeficiency virus 
HLA 
human leukocyte antigen 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IDE 
Investigational Device Exemption 
IEC 
Independent Ethics Committee 
IMP 
investigational medicinal product 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
IUD 
intrauterine devices 
IUS 
intrauterine systems 
LEV 
levetiracetam 
NCA 
non-compartmental analysis 
NCI-CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
OTC 
over-the-counter 
PD 
pharmacodynamics(s) 
PDILI 
potential drug-induced liver injury 
PD-PPS 
Pharmacodynamic Per Protocol Set 
PK 
pharmacokinetic(s) 
PK-PPS 
Pharmacokinetic Per Protocol Set 
PR 
pulse rate 
PS 
Patient Safety 
PSL 
Padsevonil 
RMF 
medical device risk management file 
RNA 
ribonucleic acid 
RR 
respiratory rate 
RS 
Randomized Set 
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SADE 
serious adverse device effect 
SAE 
serious adverse event 
SBP 
systolic blood pressure 
SD 
standard deviation 
SmPC 
Summary of Product Characteristics 
SOP 
Standard Operating Procedure 
SPC 
Summary of Product Characteristics 
SUSAR 
suspected unexpected serious adverse reactions 
SV2 
synaptic vesicle protein 2 
TMF 
trial master file 
UADE 
unanticipated adverse device effect 
ULN 
upper limit of normal 
USADE 
unanticipated serious adverse device effect 
 
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10.11 
Appendix 11: Protocol amendment history 
Not applicable. 
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11 
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SPONSOR DECLARATION 
I confirm that I have carefully read and understand this protocol and agree to conduct this 
clinical study as outlined in this protocol and according to current Good Clinical Practice. 
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Approval Signatures
Name:
up0071-protocol-amend-1
Version:
1. 0
Document Number:
CLIN-000137909
Title:
UP0071 Protocol Amendment 1
Approved Date:
25 Jul 2019
Document Approvals
Approval
Verdict: Approved
Name: 
Capacity: Clinical
Date of Signature: 25-Jul-2019 14:10:45 GMT+0000
Approval
Verdict: Approved
Name: 
Capacity: Clinical
Date of Signature: 25-Jul-2019 14:13:45 GMT+0000
Approval
Verdict: Approved
Name: 
Capacity: Subject Matter Expert
Date of Signature: 25-Jul-2019 15:55:31 GMT+0000
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SAP_001.pdf: 
UCB 
 
27th Jan 2020 
Statistical Analysis Plan 
Padsevonil 
UP0071 
 
 
 
Confidential 
Page 1 of 39 
 
STATISTICAL ANALYSIS PLAN  
Study: UP0071 
Product: Padsevonil 
 
A DOUBLE-BLIND, PLACEBO-CONTROLLED, RANDOMIZED, 
SINGLE-CENTER, CROSS-OVER STUDY TO INVESTIGATE 
THE PHARMACODYNAMIC, PHARMACOKINETIC, SAFETY, 
AND TOLERABILITY PROFILES OF PADSEVONIL IN 
HEALTHY STUDY PARTICIPANTS RECEIVING EITHER 
ETHANOL OR CANNABIDIOL 
PHASE 1 
 
 
 
SAP/Amendment Number Date 
Final SAP v1.0 
27 Jan 2020 
Confidentiality Statement 
Confidential 
This document is the property of UCB and may not – in full or in part – be passed on, 
reproduced, published, or otherwise used without the express permission of UCB. 
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Statistical Analysis Plan 
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UP0071 
 
 
 
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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS .................................................................................................... 5 
1 
INTRODUCTION ............................................................................................................. 7 
2 
PROTOCOL SUMMARY ................................................................................................. 7 
2.1 Study objectives and endpoints .......................................................................................... 7 
2.1.1 
Part A ..................................................................................................................... 7 
2.1.2 
Part B ..................................................................................................................... 8 
2.2 Study design and conduct ................................................................................................ 10 
2.2.1 
Overall study design ............................................................................................ 10 
2.2.2 
Part A ................................................................................................................... 10 
2.2.3 
Part B ................................................................................................................... 11 
2.3 Determination of sample size ........................................................................................... 12 
3 
DATA ANALYSIS CONSIDERATIONS ...................................................................... 13 
3.1 General presentation of summaries and analyses ............................................................ 13 
3.2 General study level definitions ........................................................................................ 14 
3.2.1 
Study day ............................................................................................................. 14 
3.3 Definition of Baseline values ........................................................................................... 14 
3.4 Protocol deviations ........................................................................................................... 15 
3.5 Analysis Sets .................................................................................................................... 16 
3.5.1 
All Study Participants .......................................................................................... 16 
3.5.2 
Safety Set ............................................................................................................. 16 
3.5.3 
Full Analysis Set .................................................................................................. 16 
3.5.4 
Pharmacokinetic Set ............................................................................................ 16 
3.6 Treatment assignment and treatment groups ................................................................... 16 
3.6.1 
Part A ................................................................................................................... 16 
3.6.2 
Part B ................................................................................................................... 18 
3.7 Center pooling strategy .................................................................................................... 21 
3.8 Coding dictionaries .......................................................................................................... 21 
3.9 Changes to protocol-defined analyses.............................................................................. 21 
4 
STATISTICAL/ANALYTICAL ISSUES ....................................................................... 21 
4.1 Adjustments for covariates............................................................................................... 21 
4.2 Handling of dropouts or missing data .............................................................................. 21 
4.2.1 
Pharmacokinetics ................................................................................................. 21 
4.2.2 
Safety laboratory data .......................................................................................... 22 
4.2.3 
Electrocardiogram data ........................................................................................ 22 
4.3 Interim analyses and data monitoring .............................................................................. 23 
4.4 Multicenter studies ........................................................................................................... 23 
4.5 Multiple comparisons/multiplicity ................................................................................... 23 
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Statistical Analysis Plan 
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4.6 Use of an efficacy subset of study participants ................................................................ 23 
4.7 Active-control studies intended to show equivalence ...................................................... 23 
4.8 Examination of subgroups ............................................................................................... 23 
5 
STUDY POPULATION CHARACTERISTICS ............................................................. 23 
5.1 Participant disposition ...................................................................................................... 23 
5.2 Protocol deviations ........................................................................................................... 24 
6 
DEMOGRAPHICS .......................................................................................................... 24 
6.1 Medical history and concomitant diseases ....................................................................... 25 
6.2 Concomitant medications ................................................................................................. 25 
7 
MEASURES OF TREATMENT COMPLIANCE .......................................................... 25 
8 
EFFICACY ANALYSES ................................................................................................ 25 
9 
PHARMACOKINETICS ................................................................................................. 25 
9.1 Analysis of pharmacokinetics variables ........................................................................... 26 
9.1.1 
Descriptive figures and summaries ...................................................................... 26 
9.1.2 
Statistical analysis of pharmacokinetics variables ............................................... 27 
9.1.2.1 
Ethanol interaction on PSL (Part A) .......................................................... 27 
9.1.2.2 
PSL interaction on ethanol (Part A) .......................................................... 27 
9.1.2.3 
CBD interaction on PSL (Part B) .............................................................. 27 
9.1.2.4 
PSL interaction on CBD (Part B) .............................................................. 28 
10 PHARMACODYNAMICS .............................................................................................. 28 
10.1 Analysis of pharmacodynamics variables ........................................................................ 28 
10.1.1 
Descriptive figures and summaries ...................................................................... 28 
10.1.2 
Statistical analysis of pharmacodynamics variables ............................................ 29 
10.1.2.1 
Ethanol and PSL (Part A) .......................................................................... 29 
10.1.2.2 
CBD and PSL (Part B) .............................................................................. 29 
11 SAFETY ANALYSES ..................................................................................................... 30 
11.1 Extent of exposure ........................................................................................................... 30 
11.2 Adverse events ................................................................................................................. 30 
11.3 Clinical laboratory evaluations ........................................................................................ 31 
11.4 Vital signs, physical findings, and other observations related to safety .......................... 33 
11.4.1 
Vital signs ............................................................................................................ 33 
11.4.2 
Electrocardiogram ................................................................................................ 34 
11.4.3 
Other safety variable(s) ........................................................................................ 35 
11.4.3.1 
Physical examination ................................................................................. 35 
11.4.3.2 
Columbia-Suicide Severity Rating Scale .................................................. 35 
12 OTHER ANALYSES ...................................................................................................... 35 
13 REFERENCES ................................................................................................................ 36 
14 APPENDICES ................................................................................................................. 37 
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14.1 Appendix 1: VAS feeling high, internal and external perception (Bowdle) .................... 37 
14.2 Appendix 2: VAS Bond-Lader ........................................................................................ 38 
STATISTICAL ANALYSIS PLAN SIGNATURE PAGE ..................................................... 39 
 
 
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Statistical Analysis Plan 
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UP0071 
 
 
 
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LIST OF ABBREVIATIONS 
AE(s) 
adverse event(s) 
AED 
antiepileptic drug 
ALT 
alanine aminotransferase 
ALQ 
above the limit of quantification 
AST 
aspartate aminotransferase 
AUCτ 
area under the curve over a dosing interval (12 hrs) 
BID 
twice daily 
BLQ 
below the limit of quantification 
BMI 
body mass index 
CBD 
cannabidiol  
CI 
confidence interval 
CL/Fss 
apparent total clearance at steady-state 
Cmax 
maximum observed plasma concentration 
Ctrough 
predose plasma concentration  
CRU 
clinical research unit 
CSR 
clinical study report 
CV 
coefficient of variation 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
DEM 
data evaluation meeting 
ECG 
electrocardiogram 
EOS 
End of Study 
ES 
Enrolled set 
EudraCT 
European Union Drug Regulating Authorities 
Clinical Trials 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
geoCV 
geometric coefficient of variation 
ICF 
Informed Consent form 
ICH 
International Council on Harmonisation 
IMP 
investigational medicinal product 
IPD 
important protocol deviation 
LLOQ 
lower limit of quantification 
MedDRA 
Medical Dictionary for Regulatory Activities 
MHD 
Mono Hydroxy Derivate 
n 
number of study participants 
number of available observations 
PD 
Pharmacodynamic(s)  
PDILI 
potential drug-induced liver injury 
PKS 
Pharmacokinetic Set 
PK 
Pharmacokinetic(s) 
PR 
pulse rate 
PSL 
Padsevonil 
PT 
preferred term 
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Statistical Analysis Plan 
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UP0071 
 
 
 
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QTcF 
QT corrected for heart rate using Fridericia’s 
formula 
RR 
respiratory rate 
SAE(s) 
serious adverse event(s) 
SAP 
statistical analysis plan 
SAS 
statistical analysis system 
SD 
standard deviation 
SFU 
Safety Follow-up 
SOC 
system organ class 
TEAE 
treatment-emergent adverse event 
TFLs 
tables, figures and listings 
tmax 
time to maximum concentration 
ULN 
upper limit of normal 
WHODD 
World Health Organization Drug Dictionary 
 
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Statistical Analysis Plan 
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UP0071 
 
 
 
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1 
INTRODUCTION 
The purpose of this statistical analysis plan (SAP) is to provide all information that is necessary 
to perform the required statistical analysis of UP0071. It also defines the summary tables, figures 
and listings (TFLs) to be included in the final clinical study report (CSR) according to the 
protocol.  
This SAP is based on the final protocol amendment 1, dated 25 July 2019.  
Unless specified in the sections below, the study will be analyzed as described in the most recent 
version of the protocol. If a future protocol amendment necessitates a substantial change to the 
statistical analysis of the study data, this SAP will be amended accordingly. In addition, if 
analysis definitions must be modified or updated prior to database lock, a SAP amendment will 
be required. If, after database lock, additional analyses are required to supplement the planned 
analyses described in this SAP, these changes will be described in the CSR together with the 
associated rationale.  
The content of this SAP is compatible with the International Council for Harmonisation 
(ICH)/Food and Drug Administration (FDA) E9 Guidance documents (Phillips et al, 2003).  
UCB is the Sponsor and ICON PLC is the Contract Research Organization (CRO) for this study. 
2 
PROTOCOL SUMMARY 
2.1 
Study objectives and endpoints 
2.1.1 
Part A  
Objectives 
Endpoints 
Primary 
To evaluate the PD interaction between 
steady-state treatment with PSL and ethanol 
 
Smooth pursuit (%) to assess eye 
movement coordination and attention 
Secondary 
To evaluate the PK interaction between 
steady-state treatment with PSL and ethanol 
 Ethanol dose infused over time 
 Cmax,ss and AUCτ, obtained from the 
plasma concentration-time profiles for 
PSL and its metabolites 
To evaluate the PD interaction between 
steady-state treatment with PSL and ethanol  
 Saccadic peak velocity (degrees/sec) to 
assess sedation 
 Adaptive tracking (%) to assess 
visuo-motor control and vigilance 
 Body Sway to assess postural stability 
To evaluate the safety and tolerability of PSL 
in study participants receiving concomitant 
ethanol  
 
Adverse events (AEs), serious adverse 
events (SAEs), treatment-related AEs, 
and AEs leading to discontinuation of the 
study 
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Other 
To evaluate the safety and tolerability of PSL 
in study participants receiving concomitant 
ethanol 
 Vital signs (pulse rate, respiratory rate, 
systolic blood pressure [SBP], and 
diastolic blood pressure [DBP]) 
 12-lead electrocardiogram (ECG) 
parameters  
 Physical examination findings 
 Clinical laboratory test results 
(hematology, clinical chemistry, and 
urinalysis) 
To evaluate the PD interaction between 
steady-state treatment with PSL and ethanol  
 Visual analogue scales (VAS) Bond & 
Lader to assess alertness, mood, and 
calmness 
 VAS feeling high, internal and external 
perception (Bowdle)  
 VAS for alcohol intoxication to assess the  
effects of ethanol  
To evaluate the PK interaction between 
steady-state treatment with PSL and ethanol 
 
tmax and Ctrough obtained from the plasma 
concentration-time profiles for PSL and 
its metabolites 
To collect and store blood for potential 
ADME genotype (if needed) 
 
Possible ADME genotyping for drug 
metabolizing enzymes (depending on the 
outcome of PSL (and metabolite) PK 
analyses 
To collect urine samples for additional PK 
analyses depending on the outcome of PSL 
(and metabolite) PK analyses, if needed 
 
Urine sample PK analysis 
2.1.2 
Part B  
Objectives 
Endpoints 
Primary 
To evaluate the PK interaction between 
steady-state treatment with PSL and CBD 
 
Cmax,ss and AUCτ obtained from the 
plasma concentration-time profiles for 
PSL and CBD  
Secondary 
To evaluate the PK interaction between 
steady-state treatment with PSL and CBD 
 t1/2, and CLss/F obtained from the plasma 
concentration-time profiles for PSL and 
CBD 
To evaluate the PD interaction between 
steady-state treatment with PSL and CBD 
 Smooth pursuit (%) to assess eye 
movement coordination and attention 
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 Saccadic peak velocity (degrees/sec) to 
assess sedation 
 Adaptive tracking (%) to assess 
visuo-motor control and vigilance 
 Body Sway to assess postural stability 
To evaluate the safety and tolerability of PSL 
in study participants receiving concomitant 
CBD 
 
Adverse events (AEs), serious adverse 
events (SAEs), treatment-related AEs, 
and AEs leading to discontinuation of the 
study 
Other 
To evaluate the safety and tolerability of PSL 
in study participants receiving concomitant 
CBD 
 Vital signs (pulse rate, respiratory rate, 
systolic blood pressure [SBP], and 
diastolic blood pressure [DBP]) 
 12-lead electrocardiogram (ECG) 
parameters  
 Physical examination findings 
 Clinical laboratory test results 
(hematology, clinical chemistry, and 
urinalysis) 
To evaluate the PD interaction between 
steady-state treatment with PSL and CBD 
 Visual analogue scales (VAS) Bond & 
Lader to assess study participant alertness, 
mood, and calmness 
 VAS feeling high, internal and external 
perception (Bowdle)  
To evaluate the PK interaction between 
steady-state treatment with PSL and CBD 
 tmax and Ctrough obtained from the plasma 
concentration-time profiles for PSL and 
CBD  
 
Cmax,ss, AUCτ, t1/2, tmax, and 
metabolite/parent ratio (based on Cmax,ss 
and AUCτ) obtained from the plasma 
concentration-time profiles for PSL 
metabolites and CBD active metabolite 
To evaluate the plasma PK of single dose of 
CBD (Treatment Period 1) 
 Cmax, AUC0-t, AUC, tmax, t1/2 and CL/F  
To collect and store blood for potential 
ADME genotype (if needed) 
 
Possible ADME genotyping for drug 
metabolizing enzymes (depending on the 
outcome of PSL (and metabolite) PK 
analyses 
To collect urine samples for additional PK 
analyses depending on the outcome of PSL 
(and metabolite) PK analyses, if needed 
 
Urine sample PK analysis 
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2.2 
Study design and conduct 
2.2.1 
Overall study design 
This is a Phase 1, double-blind, randomized, placebo-controlled, single-center, cross-over study 
to evaluate the PK, PD, safety, and tolerability of steady state treatment of PSL in healthy study 
participants receiving either ethanol (Part A) or steady-state treatment of CBD (Part B). Study 
participants that participate in Part A of the study are not eligible to participate in Part B; 
similarly, study participants that participate in Part B are not eligible to participate in Part A. 
2.2.2 
Part A 
Treatment Periods 1 and 2, and 4 and 5 are 2-way cross-over, placebo-controlled, 
ethanol-clamping periods with a washout of at least 2 days between Treatment Periods 2 and 3; 
PSL is not administered in Treatment Periods 1 and 2. Treatment Period 3 is an open-label PSL 
up-titration period toward a maintenance level of 200mg BID and is immediately followed by 
Treatment Period 4 and Treatment Period 5. Treatment Period 6 is the PSL tapering open-label 
period. A detailed schematic diagram of Part A of the study is provided in Figure 2-1.  
The objectives of Part A are to evaluate the: plasma PK, safety and tolerability of PSL and its 
metabolites in the presence and absence of ethanol; metabolizing capacity of ethanol in the 
presence and absence of PSL; effect of PSL on PD parameters in the presence and absence of 
ethanol; effect of ethanol on PD parameters in the presence and absence of PSL.   
Figure 2-1: Study schematic – Part A 
 
BID=twice daily; CBD=cannibidiol; D=day; FU=Follow-up Period; PBO=placebo; PSL=padsevonil; W=week 
Note: Follow up will occur between 7 to 10 days after the final dose of PSL. 
Note: A WO of at least 2 days will occur between Treatment Period 2 and Treatment Period 3. 
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Study participants will be randomized to one of four treatment sequences:  
Table 2-2: Treatment Sequences – Part A 
Sequence 
ID 
Randomization Sequence   
Sequence in Full  
1 
Ethanol(TP1)/Placebo(TP2)/ 
Ethanol(TP4)/Placebo(TP5) 
Ethanol (TP1)/Placebo (TP2)/PSL(TP3)/ 
PSL+Ethanol (TP4)/PSL+Placebo 
(TP5)/PSL(TP6) 
2 
Ethanol(TP1)/Placebo(TP2)/ 
Placebo(TP4)/Ethanol(TP5) 
Ethanol(TP1)/Placebo(TP2)/PSL(TP3)/ 
PSL+Placebo (TP4)/PSL+Ethanol(TP5)/ 
PSL(TP6) 
3 
Placebo(TP1)/Ethanol(TP2)/ 
Ethanol(TP4)/Placebo(TP5) 
Placebo(TP1)/Ethanol(TP2)/PSL(TP3)/ 
PSL+Ethanol(TP4)/PSL+Placebo(TP5)/PSL(TP6) 
4 
Placebo(TP1)/Ethanol(TP2)/ 
Placebo(TP4)/Ethanol(TP5) 
Placebo(TP1)/Ethanol(TP2)/PSL(TP3)/ 
PSL+Placebo(TP4)/PSL+Ethanol(TP5)/ 
PSL(TP6) 
TP=Treatment Period.  
2.2.3 
Part B 
Treatment Period 1 of Part B will be conducted in a sentinel cohort of healthy study participants 
in order to evaluate CBD safety and PK exposure under a single dose of CBD 10mg/kg (fasted 
conditions).  
A washout of at least 6 days will occur between Treatment Period 1 and Treatment Period 2. 
Treatment Period 2 will include 7 days of treatment with open-label PSL treatment. Treatment 
Period 3 starts after a washout of minimally 6 days for all study participants and includes an 
ambulatory open-label CBD up titration of 16 days toward a maintenance level of 10mg/kg BID. 
Treatment Periods 4 and 5 is a 2-way cross-over, double-blind and placebo-controlled periods 
with PSL up titrated to a maintenance level of 200mg BID through Day 5 and subsequent down 
titration until Day 8. A maintenance dose of 10mg/kg BID CBD will occur in-house between 
Treatment Periods 4 and 5. Cannabidiol down titration starts in Treatment Period 6. 
A detailed schematic diagram of Part B of the study is provided in Figure 2-2. 
The objectives of Part B are to evaluate the: plasma PK, safety and tolerability of PSL and its 
metabolites in the presence and absence of CBD; plasma PK of CBD and its metabolites in the 
presence and absence of PSL; effect of PSL on PD parameters in the presence and absence of 
CBD; effect of CBD on PD parameters in the presence and absence of PSL.  
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Figure 2-2: Study schematic – Part B 
 
Note: Follow up will occur between 7 to 10 days after the final dose of CBD. 
Note: A WO of at least 6 days will occur following Treatment Period 1 and Treatment Period 2. 
BID=twice daily; CBD=cannabidiol; D=day; FU=Follow-up Period; PBO=placebo for PSL; PSL=padsevonil; SD=single dose; 
W=week 
 
Study participants will be randomized to one of two treatment sequences:  
Table 2-2: Treatment Sequences – Part B 
Sequence 
ID 
Randomization Sequence   
Sequence in Full  
1 
CBD 10mg/kg BID+PSL(TP4)/ 
CBD 10mg/kg 
BID+Placebo(TP5) 
PSL(TP2)/CBD(TP3)/ 
CBD 10mg/kg BID+PSL(TP4)/ 
CBD 10mg/kg BID+Placebo(TP5)/ 
CBD(TP6) 
2 
CBD 10mg/kg 
BID+Placebo(TP4)/ 
CBD 10mg/kg BID+PSL(TP5) 
PSL(TP2)/CBD(TP3)/ 
CBD 10mg/kg BID+Placebo(TP4)/ 
CBD 10mg/kg BID+PSL(TP5)/CBD(TP6) 
TP=Treatment Period.  
2.3 
Determination of sample size 
Based on the study PK and PD objectives, the total planned number of healthy study participants 
will be 44, including 22 evaluable participants for Part A and 22 evaluable participants for 
Part B. 
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For Part A, the sample size is based on pragmatic considerations and the ability to detect an 
ethanol effect on PD assessments (CNS variable). A sample size of 22 evaluable study 
participants provides 80% power to detect an ethanol effect in a difference in means of 
3.96 (% points) for the smooth pursuit test, which is the most sensitive CNS variable to ethanol 
effects, assuming a SD of difference of 6.0 (% points) based on previous ethanol clamp 
interaction studies and using a paired t-test 2-sided with a 0.05 significance level. This sample 
size is also valid for the CBD effect assessment (Part B). The sample size calculation performed 
does not assess the difference in means between PSL+Ethanol effect vs PSL+Placebo, as the 
expected difference between the interaction is unknown but similarly a difference of 3.96 (% 
points) could be detected.  
For Part B, a sample size of 22 evaluable study participants is needed to assess the PK interaction 
between PSL and CBD, and to estimate the mean PSL AUCτ ratio of with/without CBD of 
1.5 with a half-width of the CI of 0.3. This sample size has been evaluated with a conditional 
probability of 90%, assuming an inter-participant coefficient of variation of 45% of PSL AUCτ 
(observed in study UP0057), correlation of 0.5, 2-sided and α = 0.05. A sufficient number of 
healthy study participants (up to 20) will be selected to have 16 completed study participants. 
Regarding the assessment of the single dose formulation of CBD (under fasted conditions) in 
Part B (study formulation vs Epidiolex formulation from literature data), 16 healthy study 
participants are required to assess the similarity of the 2 formulations (equivalence range of 50 to 
200% based on the high variability of CBD) with a 80% power and assuming an expected 
geometric mean ratio of AUC and Cmax between 0.8 and 1.3, and inter-participant CV of 80% 
(based on CBD literature) and correlation of 0.5.  
Sample size computations were performed using SAS version 9.4 (Proc Power). 
Drop outs will be replaced at the discretion of the Investigator and Sponsor. 
3 
DATA ANALYSIS CONSIDERATIONS 
3.1 
General presentation of summaries and analyses 
Each study part will be summarized and analyzed separately.  
Statistical evaluation will be performed by ICON PLC with the exception of PD which will be 
conducted to UCB. The datasets will follow the UCB analysis data model (ADaM) data 
specifications.  
All analyses will be performed using SAS version 9.4 or higher (SAS Institute, Cary, North 
Carolina, United States). The PK noncompartmental analysis (NCA) will be performed using 
Phoenix WinNonlin®v6.3 or higher (Certara L.P., Princeton, NJ, USA) for pharmacokinetics 
parameters estimation. All non-PD TFLs will be produced by ICON PLC SAS programming 
(Early Phase).  
Continuous variables will be summarized by phase (defined in Section 3.5), treatment and 
timepoint (where applicable) including number of study participants (n), mean, standard 
deviation (SD), median, minimum, maximum and 95% confidence intervals (CI) for the mean. 
Geometric coefficient of variation (geoCV), geometric mean and 95% confidence interval (CI) 
for the geometric mean will also be presented in the descriptive statistics for the PK 
concentration data and PK parameters of; PSL and its metabolites (
 and 
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), and CBD and its active metabolite. In all outputs the confidence limits will 
be restricted to the possible values that the variable can take.  
Categorical variables will be summarized by phase, treatment and timepoint (where applicable) 
with frequency counts and percentages.   
3.2 
General study level definitions 
3.2.1 
Study day 
For Part A, study day consist of Day -1 (prior to Treatment Period 1) to approximately Day 16 
(last day of Treatment Period 6).  
For Part B, study day consists of Day -1 (prior to Treatment Period 1) to approximately Day 53 
(last day of Treatment Period 6). 
Relative day will not be used in this study. Instead refer to Section 3.2.1 for use of Study Day.  
3.3 
Definition of Baseline values 
Measurement-specific Baseline timepoints are presented in Table 3‒1. 
Table 3‒1: 
Definition of Baseline 
Measurement 
Definition of Baseline 
Hematology, serum chemistry, 
urinalysis 
For Part A, baseline is defined as the visit at which study participants 
were randomized to one of the four treatment sequences i.e. Day -1 prior 
to Treatment Period 1.  
For Part B, baseline is defined as Day -1 prior to Treatment Period 2.  
For both study parts, if Day -1 is missing or multiple assessments occur, 
the last measure prior to dosing will be used. 
Vital Signs  
For Part A, baseline is defined as predose on Day 1 of Treatment Period 
1.  
For Part B, baseline is defined as predose on Day 1 of Treatment Period 
2.  
For both study parts, if predose on Day 1 is missing or multiple 
assessments occur, the last measure prior to dosing will be used. 
ECG 
For Part A, the mean of the last three measurements predose on Day 1 of 
Treatment Period 1 will be taken as baseline.  
For Part B, the mean of the last three measurements predose on Day 1 of 
Treatment Period 2 will be taken as baseline.  
For both study parts. if less than three replicates are available predose, 
the mean of the available replicates (predose) will be taken as baseline. 
C-SSRS 
For both study parts, separate baseline questionnaire for C-SSRS.  
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Measurement 
Definition of Baseline 
PD variables 
For both study parts, baseline for change from baseline summaries and 
tables is defined as the average of the two values measured at predose of 
given day. Baseline definition for the model is defined in Section 10.1.2. 
The change from Baseline to any subsequent post-Baseline visit will be calculated as the simple 
difference between that post-Baseline visit’s value and the Baseline visit value, as below:    
𝑃𝑜𝑠𝑡 𝐵𝑎𝑠𝑒𝑙𝑖𝑛𝑒 𝑉𝑖𝑠𝑖𝑡 𝑉𝑎𝑙𝑢𝑒 − 𝐵𝑎𝑠𝑒𝑙𝑖𝑛𝑒 𝑉𝑖𝑠𝑖𝑡 𝑉𝑎𝑙𝑢𝑒 
3.4 
Protocol deviations 
Important protocol deviations (IPD) are deviations from the protocol which potentially could 
have a meaningful impact on study conduct or on either the primary outcome or key secondary 
outcome for an individual study participant. The criteria for identifying such protocol deviations 
will be defined within the protocol deviation specifications document. 
Important protocol deviations will include the following categories:  
 Inclusion/exclusion criteria deviations 
 Administration of prohibited concomitant medications  
 Deviations relating to withdrawal criteria  
 Visit schedule deviations  
 Study drug administration deviations (including incorrect treatment received, handling and 
storage deviations and incorrect dosage received) and any vomiting episode(s) (that could 
impact PK concentrations)  
 Procedural noncompliance  
 Missing data  
All IPDs will be reviewed as part of the ongoing data cleaning process and data evaluation. After 
all data have been verified/coded/entered into a database, a data evaluation meeting (DEM) will 
be performed.  
At least one DEM will be performed at the following time:  
 Prior to the final analysis after all data have been verified/coded/entered into the database 
Additional DEMs may be conducted as deemed necessary.  
The purpose of these DEM reviews will be to review all protocol deviations, define the analysis 
sets, and check the quality of the data. The reviews will also help decide how to manage 
problems in the study participants’ data (e.g. missing values, withdrawals and protocol 
deviations).  
Accepted deviations from scheduled time points will be described in the appropriate documents 
and included in the Study Master File. After the pre-analysis review, resolution of all issues, and 
documentation of all decisions (including inclusion into each of the analysis sets) at the final 
DEM, the database will be locked. 
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3.5 
Analysis Sets  
The following analysis sets apply and will be created separately for each study part.  
3.5.1 
All Study Participants  
All Study Participants will consist of all participants who have signed the Informed Consent 
form (ICF). This set was previously referred to as Enrolled Set in the Study Protocol.  
3.5.2 
Safety Set   
The Safety Set (SS) will consist of all study participants who are randomized and have received 
at least 1 dose (any amount) of study medication. Safety variables will be analyzed using the SS.  
It is expected that study participants will receive treatment as randomized; hence, safety analyses 
will be based on the randomized treatment group. However, if after unblinding it is determined 
that study participants received the incorrect treatment (i.e. not as per the randomization 
schedule), then for safety analyses study participants will be allocated to the actual treatment 
they received (as-treated) for the data summaries.   
3.5.3 
Full Analysis Set   
The Full Analysis Set (FAS) consists of all study participants that were randomized, received 
study medication, and had at least one valid post-baseline primary PD assessment observation.  It 
is intended that study participants will be classified according to the treatment which was 
actually received. 
3.5.4 
Pharmacokinetic Set  
The Pharmacokinetic Set (PKS) consists of all study participants that received at least one dose 
of active study drug and have at least one observable PK measurement.  If a study participant in 
the PK set is missing individual timepoints or are otherwise unobservable will be included in the 
PK set but those timepoints will be omitted from the PK summaries, as appropriate. 
3.6 
Treatment assignment and treatment groups 
3.6.1 
Part A 
For all analyses (where applicable) the results will be presented by phase and treatment. For 
summary tables, results from Treatment Period 3 and 6 will be presented by PSL. Sequence in 
full will be used where applicable (defined in Section 2.2.2). 
Phase, phase day, treatment (for listings and tables) and the corresponding treatment period and 
day from the protocol are defined in Table 3-2.   
 
 
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Table 3‒2: 
Definition of Phase - Part A 
Protocol 
Treatment 
Period 
Protocol 
Treatment 
Period Day 
Phase 
Phase Day 
Treatment for Listings  
Treatment for Tables  
Screening  
-28 to -2 
Screening  
-28 to -2 
N/A 
N/A 
1 
-1 to 2  
Ethanol Phase 
-1 to 2  
Ethanol/Placebo 
Ethanol/Placebo 
2 
1 to 2  
Ethanol Phase 
3 to 4 
Ethanol/Placebo 
Ethanol/Placebo 
Washout 
Period  
- 
Ethanol Phase 
5 to 6 
Ethanol/Placebo 
Ethanol/Placebo 
3  
-1  
Interaction Phase  
-1 
Ethanol/Placebo 
Ethanol/Placebo* 
3 
1 
Interaction Phase 
1 
PSL up-titration 
PSL 
3 
2 to 4 
Interaction Phase 
2 to 4 
PSL maintenance  
PSL 
4 
5  
Interaction Phase 
5  
PSL+Ethanol/PSL+Placebo   
PSL+Ethanol/PSL+Placebo 
4 
6 
Interaction Phase 
6 
PSL maintenance  
PSL 
5 
7 
Interaction Phase 
7 
PSL+Ethanol/PSL+Placebo   
PSL+Ethanol/PSL+Placebo   
5 
8 
Interaction Phase 
8 
PSL tapering  
PSL 
6 
9 to 10  
Interaction Phase 
9 to 10  
PSL tapering  
PSL  
Follow-up  - 
Follow-up 
17 or 20  
N/A 
N/A 
- = Day not specified in protocol; * If assessments are summarized by treatment, phase and day, then data will be presented as: PSL, Interaction Phase, Day -1. If 
assessments are summarized by treatment, then data from Day -1 will attribute to either Ethanol or Placebo e.g. if an AE occurs on Day -1, then the AE will be 
summarized where treatment is Ethanol or Placebo since this is the most recent treatment received.  
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3.6.2 
Part B 
For all analyses (where applicable) the results will be presented by phase and treatment. For 
summary tables, results from Treatment Period 3 and 6 will be presented by CBD. Listings will 
also include phase day. Sequence in full will be used where applicable (defined in Section 2.2.3). 
Phase, phase day, treatment (for listings and tables) and the corresponding treatment period and 
day from the protocol are defined in Table 3-3.   
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Table 3‒3: 
Definition of Phase - Part B 
Protocol 
Treatment 
Period 
Protocol 
Treatment 
Period Day 
Phase 
Phase Day 
Treatment for Listings 
Treatment for Tables  
Screening  
-28 to -2 
Screening  
-28 to -2 
N/A 
N/A 
1 
-1 to 2 (optional 
15-16) 
CBD Phase 
-1 to 2 (optional 15-
16) 
CBD SD 
CBD  
Washout Period  
- 
CBD Phase 
3 to 8 (or 17 to 22) 
CBD SD 
CBD 
2 
-1 
PSL Phase 
-1 
CBD SD 
CBDa 
2 
1 to 8  
PSL Phase 
1 to 8 
PSL 
PSL 
Washout Period  
- 
PSL Phase 
9 to 14   
PSL 
PSL 
3 
-1 
Interaction Phase 
-1 
PSL 
PSLb 
3  
1 to 16 
Interaction Phase  
1 to 16 
CBD up-titration 
CBD 
4  
1 to 7  
Interaction Phase 
17 to 23 
CBD+PSL/CBD+Placebo 
CBD+PSL/CBD+Placebo 
CBD Dose 
Maintenance  
- 
Interaction Phase 
24 to 27c 
CBD maintenance  
CBD 
5  
1 to 7  
Interaction Phase 
28 to 34 
CBD+PSL/CBD+Placebo 
CBD+PSL/CBD+Placebo 
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Protocol 
Treatment 
Period 
Protocol 
Treatment 
Period Day 
Phase 
Phase Day 
Treatment for Listings 
Treatment for Tables  
6  
1 to 7 
Interaction Phase 
35 to 41 
CBD tapering  
CBD 
Follow-up 
- 
Follow-up 
47 or 50  
N/A 
N/A 
- = Day not specified in protocol; a If assessments are summarized by treatment, phase and day, then data will be presented as: PSL, PSL Phase, Day -1. If 
assessments are summarized by treatment, then data from Day -1 will attribute to CBD. b If assessments are summarized by treatment, phase and day, then data 
will be presented as: CBD, Interaction Phase, Day -1. If assessments are summarized by treatment, then data from Day -1 will attribute to PSL. 
c CBD dose maintenance will occur for at least 4 days. If dosing is maintained for more than 4 days, the phase day will need to be changed accordingly;  
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3.7 
Center pooling strategy 
This is a single center trial. 
3.8 
Coding dictionaries 
Adverse events and medical history will be coded using the latest available version of the 
Medical Dictionary for Regulatory Activities (MedDRA®) (Version 22.1). Medications will be 
coded according to the World Health Organization Drug Dictionary (WHODD) (Version 
SEP/2017). Medical procedures will not be coded. 
3.9 
Changes to protocol-defined analyses 
 Due to changes in ClinPharm Standards, Enrolled Set has been changed to All Study 
Participants Set, Pharmacokinetic Per-Protocol Set has been changed to Pharmacokinetic Set 
and Pharmacodynamic Per-Protocol Set has been removed. 
 For Part A and B, period has been removed from the mixed analysis of variance (ANOVA) in 
the cases where it is confounded with treatment for PK and PD.   
 For Part B, analysis of metabolite to parent ratio based on AUCτ has been included for 
completeness.  
 For Part A and B baseline by time interactions have been added.  
 The following parameters were intended but omitted from the protocol and are included for 
completeness: 
o For Part A, tmax and Ctrough have been included as PK parameters for PSL and its 
metabolites  
o For Part A, Cmax,ss and AUCτ have been included as PK parameters for PSL metabolites 
o For Part B, Ctrough has been included as PK parameters for PSL and CBD 
o For Part B, Cmax, AUC0-t, AUC, tmax, t1/2 and CL/F have been included as PK parameters 
for the single dose of CBD within Treatment Period 1  
4 
STATISTICAL/ANALYTICAL ISSUES 
4.1 
Adjustments for covariates 
For the analysis of PD parameters, the within study participant baseline and between study 
participant baseline (defined in Section 10.1.2) will be included in the model as a covariate.  
4.2 
Handling of dropouts or missing data 
In general, there will be no imputation of missing data unless otherwise stated below. Missing 
data will be handled as described in the sections below for safety laboratory and PK results. No 
other imputations will be performed. 
4.2.1 
Pharmacokinetics  
The 95% CI lower and 95% CI upper should be left blank if the SD (or equivalently, the 
geometric CV) is 0. Measurements of PK concentrations that are below the limit of 
quantification (BLQ) and which are occurring prior to tmax will be imputed with half of the lower 
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limit of quantification (LLOQ/2), except for embedded BLQ values (between two measurable 
data points) which will be treated as missing, for the purpose of calculating the geometric mean 
and its 95% CI, the geometric CV, the arithmetic mean and SD for summaries and figures. Post- 
tmax, BLQ values will be treated as missing. Descriptive statistics of concentrations will be 
calculated if at least 2/3rd of the individual data points are quantifiable (≥LLOQ).   
For all individual PK concentration figures any concentrations that are BLQ will be regarded as 
missing, with the exception of predose BLQ measurements which will be imputed with 
“LLOQ/2” for linear scale plots.  
The following rules will apply for PK data listings and summaries:  
 Values below the LLOQ will be reported as “(BLQ)” in the listings 
 Descriptive statistics of plasma and dried blood concentrations will be calculated if more than 
2/3rd of individual data points are quantifiable (>=LLOQ) at the given time-point. Values 
that are BLQ will be replaced by the numerical value of the LLOQ/2 in this instance.  
However, if n<3, then only n, minimum and maximum will be presented, and the median will 
also be presented if n=3. The other descriptive statistics will be left blank.  
 For tmax, only N, median, minimum and maximum will be displayed into the summary 
statistics 
 For plasma concentrations, all BLQ values occurring prior to tmax will be replaced by 
“LLOQ/2”, except for embedded BLQ values (between two measurable data points) which 
will be treated as missing. Post- tmax, BLQ values will be treated as missing. The 
Pharmacokinetic analysis will be performed in accordance to the Guideline on performing 
NCA analysis dated 08 Nov 2017.  
 For the individual figures, any concentrations that are BLQ will be regarded as missing, with 
the exception of predose BLQ measurements which will be imputed with “LLOQ/2” for linear 
scale plots. 
 If no study participants have data, only n=0 will be presented. The other descriptive statistics 
will be left blank.  
 The geometric CV will be calculated using the following formula where SD is the standard 
deviation from the log-transformed data:  
Geometric CV (%) =  sqrt[(exp (SD^2) –  1)] x 100 
4.2.2 
Safety laboratory data  
The rules for handling values that are BLQ or above the limit of quantification (ALQ) in the 
safety laboratory data will be the same as those described for PK data in Section 4.2.1. 
4.2.3 
Electrocardiogram data  
For the 12-lead ECG data, all calculations of changes from Baseline and descriptive statistics 
will be based on the mean of the triplicate assessments at each timepoint. In the event that there 
are not 3 available measurements at a given timepoint, the mean will be calculated based on the 
number of measurements for which data are provided. 
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4.3 
Interim analyses and data monitoring 
Treatment Period 1 of Part B will be conducted in a sentinel cohort of healthy study participants 
in order to evaluate the PK exposure under a single dose of CBD 10mg/kg (fasted conditions). 
The results of the PK analysis from the first dose of CBD in Treatment Period 1 (Part B) will be 
compared to published PK data of CBD (dose of 750mg in fasted conditions) obtained in similar 
conditions with Epidiolex® (Taylor et al, 2018). The UCB study team will determine whether it is 
appropriate to proceed to Treatment Period 2, to proceed with the second single dose of CBD 
20mg/kg or to terminate Part B of the study.  
If the observed CBD exposure matches the data from the literature, then study will proceed 
directly to Treatment Period 2 of Part B (no second dosing of CBD will be required). A 
difference between the PK results in the present study and the literature findings requiring a >2-
fold dose adjustment will be considered as not manageable and would result in termination of 
Part B of the study. If a dose adjustment ≤2-fold is needed, then there may be a second dose of 
CBD administered to a cohort of healthy study participants within Treatment Period 1 in Part B.  
If the second dose is required, the results of the PK analysis from the second dose of CBD will 
be compared to published PK data of CBD. The UCB team will determine whether it is 
appropriate to proceed to Treatment Period 2 or to terminate Part B of the study.  
Treatment Period 2 cannot commence until the PK results from Treatment Period 1 are assessed. 
Pre-programming on the PD data has the potential to unblind study personnel. Hence the 
programming of SDTM (ICON) and ADaM and TFLs (UCB) will be done by teams independent 
to the study team. 
No interim analysis or data monitoring are planned in this study. 
4.4 
Multicenter studies 
Not applicable. 
4.5 
Multiple comparisons/multiplicity 
Multiple comparisons will not be accounted for. 
4.6 
Use of an efficacy subset of study participants 
Not applicable. 
4.7 
Active-control studies intended to show equivalence 
Not applicable. 
4.8 
Examination of subgroups 
Not applicable. 
5 
STUDY POPULATION CHARACTERISTICS 
5.1 
Participant disposition 
Study participant disposition will be listed by treatment sequence for All Study Participants and 
will include the following information: study participant status (screen failure, study completed 
or discontinued, study drug completed or discontinued, study drug discontinued, but study 
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continued), date of informed consent, date of randomization, date of first and last dose of study 
drugs, date of premature study and/or study drug termination (if applicable) and primary reason 
for study and/or study drug termination (if applicable). The listing will also include the date and 
reason for breaking the randomization code (if applicable) as well as the date of final contact for 
the study participant and the previous study participant number, if a study participant was re-
screened. 
Study participant disposition will be summarized overall for All Study Participants Screened 
including the reasons for screen failure, the number of study participants re-screened, the number 
of study participants randomized, reasons for discontinuation of study and/or study drug and the 
number of study participants with premature termination of study drug but not early withdrawn 
from the study.  
The number and percentage of study participants included in each of the analysis sets will be 
summarized for All Study Participants by treatment sequence. Percentages will be calculated 
based on All Study Participants for the purpose of this summary. 
5.2 
Protocol deviations 
Important protocol deviations will be identified and classified by the deviation types in the IPD 
document. A listing of all IPDs identified at the DEM will be presented for all study participants 
by phase based on the FAS and will include the deviation type and description. 
6 
DEMOGRAPHICS 
A listing of demographics by study participant and treatment sequence will be presented for All 
Study Participants. This will include the year of birth, age (in years), sex, race, ethnicity, height 
(cm), weight (kg) body mass index (BMI, in kg/m2). The body weight will be the measurement 
obtained at Screening. 
Body mass index (kg/m2) is calculated based on the height (m) and the weight (kg) using the 
following formula: 
𝐵𝑀𝐼 (𝑘𝑔/𝑚2) = 𝑤𝑒𝑖𝑔ℎ𝑡(𝑘𝑔)/[ℎ𝑒𝑖𝑔ℎ𝑡(𝑚)]2 
The BMI will be reported to 1 decimal place. 
All demographic characteristics (except for date of birth) will be summarized for the SS by 
sequence and overall. The summary of age will include descriptive statistics and categorical 
summaries, the latter based on requirements for European Union Drug Regulating Authorities 
Clinical Trials (EudraCT) and clinicaltrials.gov reporting. 
For the EudraCT reporting, the categories will include: 
 18 to <65 years  
 65 to <85 years  
 ≥85 years  
For clinicaltrials.gov reporting, the categories will include: 
 ≤18 years  
 19 to <65 years   
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 ≥65 years  
6.1 
Medical history and concomitant diseases 
Medical history and ongoing medical conditions will be listed and summarized for the SS by 
treatment sequence, MedDRA system organ class (SOC) and preferred term (PT). The reported 
term will be included in the listing. The summary will include the number and percentage of 
study participant and will be sorted alphabetically by SOC and by descending incidence of PT 
within each SOC, based on the ‘All Study Participants’ column.   
6.2 
Concomitant medications  
Concomitant medications will be listed and summarized for the SS by treatment sequence and 
will include WHODD Anatomical Main Group [Level 1 term text], Pharmacological Subgroup 
[Level 3 term text] and PT. The reported term will be included in the listing. Separate tabulations 
will be presented for prior medications and concomitant medications. All tabulations will be 
sorted alphabetically by Level 1 term, alphabetical Level 3 term within Level 1 and decreasing 
frequency of PT in the ‘All Study Participants’ column.  
7 
MEASURES OF TREATMENT COMPLIANCE  
As dosing is performed in-house by the investigator or member of staff, no specific assessment 
or compliance is warranted. Any dosing deviation will be addressed in the DEM and described in 
the CSR. Administration of study medications will be listed.  
8 
EFFICACY ANALYSES 
Not applicable.  
9 
PHARMACOKINETICS  
The calculation of the PK parameters of PSL and its metabolites (
 
), CBD and its metabolite (7-hydroxy-CBD) will be performed by the 
Quantitative Clinical Development Department, ICON PLC.  
Pharmacokinetic concentrations and parameters will be summarized by phase and treatment 
using the PKS. Figures of summaries will be based on the PKS and figures of individual 
concentrations will be based on the FAS.  
Pharmacokinetic parameters of PSL, CBD and metabolites will be calculated using the actual 
blood sampling times. Cmax,ss and tmax will be determined from the observed concentration and 
time data. When two or more identical peak concentrations are observed, tmax will be defined as 
the time of the first occurrence. AUCτ will be computed using the linear trapezoidal rule.  
For Part A, the PK variables used for PSL and its metabolites are: Cmax,ss, AUCτ, tmax and Ctrough; 
and for ethanol, total ethanol dose will be used.  
For Part B, the following PK variables used for PSL and CBD:  
 Primary: Cmax,ss and AUCτ 
 Secondary: CLss/F and t1/2 
 Other: tmax 
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In addition, the other PK variables (for Part B) used are: 
 Cmax, AUC0-t, AUC, tmax, t1/2 and CL/F for the single dose of CBD (Treatment Period 1) 
 Cmax,ss, AUCτ and tmax for PSL metabolites and CBD metabolite 
 The metabolite to parent ratio (based on Cmax,ss and AUCτ) obtained from the plasma 
concentration-time profiles for PSL metabolites and CBD active metabolite 
Metabolite to parent ratios will be corrected for molecular weight. The molecular weight (MW) 
of: PSL is 432.8; metabolite 
 is 
; metabolite 
 is 
; 
CBD is 314 and 7-hydroxy-CBD is 330. 
For both study parts, depending on the outcome of the PK analyses of PSL and its metabolites, 
urine samples for additional PK analyses will be collected for measurement of urine 
concentrations of PSL and its metabolites if needed.  
9.1 
Analysis of pharmacokinetics variables  
Pharmacokinetic variables will be analyzed separately for each study part.    
9.1.1 
Descriptive figures and summaries  
The PK plasma concentrations and the PK parameters of PSL, CBD and metabolites will be 
summarized by phase, treatment and nominal sampling times using descriptive statistics (number 
of available observations [n], arithmetic mean, median, SD, minimum, maximum, geometric 
mean, geometric CV and 95% CI for the geometric mean [assuming lognormally distributed 
data]). Any samples that are obtained outside the tolerance window permitted at the specified 
time point will be discussed at the DEM and any possible exclusion from analysis will be 
documented accordingly. Values below the LLOQ will be reported with a clear sign (flag 
variable in the dataset) indicating that they were below the LLOQ. The plasma trough 
concentrations of PSL, CBD and metabolites will be summarized separately. 
Individual participant concentration-time profiles of PSL and CBD by treatment (For Part A: 
PSL+Ethanol and PSL+Placebo, for Part B: CBD (single dose from Treatment Period 1), 
CBD+PSL and CBD+Placebo) will be displayed graphically in linear and semi-logarithmic 
scale. 
Combined individual (spaghetti) plots will be displayed by treatment with all participants 
overlaid on the same plot (linear and semi-logarithmic scale). 
Geometric mean profiles of plasma concentrations for PSL and CBD over time will be presented, 
with all treatments overlaid on the same plot, in both linear and semi-logarithmic scale. For the 
linear scale plot only, the lower and upper 95% confidence interval (CI) for the geometric mean 
will be displayed.   
All plasma concentration figures will include the LLOQ on the semi-logarithmic scale plots and 
will be based on scheduled times. 
Individual breath ethanol concentration-time data will be summarized by phase, treatment and 
nominal sampling times presenting the number of observations, geometric mean, lower and 
upper limit of the 95% CI for the geometric mean, geoCV(%), arithmetic mean, SD, median, 
minimum, and maximum. Individual participant breath ethanol concentration-time profiles will 
be displayed graphically in linear scale. Total ethanol dose will also be summarized by treatment.   
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The amount of urinary excretion of PSL (mg) per time interval after oral administration of PSL 
will be summarized by phase and treatment if measured. 
9.1.2 
Statistical analysis of pharmacokinetics variables 
The log-transformed PK parameters (Cmax,ss, AUCτ) of PSL, CBD and metabolites, metabolite to 
parent ration based on AUCτ (for Section 9.1.2.3 and Section 9.1.2.4 only) and total ethanol dose 
will be analyzed separately by a mixed analysis of variance (ANOVA) with period, treatment 
and sequence as fixed effects and study participant by period and study participant as the random 
effects. 
Due to the confounding of treatment within period within the design only the periods of interest 
will be included in any given comparison. For example, if the comparison is within the 
interaction phase then only Periods 4 and 5 will be kept in the model. 
Period should be removed from the model statement due to confounding with treatment in any 
comparisons where either test or reference period only contains one treatment option. It will be 
left in the random statement as period is synonymous with treatment. 
The PK parameter, tmax, of PSL, CBD and metabolites will be analyzed separately with the non-
parametric Hodges-Lehmann method to compute point estimates and associated 90% confidence 
intervals for the median of differences ((PSL+CBD) – CBD, and (PSL+CBD) – PSL). 
9.1.2.1 
Ethanol interaction on PSL (Part A) 
The log-transformed PK parameters (Cmax,ss, AUCτ) of PSL and its metabolites will be analyzed 
separately by a mixed ANOVA with period (Treatment Period 4 and 5) and treatment 
(PSL+Ethanol and PSL+Placebo) as fixed effects and study participant as the random effect to 
assess the effects of ethanol on PSL.  
Point estimates for the ratio of geometric means with and without ethanol (PSL+Ethanol vs 
PSL+Placebo) and the respective 2-sided 90% CIs will be computed using the least squares 
means and the root mean squares of error from the mixed effects model, based on the log-
transformed data with subsequent exponential transformation. 
Lack of ethanol effect on PSL will be concluded if the 90% CI of the ratio between PSL+Ethanol 
and PSL+Placebo of the least squares means for the log transformed AUCτ, and Cmax,ss is within 
the conventional acceptance range of 80% to 125%. 
9.1.2.2 
PSL interaction on ethanol (Part A) 
The individual metabolizing capacity will be characterized by calculating the total ethanol dose, 
i.e. the total amount of ethanol infused during Treatment Period 1/2 and Treatment Period 4/5.  
Total ethanol dose will be analyzed by the model specified in Section 9.1.2, where period 
includes Treatment Periods 1 or 2 and 4 or 5, and treatment includes PSL+Ethanol and Ethanol, 
to assess potential differences of metabolizing capacity between treatments. The ratio of the least 
squares means with and without PSL (PSL+Ethanol vs Ethanol), and its 90% CI will be 
calculated. 
9.1.2.3 
CBD interaction on PSL (Part B) 
The log-transformed PK parameters (Cmax,ss, AUCτ) of PSL and its metabolites, and the 
metabolite to parent ratio based on AUCτ (no transformation required) will be analyzed 
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separately by a mixed ANOVA with treatment (PSL (Treatment Period 2) and CBD+PSL 
(Treatment Period 4/5)) as a fixed effect and study participant as the random effect to assess the 
effects of CBD on PSL. The SAS code stated in Section 9.1.2 will be used with period removed.  
Point estimates for the ratio of geometric means with and without CBD (CBD+PSL vs PSL) and 
the respective 2-sided 90% CIs will be computed using the least squares means and the root 
mean squares of error from the mixed effects model, based on the log-transformed data with 
subsequent exponential transformation. 
9.1.2.4 
PSL interaction on CBD (Part B) 
The log-transformed PK parameters (Cmax,ss, AUCτ) of CBD and its metabolite, and the 
metabolite to parent ratio based on AUCτ (no transformation required) will be analyzed by the 
model specified in Section 9.1.2, where period includes Treatment Periods 4 and 5 and treatment 
includes CBD+PSL and CBD+Placebo, to assess the effects of PSL on CBD.  
Point estimates for the ratio of geometric means with and without PSL (CBD+PSL vs 
CBD+Placebo) and the respective 2-sided 90% CIs will be computed using the least squares 
means and the root mean squares of error from the mixed effects model, based on the log-
transformed data with subsequent exponential transformation. 
10 
PHARMACODYNAMICS  
Pharmacodynamic parameters (absolute values and change from Baseline) will be summarized 
by phase, treatment, phase day and timepoint using the FAS. Figures of summaries and 
individual assessments will be based on the FAS.  
The PD parameters include:  
 Smooth Pursuit Eye Movements  
 Body Sway 
 VAS Mood and Alertness (Bond & Lader) 
 VAS feeling high, internal and external perception (Bowdle) 
 Saccadic eye movements  
 Adaptive tracking 
 VAS alcohol intoxication (Part A only) 
For the derivation of VAS feeling high, internal and external perception (Bowdle) and VAS 
Mood and Alertness (Bond & Lader) see Appendix 14.1 and Appendix 14.2 respectively. The 
raw values of VAS alcohol intoxication will be presented, and any derivation required will be 
outlined in CSR. 
10.1 
Analysis of pharmacodynamics variables  
Pharmacodynamic parameters will be analyzed separately for each study part. 
10.1.1 
Descriptive figures and summaries  
The PD parameters (absolute values and changes from baseline) will be summarized by phase, 
treatment and timepoint using descriptive statistics (number of available observations [n], 
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arithmetic mean, median, SD, minimum, maximum, geometric mean, geometric CV and 95% CI 
for the geometric mean [assuming lognormally distributed data]). 
Individual participant profiles of PD parameters over time will be generated using the FAS. 
Graphs of the Least Squares Means estimates over time by treatment will be presented with 95% 
confidence interval (CI) as error bars. 
10.1.2 
Statistical analysis of pharmacodynamics variables 
For the analysis of PD variables, there will be two baselines per study participant (Kenward- 
Rogers, 2010):  
1. Between subject baseline = mean of all predose PD parameter for each subject  
2. Within subject baseline = baseline at given day – between subject baseline  
The PD parameters will be analyzed separately by a repeated measures ANOVA with treatment, 
time, treatment by time, period and sequence as fixed effects; time as repeated measure; with 
subject by period and subject as random effects and within subject baseline and between subject 
baseline and the baseline interactions with time as covariates. Section 10.1.2.1 and Section 
10.1.2.2 specify which treatments to include in the model. 
Due to the confounding of treatment within period within the design only the periods of interest 
will be included in any given comparison. For example, if the comparison is within the 
interaction phase then only Periods 4 and 5 will be kept in the model. 
Period should be removed from the model statement due to confounding with treatment in any 
comparisons where either test or reference period only contains one treatment option. It will be 
left in the repeated statement as period is synonymous with treatment. 
The following SAS code may be used for the repeated measures ANOVA stated above:  
Contrasts for each PD variable will be reported along with 95% CI. Variables will initially be 
analyzed without transformation, but if visual inspection of the residual plots suggest otherwise 
(data are not normally distributed), an appropriate transformation may be applied. 
Further exploratory analyses for PD variables may be conducted by UCB. 
10.1.2.1 
Ethanol and PSL (Part A) 
The similarity of PD parameters between treatments will be analyzed using the model specified 
in Section 10.1.2, where treatment includes Ethanol, Placebo, PSL+Ethanol and PSL+ Placebo.  
The following contrasts will be calculated within the model:  
 PSL+Ethanol (Treatment Period 4/5: Day 5/7) vs PSL+Placebo (Treatment Period 4/5: Day 
5/7) (primary comparison) 
 PSL+Placebo (Treatment Period 4/5: Day 5/7) vs Placebo (Treatment Period 1/2: Day 1) 
 Ethanol (Treatment Period 1/2: Day 1) vs Placebo (Treatment Period 1/2: Day 1) 
 PSL+Ethanol (Treatment Period 4/5: Day 5/7) vs Ethanol (Treatment Period 1/2: Day 1) 
10.1.2.2 
CBD and PSL (Part B) 
The similarity of the PD parameters between treatment will be analyzed using the model 
specified in Section 10.1.2, where treatment includes CBD, PSL, CBD+PSL and CBD+Placebo. 
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The following contrasts will be calculated within the model:  
 CBD+PSL (Treatment Period 4/5: Day 5) vs PSL (Treatment Period 2: Day 5) (primary 
comparison)   
 CBD+PSL (Treatment Period 4/5: Day 5) vs CBD (Treatment Period 3: Day 16) 
 CBD+PSL (Treatment Period 4/5: Day 5) vs CBD+Placebo (Treatment Period 4/5: Day 5) 
This analysis will also be performed for PD variables measured in Treatment Period 4/5, Day 1. 
Any treatment effect may be compounded by time in the first and second comparison stated 
above. Additionally, there may be a learning effect due to study participants performing the PD 
assessments multiple times.  
11 
SAFETY ANALYSES 
All safety summaries and listings will be performed using the SS.  
11.1 
Extent of exposure 
Administration of treatments will be listed by study participant. For PSL and CBD, the listing 
will include the date and time of administration of the morning and evening dose, and total daily 
dose. For ethanol infusion, the listing will include the date of infusion, start and stop time of 
infusion, duration of infusion and total volume of ethanol given.  
Exposure data will be listed only. 
11.2 
Adverse events 
All AEs will be coded using the MedDRA® and characterized as pre-treatment and treatment 
emergent according to the intake of each treatment. Adverse events with a start date prior to the 
first dose of treatment will be defined as pre-treatment AEs. A treatment-emergent AE (TEAE) 
is defined as any AE with a start date/time on or after the first dose of treatment or any 
unresolved event already present before administration of treatment that worsens in intensity 
following exposure to the treatment. 
Adverse events will be attributed to the most recent treatment received. Adverse events that 
occur during the washout periods will be assigned as treatment emergent with regards to the 
treatment of the previous period. 
The number and percentage of participants who experience TEAEs will be summarized by 
MedDRA SOC, PT and treatment.  
Summaries of TEAEs will include the following:  
 Incidence of overall TEAEs (overview including number and percentage of study participants 
with any TEAEs, serious TEAEs, discontinuations due to TEAEs, drug-related TEAEs, 
severe TEAEs and TEAEs leading to death; event counts will also be included) 
 Incidence of TEAEs  
 Incidence of TEAEs by maximum intensity 
 Incidence of TEAEs by relationship  
 Incidence of non-serious TEAEs above reporting threshold of 5% of study participants  
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Additional summary tables of fatal, serious and discontinuations due to TEAEs by relationship 
will be produced if more than one of these events occurs. 
Summary tables will contain counts of study participant, percentages of study participants in 
parentheses and the number of events where applicable. A participant who has multiple events in 
the same SOC and PT during a given treatment will be counted only once in the participant 
counts for that treatment, but all events will be included.  
In summaries including relationship, the following relationships will be summarized: ‘Not 
related’, ‘Related’. Participants who experience the same event multiple times will be included in 
the most related category for tabulations by maximum relationship. Events with missing 
relationship will be considered as ‘Related’ but recorded as missing in the listings.   
In summaries including intensity, the following intensity categories will be summarized: ‘Mild’, 
‘Moderate’, ‘Severe’. Participants who experience the same event multiple times will be 
included in the most severe category for tabulations by maximum intensity. Events with missing 
intensity will be considered as ‘Severe’ events for summary purposes but recorded as missing in 
the listings.  
Adverse event summaries will be ordered alphabetically by SOC and decreasing frequency of PT 
within SOC in the group column for tables including event counts. For tables including only 
number and percentage of study participants, summaries will be ordered alphabetically by SOC 
and decreasing incidence of PT within SOC in the group column.  
Listings of AEs and TEAEs will include the following:  
 All AEs 
 Incidence of all TEAEs  
 All Serious AEs 
 Discontinuation due to AEs 
All listings (expect incidence of all TEAEs) will be presented by study participant and treatment 
sequence and will include the onset date/time and outcome date/time of the event, most recent 
treatment received, the event duration (derived), time to onset (derived), pattern of event, 
intensity, relationship, action taken, outcome and AEs that led to discontinuation, TEAEs and 
SAEs will be flagged.  
The listing of incidence of all TEAEs will be presented by treatment and will include intensity, 
relationship, severity, number of study participants reporting at least one TEAE within SOC/PT, 
number of individual occurrences of TEAE and site-study participant number.   
11.3 
Clinical laboratory evaluations 
All laboratory results (clinical chemistry, hematology and urinalysis) outside the normal ranges 
will be listed by study participant, phase, treatment sequence, timepoint and parameter including 
most recent treatment received, changes from Baseline for numeric variables, the reference 
ranges and a flag to indicate whether values are below the lower limit of the reference range or 
above the upper limit of the reference range. The listing will include any laboratory value out of 
normal range at the timepoint it occurred only.  
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Separate listings of clinical chemistry and hematology laboratory results outside the normal 
ranges will be provided. These listings will include all data for a parameter for which a 
participant has at least one abnormal value during the study.  
Urinalysis results will be listed by study participant, phase, treatment and timepoint including 
changes from Baseline for numeric variables, the reference ranges and flags for values outside 
the normal ranges. 
A separate listing for laboratory results meeting the criteria for potential drug-induced liver 
injury (PDILI) will be provided. The listing will present the study participant who meets one or 
more of the following criteria for PDILI at any time point:  
 Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥3x upper limit of 
normal (ULN)  
 Alkaline phosphatase ≥2xULN  
 Total bilirubin increase ≥2xULN  
Clinical chemistry and hematology parameters will be summarized by phase, treatment and 
timepoint for both absolute values and changes from Baseline.   
Laboratory variables will be grouped according to the laboratory function panel (Table 10-1) and 
categorized as normal, high or low, if applicable, based on the reference range supplied by the 
analytical laboratory. For selected variables that are identified in Table 10-1 the change in 
category from Baseline will be presented in shift table at all post-Baseline time points.  
Any additional laboratory variables not included in the outputs described previously will be 
listed separately. These will include the following:  
 Serology 
 Alcohol breath test  
 Serum pregnancy test (for women of childbearing potential)  
 Urine toxicology screen  
Figures of mean and mean change from Baseline may be presented for selected laboratory 
variables that will be identified at the DEM.  
Table 11-1: Laboratory measurements 
Laboratory 
Assessments 
Parameters 
Hematology1 
Platelet Count2  
RBC Indices: 
MCV 
MCH 
%Reticulocytes 
WBC Count with 
Differential: 
Neutrophils2 
Lymphocytes2 
Monocytes 
Eosinophils 
Basophils 
RBC Count 
Hemoglobin 
Hematocrit 
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Laboratory 
Assessments 
Parameters 
Clinical 
Chemistry1 
Blood Urea 
Nitrogen2 
(BUN) 
Potassium 
Aspartate 
Aminotransferase2 
(AST)/Serum Glutamic-
Oxaloacetic Transaminase 
(SGOT) 
Total and direct 
bilirubin (direct 
is only measured 
if total >1xULN) 
 
Creatinine2 
Sodium 
Alanine Aminotransferase2 
 (ALT)/Serum Glutamic-
Pyruvic Transaminase 
(SGPT) 
Total Protein 
 
Glucose 
(fasting at 
Screening)  
Calcium 
Alkaline phosphatase2 
(ALP) 
 
Routine 
Urinalysis1 
Specific gravity, pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, 
nitrite, leukocyte by dipstick. 
 
If protein or blood or leukocytes are abnormal (positive), a microscopic 
examination of the sediment will be performed. 
Other 
Screening 
Tests 
 Follicle-stimulating hormone (at Screening only to confirm postmenopausal 
status in female study participants 
 Urine drug screen (to include at minimum: amphetamines, barbiturates, 
cocaine, opiates, cannabinoids and benzodiazepines) 
 Breath alcohol test 
 Pregnancy test: Urine or serum beta human chorionic gonadotropin (hCG) 
test (as needed for women of childbearing potential; serum hCG test used at 
Screening only) 
 Serology (HIV 1 and 2 Ab, HBsAg, HCV-Ab)  
ALP=alkaline phosphatase; ALT=alanine aminotransferase; AST=aspartate aminotransferase; HBsAG=hepatitis B 
surface antigen; HCV-Ab=hepatitis C antibody; HIV-1/2Ab=human immunodeficiency virus-1/2 antibodies 
1 Hematology, clinical chemistry, and urinalysis assessments will be performed under fasting conditions at 
Screening and non-fasting conditions at all other assessments.  
2 Shift tables will be presented for these variables.  
11.4 
Vital signs, physical findings, and other observations related to 
safety 
11.4.1 
Vital signs 
The following vital signs measurements will be assessed: 
 Systolic and diastolic blood pressure  
 Pulse rate 
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 Body temperature (aural) 
 Respiratory rate  
Vital signs measurements will be summarized and listed by phase, treatment sequence, position 
(standing (screening only) and supine) and timepoint including changes from Baseline and most 
recent treatment received. The listing will also include details to abnormal values. Vital signs 
with values below lower limit of normal and a decrease greater than the limit given in the 
following table or vital signs with values above upper limit of normal and an increase greater 
than the given value in the table will be classified as abnormal. 
Table 11‒2: Reference ranges for vital signs 
Variable 
Unit 
Lowa 
Higha 
Systolic blood pressure 
mmHg 
Value <90 and/or ≥20 
decrease from Baseline 
Value >140 and/or ≥20 increase 
from Baseline 
Diastolic blood pressure 
mmHg 
Value <50 and/or ≥15 
decrease from Baseline 
Value >90 and/or ≥15 increase 
from Baseline 
Pulse rate 
bpm 
Value <45 and/or ≥15 
decrease from Baseline 
Value >90 and/or ≥15 increase 
from Baseline 
11.4.2 
Electrocardiogram  
12-lead ECG will be recorded 3 times at each time point. The individual mean at each time point 
will be calculated as raw parameters for descriptive analysis. The individual mean and change 
from Baseline will be summarized using descriptive statistics by phase and treatment at each 
time point. 
All standard 12-lead ECD recordings will be taken in triplicate with the study participant resting 
in the supine position for at least 5 minutes. The following ECG parameters will be reported:  
 PR interval  
 QT interval  
 QRS interval  
 QTc interval (QT corrected for heart rate using Fridericia’s formula [QTcF])  
 Heart rate 
The individual measurements and the mean of the triplicate measurements will be reported in the 
by- participant listings including change from Baseline and most recent treatment received and 
will be presented by phase, treatment sequence and timepoint.  
Measured values and change from Baseline will be summarized by phase, treatment and ECG 
variable at each timepoint (based on the mean of the triplicate values at each timepoint). The 
mean change for ECG parameter will also be displayed graphically. Additionally, the following 
cut-points in QTcF (observed data and change from Baseline), based on the mean of the triplicate 
data, will be summarized categorically (number and percentage of participants) by treatment 
group at each timepoint. For observed data:  
 <450 msec  
 ≥450 to <480 msec  
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 ≥480 to <500 msec  
 ≥500 msec  
Absolute change from Baseline in QTcF:  
 <30 msec  
 ≥30 to <60 msec  
 ≥60 msec  
All ECG findings for the individual triplicate measurements will be listed separately.  
Any incomplete triplicate measurements at a given timepoint will be handled as described in 
Section 4.2.3. 
11.4.3 
Other safety variable(s) 
11.4.3.1 
Physical examination  
Study participants with abnormalities in the physical examination will be listed including details 
of the abnormality.  
11.4.3.2 
Columbia-Suicide Severity Rating Scale 
Columbia-Suicide Severity Rating Scale (C-SSRS; Posner et al, 2011) data will be listed by 
treatment sequence. Module of the questionnaire, time point, question and the associated 
response will be listed for all the visit days where this questionnaire is collected. 
12 
OTHER ANALYSES  
Not applicable.  
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13 
REFERENCES 
Bond A and Lader M. The use of analogue scales in rating subjective feelings.  Br J Med 
Psychol. 1974; 47:211-8. 
Bowdle, TA, Radant, AD, Cowley, DS, Kharasch, ED, Strassman, RJ, Roy-Byrne, PP 
Psychedelic effects of ketamine in healthy volunteers: relationship to steady-state plasma 
concentrations. Anesthesiology. 1998; 88: 82–88.  
Michael G. Kenward, James H. Roger, The use of baseline covariates in crossover 
studies, Biostatistics, Volume 11, Issue 1, January 2010, Pages 1-17, 
https://doi.org/10.1093/biostatistics/kxp046 
Taylor L, Gidal B, Blakey G, Tayo B, Morrison G. A phase I, randomized, double-blind, 
placebo-controlled, single ascending dose, multiple dose, and food effect trial of the safety, 
tolerability and pharmacokinetics of highly purified cannabidiol in healthy subjects. CNS Drugs. 
2018 Nov; 32(11):1053-1067. 
Watson PE, Watson ID, Batt RD. Total body water volumes for adult males and females 
estimated from simple anthropometric measurements. Am J Clin Nutr. 1980:33:27-39. 
Zuurman L, Roy C, Schoemaker RC, et al. 2008: Effect of intrapulmonary tetrahydrocannabinol 
administration in humans. J Psychopharmacol 22: 707–16. 
 
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14 
APPENDICES 
14.1 
Appendix 1: VAS feeling high, internal and external perception 
(Bowdle)  
The Bowdle Visual Analogue Scale (B-VAS) evaluates psychedelic effects (Bowdle et al, 1998). 
It consists of 13 100-mm self-rated visual analogue scales from which two composite scales are 
calculated: internal perception (six items) and external perception (5 items).  
The individual items of the B-VAS are listed below:  
1. My body or body parts seemed to change their shape or position 
2. My surroundings seemed to change in size, depth, or shape 
3. The passing of time was altered 
4. I had feelings of unreality 
5. It was difficult to control my thoughts 
6. The intensity of colors changed 
7. The intensity of sound changes 
8. I heard voices or sounds that were not real 
9. I had the idea that events, objects, or other people had particular meaning that was specific 
for me 
10. I had suspicious ideas or the belief that others were against me 
11. I felt anxious 
12. I felt high  
13. I felt drowsy  
The two composite scales, internal perception and external perception, are calculated as follows 
(Zuurmann et al, 2008): 
 External perception = [log10(Item1+2) + log10(Item2+2) + log10(Item3+2) + log10(Item5+2) + 
log10(Item6+2) + log10(Item7+2)]/6  
 Internal perception = [log10(Item4+2) + log10(Item8+2) + log10(Item9+2) + log10(Item10+2) + 
log10(Item11+2)]/5 
Item 12 is the individual VAS feeling high (no derivation is required).  
 
 
 
 
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14.2 
Appendix 2: VAS Bond-Lader  
The Bond-Lader VAS evaluates mood and alertness (Bond and Lader, 1974). It consists of 16 
100-mm self-rated visual analogue scales (Figure 14-1) from which three factors are calculated: 
alertness, calmness, and contentment.  
The three factors are calculated as follows:  
 Alertness = (Item1 + Item3 + Item4 + Item5 + Item6 + Item9 + Item11 + Item12 + Item15)/9 
 Calmness = (Item7 + Item8 + Item13 + Item14 + Item16)/5 
 Contentment = (Item2 + Item10)/2 
Certain scale scores may need to be inversed prior to calculation (Bond and Lader, 1974) based 
on the frequency distribution of the scales.  
Figure 14-1: Bond-Lader VAS 
 
 
 
 
Note: Scales not to size. 
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STATISTICAL ANALYSIS PLAN SIGNATURE PAGE 
This document has been reviewed and approved per the Review and Approval of Clinical 
Documents Standard Operating Procedures. Signatures indicate that the final version of the SAP 
or amended SAP is released for execution. 
 
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Approval Signatures
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Document Number:
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Title:
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Approved Date:
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Date of Signature: 28-Jan-2020 12:45:16 GMT+0000
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Date of Signature: 28-Jan-2020 17:06:30 GMT+0000
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