Clinical trial NCT06118385
Conditions: Healthy Volunteer Study
Sponsor: BenevolentAI Bio
Start date: 2023-08-30; Completion date: 2024-03-18
Enrollment: 76 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
BEN8744 is an experimental new medicine for treating inflammatory bowel diseases such as Ulcerative Colitis.

The study will test single and repeated oral doses of BEN8744 or placebo. BEN8744 is a first in human study, so will start with a small dose and the dose will be increased as the study progresses. The goal is to find out its side effects and blood levels when taken by mouth and whether food affects the blood levels.

This is a 3-part study (Parts A, B and C) in up to 108 healthy people, aged 18-65.

Part A, will include up to 64 participants, single doses of BEN8744 or placebo. They'll take about 2 weeks to finish the study, stay on the ward for 4 nights and 5 days in a row and make 2 outpatient visits.

Part B, will include up to 12 participants, single doses of BEN8744 with and without food. They'll take up to 3 weeks to finish the study, stay on the ward for 4 nights and 5 days in a row on 2 occasions, and make 2 outpatient visits.

Part C will include up to 32 participants repeat doses of the BEN8744 or placebo for 14 days. They'll take about 4 weeks to complete the study, stay on the ward for 17 nights and 18 days in a row and make 2 outpatient visits.

Detailed description:
This first time in human, study will investigate the safety, tolerability, pharmacokinetics (PK) of BEN8744 after single and multiple ascending oral doses in healthy subjects, in both the fed and fasted state. The results of this study will be used to select doses for subsequent studies in patients. This is an exploratory study in healthy volunteers, with no anticipated therapeutic benefit to the participants; involvement of patients, service users or members of the public in the design of the trial is not appropriate.

Primary objectives Part A: To assess the safety and tolerability of single ascending oral doses of BEN8744 in healthy subjects Part B: To characterise the effect of food on the pharmacokinetic profile of at least 1 dose of BEN8744 Part C: To assess the safety and tolerability of multiple ascending oral doses of BEN8744 in healthy subjects

Secondary objectives Part A: To assess the PK profile of BEN8744 after single oral doses in healthy subjects Part B: To assess the safety and tolerability of a single dose of BEN8744 following high-fat food intake relative to fasting conditions in healthy subjects Part C: To assess the PK profile of BEN8744 after repeated oral doses in healthy subjects

Exploratory objective

Part B (and optional in Part C):

To measure BEN8744 in urine and determine renal clearance in healthy subjects. Exploratory characterisation of BEN8744 and its metabolites in plasma, urine, and faeces.

For part A

* Up to 64 subjects, 5 cohorts + 3 optional, 6 active, 2 placebo.
* Subjects will receive a single dose of BEN8744 or placebo, as capsules, after an overnight fast of at least 10 h.
* At each dose level, 6 subjects will receive BEN8744 and 2 will receive matching placebo in an overall ratio of 3:1.
* The starting dose for Group 1 is 2 mg BEN8744 or placebo. It is intended that subsequent cohorts will receive higher doses. The planned doses are:

A1- 2mg A2- 6mg A3- 20mg A4- 60mg A5- 100mg A6 (optional) - 120mg

For Part B

* Up to 12 subjects, 1 cohorts + 1 optional, 2 sessions fasted/fed.
* Each subject in Part B will have 2 study sessions (Sessions 1 and 2), in which they will receive a single dose of BEN8744, by mouth.
* Each subject will receive BEN8744 after an overnight fast of at least 10 h in one session, and after an FDA high-fat breakfast (1,013 kcal, 59.2 g fat \[of which 28.1 g saturated fat) in the other session; the order will be randomised 1:1.
* A subject's doses will be separated by a washout of at least 7 days (or 5 half-lives as determined in Part A, whichever is longer).
* Subjects dosed on the same day may be dosed at intervals of at least 10 min.

For Part C:

* Up 32 subjects, 3 cohorts + 1 optional, 6 active, 2 placebo.
* Each subject will receive daily doses of BEN8744 or placebo, by mouth, for 14 days.
* Doses will be taken once or twice daily in the fasted state, unless emerging data indicate they should be taken in the fed state.
* Part C will not start until at least 3 dose levels have been completed in Part A and may also be conducted in parallel with Part B.

Arms: arm 1: Part A Dose 1 Single dose of 2 mg BEN8744 arm 2: Part A Dose 2 Single dose of 6 mg BEN8744 arm 3: Part A Dose 3 Single dose of 20 mg BEN8744 arm 4: Part A Dose 4 Single dose of 60 mg BEN8744 arm 5: Part A Dose 5 Single dose of 100 mg BEN8744 arm 6: Part A Dose 6 Single dose of 120 mg BEN8744 arm 7: Part A placebo Single dose of placebo arm 8: Part B Dose 1 Fed Single dose of BEN8744 after high-fat meal (Dose 30mg QD) arm 9: Part B Dose 1 Fasted Single dose of BEN8744 after 10 hours fasting (Dose 30mg QD) arm 10: Part B Dose 2 Fed Single dose of BEN8744 after high-fat meal (Dose 50mg QD) arm 11: Part B Dose 2 Fasted Single dose of BEN8744 after 10 hours fasting (Dose 50mg QD) arm 12: Part C Dose 1 14 daily doses of BEN8744 (Dose 30mg BID) arm 13: Part C Dose 2 14 daily doses of BEN8744 (Dose 50mg BID) arm 14: Part C placebo 14 daily doses of placebo
Interventions: intervention 1: BEN8744 intervention 2: Matching Placebo
Intervention descriptions: intervention 1: Formulated powder in capsule for oral administration. Supplied as filled Size 0 Swedish Orange capsule. Doses: 2mg, 10mg and 40mg. intervention 2: Formulated powder in capsule for oral administration. Supplied as filled Size 0 Swedish Orange capsule. Doses: 2mg, 10mg and 40mg.

Protocol documents:
Prot_SAP_000.pdf: 
HMR Ltd - Confidential
BenevolentAI Cambridge Ltd
Trial Protocol
Confidential
Trial title
A randomised, double-blind, placebo-controlled, 
phase 1 first-in-human study to investigate the safety, 
tolerability, pharmacokinetics, and food effect of 
single- and multiple-ascending doses of BEN8744 in 
healthy subjects
Short title
Safety, PK, and food effect of BEN8744
Version and date of protocol
Version 3, dated 11 December 2023   
HMR code
22-014
Sponsor code
BB-8744-1001
IRAS number
1006884
EudraCT no
2022-003721-22
Trial medication
BEN8744
Phase of trial
Phase 1
Place of trial
HMR
Cumberland Avenue
London NW10 7EW
UK
Tel:  020 8961 4130
Fax:  020 8961 8665
Principal investigator
Denisa Wilkes MD
HMR
Sponsor
BenevolentAI Cambridge Ltd
4-8 Maple Street
London W1T 5HD
UK
Tel:  020 3781 9360
Planned dates of trial
JUN 2023 to APR 2024


Safety, PK, and food effect of BEN8744  
Trial Codes:  22-014 and BB-8744-1001 
 
 
Protocol Version 3, dated 11 December 2023   
 
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CONFIDENTIALITY STATEMENT 
The information provided in this document is strictly confidential and is available for review to 
Investigators, potential Investigators, appropriate ethics committees and other national 
authorities.  No disclosure should take place without the written authorisation from the Sponsor, 
except to the extent necessary to obtain informed consent from potential patients. 
Version control history 
Version  
Reason for change 
1, dated 16 December 2022 
N/A 
2, dated 03 February 2023 
Updates made to the protocol in response to GNA 
remarks from the MHRA 
3, dated 11 December 2023 
The pharmacokinetic exposure threshold has been 
updated to allow dosing to a higher level in Part A, based 
on emerging safety and pharmacokinetic data from 
completed Cohorts A1 A4.  (Substantial) 
Implemented non-substantial administrative and file note 
changes 
Protocol amendment summary 
Substantial amendment 2 (Protocol version 3) 
This amendment incorporates emerging safety and pharmacokinetic (PK) data from 
completed Cohorts A1 A4 to 
PK exposure 
threshold to allow dosing to a higher level in Part A.  Clarifications or non-substantial 
changes which were previously documented in file notes have also been implemented. 
The protocol was updated from version 2 (dated 03 February 2023) to version 3 (dated 11 
December 2023).  The following changes were made. 
Section(s), table(s) and 
figure(s) affected 
Change 
Section 2.5, 2.6.1, 6.2.3, 
6.2.4, 6.5, 6.5.1, 6.5.2, 
8.1.1, 8.4.2, 8.5.2, 8.5.5, 
9.1, and Table 1 4, 6, and 8 
and Figures 1 4 
The PK exposure threshold has updated to the NOAEL in 
the most sensitive species (dog).  The rationale for 
increasing the PK exposure threshold has been added, 
including safety and PK data from Cohorts A1 A4. 
The planned dose in Cohort A5 has been updated to 100 mg 
QD.  The dose given in completed Cohort A4 (60 mg) has 
been updated throughout. 
Cohort A6 has been made optional. 


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Section(s), table(s) and 
figure(s) affected 
Change 
Section 2.5 
ignificant suicidality history or suicidality risk 
(assessed by C-SSRS); history of seizures
exclusion criteria. 
Section 4 
Updated the abbreviations list. 
Section 5, 14.3, 14.5 
 
Updated contact details for the pharmacovigilance provider 
 
Section 9.3 
Updated exclusion criterion 23 for consistency with 
Table 13. 
Section 11 
Updated contraception requirements to list only low user 
dependent, highly effective methods for women of 
childbearing potential.  
Table 8 
Updated subject and sentinel numbers so that Cohorts A7 
and A8 are consecutive. 
Section 2.7.1, 12, 12.1 
Updates to the schedules of procedures, as follows. 
All study parts: 
- 
urine drug screen and alcohol and cotinine tests have 
been removed from follow-up visits. 
- 
the OAAS and VAS have been removed from the 12, 16 
and 36 h timepoints.  Text has been updated in 
section 2.7.1 and 12 to reflect this. 
Parts A and B: 
Correction to footnote 9. 
Part C: 
- 
 urine drug screen, alcohol and cotinine tests will be 
done on Day 1 (admission). 
- 
OAAS/S and VAS assessments will not be done at 12, 
12.5, 13, 14, 15, 16, 20 and 36 h postdose for twice-daily 
dosing.  
- 
weight measurements will be done at follow-up. 
- 
for twice-daily dosing, vital signs and ECGs will be done 
before the morning dose only.  When vital signs and 
ECGs are to be taken on Day 1, 24 h and Day 2 predose, 
only a Day 2 predose measurement will be taken.  


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Section(s), table(s) and 
figure(s) affected 
Change 
Section 12.4, 12.5 
Updated blood collection tube sizes and the volume of blood 
taken for laboratory safety tests. 
Section 12.4 
Removed subsections on processing of blood samples, urine 
collection, and faecal sample collection for PK analysis.  
Details are provided in the study procedures manual. 
Table 10 
24 h. 
Section 12.1.3, 12.5 
(Tables 14 16) 
Removed PK sampling timepoints at 12.5, 13, 14, 15, 16 and 
20 h on Day 14 for twice daily dosing, and 16 h on Days 1 
and 14 for once daily dosing, in Part C.  As a result, the total 
volume of blood in Part C has also been updated.   
The total volume of blood for all study parts has been 
updated to account for discard (when using a cannula) up to 
24 h postdose. 
Section 8.5.3 
Corrected the PK data requirements for dose selection in 
Part B. 
Previous protocol amendments 
-acceptance. 


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1
Signatures
The investigator and the sponsor have discussed this protocol. The investigator 
agrees to perform the investigation and to abide by this protocol and any future 
agreed amendments, except in case of medical emergency.
Principal investigator
Dr Denisa Wilkes
HMR
Signature
Date
Statistician
Dr Steven Whaley
HMR
Signature
Date
Sponsor
Dr Arpeat Kaviya
BenevolentAI Cambridge Ltd
Signature
Date


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2 
Summary 
2.1 
Trial medication  
BEN8744 is a potent, and selective small molecule inhibitor of 
phosphodiesterase 10A (PDE10A).  It is being developed as an orally administered 
treatment for inflammatory bowel diseases (IBDs), including ulcerative colitis (UC) 
 (CD). 
2.2 
Objectives 
2.2.1 
Primary objectives 
Part A: 
To assess the safety and tolerability of single ascending oral doses of 
BEN8744 in healthy subjects 
Part B: 
To characterise the effect of food on the pharmacokinetic (PK) profile 
of at least 1 oral dose of BEN8744  
Part C: 
To assess the safety and tolerability of multiple ascending oral doses of 
BEN8744 in healthy subjects 
2.2.2 
Secondary objectives 
Part A: 
To assess the PK profile of BEN8744 after single oral doses in healthy 
subjects 
Part B: 
To assess the safety and tolerability of a single dose of BEN8744 
following high-fat food intake relative to fasting conditions in healthy 
subjects 
Part C: 
To assess the PK profile of BEN8744 after repeated oral doses in 
healthy subjects 
2.2.3 
Exploratory objectives  
Part B (and optional in Part C): 
To measure BEN8744 in urine and determine renal clearance in healthy 
subjects* 
Exploratory characterisation of BEN8744 and its metabolites in plasma, 
urine, and faeces  
*If significant amounts of the parent compound are detected in Part B, the parent 
compound may be measured in Part C (in urine at 2 dose levels [low and high]). 
Faeces will be analysed in Part B only.  If significant amounts of metabolites are 
detected in Part B, exploratory metabolite analyses may be conducted in Part C (in 
plasma and urine at 2 dose levels [low and high] on Day 1 and Day 14). 


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2.3 
Endpoints 
2.3.1 
Primary endpoints 
Safety and tolerability (Parts A and C):  vital signs (blood pressure, pulse rate, 
tympanic temperature, and respiratory rate), 12-lead electrocardiogram (ECG), 
cardiac telemetry (Part A only), physical examination, laboratory safety tests 
(haematology, clinical chemistry, and urinalysis), adverse events (AEs), and 
Observer's Assessment of Alertness/Sedation scale (OAAS/S), visual analogue scale 
(VAS) to monitor sedation, and Columbia-Suicide Severity Rating Scale (C-SSRS; 
Part C only).  
PK (Part B): 
 Cmax, tmax, AUC24, AUC72, AUClast, AUCinf, %AUCextrap, t½, Z, 
CL/F, VZ/F 
2.3.2 
Secondary endpoints 
PK (Part A): 
 Cmax, tmax, AUC24, AUC72, AUClast, AUCinf, %AUCextrap, t½, Z, 
CL/F, VZ/F 
Safety and tolerability (Part B):  vital signs (blood pressure, pulse rate, tympanic 
temperature, and respiratory rate), 12-lead ECG, physical examination, laboratory 
safety tests (haematology, clinical chemistry, and urinalysis), AEs, and OAAS/S and 
VAS to monitor sedation. 
PK (Part C): 
 Cmax, tmax, Ctrough, AUCtau, AUClast, AUC72, AUCinf, %AUCextrap, 
t½, Z, CLSS/F, VZ/F, Rac(AUC), Rac(Cmax), SR(AUC) 
2.3.3 
Exploratory endpoints 
PK (Part B and optional in Part C): 
Ae72, fe
, CLR 
2.4 
Type of trial 
This is a Phase 1, single-centre trial to assess the safety, tolerability, PK and food 
effect of BEN8744 in healthy volunteers.   
This trial will be in 3 parts, as follows: 
Part A will test single doses of BEN8744 in a double-blind, randomised, 
placebo-controlled and dose-escalating design. 
Part B will test the effect of food on the PK of BEN8744 in an open-label, 
randomised, 2-way crossover design. 
Part C will test repeated doses of BEN8744 (once or twice daily for 14 days) in a 
double-blind, randomised, placebo-controlled and dose-escalating design. 


Safety, PK, and food effect of BEN8744  
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2.5 
Trial population 
a 
Total Up to 108 healthy volunteers, excluding replacements:  up to 64 in 
Part A (including 3 optional groups); up to 12 in Part B; and up to 32 in Part C 
(including 1 optional group).   
b 
Age 
18 65 years 
c 
Main inclusion criteria 
Healthy male or female volunteers, with a body mass index (BMI) of 
18.0 30.9 kg/m2; deemed healthy on the basis of a clinical history, physical 
examination, ECG, vital signs, and laboratory tests of blood and urine; agree to 
follow the contraception requirements of the trial; able to give fully informed written 
consent. 
d 
Main exclusion criteria 
Positive tests for hepatitis B & C, HIV; severe adverse reaction to any drug; 
sensitivity to trial medication or excipients; drug or alcohol abuse; habitual users of 
tobacco and/or nicotine containing products, as defined in the protocol; use of 
non-prescription or over-the-counter medication (with the exception of up to 2 g 
paracetamol [acetaminophen]) during the 7 days before and up to 24 h before the 
first dose of trial medication, or prescribed medication during the 28 days before first 
dose of trial medication; participation in other clinical trials of investigational 
medical products, or loss of more than 400 mL blood, within the previous 3 months; 
clinically relevant abnormal findings at the screening assessment; acute or chronic 
illness; clinically relevant abnormal medical history or concurrent medical condition; 
significant suicidality history or suicidality risk (assessed by C-SSRS); history of 
seizures; possibility that volunteer will not cooperate; pre-menopausal females who 
are pregnant or lactating, or who are sexually active and not using a reliable method 
of contraception. 
2.6 
Trial design and methods 
The trial will be in 3 parts (Parts A, B, and C), as described below.  In each part, 
subjects will be screened within 28 days before their (first) dose of trial medication. 
Part A will test single ascending oral doses of BEN8744; Part B is a 2-way crossover 
assessment of the effect of food on the PK of BEN8744; and Part C will test multiple 
ascending oral doses of BEN8744.  
2.6.1 
Part A 
Part A will test single oral doses of BEN8744 in a double-blind, randomised, 
placebo-controlled and dose-escalating design. 


Safety, PK, and food effect of BEN8744  
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Up to 5 groups of 8 subjects will be enrolled in Part A (Groups A1 A5).  Each 
subject will have 1 study session, in which they will receive a single dose of 
BEN8744 or placebo, by mouth in the fasted state.  The planned dose levels 
are:  2 mg (Group A1), 6 mg (Group A2), 20 mg (Group A3), 60 mg (Group A4), 
and 100 mg (Group A5).  Additional intermediate or higher dose levels may be 
explored in 3 optional groups (Groups A6 A8), as detailed in section 8.5.2.  At each 
dose level, 6 subjects will receive BEN8744 and 2 will receive matching placebo.   
The dose will be escalated only if the safety and tolerability of the previous highest 
dose are acceptable, and the plasma concentrations of BEN8744 are predicted to 
remain below the exposure limit, as determined by the Safety Review Group (SRG).  
A dose level may be repeated or decreased, as required, based on emerging results.   
Each new ascending dose will be staggered, such that 2 sentinel subjects will be 
dosed first, and randomised such that 1 subject receives BEN8744 and the other 
receives placebo.  The remaining 6 subjects will be dosed at least 23 h later, at 
intervals of at least 10 min.  If the planned dose escalation is changed such that a 
selected dose is no higher than a dose previously shown to cause no safety concerns, 
then sentinel subjects will not be required. 
Subjects will be resident on the ward from 1 day before their dose (Day 1) until up 
to 72 h after dosing (Day 4).  They will return for a follow-up visit 7 (±2) days after 
their inpatient stay (Day 11 ±2 days). 
2.6.2 
Part B 
Part B will test the effect of food on the PK of BEN8744 in an open-label, 
randomised, two-way crossover design. 
Up to 2 groups of 6 subjects will be enrolled in Part B (Groups B1 and B2).  Each 
subject will have 2 study sessions, in which they will receive at least 1 dose of 
BEN8744, by mouth after either an overnight fast in one session or a high-fat 
breakfast in the other session.  
least 7 days (or 5 half-lives as determined in Part A, whichever is longer). 
The dose to be tested in Group B1 will be decided following review of the interim 
safety, tolerability, and PK data from at least 3 dose levels in Part A.  Group B2 is 
optional and may be required if the Sponsor decides to test the effect of food at an 
additional dose level, or under different conditions (eg different fasting conditions or 
after a different meal such as a standard breakfast). 
In each Session, subjects will be resident on ward from 1 day before their dose 
(Day 1) until up to 72 h after dosing (Day 4).  They will return for a follow-up visit 
7 (±2) days after their inpatient stay in Session 2 (Day 11 ±2 days). 


Safety, PK, and food effect of BEN8744  
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2.6.3 
Part C 
Part C will assess the safety, tolerability, and PK of multiple ascending doses of 
BEN8744 in a double-blind, placebo-controlled, parallel-group design. 
Up to 3 cohorts of 8 subjects will be enrolled in Part C (Groups C1 C3).  Each 
subject will have 1 study session, in which they will receive daily doses of BEN8744 
or placebo, by mouth for 14 days.  At each dose level, 6 subjects will receive 
BEN8744 and 2 will receive matching placebo.  An additional intermediate or higher 
dose level may be explored in 1 optional group (Group C4), as detailed in 
section 8.5.4.   
Doses will be taken once or twice daily in the fasted state, unless emerging data 
indicate they should be taken in the fed state.  The dose, dosing regimen (once or 
twice daily), and whether the dose is taken fed or fasted, will be determined based on 
review of the available safety, tolerability and PK results from Parts A and B, and 
previous groups in Part C. 
Subjects will be resident on ward from the day before their dose (Day 1) until up to 
72 h after their final dose (Day 17).  They will return for a follow-up visit 7 (±2) days 
after their inpatient stay (Day 24 ±2 days). 
2.7 
Assessments 
The following assessments will be made. 
2.7.1 
Safety and tolerability   
Laboratory assessments (routine haematology, clinical chemistry, and urinalysis), 
physical examinations, 12-lead ECGs, and vital signs (blood pressure, pulse rate, 
respiratory rate, and tympanic temperature) and C-SSRS (in Part C) will be done 
  Cardiac telemetry (Part A 
only) will be done from 1 h before until 24 h after dosing.  The OAAS/S and VAS 
will be done frequently at specific timepoints immediately before PK blood samples,  
up to 72 h after dosing in Parts A and B, and up to 72 h after dosing on Day 1 in 
Part C, to monitor sedation.  AEs will be recorded from time of consent until the 
 last visit. 


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2.7.2 
Pharmacokinetics 
Blood samples for assay of BEN8744 will be taken before, and frequently up to 72 h 
after dosing in Parts A and B, and up to 72 h after dosing on Day 1 and Day 14 in 
Part C.   
Urine will be collected continuously for up to 72 h after dosing in Part B, and may be 
collected for up to 72 h after dosing on Days 1 and 14 in Part C, for assay of 
BEN8744 and its metabolites. 
A predose faecal sample will be collected from Day 2 to predose on Day 1 in Part B 
Session 1.  Faecal samples will be collected continuously for up to 72 h after dosing 
in Part B for the exploratory characterisation of BEN8744 and its metabolites. 
 
 


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3 
Contents 
Version control history 
2 
Protocol amendment summary 
2 
1 
Signatures 
5 
2 
Summary 
6 
2.1 
Trial medication 
6 
2.2 
Objectives 
6 
2.2.1 
Primary objectives 
6 
2.2.2 
Secondary objectives 
6 
2.2.3 
Exploratory objectives 
6 
2.3 
Endpoints 
7 
2.3.1 
Primary endpoints 
7 
2.3.2 
Secondary endpoints 
7 
2.3.3 
Exploratory endpoints 
7 
2.4 
Type of trial 
7 
2.5 
Trial population 
8 
2.6 
Trial design and methods 
8 
2.6.1 
Part A 
8 
2.6.2 
Part B 
9 
2.6.3 
Part C 
10 
2.7 
Assessments 
10 
2.7.1 
Safety and tolerability 
10 
2.7.2 
Pharmacokinetics 
11 
3 
Contents 
12 
3.1 
Table of Figures 
15 
3.2 
Table of Tables 
15 
4 
List of abbreviations 
17 
5 
Trial personnel 
21 
6 
Introduction 
22 
6.1 
Background 
22 
6.2 
Review of investigational medicinal product 
23 
6.2.1 
Non-clinical pharmacology 
23 
6.2.2 
Non-clinical pharmacokinetics 
23 
6.2.3 
Non-clinical safety and toxicology 
24 
6.2.4 
Clinical experience 
26 
6.3 
Rationale for the trial 
29 
6.4 
Participant input into trial design 
29 
6.5 
Rationale for choice of dose(s) 
29 
6.5.1 
Doses up to Cohort A4 
30 
6.5.2 
Subsequent dose levels 
32 


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6.6 
Assessment and management of risk 
33 
6.7 
Conducting the trial during the COVID-19 pandemic 
36 
7 
Objectives and endpoints 
36 
7.1 
Objectives 
36 
7.1.1 
Primary objectives 
36 
7.1.2 
Secondary objectives 
37 
7.1.3 
Exploratory objective 
37 
7.2 
Endpoints 
37 
7.2.1 
Primary endpoints 
37 
7.2.2 
Secondary endpoints 
38 
7.2.3 
Exploratory endpoints 
38 
8 
Overall trial design 
38 
8.1 
Trial design 
38 
8.1.1 
Part A 
38 
8.1.2 
Part B 
39 
8.1.3 
Part C 
40 
8.2 
Study flow chart 
42 
8.3 
Definition of the end of the trial 
44 
8.4 
Stopping criteria 
44 
8.4.1 
Trial stopping criteria 
44 
8.4.2 
Dose escalation stopping criteria 
44 
8.5 
Criteria for dose selection 
45 
8.5.1 
Review of data by the Safety Review Group 
45 
8.5.2 
Dose escalation Part A (SAD) 
46 
8.5.3 
Dose selection Part B (food effect) 
46 
8.5.4 
Dose escalation Part C (MAD) 
47 
8.5.5 
Repeating a dose level or selection of a lower dose level (Parts A and C) 
47 
9 
Trial population 
48 
9.1 
Planned number of subjects 
48 
9.2 
Inclusion criteria 
48 
9.3 
Exclusion criteria 
49 
9.4 
Withdrawal of subjects from the trial 
51 
9.4.1 
Subject withdrawal 
51 
9.4.2 
Individual subject stopping criteria 
51 
9.4.3 
Replacement of withdrawn subjects 
52 
10 
Treatments 
52 
10.1 
Treatments administered 
52 
10.2 
Overdose 
52 
10.3 
Blinding (Parts A and C only) 
52 
10.4 
Unblinding procedure 
53 
10.5 
Method of assigning subjects to treatment groups 
53 
10.6 
Selection and timing of dose for each subject 
54 


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10.7 
Previous and concomitant treatment 
54 
10.8 
Assessment of compliance 
55 
11 
Dietary and lifestyle restrictions 
55 
12 
Procedures and observations 
58 
12.1 
Schedules of procedures 
59 
12.1.1 Schedule of procedures (Part A) 
59 
12.1.2 Schedule of procedures (Part B) 
61 
12.1.3 Schedule of procedures (Part C) 
63 
12.2 
Sampling timepoints and additional tests 
66 
12.3 
Follow-up 
67 
12.4 
Methods 
68 
12.5 
Total volume of blood removed 
72 
13 
Trial materials 
73 
13.1 
Identity of test product(s) 
73 
13.2 
Packaging and labelling 
74 
13.3 
Storage and accountability of IMP 
74 
14 
Adverse events 
74 
14.1 
Definitions of adverse events 
74 
14.2 
Procedures for recording adverse events 
75 
14.3 
Procedures for dealing with serious adverse events 
77 
14.4 
Procedures for handling withdrawals due to adverse events 
77 
14.5 
Procedures for reporting pregnancies 
78 
15 
Data management and quality assurance 
78 
16 
Statistical methods 
79 
16.1 
Pharmacokinetic methods 
79 
16.1.1 Plasma parameters 
79 
16.1.2 Urine sample parameters (Parts B and C) 
83 
16.2 
Statistical methods 
83 
16.2.1 Planned analyses 
83 
16.2.2 Statistical hypotheses 
83 
16.2.3 Analysis populations 
83 
16.2.4 General considerations for data analyses 
84 
16.2.5 Study population analyses 
84 
16.2.6 Safety data analyses 
85 
16.2.7 Pharmacokinetic data analyses 
86 
16.3 
Determination of sample size 
87 
17 
Ethical and regulatory requirements 
87 
18 
Trial documentation 
88 
18.1 
Protocol amendments 
88 
18.2 
Case report forms 
89 


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18.3 
Reporting of results 
89 
19 
Obligations of the sponsor and investigator 
90 
19.1 
Monitoring, auditing and inspection 
90 
19.2 
Compensation of volunteers 
90 
19.3 
Confidentiality 
90 
19.4 
Publication 
90 
19.5 
Archiving 
91 
20 
Premature termination of the trial 
91 
21 
References 
92 
 
3.1 
Table of Figures 
Figure 1: 
Mean (min, max) VAS scores* vs mean BEN8744 plasma concentration 
following single doses of 2 60 mg in healthy subjects .................................... 27 
Figure 2: 
Mean (SD) BEN8744 plasma concentration time profiles after single oral 
doses of 2 60 mg (observed) and 100 mg (individual predicted) in healthy 
subjects (linear and semilogarithmic scale) ...................................................... 28 
Figure 3: 
Predicted BEN8744 plasma concentration time profiles following 20 and 50 
mg twice-daily oral administration in healthy subjects .................................... 33 
Figure 4: 
Schematic of the overall study design............................................................... 42 
Figure 5: 
Schematic of the study design of Parts A, B, and C ......................................... 43 
3.2 
Table of Tables 
Table 1: 
Adverse Events (Cohorts A1 A4) .................................................................... 26 
Table 2:  
Summary of (mean [range]) actual and predicted (100 and 140 mg) BEN8744 
plasma PK parameters after single oral doses of 2 60 mg in healthy subjects 28 
Table 3: 
Safety Margins to Predicted Human Exposure for a starting dose, PAD, 
MRSD, top dose and HED. ............................................................................... 31 
Table 4: 
Predicted BEN8744 plasma pharmacokinetic parameters (maximum and mean) 
following BID administration at 20 and 50 mg ................................................ 33 
Table 5: 
Summary of study risk mitigation strategy ....................................................... 34 
Table 6: 
Planned doses in Part A .................................................................................... 39 
Table 7 
Treatment sequence for each group (n=6 each) in Part B ................................. 40 
Table 8: 
Subject and sentinel numbers ............................................................................ 54 
Table 9: 
Acceptable deviation times for Parts A and B .................................................. 66 
Table 10: 
Acceptable deviation times for Part C  ............................................................. 67 
Table 11: 
Laboratory safety tests ...................................................................................... 69 
Table 12: 
Vital signs ranges .............................................................................................. 70 
Table 13: 
ECG ranges ....................................................................................................... 71 
Table 14: 
Planned blood volume (Part A) ......................................................................... 72 


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Table 15: 
Planned blood volume (Part B) ......................................................................... 72 
Table 16: 
Planned blood volume (Part C) ......................................................................... 73 
 


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4 
List of abbreviations 
ABPI 
Association of the British Pharmaceutical Industry 
AE 
adverse event 
Ae72 
cumulative amount of unchanged drug excreted into urine at 72 h  
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANOVA 
analysis of variance 
AST 
aspartate aminotransferase 
%AUCextrap 
percentage of AUC that was extrapolated 
AUC 
area under the curve 
AUC24 
area under the concentration time curve from time zero to time 
24 h 
AUCinf 
area under the concentration time curve extrapolated to infinite 
time 
AUClast 
area under the concentration time curve to last measurable 
concentration 
AUCtau 
area under the concentration time curve during the dosing 
interval 
BID 
twice-daily 
BLQ 
below the limit of quantification 
BMI 
body mass index 
BSA-CF 
body surface area conversion factor 
cAMP 
cyclic adenosine monophosphate 
CD 
 
cGMP 
cyclic guanosine monophosphate 
Cavg 
average plasma concentration during multiple-dose 
administration 
CI 
confidence interval 
CL/F 
apparent total clearance from plasma after oral administration 
CLR 
renal clearance from plasma 
CLSS/F 
apparent total clearance from plasma at steady state after 
non-intravenous administration 
Cmax 
maximum plasma concentration 
Cmin 
minimum measured concentration 
CNS 
central nervous system 
CRF 
case report form 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CTA 
clinical trial authorisation 
Ctrough 
trough plasma concentration 
CYP 
cytochrome P450 


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CV 
coefficient of variation 
CYP3A4 
cytochrome p450 3A4 
D 
decreased by more than predetermined amount 
ECG 
electrocardiogram 
EDTA 
ethylenediaminetetraacetic acid 
EU 
European Union 
fe F 
fraction of non-intravenously administered drug excreted into the 
urine 
FDA 
United States Food and Drug Administration 
FTIH 
first time in human 
FSH 
follicle-stimulating hormone 
g 
gram(s) 
G 
G force 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyl transferase 
GI 
gastrointestinal 
GLP 
Good Laboratory Practice 
GMP 
Good Manufacturing Practice 
GP 
General Practitioner 
h 
hour(s) 
Hb 
haemoglobin 
HED 
human equivalent dose 
HIV 
human immunodeficiency virus 
HMR 
Hammersmith Medicines Research 
HRA 
Health Research Authority 
IB 
 
IBD 
inflammatory bowel diseases 
IC50/90 
concentration required for 50%/90% inhibition 
ICH 
International Council for Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human Use 
IMPD 
investigational medicinal product dossier 
INR 
international normalised ratio 
IUD 
intrauterine device 
IUS 
intrauterine hormone-releasing system 
kg 
kilogram(s) 
LIMS 
laboratory information management system 
MCH 
mean corpuscular haemoglobin 
MCHC 
mean corpuscular haemoglobin concentration 
MCV 
mean corpuscular volume 


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MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
milligram 
MHRA 
Medicines and Healthcare Products Regulatory Agency 
MIA(IMP) 
manufacturing authorisation for investigational medicinal 
products 
min 
minute(s)  
mm Hg 
millimetres of mercury 
MRSD 
maximum recommended starting dose 
NOAEL 
no observed adverse effect level 
OAAS/S 
Observer s Assessment of Alertness/Sedation scale 
PAD 
pharmacologically active dose 
PDE 
phosphodiesterase 
PDE10A 
phosphodiesterase 10A 
P-gp 
P-glycoprotein 
PK 
pharmacokinetic(s) 
QTc 
QT interval corrected for pulse rate 
QTcF 
QT 
 
Rac 
accumulation ratio 
RBC 
red blood cells 
REC 
research ethics committee 
RES 
Research Ethics Service 
SAE 
serious adverse event 
SD 
standard deviation 
SOP(s) 
standard operating procedure(s) 
SRG 
safety review group 
SUSAR 
Suspected Unexpected Serious Adverse Reaction  
T 
time 
t½ 
terminal elimination half-life 
TEAE 
treatment-emergent adverse event 
tmax 
time of maximum plasma concentration 
TNF-  
 
UC 
ulcerative colitis  
UK 
United Kingdom 
ULN 
upper limit of normal 
USA 
United States of America 
VAS 
visual analogue scale 
VZ/F 
apparent volume of distribution/fraction of dose absorbed 
WBC 
white blood cells 
WHO 
World Health Organization 


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WHO DDE 
WHO Drug Dictionary Enhanced 
z 
terminal rate constant 
 
 


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5 
Trial personnel 
Principal 
investigator 
Denisa Wilkes MD  
HMR 
Cumberland Avenue 
London NW10 7EW 
Tel: 
020 8961 4130 
Email: dwilkes@hmrlondon.com
HMR emergency 
contact
On-call physician 
Tel:
07930 323 244
Statistician 
Steven Whaley MSc PhD 
HMR 
representative 
Adeola Adenuga 
BenevolentAI Cambridge Ltd 
4-8 Maple Street 
London W1T 5HD 
UK 
Tel:  020 3781 9360 
Email:  adeola.adenuga@benevolent.ai
expert 
Dr Arpeat Kaviya MRCP MSc 
Tel:  07753 828 096 
Email:  arpeat.kaviya@benevolent.ai 
Laboratory safety 
tests 
The HMR Analytical Laboratory 
HMR 
Derivation of 
pharmacokinetic 
(PK) parameters
Nick Jackson BSc 
HMR 
Pharmacovigilance 
QbD Group Ltd 
Tel:  +44 (0) 1865 893 290  
Email:  carole.pugh@qbdgroup.com    
SAE reporting: 
pv@qbdgroup.com 
 


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6 
Introduction  
6.1 
Background 
Ulcerative colitis (UC) 
-mediated 
diseases collectively referred to as inflammatory bowel diseases (IBDs).  UC is the 
most common form of IBD, currently estimated to affect 5 500 in every 
100,000 people worldwide, with the incidence increasing 1,2 and higher prevalence in 
industrialised areas like Western Europe and the United States 3,4,5.  IBDs are 
characterised by dysregulated, aberrant immune responses of the intestinal mucosa6; 
in UC, diffuse mucosal inflammation originates in the rectum and extends to the 
proximal colon.  Symptoms include bloody diarrhoea, abdominal pain, faecal 
urgency, and incontinence; some patients may present with extra-intestinal 
manifestations, and patients with more extensive disease may also have fever, weight 
loss, malaise, and fatigue7,8,9.   
Current therapies for IBDs focus on symptom control, clinical remission, and 
preventing flare-ups or disease progression by eliminating or controlling 
inflammatory burden10.  Treatment is based on disease activity and severity; 
however, as there is no single method for determining severity, treatment options 
vary considerably between patients11,12.  There are numerous approved treatments for 
IBDs, such as 5-aminosalicylates, corticosteroids, immunomodulatory agents, and 
monoclonal antibodies directed against tumour necrosis factor  (TNF- ).  However, 
these therapies have multiple limitations, including:  low remission rates (eg after 
treatment with 5-aminosalicylates, 30% of UC patients do not reach remission after 
8 weeks13 and 50% do not maintain complete remission after 12 months14), slow 
onset (immunomodulatory agents, precluding them for use in disease flare-ups), and 
deleterious side-effects (including increased risk of infection from corticosteroid and 
TNF-
and increased risk of lymphoma from TNF-
15 and 
immunomodulatory agent use16).  Patients with refractory UC may undergo a 
colectomy, though this surgery may have complications (high stool frequency17, 
female infertility18, cumulative incidence of pouchitis19).  These factors indicate an 
urgent need for a more effective, safe, targeted therapy for IBDs like UC.  
Cyclic nucleotide phosphodiesterases (PDEs) are a family of enzymes that are 
involved in numerous inflammatory diseases20,21,22.  PDEs play a role in regulation of 
signal transduction, by catalysing degradation of cyclic adenosine monophosphate 
(cAMP) and/or cyclic guanosine monophosphate (cGMP).  Cyclic nucleotide 
signalling is involved in the pathology of IBDs; the cGMP synthetic enzyme 
guanylate cyclase-C and its activators are downregulated in UC23 and decreases in 
expression of these molecules correlate with disease severity24.  Additionally, cGMP 
in the gastrointestinal (GI) tract is involved in fluid and electrolyte secretion, barrier 
function, inflammation, and proliferation25.  One PDE, phosphodiesterase 10A 
(PDE10A), hydrolyses both cAMP and cGMP26.  In healthy individuals, PDE10A 
expression is limited, with high levels only seen in the striatum (caudate nucleus and 


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putamen) of the brain and in the testes27, and PDE10A inhibitors have primarily been 
investigated to treat neurological conditions28.  However, upregulation of PDE10A 
was observed in the colon in UC patients in non-clinical studies done by 
BenevolentAI Cambridge Ltd, compared to low expression levels in healthy colon 
samples.  Upregulation of cGMP hydrolysing PDE10A alongside reduction in cGMP 
synthesis in UC suggest that inhibiting PDE10A could restore cGMP signalling to 
normal levels and reverse pathological changes in UC.  
6.2 
Review of investigational medicinal product 
BenevolentAI Cambridge Ltd is developing BEN8744 as an oral treatment for UC.  
BEN8744 is a potent and selective small molecule PDE10 inhibitor that inhibits 
cAMP and cGMP targeted hydrolytic activity of PDE10A, which is upregulated in 
UC colonic mucosa when compared with healthy colonic mucosa.  It is expected that 
BEN8744 will reduce colonic inflammation, as seen in UC and IBDs. 
This trial is the first time that BEN8744 has been administered to humans.  Several 
non-clinical studies of BEN8744 have been conducted to date.  Non-clinical data are 
presented in the 
29 and summarised below.  
6.2.1 
Non-clinical pharmacology 
In vitro, BEN8744 was found to be a potent inhibitor of human PDE10A cell-free 
hydrolysis of cAMP (IC50 0.2 nM) and cGMP (IC50 0.1 nM), with comparable 
inhibition of mouse PDE10A, and predicted comparable inhibition in rat and dog (as 
the binding pocket of PDE10A is fully conserved across species).  Potency of 
inhibition was demonstrated in a human embryonic kidney cell line 293 (HEK293) 
expressing recombinant human PDE10A (IC50 1.2 nM).  BEN8744 (
 
) 
had > 1,000-fold selectivity for PDE10A in an activity assay of PDEs 1 11.   
PDE10A expression was found to be significantly upregulated in UC colon tissue 
samples compared with healthy controls, and when tested ex vivo on inflamed 
colonic mucosa biopsies from IBD patients, BEN8744 demonstrated a significant, 
dose-dependent reduction in release of inflammatory cytokines.   
In vivo, in a model of colitis (induced by adoptive transfer of CD44-/CD62L+ T-cells 
enriched from C57Bl/6 donor mice into RAG2-/- recipient mice), BEN8744 showed 
improvement in body weight gain and colitis severity scores that was comparable to 
an anti-
 monoclonal antibody reference control.  
6.2.2 
Non-clinical pharmacokinetics 
The non-clinical PK of BEN8744 have been investigated in the mouse, rat, dog, and 
cynomolgus monkey.   
After oral dosing, BEN8744 plasma PK was characterised by rapid absorption, with 
tmax ranging 0.31  1.3 h, and t½ ranging 2.1 4.0 h.  Both mouse and rat were dosed 


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in the fed state, whereas dog and monkey were dosed in the fasted state.  
Bioavailability (F) or the oral dose relative to the intravenous doses ranged 18 31% 
in rat, mouse, and monkey, and was > 90% in dog.  Appreciable levels of unchanged 
drug were found in the faeces of all species after both IV and oral administration.   
Distribution and metabolism studies using mouse, rat, cynomolgus monkey, dog and 
human plasma, and rat colon tissue, showed high binding of BEN8744 (at 1 µM) to 
plasma proteins in all species.  In plasma samples, binding was highest in mouse and 
rat (97%) and lowest in dog (95%); binding in the rat colon was 3-fold higher than in 
plasma.   
BEN8744 was designed not to cross into the brain, to reduce side effects seen in 
other drugs with the same mechanism of action.  In rats, BEN8744 concentration was 
significantly greater in the plasma than in the brain (mean brain:plasma ratio was 
0.03), indicating limited blood brain barrier penetration.    
BEN8744 is moderately stable in microsomes and hepatocytes across species and is 
metabolised predominantly by CYP3A4 with negligible contribution from other 
cytochrome P450 (CYP) enzymes.  BEN8744 is an inhibitor of CYP2C8; however, 
human unbound exposure is expected to be approximately 30-fold lower than the 
IC50 for that isoform.  BEN8744 demonstrated some induction of CYP3A4 at 10 uM, 
but no significant induction of CYPs was observed at 0.1 or 1 uM relative to the 
positive control.  BEN8744 is therefore not expected to trigger direct drug-drug 
interactions by interfering with CYP enzymes at the concentrations used in this 
study.   
BEN8744 is primarily eliminated in rat faeces as unchanged drug, with some 
elimination in urine (approximately 1%).   
6.2.3 
Non-clinical safety and toxicology 
Safety pharmacology  
Safety pharmacology endpoints were primarily investigated in 28-day repeat-dose 
toxicology studies in rats and dogs.   
No BEN8744 related effects were detected at single doses of 40 mg (respiratory 
system and in an Irwin study) or  200 mg/kg twice-daily (BID) (other central 
nervous system [CNS]) in rats.  BEN8744 produced a dose-dependent, statistically 
significant decrease in respiratory rate at single oral doses of 100 and 200 mg/kg in 
rats.  No effects were observed on tidal volume or minute volume at any of the doses 
tested. 
No BEN8744 related cardiovascular system effects were detected up to 5 mg/day in 
Beagle dogs.  Additionally, there were no ECG or heart rate effects noted in the dog 
4-week toxicity study at doses up to 10 mg/kg/day. 
BEN8744 produced a concentration-dependent inhibition of the human 
Ether-à-go-go-Related Gene (hERG) tail current repolarisation in hERG channel 


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expressing Chinese hamster ovary cells in vitro, but only at high concentrations of 
BEN8744 (IC50 = 9.3 µM [4.8 µg/mL], which exceeds the expected Cmax in humans 
by > 50-fold). 
Toxicology 
In a 28-day good laboratory practice (GLP) repeat-dose study, doses of 
40 200 mg/kg (equivalent to 80 400 mg/kg/day) BID, administered by oral gavage, 
was well tolerated in both male and female rats.  Reversibility of BEN8744 related 
effects was assessed after 14-day washout in rats dosed with 400 mg/kg/day.  An 
overall decrease in body weight (13%) was seen in male rats at the highest tested 
dose, and a statistically significant decrease in terminal body weight.  Minor 
haematology changes were seen in females at 200 and 400 mg/kg/day, and males at 
400 mg/kg/day, but these were reversible after a 14-day washout period.  Statistically 
significant increases in relative heart and kidney weights and decreases in thymus 
weights, were also seen after 400 mg/kg/day.  None of these changes correlated with 
microscopic findings and all were at least partially reversible after 14-day washout; 
changes were therefore considered non-adverse.  Based on these results, the no 
observed adverse effect level (NOAEL) was 400 mg/kg/day (equivalent at 28-days to 
mean AUClast of 429 or 614 µg·hour/mL and mean Cmax of 34 or 45.7 µg/mL, for 
males and females, respectively).  
In a 7-day dose range finding study in Beagle dogs, a maximum tolerated dose of 
60 mg/kg/day was determined.  In a 28-day GLP repeat-dose study, doses of 
5 30 mg/kg BID (equivalent to 10 60 mg/kg/day) was given by oral gavage in 
Beagle dogs.  However, doses of 15 and 30 mg/kg were not tolerated after a single 
dose.  Dosing was ceased in all animals, and adverse clinical signs included tremors, 
poor co-ordination, decreased activity, and dry gums.  One animal receiving 
15 mg/kg was euthanised on Day 1 due to severity of adverse effects. 
BEN8744 was administered by oral gavage at doses of 1.5 5 or 7.5 mg/kg 
(equivalent to 3 10 or 15 mg/kg/day) when the study restarted after 33 days.  
Reversibility of BEN8744 related effects was assessed after 14-day washout in dogs 
dosed with 10/15 mg/kg/day.  A single dose of 7.5 mg/kg (the first of BID dosing to 
give a total daily dose of 15 mg/kg/day) was not tolerated (with similar adverse 
clinical signs to those seen at 15 and 30 mg/kg), and the dose was subsequently 
lowered to 5 mg/kg in those animals, to give a total daily dose of 10 mg/kg/day.  
Doses of 10 mg/kg/day were associated with transient decreased activity and/or 
subdued behaviour, and slight head tremors in some animals at Day 4  these were 
deemed to be non-adverse.  Transient poor co-ordination was seen in 2 animals after 
6 mg/kg/day after first administration, and decreased activity seen in 1 animal on 
Day 5.  After 28-days of doses up to 10 mg/kg/day, there were no BEN8744 related 
effects on body weight, ophthalmology, electrocardiology, clinical pathology 
parameters or organ weights and there were no macroscopic or microscopic findings.  
Based on these results, the NOAEL was 10 mg/kg/day (equivalent at 28-days to 


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mean AUClast of 23.8 or 25.3 µg·hour/mL, and mean Cmax of 4.45 or 4.97 µg/mL, for 
males and females, respectively).   
Other studies 
No carcinogenicity or reproductive and development toxicity studies have been 
conducted with BEN8744.   
The mutagenic and clastogenic potential of BEN8744 was assessed in bacterial and 
mammalian assays.  There was no evidence of mutagenicity or genotoxicity in vitro 
or in vivo.  Additionally, no impurities of known or potential mutagenic concern 
were considered likely to be present in final drug substance at a level exceeding the 
appropriate threshold of toxicological concern as per International Conference on 
Harmonisation M7 guidance30 at the planned clinical dose range. 
BEN8744 showed no phototoxic potential when tested up to the maximum 
recommended concentration of 100 µg/mL in the Neutral Red Uptake test in 
BALB/3T3 fibroblasts, clone A31. 
6.2.4 
Clinical experience 
Experience with BEN8744 in humans is limited.  To date, 32 healthy subjects have 
received single oral doses of 2, 6, 20, or 60 mg BEN8744, or placebo (Part A, 
Cohorts A1 A4).   
Safety and tolerability 
Single doses of 2 60 mg BEN8744 were safe and well tolerated: there were no 
serious AEs, and all AEs were mild or moderate in severity (see Table 1).  There 
were no withdrawals due to an AE.  The study is still blinded, it is not known which 
subjects received placebo or active treatment, meaning assigning causality to 
BEN8744 cannot yet be done. 
Table 1: 
Adverse Events (Cohorts A1 A4) 
Subject 
Dose 
(mg) 
Adverse Event 
Severity 
Related to administration of 
BEN8744 
1005 
2 
Toothache 
Moderate
Unlikely to be related  
1009 
6 
Costochondritis  
Mild 
Unlikely to be related  
1022 
20 
Acid reflux 
Mild 
Unlikely to be related 
1023 
20 
Fatigue 
Mild 
Possibly related  
1024 
20 
Sleepiness 
Mild 
Possibly related  
1028 
60 
Gastroenteritis 
(shigella)
Moderate 
Not related  
1032 
60 
Headache 
Mild 
Possibly related 


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There were no clinically significant changes in laboratory assessments (routine 
haematology, clinical chemistry, and urinalysis), physical examination, 12-lead ECG, 
vital signs (blood pressure, pulse rate, respiratory rate, and tympanic temperature) 
OAAS/S and VAS (for sedation).  In humans, sedation is the most common AE seen 
with PDE10 inhibitors, that cross the blood brain barrier and penetrate the brain, and 
BEN8744 has been designed to be a non-brain penetrant inhibitor.  Results from 
Cohort A1-A4 support this, there were no dose-related CNS AEs.  Of note, analysis 
of mean VAS scores (for sedation) vs BEN8744 plasma concentrations (Figure 1) 
showed no trend for an increase in sedation with increasing plasma concentrations.   
VAS = visual analogue scale; min = minimum; max = maximum.  *VAS to monitor sedation. 
Pharmacokinetics 
PK data has been reviewed from Cohorts A1 A4, and mean (range) PK parameters 
and plasma concentration time profiles for single oral doses of 2 60 mg (observed) 
and 100 mg (predicted) BEN8744 are presented in Table 2 and Figure 2, 
respectively.   
A linear non-parametric superposition approach was used to predict drug 
concentrations after single or multiple dosing using Phoenix WinNonlin® 
Version 8.4.  Predicted drug concentrations at 100 and 140 mg QD, and 50 mg BID, 
were based on both mean plasma concentration profiles and the individual plasma 
profile of the subject with the highest exposure to date (Cohort A4 [60 mg]). 
Figure 1: Mean (min, max) VAS scores* vs mean BEN8744 plasma 
concentration following single doses of 2 60 mg in healthy 
subjects


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Table 2: 
Summary of (mean [range]) actual and predicted (100 and 140 mg) 
BEN8744 plasma PK parameters after single oral doses of 2 60 mg 
in healthy subjects  
Dose 
(mg) 
N 
Mean (range) 
Cmax (ng/mL) 
tmaxa 
(h) 
AUC24 
(ng*h/mL) 
AUCinf 
(ng*h/mL) 
2b 
6 
1.34 
(0.59 2.68) 
2.00 
(2.00 2.00) 
 
 
6 
6 
5.03 
(1.33 11.30) 
1.50 
(0.50 3.00) 
15.23 
(5.68 26.6) 
15.16 
(5.67 26.4) 
20 
6 
46.1 
(20.7 57.7) 
2.00 
(1.00-3.00) 
163.25 
(77.40 210) 
164.12 
(77.30 210) 
60 
6 
352.83 
(130 688) 
1.00 
(1.00-2.00) 
1,057.27 
(494 2,380) 
1,059.2 
(494 2,390) 
100 
predc 
 
1,100 
1.35 
3,950 
3,986 
140 
predc 
 
1,541 
1.35 
5,530 
5,581 
SD = standard deviation; Cmax = maximum plasma concentration; tmax = time of Cmax; AUC24 = area 
under the concentration time curve from time zero to time 24 h; AUCinf = area under the 
concentration  time curve extrapolated to infinite time; pred:  predicted:  max:  maximum. 
a Median (min  max). 
b Insufficient plasma concentration data at terminal phase to estimate terminal phase related pk 
parameters. 
C 100 mg and 140 mg profiles predicted based on the individual plasma profile of the subject with the 
highest exposure to date (Cohort A4 [60 mg]), using a nonparametric superposition function. 
SD = standard deviation; IC50/90 = concentration required for 50%/90% inhibition.  
Figure 2: Mean (SD) BEN8744 plasma concentration time profiles after 
single oral doses of 2 60 mg (observed) and 100 mg (individual 
predicted) in healthy subjects (linear and semilogarithmic scale) 


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After single doses of 2 60 mg, BEN8744 demonstrated a shorter than expected 
elimination half-life, ranging approximately 2 4 h.  At the highest dose tested 
(60 mg), mean Cavg was below IC90.  However, a single subject had a higher AUCinf, 
approximately 2-fold above the mean and above IC90.  In all subjects after 60 mg 
BEN8744, plasma concentrations decreased below the IC50 by 11 h postdose.  
Considering the observed short half-life, and predicted required time above IC50 for 
efficacy in patients, a twice daily dosage regimen will be required in Part C (MAD 
Phase) to achieve exposures above IC50 for up to 18 24 h.  
The impact of gut P-glycoprotein (P-gp) efflux and gut cytochrome p450 3A4 
(CYP3A4) mediated metabolism was not expected to be significant in humans; 
however, emerging clinical data suggests there is an impact which is significant at 
lower doses.  Between 2 and 6 mg QD the increase in PK parameters appeared 
dose-proportional, but escalation between 6, 20 and 60 mg QD resulted in a greater 
than proportional increase in AUCinf, suggestive of non-linear PK.  Additionally, 
between-subject variation was high.  While the linear approach overpredicted 
exposures at low doses, the mean Cmax and AUCinf at 60 mg aligns with predicted 
exposures.  Mean apparent clearance (CL/F) decreased with an increase in dose from 
6 to 60 mg QD, which may indicate approaching saturation of gut P-gp and 
CYP3A4.  Hence, at higher doses exposure is expected to be closer to 
dose-proportional. 
6.3 
Rationale for the trial 
This first time in human (FTIH) study will investigate the safety, tolerability, PK of 
BEN8744 after single and multiple ascending oral doses in healthy subjects, in both 
the fed and fasted state.  The results of this study will be used to select doses for 
subsequent studies in patients.  Part B of this study was designed in line with the US 
Food and Drug Administration (FDA) guidelines on food-effect bioavailability 
studies. 
6.4 
Participant input into trial design 
This is a phase 1, exploratory study in healthy volunteers, with no anticipated 
therapeutic benefit to the participants; involvement of patients, service users or 
members of the public in the design of the trial is not appropriate. 
6.5 
Rationale for choice of dose(s) 
At the time of writing, Cohorts A1 A4 (Part A) have completed the study (see 
section 6.2.4 for details).  After a single 60 mg dose (Cohort A4), 1 subject met 89% 
of the protocol-defined AUCinf threshold (based on IC90 predicted ex vivo data).  The 
protocol (section 8.5.4) states that doses in Part C (MAD) cannot be predicted to 
exceed the maximum observed Cmax and AUCinf achieved in Part A (SAD).  Due to 
the PK profile and indication-specific tissue exposure requirements, further dose 


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escalation in Part A up to a maximum of 140 mg QD may be required to support the 
MAD phase of the study, and future studies of BEN8744.  So, the protocol has been 
subject to a substantial amendment, incorporating data from completed 
Cohorts A1 A4, to provide rationale to allow dosing up to 140 mg QD in Part A 
(which is expected to exceed the previous threshold but remain within the updated 
PK threshold:  the NOAEL in the most sensitive species [dog]). 
6.5.1 
Doses up to Cohort A4 
Before the present study (BB-8744-1001), BEN8744 had not yet been administered 
to humans, so no human exposure data existed.  However, PDE10 inhibition as a 
mechanism of action has been described in humans, with numerous molecules under 
development as therapeutic agents.  Two such examples are Mardepodect and 
Balipodect, both of which have completed clinical trials.  The most frequently 
reported adverse effects from acute dosing of both agents is somnolence, which is 
often reported in a dose-dependent manner and is attributed to on-target activity of 
PDE10A inhibition in the brain when receptor occupancy exceeds 20%.  This effect 
has also been seen in other preclinical species.   
Based on in vitro potency and prediction of human PK from animal studies, it was 
calculated that a starting dose of 2 mg for BEN8744 was predicted to have < 1% 
PDE10A enzyme occupancy in the brain and about 20% average enzyme occupancy 
in the periphery.  At this low dose on BEN8744, any potential side effects 
(ie sedation) are minimised (in contrast to other PDE10A inhibitors where uptake 
into the brain is about 10-fold higher than that predicted for BEN8744).  The 
exposure level at this dose was predicted to be > 690-fold below levels where 
sedation occurs in pre-clinical animals. 
The proposed doses in Part A of this study were selected based on physiologically 
based PK modelling, analysis of safety, tolerability and PK data from non-clinical 
studies, and previous published information on compounds with a similar mechanism 
of action.  The rationale for dose selection is discussed in detail in the IB29, and 
summarised below.   
Toxicology-based safe starting dose 
The maximum recommended starting dose in man (MRSD) was estimated using the 
method outlined by the FDA31, calculating a human equivalent dose (HED) using the 
body surface area conversion factor (BSA-CF) and a safety factor.  Pharmacological 
activity was also taken into account in selecting the human starting dose. 
For the purposes of the calculation, a normal human volunteer was assumed to weigh 
70 kg.  The most appropriate species for estimating the MRSD was selected 
according to the FDA guidance, as the lowest estimate between the 2 safety species 
(rat and dog). 


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The HED at the lowest NOAEL was in dog, obtained in repeat-dose toxicity studies
(BenevolentAI Cambridge Ltd, report CRL-522041).  The dog was selected as the 
species most sensitive to the effects of BEN8744, as adverse clinical signs related to 
the test item were observed (see section 6.2.3).  In the 4-week dog study, the NOAEL 
was 10 mg/kg, producing a Cmax of 4,710 ng/mL and AUClast of 24,500 ng.h/mL.  
Using a conversion factor of 0.54, that corresponds to a HED of 5.4 mg/kg/day (or 
approximately 378 mg/day for a human weighing 70 kg).  Once a safety factor of 10 
is applied, the MRSD would be 37.8 mg/day in humans with a body weight of 70 kg.   
In the SAD part (Part A), the proposed starting dose was 2 mg.  Details of the PK/PD 
modelling used are included in the IB29.  The predicted data are shown in Table 3.  
Subsequent doses were decided by the SRG as described in section 8.5. 
Relative to the NOAEL in the most sensitive species (dog), large safety margins 
exist.  Additionally, the Caverage,u for a single starting dose of 2 mg would result in 
about 20% PDE10A occupancy in the periphery.  Taking into account brain to 
plasma ratios, Caverage,u in the brain is predicted to result in PDE10A occupancy of 
< 1%.  This is > 690-fold below the exposure (AUC24) where adverse effects were 
observed in the dog.  The proposed starting dose of 2 mg was therefore supported 
from a non-clinical safety perspective. 
Table 3: 
Safety Margins to Predicted Human Exposure for a starting dose, 
PAD, MRSD, top dose and HED.  
  
  
Human dose 
Predicted  
% receptor 
occupancy Cavg 
(plasma)
Cmax 
(ng/ml) 
AUC24 
(ng.h/ml) 
Safety 
margin 
Cmax 
Safety 
margin 
AUC24 
Starting 
dose 
2 mg QD  
19 
6.6 
48  
714 
510 
PAD  
10 mg QD 
56 
75  
261 
63  
94 
MRSD   
38 mg QD 
 82 
346 
936 
14  
26 
Top dose
140 mg QD 
90 
1,190 
2,674 
4 
9 
HED 
380 mg QD 
98 
3,704 
9,794 
1 
3 
Abbreviations:  HED = human equivalent dose; MRSD = maximum recommended starting dose; 
PAD = pharmacodynamically active dose; QD = once-daily; Cmax = maximum plasma concentration; Cavg = 
average plasma concentration during multiple-dose administration; AUC24 = area under the concentration time 
curve from time zero to time 24 h. 
Safety margins are calculated based on the NOAEL in the dog (5 mg/kg BID) from a 28-day toxicity 
data (Report CRL-522041); Dog NOAEL 10mg/kg/day.  HED calculated by multiplying mg/kg/day 
by appropriate conversion factor (0.54 for dogs) to obtain the HED in mg/kg, and multiply by body 
weight, based on 70 kg human.  MRSD calculated using a 10-fold safety margin from the HED.   
PK dose simulations and receptor occupancy calculations for doses reported in 22-8744-005PK.  
Anticipated human pharmacologically active dose range 
Before the start of this study, PAD doses were predicted based on the target unbound 
average plasma concentrations (Caverage) of 0.7 to 7.0 nM (the IC50 IC90 of BEN8744) 
after BID dosing of BEN8744 for 14 days.  Considering the variability in the model 
predictions, a dose range was predicted to be 5 12 mg BID and 46 69 mg BID based 
on Caverage,u for free IC50 and IC90 levels, respectively, in humans.  These dose 


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estimations are theoretical, based on in vitro IC50, plasma protein binding, and 
predicted PK in humans.  A single dose of 10 mg BEN8744 was predicted to provide 
about 50% enzyme occupancy in the periphery.  The highest planned dose in this 
study is 140 mg, which is predicted to achieve the theoretical IC90 Caverage,u.  Dose 
levels may change (upwards or downwards) depending on observed human exposure, 
but no dose will exceed 140 mg/day.  
6.5.2 
Subsequent dose levels 
Based on the observed PK profile so far, and the relationship between PDE10 
theoretical target engagement and BEN8744 concentrations seen in this study to date, 
it is predicted that due to the short half-life of BEN8744 (~2 4 h) an estimated daily 
dose of approximately 100 mg (50 mg BID) will be required to maintain sufficient 
target engagement in all target tissues over a 24 h period in future studies.   
The maximum planned dose for Part A (140 mg QD), is predicted to achieve an 
absolute maximum blood concentration of Cmax = 1,541 ng/mL, AUC24 = 
5,530 ng*h/mL, and AUCinf = 5,581 ng*h/mL (see Table 2).  That is 3- and 4-fold 
below the NOAEL in the 28-day dog study for Cmax and AUC, respectively, and will 
not be exceeded in any 24 h period.  The planned dose for Cohort A5 is 100 mg QD.  
Planned doses for Parts B and C may be adjusted to account for differences between 
predicted and actual/observed PK, in line with the dose escalation criteria in 
section 8.5.   
Based on non-parametric superposition modelling (see Table 4), using data from the 
subject with the highest exposure to date (Cohort A4 [60 mg]), it is anticipated that 
the BEN8744 pharmacologically active dose will be ~ 50 mg BID.  As shown in 
Figure 3, the 50 mg BID dose is expected to a achieve a time (T) > IC50 of 18 (mean) 
to 24 h (maximum) with a Ctrough/IC50 ratio of approximately 1.  In order to proceed 
with Part C (MAD) dosing at > 30 mg BID, the limit in section 8.5.2 has been 
updated to the NOAEL in the most sensitive species (dog), to allow dosing up to 
140 mg to achieve the T > IC50 and Ctrough/IC50 ratio predicted to achieve the required 
efficacy for BEN8744.   
 
 


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Table 4: 
Predicted BEN8744 plasma pharmacokinetic parameters (maximum 
and mean) following BID administration at 20 and 50 mg 
Cohort/Dose 
(BID)* 
Cmax 
(ng/mL) 
AUC24 
(h*ng/mL) 
T > IC50 
(h) 
Ctrough/IC50 
Ratio 
Margin to dog 
NOAEL 
(Cmax/AUC) 
20 mg 
Observed 
57.36 
(mean 42) 
488.12 
(mean 320) 
11.57 
(mean 
10) 
0.17 
82/50 
50 mg 
Predicted 
550.21 
(mean 
264) 
4,063.33 
(mean 
1,744) 
24.53 
(mean 
18) 
1.06 
9/6 
BID:  twice-daily; Cmax:  maximum plasma concentration; AUC:  area under the concertation time 
curve; AUC24:  AUC from time 0 to 24 h; IC50: concentration required for 50% inhibition; Ctrough:  
trough plasma concentration.  NOAEL: no observed adverse effect level; T = time.  
* The 20 mg BID profile predicted based on observed A3-20 mg QD mean PK profile and 50 mg BID 
profile predicted based on Subject ID YUJ (highest exposed subject) 60 mg QD profile, using 
nonparametric superposition. 
Figure 3: Predicted BEN8744 plasma concentration time profiles following 
20 and 50 mg twice-daily oral administration in healthy subjects 
BID:  twice-daily; QD:  once-daily; NOAEL:  no observed adverse effect level; IC50/75/90:  
concentration required for 50%/75%/90% inhibition. 
6.6 
Assessment and management of risk 
Any safety risk to study participants is mitigated by the considerations in Table 5.  
Any risks are adequately mitigated by safety assessments, and by the medical cover 
provided by the investigator site, and by appropriate IMP manufacture, according to 
Good Manufacturing Practice (GMP). 
There will be no direct health benefit for study participants from receipt of study 
medication.  An indirect health benefit to the healthy subjects enrolled in this trial is 
the free medical examination received at screening and during the study. 
Overall, the investigators consider the overall risk benefit balance to be acceptable. 






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6.7 
Conducting the trial during the COVID-19 pandemic 
The investigator and sponsor have reviewed the risks of conducting the trial during 
the current COVID-19 pandemic.  Our priority is the safety of trial subjects and staff, 
but we also have an ethical duty to preserve the scientific integrity of the trial as far 
as possible. 
BEN8744 is unlikely to increase the risk of contracting COVID-19 infection, or to 
worsen the severity of an infection.  BEN8744 has no immunosuppressive effect, and 
is not associated with cough, pyrexia, or anosmia, which would require isolation of 
subjects. 
BEN8744 is unlikely to affect the efficacy of a vaccine against SARS-CoV-2.  
However, to delineate adverse events (AEs) caused by BEN8744 or a vaccine, 
vaccines will be prohibited from 28 days before (first) dosing until the follow-up 
subject. 
-19 risk mitigation 
-19 virus testing strategy for 
volunteers and staff, social distancing measures, and management of COVID-19-like 
P was first notified to the Medicines and Healthcare Products 
Regulatory Agency (MHRA) and Health Research Authority (HRA) on 22 May 2020 
COVID-19 RMP are deemed adequate for this trial.  Any deviations from the RMP 
will be documented in a separate COVID-19 trial-specific risk assessment, prepared 
by the investigator.  Any deviations from the protocol that result from the COVID-19 
pandemic, and COVID-19 related AEs or serious adverse events (SAEs), will be 
documented. 
Taking the above factors into account, and the proposed mitigation, we believe that it 
is medically and ethically acceptable to proceed with the trial during the current 
COVID-19 pandemic. 
7 
Objectives and endpoints 
7.1 
Objectives 
7.1.1 
Primary objectives 
Part A: 
To assess the safety and tolerability of single ascending oral doses of 
BEN8744 in healthy subjects 
Part B: 
To characterise the effect of food on the pharmacokinetic (PK) profile 
of at least 1 dose of BEN8744  


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Part C: 
To assess the safety and tolerability of multiple ascending oral doses of 
BEN8744 in healthy subjects 
7.1.2 
Secondary objectives 
Part A: 
To assess the PK profile of BEN8744 after single oral doses in healthy 
subjects 
Part B: 
To assess the safety and tolerability of a single dose of BEN8744 
following high-fat food intake relative to fasting conditions in healthy 
subjects 
Part C: 
To assess the PK profile of BEN8744 after repeated oral doses in 
healthy subjects 
7.1.3 
Exploratory objective 
Part B (and optional in Part C): 
To measure BEN8744 in urine and determine renal clearance in healthy 
subjects* 
Exploratory characterisation of BEN8744 and its metabolites in plasma, 
urine, and faeces  
*If significant amounts of the parent compound are detected in Part B, the parent 
compound may be measured in Part C (in urine at 2 dose levels [low and high]). 
Faeces will be analysed in Part B only.  If significant amounts of metabolites are 
detected in Part B, exploratory metabolite analyses may be conducted in Part C (in 
plasma and urine at 2 dose levels [low and high] on Day 1 and Day 14). 
7.2 
Endpoints 
7.2.1 
Primary endpoints 
Safety and tolerability (Parts A and C):  vital signs (blood pressure, pulse rate, 
tympanic temperature, and respiratory rate), 12-lead electrocardiogram (ECG), 
cardiac telemetry (Part A only), physical examination, laboratory safety tests 
(haematology, clinical chemistry, and urinalysis), adverse events (AEs), and 
Observer's Assessment of Alertness/Sedation scale (OAAS/S), visual analogue scale 
(VAS) to monitor sedation, and C-SSRS (Part C only).    
PK (Part B): 
 Cmax, tmax, AUC24, AUC72, AUClast, AUCinf, %AUCextrap, t½, Z, 
CL/F, VZ/F 


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7.2.2 
Secondary endpoints 
PK (Part A): 
 Cmax, tmax, AUC24, AUC72, AUClast, AUCinf, %AUCextrap, t½, Z, 
CL/F, VZ/F 
Safety and tolerability (Part B):  vital signs (blood pressure, pulse rate, tympanic 
temperature, and respiratory rate), 12-lead ECG, physical examination, laboratory 
safety tests (haematology, clinical chemistry, and urinalysis), AEs, and OAAS/S and 
VAS to monitor sedation. 
PK (Part C): 
 Cmax, tmax, Ctrough, AUCtau, AUClast, AUC72, AUCinf, %AUCextrap, 
t½, Z, CLSS/F, VZ/F, Rac(AUC), Rac(Cmax), SR(AUC) 
7.2.3 
Exploratory endpoints 
PK (Part B and optional in Part C): 
Ae72, fe
R 
8 
Overall trial design 
8.1 
Trial design 
This is a Phase 1, FTIH, single-centre, randomised, double-blind, placebo-controlled, 
dose escalation trial to assess the safety and tolerability, PK, and food effect of 
BEN8744 in healthy subjects. 
The trial will be in 3 parts:  Part A will investigate single ascending oral doses of 
BEN8744; Part B is a 2-way crossover assessment of the effect of food on the PK of 
BEN8744; and Part C will investigate multiple ascending oral doses of BEN8744.  
A schematic diagram of the study design is in section 8.2. 
8.1.1 
Part A 
Enrolment of up to 64 healthy subjects is planned, in up to 5 groups (Groups A1 A5) 
and 3 optional groups (Groups A6 A8).  Each group will consist of 8 subjects. 
Subjects will receive a single dose of BEN8744 or placebo, as capsules, after an 
overnight fast of at least 10 h.  At each dose level, 6 subjects will receive BEN8744 
and 2 will receive matching placebo in an overall ratio of 3:1. 
The starting dose for Group 1 is 2 mg BEN8744 or placebo.  It is intended that 
subsequent cohorts will receive higher doses.  The planned doses are in Table 6. 


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Table 6: 
Planned doses in Part A 
Group 
Dose of BEN8744 
A1 
2 mg 
A2 
6 mg 
A3 
20 mg 
A4 
60 mg 
A5 
100 mg 
A6 (optional) 
TBC 
A7 (optional) 
TBC 
A8 (optional) 
TBC 
Additional intermediate or higher dose levels may be explored in 3 optional groups 
(Groups A6 A8).  The dose levels will be selected by the safety review group (SRG) 
as described in section 8.5.   
The dose will not be escalated unless the safety and tolerability of the previous dose 
are acceptable, and the conditions in section 8.5 are met.  There will be an 
appropriate interval between sequential groups, to allow for review of those data. 
Because BEN8744 has never been given to humans before, each new ascending dose 
will be staggered:  2 sentinel subjects will be dosed first, and the remaining subjects 
will be dosed at least 23 h later.  To maintain the blind nature of the study, the 2 
sentinel subjects will be randomised to ensure that 1 subject receives active treatment 
and the other receives placebo.  Since one subject will receive placebo treatment, the 
sentinel subjects may be dosed at least 5 min apart.  Provided the investigator 
considers the safety and tolerability in the sentinel subjects to have been acceptable, 
the remaining subjects will be dosed, at intervals of at least 10 min. 
If the dose level selected is no higher than one that has already been shown to cause 
no safety concerns, sentinel subjects will not be required, and subjects will be dosed 
at intervals of at least 10 min. 
Subjects will be screened within 28 days before their (first) dose of trial medication.  
Subjects will be resident on the ward from 1 day before their dose (Day 1) until up 
to 72 h after dosing (Day 4).  They will return for a follow-up visit 7 (±2) days after 
their inpatient stay (Day 11 ±2 days). 
8.1.2 
Part B 
Enrolment of up to 12 healthy subjects is planned, in up to 2 groups (Groups B1 
and B2).   
Each subject in Part B will have 2 study sessions (Sessions 1 and 2), in which they 
will receive a single dose of BEN8744, by mouth.  Each subject will receive 
BEN8744 after an overnight fast of at least 10 h in one session, and after an FDA 
high-fat breakfast (1,013 kcal, 59.2 g fat [of which 28.1 g saturated fat]) in the other 
session; the order will be randomised 1:1, as shown in Table 7


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will be separated by a washout of at least 7 days (or 5 half-lives as determined in 
Part A, whichever is longer).  Subjects dosed on the same day may be dosed at 
intervals of at least 10 min. 
Table 7 
Treatment sequence for each group (n=6 each) in Part B 
 
Session 1  
Session 2 
n=3 subjects 
Fed 
Fasted 
n=3 subjects 
Fasted 
Fed 
The dose to be tested in Group B1 will be decided following review of the interim 
safety, tolerability, and PK data from at least 3 dose levels in Part A, as described in 
section 8.5.3.   
To reduce the risk of unexpectedly high plasma concentrations, the dose selected for 
Group B1 will be no higher than 50% of the highest dose tested in Part A that caused 
no safety concerns.   
Group B2 is optional and may be required if the Sponsor decides to test the effect of 
food at an additional dose level (for example, if absorption and hence exposure is not 
proportional to dose in Part A) or under different conditions (eg with different fasting 
requirements or after a different meal such as a standard breakfast).  The dose and 
food requirements for Group B2 will be decided following review of the interim 
safety, tolerability, and PK data from Group B1 and all available data from Part A. 
Subjects will be screened within 28 days before their first dose of trial medication.  
Subjects will be resident on ward from 1 day before their dose (Day 1) until up to 
72 h after dosing (Day 4).  They will return for a follow-up visit 7 (±2) days after 
their inpatient stay in Session 2 (Day 11 ±2 days). 
8.1.3 
Part C 
Enrolment of up to 32 healthy subjects is planned, in up to 3 groups (Groups C1 C3) 
and 1 optional group (Group C4).  Each group will consist of 8 subjects.   
Each subject will receive daily doses of BEN8744 or placebo, by mouth, for 14 days.  
At each dose level, 6 subjects will receive BEN8744 and 2 will receive matching 
placebo.  Doses will be taken once or twice daily in the fasted state, unless emerging 
data indicate they should be taken in the fed state.   
Part C will not start until at least 3 dose levels have been completed in Part A, as 
described in section 8.5.4.  Part C may also be conducted in parallel with Part B.  The 
dose, dosing regimen (once or twice daily), and whether the dose is taken fed or 
fasted, will be determined based on review of the available safety, tolerability and 
PK results from Parts A and B, and previous groups in Part C, as described in 
section 8.5.   


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The first total daily dose (ie, morning plus evening dose, if a twice-daily dosing 
regimen is chosen) tested in Part C (Group C1) will be the same as, or lower than, a 
single dose that has been given in Part A without any safety concerns.  See also 
section 8.5. 
Subjects will be screened within 28 days before their first dose of trial medication.  
Subjects will be resident on ward from the day before their dose (Day 1) until up to 
72 h after their final dose (Day 17).  They will return for a follow-up visit 7 (±2) days 
after their inpatient stay (Day 24 ±2 days). 
 






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8.3 
Definition of the end of the trial 
The end of the trial is defined as the final follow-up visit by the last subject.  If the 
trial is terminated prematurely, the trial ends when the sponsor notifies the 
investigator in writing that the trial has finished, or when the last subject attends the 
final follow-up visit, whichever is later.  
8.4 
Stopping criteria 
8.4.1 
Trial stopping criteria 
The trial will be stopped if either of the following occurs: 
 1 or more SAEs considered to be at least possibly related to study treatment; or 
 2 or more severe or clinically significant adverse events (AEs) that are 
considered to be at least possibly related to study treatment at any dose level. 
In Parts A and C, treatment allocations may be unblinded to aid safety review, 
provided that the unblinding is appropriately documented.  In Part B, all subjects will 
receive BEN8744. 
If, after an internal safety review, it is appropriate to restart the trial, a substantial 
amendment will be submitted to the MHRA and research ethics committee (REC).  
The trial will not restart until the amendment has been approved by the MHRA and 
REC. 
8.4.2 
Dose escalation stopping criteria 
A dose level will not be repeated, or exceeded, if: 
 the results of safety tests for that dose level give the sponsor or investigator cause 
for concern, 
 the investigator or sponsor considers that dose level to be poorly tolerated. 
In addition, a dose level will not be exceeded if: 
 plasma concentrations at higher doses in any individual subject are predicted to 
exceed the exposure threshold (see section 8.5). 
 
alanine aminotransferase 
(ALT) and/or aspartate aminotransferase (AST) elevations  3 × upper limit of 
normal (ULN) in the presence of a total bilirubin increase  2 × ULN in the 
absence of other findings of cholestasis such as a significant increase in alkaline 
phosphatase (ALP) and without an alternative diagnosis that could explain the 
increase in ALT/AST and bilirubin. 
 


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2 or more subjects have a mean QTcF of > 500 msec or increase from baseline of 
> 60 msec  
The trial will be stopped if any criterion in section 8.4.1 is met. 
Dosing will be discontinued in an individual subject if any criterion in section 9.4.2 
is met. 
8.5 
Criteria for dose selection 
8.5.1 
Review of data by the Safety Review Group 
During the study, the dose will be increased only if the safety, tolerability, and PK of 
the previous dose are acceptable. 
All doses will be selected by the Safety Review Group (SRG), which will include (as 
a minimum) the principal investigator (or delegate) and 
qualified representative (or delegate).  Each dose decision will be made and 
documented in line with HMR standard operating procedures (SOPs). 
Before selecting a new dose level (for any group), the SRG will review, as a 
minimum, the safety, tolerability, and PK data from the previous dose level and (if 
different) the highest dose level tested to date, as described below.  Safety, 
tolerability, and PK data obtained from the previous group(s) will also be reviewed, 
if applicable.  All data used to support dose selection will be quality checked. 
Review of safety and tolerability data 
The SRG will review (as a minimum) safety and tolerability data, up to 48 h after 
final dosing, from at least 4 evaluable subjects who have received active treatment at 
the highest dose level tested to date.  An evaluable subject is one who completes 
dosing and has undergone procedures until 24 h after final dosing, and had no major 
protocol deviations.  To maintain blinding, data from at least 6 of the 8 subjects in 
each group must be reviewed to ensure that the dataset includes at least 4 evaluable 
subjects on active treatment.  If fewer subjects than planned are dosed, any subjects 
required to complete the group may be dosed in parallel with subsequent groups.   
The safety data reviewed will include, as a minimum:  
 AEs and SAEs, including description, frequency, intensity, onset, duration, and 
relationship to treatment 
 physical examinations 
 vital signs 
 12-lead safety ECG 
 telemetry (Part A) 
 laboratory safety tests 


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 C-SSRS (Part C) 
Review of pharmacokinetic data 
The SRG will review (as a minimum) PK data up to at least 24 h after final dosing 
from at least 4 evaluable subjects on active treatment at the highest dose level tested 
to date before the dose is escalated. 
When PK data are reviewed, dummy-subject identifiers will be applied to the data by 
the bioanalytical laboratory, or an unblinded programmer at HMR, so that individual 
data may be reviewed without unblinding the sponsor and investigator.  If fewer 
subjects are dosed than planned, to avoid potential unblinding, individual data will 
not be reviewed  mean, minimum and maximum data will be reviewed, and number 
of subjects will not be presented.  If there are missing PK data at a particular 
timepoint, the missing data may be replaced by an interpolated value to maintain 
blinding.   
8.5.2 
Dose escalation Part A (SAD) 
The dose will be increased such that the predicted plasma concentrations in any 
subject (Cmax and AUC) after the top dose do not exceed the following limits, which 
are based on the NOAEL in the most sensitive species (dog). 
Cmax:  4,710 ng/mL 
AUClast:  24,500 ng.h/mL 
Dose escalation in Cohorts A1 A4 is complete.  The planned dose for A5 is 100 mg.  
Three further intermediate or higher dose levels may be explored in the optional 
groups of subjects (Groups A6 A8).   
The maximum dose in Part A will not exceed 140 mg.  The predicted plasma 
concentrations in any subject at the maximum dose (140 mg) are predicted to be 
3-fold and 4-fold below the Cmax and AUC limits above, respectively.  The predicted 
plasma concentrations and rationale for the maximum dose (140 mg) are provided in 
section 6.5.2. 
The trial will be stopped if the criteria in section 8.4.1 are met. 
8.5.3 
Dose selection Part B (food effect) 
Part B will not proceed until the SRG has reviewed safety, tolerability (up to 48 h  
after dosing), and PK data (up to 24 h after dosing) from at least 3 groups in Part A, 
as described in section 8.5.1. 
The dose selected for Group B1 will be no higher than 50% of the highest dose tested 
in Part A that caused no safety concerns. 
If Group B2 is required, it will proceed once the SRG has reviewed safety and 
tolerability (up to 48 h), and PK data from at least 4 subjects in Group B1, up to 24 h 


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after dosing in each treatment session, and available data from Part A.  The dose 
selected for Group B2 will be the same or lower than one that has been given in 
Part A without any safety concerns.   
8.5.4 
Dose escalation Part C (MAD) 
Part C may start before the completion of Part A.  At a minimum, Part C will not 
proceed until the SRG has reviewed safety and tolerability (up to 48 h), and PK data 
(up to 24 h after dosing) from at least 3 groups in Part A, as described in 
section 8.5.1. 
The dose, dosing regimen (once or twice daily), and whether the dose is taken fed or 
fasted, will be determined by the SRG based on review of available safety, 
tolerability, and PK data from Parts A and B and previous cohorts in Part C. 
Dose selected for Group C1:  The first total daily dose (ie, morning plus evening 
dose, if a twice-daily dosing regimen is chosen) selected for Part C (Group C1) will 
be the same as, or lower than, a single dose that has been given in Part A without any 
safety concerns.  Additionally, to account for possible accumulation, at the proposed 
first dose level the predicted Cmax and AUCtau (at steady state) in any individual 
subject must not exceed the maximum observed Cmax and AUCinf achieved so far in 
Part A. 
Doses selected for Groups C2 C3 and optional group C4:  It is expected that the dose 
level tested will increase in each new group.  However, the dose will be increased 
only if, at the new proposed dose level, Cmax and AUCtau (at steady state) in any 
individual subject are not predicted to exceed the maximum observed Cmax and 
AUCinf achieved following a single dose in Part A that caused no safety concerns.   
The daily dose will be increased such that it does not exceed 3.5 times the highest 
daily dose previously tested in Part C that was safe and well tolerated.  Dosing will 
be discontinued if the criteria in section 8.4.1 are met. 
8.5.5 
Repeating a dose level or selection of a lower dose level (Parts A and C) 
In Parts A and C, the SRG may decide to test a lower dose level of BEN8744, or to 
repeat a dose level, provided it does not meet the criteria in section 8.4.  Such 
decisions will be made and documented in line with HMR SOPs.   
A dose level may be repeated under the following circumstances. 
 If it was safe and well tolerated, and resulted in BEN8744 plasma concentrations 
within the limit (section 8.5.2).   
 If AEs occurred that caused mild or moderate discomfort, but did not in any way 
threaten the health of the subject, that dose level may be repeated with the aim of 
judgement, it would be unreasonable to expose further subjects to the level of 


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discomfort experienced by the subjects who have already received the dose, a 
lower dose may be tested.  The selected dose will be either a lower dose level that 
has already been given, or an intermediate level that has not previously been 
given; in either case, the aim is to learn more about the relationship between AEs 
and dose (or plasma concentration) of BEN8744. 
9 
Trial population 
9.1 
Planned number of subjects 
Up to 108 healthy volunteers, excluding replacements:  up to 64 in Part A (including 
3 optional groups); up to 12 in Part B; and up to 32 in Part C (including 1 optional 
group).   
9.2 
Inclusion criteria 
The inclusion criteria detailed below should be used to determine eligibility at 
screening only (unless otherwise specified). 
1. Male or female healthy volunteer in good health, as determined by medical 
history, physical examination, vital signs, 12-lead ECG, and clinical laboratory 
assessments at the time of screening, as judged by the Investigator.   
2. Aged 18 65 years at the time of consent. 
3. A body mass index (BMI; Quetelet index) in the range 18.0 30.9 and 
weight  50 kg 
Body Mass Index  = 
   
4. Ability to understand the nature of the trial and any hazards of participating in it.  
Ability to communicate satisfactorily with the investigator and to participate in, 
and comply with the requirements of, the entire trial. 
5. Willingness to give written consent to participate after reading the information 
and consent form, and after having the opportunity to discuss the trial with the 
investigator or their delegate.  
6. Willing and able to comply with scheduled visits, treatment plan, laboratory 
tests, and other study procedures. 
7. Agree to follow the contraception requirements of the trial as described in 
section 11. 
8.
Agree not to donate blood or blood products during the study and for up to 
3 months after the administration of the trial medication. 
9. Registered with a General Practitioner (GP) in the UK (Part A only). 
 weight [kg]
(height [m])2


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10. Willingness to give written consent to have data entered into The 
Overvolunteering Prevention System. 
9.3 
Exclusion criteria 
The exclusion criteria detailed below should be used to determine eligibility at 
screening only (unless otherwise specified). 
1. Woman who is pregnant or lactating, or pre-menopausal woman who is sexually 
active and not using a reliable method of contraception (see section 11). 
2. Clinically relevant abnormal history, physical findings, ECG, or laboratory 
values at the pre-trial screening assessment that could interfere with the 
objectives of the trial or the safety of the volunteer.  
3. Presence of acute or chronic illness or history of chronic illness sufficient to 
hazardous.   
4. History of seizures or at risk of seizure (eg history of significant head trauma).  
5. Significant suicidality history or suicidality risk (as assessed by the C-SSRS 
assessment).  
Ideation Section of the C-SSRS with the ideation occurring in the past six 
. 
6. Impaired endocrine, thyroid, hepatic, respiratory or renal function, diabetes 
mellitus, coronary heart disease, or history of any psychotic mental illness. 
7. Surgery (eg stomach bypass) or medical condition that might affect absorption of 
medicines. 
8. History of severe adverse reactions or allergies, or history of an anaphylactic 
reaction to prescription or non-prescription medication or food (non-active 
hay-fever is acceptable). 
9. Use of a prescription medicine during the 28 days before the first dose of trial 
medication or use of a non-prescription or over-the-counter medicine (including 
herbal and nutritional supplements), with the exception of up to 2 g 
acetaminophen (paracetamol) during the 7 days before and up to 24 h before the 
first dose of trial medication. 
10. COVID-19 symptoms at screening or admission, or positive for COVID-19 
testing on admission, as per HMR standard procedures. 
11. Subjects with a COVID-19 vaccination within 28 days of their first dose of trial 
medication, or who are due to receive a dose of a COVID-19 vaccine while 
participating in the study. 


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12. Receipt of an investigational product (including prescription medicines) as part 
of another clinical trial within the 3 months before admission to this study; in the 
follow-up period of another clinical trial at the time of admission for this study. 
13. Presence or history of drug or alcohol abuse, or intake of more than 14 units of 
alcohol weekly. 
14. Habitual, regular use of tobacco and/or nicotine containing products (including 
e-cigarettes) within 3 months of screening, until the end of the study.  Social 
smokers or vapers may be included in the study (at the discretion of the 
investigator) provided they can abstain from use of those products from 1month 
before the study until the end of the study. 
15. Habitual and heavy consumption of caffeinated drinks (> 8 cups of coffee or 
equivalent per day). 
16. Mean blood pressure and pulse rate in supine position at the screening 
examination outside the ranges:  blood pressure 90 140 mm Hg systolic, 
40 90 mm Hg diastolic; pulse rate 40 100 beats/min.  
One set of repeats in triplicate is permitted if the mean values are borderline 
(ie values that are within 5 mm Hg for blood pressure or 5 beats/min for pulse 
rate) or if requested by the investigator.  Subjects can be included if the repeat 
mean value is within range.   
17. Possibility that the volunteer will not cooperate with the requirements of the 
protocol. 
18. Evidence of drug abuse on urine testing. 
19. Positive test for hepatitis B, hepatitis C or HIV. 
20. Loss of more than 400 mL blood during the 3 months before the trial, eg as a 
blood donor. 
21. Objection by GP to volunteer entering trial. 
22. AST, ALT, gamma-glutamyl transferase (GGT), or total bilirubin 
× ULN.  
A repeat is allowed on one occasion for determination of eligibility.   
23. QT, PR, or QRS value, measured at screening visit on 12-lead ECG, outside of 
the following ranges:  QT value > 450 msec (men) or > 470 msec (women), using 
for correction; PR value outside the range 110
220 msec; QRS value > 120 msec.   
Triplicate measurements will be made, and a mean value used to determine 
eligibility.  A repeat (in triplicate) is allowed on one occasion for determination 
of eligibility.   
24. Clinically significant findings on 24-hour Holter testing at screening as 
determined by the Investigator (Part A only).   


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25. Vegetarian or vegan, or unwilling to eat a high-fat breakfast including bacon 
(eg for personal or religious reasons) (Part B only).   
9.4 
Withdrawal of subjects from the trial 
9.4.1 
Subject withdrawal 
Subjects are free to withdraw from the trial at any time without giving reasons.  
Furthermore, the investigator may withdraw a subject for reasons such as intolerance 
to trial medication, intercurrent illness, need for medication which is contraindicated, 
significant non-compliance with the requirements of the trial, or withdrawal of 
consent.  The investigator will assess the reasons for withdrawal as far as possible 
and will fully record the circumstances and medical details. 
Subjects will be informed before they agree to take part in the trial that, if they 
withdraw or are withdrawn: 
 the investigator will stop collecting information about them; and  
 they can ask the investigator to destroy any identifiable samples taken from them.  
The investigator will ask withdrawn subjects to consent to a follow-up examination, 
to check that they have come to no harm as a result of taking part in the trial.  
Provided that the subject agrees, they will undergo, at withdrawal from the trial (or 
as soon as possible afterwards), the standard medical examination and laboratory 
tests which they would have undergone had they completed it.  The investigator will 
record in the case report form (CRF) the results of the follow-up examination of 
withdrawn subjects, if they give their consent for that. 
9.4.2 
Individual subject stopping criteria 
A subject who meets any of the following criteria will receive no further doses. 
 SAE considered related to study treatment. 
 mean QTcF of > 500 msec or increase from baseline of > 60 msec 
 
× ULN. 
 
 3 × 
 2 × ULN or international normalised ratio 
(INR) of 
1.5, as per the guidelines for acute liver failure.  (If a subject meets 
that withdrawal criterion, serum bilirubin fractionation should be performed.)  
 
× ULN if associated with the appearance or worsening of rash or 
hepatitis symptoms (fatigue, nausea, vomiting, right upper quadrant pain or 
× ULN and 
< 5 × ULN, and total bilirubin < 2 × ULN, who do not exhibit hepatitis 
symptoms or rash, can continue in the study (and continue receiving trial 


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medication) as long as they can be monitored weekly until liver chemistries 
return to within baseline values. 
Subjects who meet the above criteria will be considered discontinued from dosing.  
However, the investigator may ask the subject to continue their participation in the 
study, so they can be monitored for safety and PK, or the investigator may withdraw 
the subject from the trial. 
9.4.3 
Replacement of withdrawn subjects 
Withdrawn subjects will be replaced at the discretion of the sponsor and investigator.  
Subjects withdrawn because of AEs considered possibly related to study treatment 
(see section 14.2) will not be replaced.  Replacements for other withdrawn subjects 
will receive the treatments intended for the withdrawn subject, from the start of the 
trial.  For subjects in Part B, the sponsor and investigator will decide which sessions 
the replacement subject will complete. 
10 
Treatments 
10.1 
Treatments administered 
In Part A, subjects will receive a single oral dose of BEN8744 or placebo. 
In Part B, subjects will receive a single oral dose of BEN8744 on 2 different 
occasions, separated by a washout of at least 7 days.   
In Part C, subjects will receive once or twice-daily oral doses of BEN8744 or 
placebo for 14 days. 
Fasting requirements are described in section 11.  
All treatments will be administered orally with approximately 240 mL of water.  All 
treatments will be given in the fasted state in Parts A, and in the fasted or fed state in 
Part C. 
10.2 
Overdose 
Symptoms of overdose of BEN8744 are not yet known.  In the case of accidental 
overdose, subjects should be treated symptomatically as no specific antidote is 
available. 
10.3 
Blinding (Parts A and C only) 
The trial medication will be repackaged and relabelled by the HMR Pharmacy, 
according to the randomisation schedule.  Active and placebo treatments will be 
labelled such that it is not possible to distinguish between them.  If the expiry dates 
of placebo and active treatment differ, both treatments will be labelled with an expiry 


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given a unique code number, traceable to the batch number of the medication.   
The placebo and active treatments for each group will be identical in appearance, and 
similar in taste and smell.  To maintain the blind nature of the trial, the same number 
of capsules will be given to each subject in a group. 
A sealed copy of the randomisation code will be kept in a locked file in the HMR 
Pharmacy.  A copy will also be kept by the bioanalytical laboratory.  The 
investigator will be supplied with sealed envelopes, each one containing the 
treatment allocation for the subject whose number appears on the outside of the 
envelope.  Those envelopes will be kept in the trial master file, readily accessible to 
clinical staff.  Emergency procedures for revealing medication codes are specified in 
section 10.4.   
The investigators, medical monitor and clinical monitor will remain blinded 
throughout the trial, unless safety concerns necessitate unblinding (see section 10.4 
below).   
10.4 
Unblinding procedure 
If unblinding is required in the interest of the safety of a subject (for example, in a 
medical emergency), the principal investigator or delegate will open the individual 
code-break envelope for that subject without prior consultation with the sponsor.  In 
that event, the principal investigator or delegate will notify the sponsor as soon as 
possible (within 24 h) that the randomisation code has been broken for the subject.  If 
unblinding may be helpful, but is not required immediately (for example, the 
information may be useful to make decisions for other subjects in the group), 
wherever possible, an investigator will discuss the matter with the sponsor before 
opening any individual code-break envelopes. 
When the trial database for the relevant part has been locked, the HMR statistician 
will inform the sponsor of his or her intention to break the randomisation code.  The 
statistician will break the code, and do the statistical analysis of the relevant data. 
10.5 
Method of assigning subjects to treatment groups 
After passing all of the screening assessments, subjects will be allocated to study part 
and group, according to their availability and the scheduled trial dates.   
Subjects will be numbered consecutively, in the order in which they arrive on the 
ward and are entered into the trial.  Subject numbers are presented in Table 8.  
Subject numbers will be allocated to treatments (active or placebo) according to a 
randomisation schedule prepared by an independent HMR statistician, using a SAS 
program.   


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Sentinel subject numbers in Part A are provided in Table 8; at each new dose level, 
1 sentinel subject will receive active treatment and 1 sentinel subject will receive 
placebo.   
Randomisation is described further in section Table 8. 
Table 8: 
Subject and sentinel numbers 
 
Group 
Subject numbers 
Sentinel subjects 
Part A 
A1
1001 1008 
1001 and 1002
A2
1009 1016 
1009 and 1010
A3
1017 1024 
1017 and 1018
 
A4 
1025 1032 
1025 and 1026 
 
A5 
1033 1040 
1033 and 1034 
 
A6 (optional) 
1041 1048 
1041 and 1042 
 
A7 (optional) 
1049 1056 
1049 and 1050 
 
A8 (optional) 
1057 1064 
1057 and 1058 
Part B 
B1 
2001 2006 
Not applicable 
 
B2 (optional) 
2007 2012 
Not applicable 
Part C
C1
3001 3008 
Not applicable
C2
3009 3016 
Not applicable
C3
3017 3024 
Not applicable
C4 (optional) 
3025 3032 
Not applicable
Replacements for withdrawn subjects will be given a number equal to that of the 
subject that they replaced plus 100.  So, Subject 1001 would be replaced by 
Subject 1101, and Subject 3017 would be replaced by Subject 3117, and so on. 
10.6 
Selection and timing of dose for each subject 
The treatments to be administered and intervals between subjects are described in 
sections 8.1 and 10.1.  Subjects will be randomly assigned to treatment, as described 
in section 10.5 above.   
Because BEN8744 has never been given to humans before, in Part A each new 
ascending dose will be staggered as described in section 10.5.  
In Part C, doses will be given at the same time each day (if once daily dosing) or 
every 12 h at the same time each day (if twice daily dosing).  Doses will be given 
±15 mins from times on Day 1.   
10.7 
Previous and concomitant treatment 
Previous treatment restrictions are described in section 9.3. 
During the trial, concomitant medication may be given if the Investigator believes it 
to be necessary.  In addition, up to 2 g paracetamol (acetaminophen) will be allowed 
per day for mild analgesia (up to 1 g per dose).  Any other concomitant treatment 


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will be given only if deemed strictly necessary by the investigator or co-investigator.  
In any case, all concomitant treatments will be reported in the CRF along with their 
daily dosage, duration, and reasons for administration.  Subjects who have received 
any concomitant treatment may be withdrawn from the trial at the discretion of an 
investigator. 
10.8 
Assessment of compliance 
Subjects will be dosed on the research ward under the supervision of 2 suitably 
trained members of HMR staff.  Mouth checks will be done immediately after 
dosing. 
11 
Dietary and lifestyle restrictions 
Subjects will abide by HMR house rules while on the ward.   
Part A 
In Part A, subjects will fast (no food or drink other than water) overnight for at least 
10 h before dosing, until 4 h after dosing.  Standard meals and drinks will be 
provided at about 4, 10 and 24 h after dosing.  Water will not be allowed for 1 h 
before and after dosing. 
Part B 
In Part B, subjects will receive a dose of trial medication in the fed and fasted states.  
The dose level, fasting requirements and whether the dose will be taken after a 
high-fat or standard breakfast will be decided by the SRG based on emerging data.   
Group B1 
 In one treatment session, subjects will fast (no food or drink other than water) 
overnight for at least 10 h before dosing, until 4 h afterwards, and water will not 
be allowed for 1 h before and after dosing.   
 In the other treatment session, subjects will take their dose of BEN8744 after a 
standard high-fat breakfast consisting of:  2 fried eggs, 2 strips of bacon, 2 slices 
of toast and butter, 4 ounces of hash brown potatoes, and a glass of whole milk.  
Subjects will fast (no food or drink other than water) overnight and will start the 
breakfast approximately 30 min before dosing, and they must eat all of the 
breakfast at least 10 min before dosing. 
 In both treatment sessions, standard meals and drinks will be provided at 4, 10 
and 24 h after dosing.  The content of those meals will be the same in both 
sessions.   


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Group B2 
 In one treatment session, subjects will fast (no food or drink other than water) 
overnight for at least 10 h before dosing, until 4 h afterwards, and water will not 
be allowed for 1 h before and after dosing.   
 In the other treatment session, subjects will take at least 1 dose of BEN8744 after 
a high-fat breakfast or a standard breakfast (consisting of 2 slices of toast, 1 bowl 
of cereal with semi-skimmed milk, 2 portions of butter/margarine, and 1 portion 
of jam) having fasted overnight.  The dose level, dosing regimen, and the predose 
meal will be decided following review of the data from Group B1 and available 
data from Part A.   
 In both treatment sessions, standard meals and drinks will be provided at 4, 10, 
and 24 h after dosing.  The content of those meals will be the same in both 
sessions.   
Part C 
In Part C, we anticipate that doses will be given once or twice daily in the fasted state 
unless emerging data indicate they should be taken in the fed state.  Fasting 
requirements in Part C will be decided by the SRG after review of results from 
Parts A and B.  Therefore, for the morning dose, subjects will either: 
 fast from midnight on the evening before each dose, until 4 h after their morning 
dose, on the first and last dosing days, and until 2 h after dosing on all other 
dosing days.  Water will not be allowed for 1 h before and after dosing; or  
 fast from midnight before each dose, until about 30 min before the morning dose 
on all dosing days.  Subject will be given a standard breakfast to finish before 
dosing, consisting of 2 slices of toast, 1 bowl of cereal with semi-skimmed milk, 
2 portions of butter/margarine, and 1 portion of jam.  Water will not be allowed 
for 1 h before and after dosing. 
In once-daily dosing sessions, standard meals and drinks will be provided at about 
4 and 10 h after dosing on all dosing days, and at 24 h after the last dose on the final 
dosing day.   
If subjects are dosed twice daily, they will take their evening doses approximately 
1 h after dinner.  Water will not be allowed for 1 h before and after dosing.   
All parts 
No food or drink containing cranberry, pomegranate, starfruit, grapefruit, pomelos, 
exotic citrus fruits or Seville oranges (including marmalade and juices made from 
these fruits) will be allowed from 14 days before (first) dosing until the end of the 
trial.  No alcoholic or caffeinated drinks, or xanthine-containing products (eg 
chocolate) will be allowed during the period from 24 h before admission until the 
end of the period of residence, and for 24 h before each outpatient visit (including 
screening).  Subjects should be advised to avoid eating food containing poppy seeds 


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from screening until the end of the study, because that can cause a positive drugs of 
abuse test result.   
No strenuous exercise will be allowed from 24 h before admission, and for 48 h 
before each outpatient visit (including screening).   
Regular smokers or users of tobacco and/or nicotine containing products (including 
e-cigarettes) are excluded from the study (see section 9.3).  
vapers must abstain from smoking/vaping from 1 month before their first dose of 
study medicine until the end of the study. 
Subjects must not sunbathe or use a sunbed during the study. 
Subjects must use a reliable method of contraception, as follows.   
Men  
Male subjects must not plan to father a child, or donate sperm, during the trial (from 
[first] dose until their follow-up visit).  
During the trial (from [first] dose until their follow-up visit), male subjects must not 
have sex without using a condom, if their partner is a woman of childbearing 
potential.   
Women  
Women of childbearing potential must use a low user dependent method of 
contraception during the trial.  They must have been using that method for at least 
28 days before the start of the trial.  Low user dependent methods of contraception 
include: 
 
intrauterine device (IUD) 
 
intrauterine hormone-releasing system (IUS) 
 
bilateral tubal occlusion 
 
vasectomised partner (with surgical success confirmed by medical assessment) 
A woman is considered to be of non-childbearing potential if she meets one of the 
following criteria: 
 
is post-menopausal (the last menstrual period was at least 12 months ago, and 
follicle-stimulating hormone (FSH) at screening confirms post-menopausal 
status) 
 
has no uterus, ovaries or fallopian tubes 
Women who are taking hormone replacement therapy (HRT) must use contraception 
(as described above) during the trial.   
Subjects who practise true abstinence or who only have same-sex relationships need 
not use contraception, provided it is in line with their preferred and usual lifestyle 
(note:  periodic abstinence (eg calendar, ovulation, symptothermal, and 
post-ovulation methods) and withdrawal are not acceptable methods of 


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HMR Ltd - Confidential 
HMR Ltd - Confidential 
contraception).  Should any such subject stop practising true abstinence, they must 
use contraception as described above. 
12 
Procedures and observations 
Only subjects who meet all the inclusion and no exclusion criteria will be eligible for 
enrolment into the trial (see section 9).  Each subject will be allocated a unique trial 
number (see section 10.5). 
The schedule of procedures is in section 12.1.   
Additional timepoints may be introduced, and changes to timepoints may be made, in 
accordance with section 12.2. 
The following assessments will be made.  
Safety and tolerability:   
Laboratory assessments (routine haematology, clinical chemistry, and urinalysis), 
physical examinations, 12-lead ECGs, and vital signs (blood pressure, pulse rate, 
respiratory rate, and tympanic temperature) and C-SSRS (Part C only) will be done 
Cardiac telemetry (Part A only) will be done 
from 1 h before until 24 h after dosing.  AEs will be recorded from screening until 
 
Laboratory safety variables to be assessed during the study are in Table 11. 
From screening until the follow-up visit, AEs and concomitant medication will be 
documented as they are reported by the subjects.  Subjects will be questioned (using 
a non-
) about AEs on admission to 
the ward, when procedures are done, and when they return to the ward at follow-up.  
As previous safety studies in animals (28-day toxicity study in dogs) indicated that 
BEN8744 may cause sedation, an OAAS/S and VAS will be used to monitor 
alertness and sedation.  The OAAS/S and VAS will be done immediately before PK 
blood samples frequently up to 72 h after dosing in Parts A and B, and up to 72 h 
after dosing on Day 1 in Part C.   
Pharmacokinetics 
Blood samples for assay of BEN8744 will be taken before, and frequently up to 72 h 
after dosing in Parts A and B, and up to 72 h after dosing on Day 1 and Day 14 in 
Part C.   
Urine will be collected continuously for up to 72 h after dosing in Part B, and may be 
taken for up to 72 h after dosing on Days 1 and 14 in Part C, for assay of BEN8744 
and its metabolites. 
A predose faecal sample will be collected from Day 2 to predose on Day 1 in Part B 
Session 1.  Faecal samples will be collected continuously for up to 72 h after dosing 
in Part B for the exploratory characterisation of BEN8744 and its metabolites. 
















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12.2 
Sampling timepoints and additional tests 
timepoints may be introduced, and changes 
to timepoints may be made, if we have reason to believe that the change might 
improve the quality of the data (for example, if we believe that an important effect of 
the IMP is occurring at a time when no measurements are scheduled), or if extra 
procedures are needed in the interest of subject safety.  However, the total volume of 
blood taken in the trial will not exceed the value given in section 12.5.  Any 
additional urine collections may include continuous, total collections, if necessary.  
Any additional faecal collections may include continuous, total collections, if 
necessary.  
 (including in each 
treatment period in Part B), and additional outpatient visits, will be permitted, in the 
event of a technical failure, and/or if extra observations or samples of blood or urine 
are needed. 
Extra procedures and changes to timepoints which have a significant impact on the 
scientific value and/or safety of the trial participants will be implemented only after 
approval of a substantial amendment from the Regulatory Authority (MHRA), unless 
the changes constitute an urgent safety measure. 
 in Part B may 
be changed, if data collected during the trial support the change.  However, the 
washout period will not be reduced to less than 5 half-lives of the trial medicine. 
The following will not be regarded as protocol deviations.  
Table 9: 
Acceptable deviation times for Parts A and B 
Procedure 
Timepoint 
Acceptable deviation  
PK blood sampling 
Predose 
Up to 30 min before dosing 
Up to and including 1 h 
postdose 
± 5 min of the scheduled time 
After 1 h to 4 h postdose 
± 10 min of the scheduled 
time 
After 4 h to 24 h postdose 
± 15 min of the scheduled 
time 
More than 24 h postdose 
± 1 h of the scheduled time 
PK urine and faecal 
sample collection  
(Part B only) 
Any timepoint (except predose 
urine spot sample and faecal 
sample) 
± 90 min of the scheduled 
time 
All other procedures* 
Predose 
Up to 90 min before dosing 
Up to and including 4 h 
postdose 
± 10 min of the scheduled 
time 
After 4 h to 24 h postdose 
± 15 min of the scheduled 
time 
More than 24 h postdose 
± 1 h of the scheduled time 
* samples for urinalysis may be collected anytime from when the subject awakes until the 
scheduled time. 


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Table 10: Acceptable deviation times for Part C  
Procedure 
Study day 
Timepoint 
Acceptable deviation  
PK blood sampling 
Days 1 and 14 
Predose 
(morning dose) 
Up to 30 min before 
dosing 
Up to and 
including 1 h 
after the morning 
dose 
± 5 min of the scheduled 
time 
After 1 h to 4 h 
after the morning 
dose 
± 10 min of the scheduled 
time 
After 4 h to 24 h 
after the morning 
dose 
± 15 min of the scheduled 
time 
Days 2 13 
Predose 
(morning dose) 
Up to 30 min before 
dosing 
Day 15 17 
> 24 h after the 
morning dose 
± 1 h of the scheduled 
time 
Day 18 onward 
Outpatient visits 
± 2 days  
PK urine and faecal 
sample collection  
(optional) 
Days 1 3 and 
14 16 
Any timepoint 
(except predose 
urine spot 
sample) 
± 90 min of the scheduled 
time 
All other procedures* 
Days 1 and 14 
Predose 
(morning dose) 
Up to 90 min before 
dosing* 
Up to and 
including 4 h 
after the morning
dose 
± 10 min of the scheduled 
time 
After 4 h to 24 h 
after the morning
dose 
± 15 min of the scheduled 
time 
Days 2 13 
Predose 
(morning dose) 
Before dosing 
Day 15 17
> 24 h after the 
morning dose 
± 1 h of the scheduled 
time 
Day 18 onward
Outpatient visits 
± 2 days  
* Samples for urinalysis may be collected anytime from when the subject awakes until the 
scheduled time. 
12.3 
Follow-up 
Subjects will return to the ward 7 ±2 days after dosing (Part A) or after their final 
dose of trial medication (Parts B and C) for a follow-up visit.  Withdrawn subjects 
who consent to a follow-up visit will undergo the same procedures (see section 9.4).
The follow-up period may be extended if: 
1. a subject has an unresolved AE at the follow-up visit, which, in the opinion of the 
investigator, merits further follow-up;  


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2. plasma concentrations of IMP were higher than predicted, and/or the half-life of 
the IMP was very long, and the investigator considers that additional follow-up is 
necessary; or 
3. new information becomes available that supports an extended follow-up period. 
The investigator will decide on the nature of the follow-up.  For example, subjects 
may have a telephone follow-up at which they are asked about AEs, or subjects may 
be asked to attend extra outpatient visits for additional monitoring of blood levels or 
effects of IMP, and for extra safety tests.  The extra safety tests might include tests 
that are not described in this protocol.  The investigator reserves the right, during or 
after the study, to repeat safety tests or to do any extra safety tests that are in the best 
interest of the subjects.   
12.4 
Methods 
Blood collection 
Blood will be taken by venepuncture or via a cannula.  Cannulae may be inserted 
under local anaesthesia with lidocaine 0.5%, for withdrawal of venous blood.   
After each blood sample, the cannula will be flushed with 3 5 mL normal saline, to 
keep it patent.  In order to minimise dilution of each subsequent blood sample with 
normal saline, the following procedure will be used:  about 1 mL will be drawn via 
the cannula into the sampling syringe, and discarded.  The definitive blood sample 
will then be taken. 
Blood volumes of specific types of samples may vary from those described below, 
but any change to the sample volumes will not cause the total volume of blood taken 
during the study to exceed that given in section 12.5.
Samples for laboratory safety tests 
Blood will be taken for: 
 haematology (2.7 mL in EDTA) 
 clinical chemistry, serology, serum pregnancy and/or FSH (4.0 mL in tubes with 
a gelatin plug) 
Blood samples will be collected into 13 × 75 mm tubes.  Urine and faeces will be 
collected in Universal containers.  Samples will then be transferred to the laboratory.  
For logistical reasons, blood, urine, and/or faecal samples may be collected in tubes 
other than those stated above.   
Processing and analysis of samples for laboratory safety tests 
Processing of samples will be done by the HMR Analytical Laboratory in accordance 
SOPs. 
The HMR Analytical Laboratory will do safety tests on blood and urine samples 
using instruments interfaced to a validated laboratory information management 


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system (LIMS).  Data from analysers that are not interfaced will be entered manually 
into the LIMS.   
Table 11: Laboratory safety tests 
Haematology: 
 haemoglobin (Hb) 
 red blood cells (RBC) 
 mean corpuscular volume (MCV) 
 mean corpuscular haemoglobin 
(MCH)  
 mean corpuscular haemoglobin 
concentration (MCHC) 
 haematocrit 
 white blood cells (WBC) and 
differential (neutrophils, lymphocytes, 
monocytes, eosinophils, basophils) 
 platelets 
Clinical chemistry: 
 urea 
 creatinine 
 uric acid 
 total bilirubin 
 total protein 
 albumin 
 globulin 
 alkaline phosphatase (ALP) 
 aspartate aminotransferase (AST) 
 alanine aminotransferase (ALT) 
 gamma-glutamyl transpeptidase 
(GGT) 
 glucose 
 phosphate 
 cholesterol 
 triglycerides 
 potassium 
 sodium 
 calcium 
 chloride 
 
Urinalysis: 
 dipstick:  protein, blood, ketones, 
glucose, bilirubin, urobilinogen, 
leukocyte esterase, specific gravity, 
nitrites, pH 
 microscopy: only if dipstick test for 
protein, blood, leukocyte esterase or 
nitrites is abnormal 
Serology: 
 hepatitis B (hepatitis B surface 
antigen)  
 hepatitis C antibody 
 HIV screen (HIV 1 and 2) 
Pregnancy and FSH tests 
Serum pregnancy and serum FSH tests will be done using an 
immunochemiluminometric method.   


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Drugs of abuse, alcohol, and cotinine tests 
Urine will be tested for drugs of abuse, alcohol, and cotinine according to the 
SOP.  Tests will include:  amphetamines, cocaine, opiates, cannabis, 
barbiturates, benzodiazepines, alcohol, and cotinine. 
Collection and processing of samples for pharmacokinetic analysis 
Details on blood, urine, and faecal sample collection and processing, including 
labelling and shipment instructions, will be documented in a separate study 
procedures manual.  
Physical examination 
Physical examination will be done by a physician.  The following will be examined:  
general appearance; head, ears, eyes, nose and throat; thyroid; lymph nodes; back 
and neck; heart; chest; lungs; abdomen; skin; and extremities.   The following 
systems will be assessed:  musculoskeletal and neurological. 
Height and weight 
Height and weight will be measured by trained staff at HMR. 
Vital signs 
Blood pressure and pulse rate will be measured using SpaceLabs oscillometric 
equipment.  Measurements will be made with subjects in a supine position; subjects 
will remain supine for at least 5 min before vital signs are measured.   
Tympanic temperature will be measured using digital thermometers. 
Respiratory rate will be measured by observation of the chest. 
Repeat vital signs measurements 
During the trial, if vital signs fall outside the ranges in Table 12, a physician will 
review and decide on an appropriate course of action.  The procedure will be 
repeated only if instructed by a physician.  
Table 12: Vital signs ranges 
Vital sign 
Range 
Supine systolic blood pressure 
90 140 mm Hg 
Supine diastolic blood pressure 
40 90 mm Hg 
Supine pulse rate 
40 100 beats/min 
Temperature 
35.5 37.8°C  
Respiration rate 
10 16 breaths/min 
If the result of the repeat measurement is still out of range, the investigator will 
decide on an appropriate course of action.   
Standard 12-lead ECGs 
12-lead ECGs will be recorded using Mortara ELI250c and ELI280 cardiographs.  
Each recording will be printed on a single A4 page at paper speed 25 mm/sec and 


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calibrated to 10 mm/mV.  Recordings will be made with subjects in a supine 
position; subjects will remain supine for at least 5 min before the ECG is recorded.  
PR, RR, QRS and QT intervals will be captured on source documents.  QT interval 
 
During the trial, if ECG values fall outside the ranges in Table 13, a physician will 
review and decide on an appropriate course of action.  The procedure will be 
repeated only if instructed by a physician. 
Table 13: ECG ranges 
ECG parameter 
Range 
Ventricular rate 
35 100 beats/min 
QRS 
 
PR interval 
110 220 msec 
QTcF (men) 
 
QTcF (women) 
 
If the result of the repeat measurement is still out of range, the investigator will 
decide on an appropriate course of action.   
Holter monitoring (Part A only) 
24-h Holter monitoring will be done at screening using recorders made either by Ela 
Medical or Burdick.  The results will not be recorded in detail in the CRF unless they 
constitute an AE. 
Telemetry (Part A only) 
Heart rhythm will be monitored continuously (telemetry, 3-lead ECG) from 1 h 
before until 24 h after dosing, using a SpaceLabs system.  Results from that safety 
monitoring will be recorded in detail in the CRF only if they constitute an AE. 
isual analogue scales 
Symptoms of sedation will be assessed using OAAS/S and VAS.   
In the OAAS/S, 
alertness on a scale of 0 to 5, where 0 is absence of response to stimulus, and 5 is 
   
In the VAS, subjects will complete a self-reported post-dosing questionnaire.  
Subjects will be asked to score/rate their alertness.  To reduce variability, subjects 
will be able to see their previous responses.  A copy of the questionnaire can be 
found in Appendix A. 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
The C-SSRS is a suicidal ideation rating scale used to evaluate suicidality35.  The 
questionnaire will be administered by the investigator or their delegate.  The 
questionnaire will be used at all other timepoints. 


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12.5 
Total volume of blood removed 
The maximum total volume of blood taken from any volunteer in the trial will be 
about 175 mL, as stated in Table 14 (Part A), Table 15 (Part B), Table 16 (Part C).  
Additional blood samples for assay of BEN8744 or for laboratory safety tests may be 
taken as described in section 12.2.  No more than an extra 50 mL of blood will be 
taken from any subject.   
Table 14: Planned blood volume (Part A) 
Test 
Planned 
number of 
tests 
Volume  
(mL) 
Total 
planned 
blood 
volume (mL) 
Haematology 
6 
2.7 
16.2 
Clinical chemistry/ 
serology/pregnancy/FSH 
6 
4.0 
24 
Pharmacokinetics 
15 
2.7 
40.5 
Discard (when using a cannula) 
12 
1 
12 
 
 
Total 
92.7 mL 
 
Table 15: Planned blood volume (Part B) 
Test 
Planned 
number of 
tests 
Volume  
(mL) 
Total 
planned 
blood 
volume (mL) 
Haematology 
10 
2.7 
27 
Clinical chemistry/ 
serology/pregnancy/FSH 
10 
4.0 
40 
Pharmacokinetics 
30 
2.7 
81 
Discard (when using a cannula) 
24 
1 
24 
 
 
Total 
172 mL 
 


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Table 16: Planned blood volume (Part C) 
Once-daily dosing 
Test 
Planned number 
of tests 
Volume  
(mL) 
Total planned 
blood volume 
(mL) 
Haematology 
7 
2.7 
18.9 
Clinical chemistry/ 
serology/pregnancy/FSH 
7 
4.0 
28 
Pharmacokinetics 
31 
2.7 
83.7 
Discard (when using a 
cannula) 
22 
1 
22 
 
 
Total 
152.6 mL 
 
Twice-daily dosing 
Test 
Planned number 
of tests 
Volume  
(mL) 
Total planned 
blood volume 
(mL) 
Haematology 
7 
2.7 
18.9 
Clinical chemistry/ 
serology/pregnancy/FSH 
7 
4.0 
28 
Pharmacokinetics 
37 
2.7 
99.9 
Discard (when using a 
cannula) 
28 
1 
28 
 
 
Total 
174.8 mL 
 
13 
Trial materials 
13.1 
Identity of test product(s) 
Size 0 Swedish orange capsules containing 2 mg, 10 mg, and 40 mg BEN8744 and 
matching placebo capsules contain excipients only, will be provided to the HMR 
Pharmacy by Quotient Sciences Ltd (Reading, UK).  The capsules are packaged in 
high density polyethylene (HDPE) bottles with child-resist polypropylene (PP) 
twist-off cap.  
Full details of BEN8744 and placebo formulations are included in the IB29 and 
Investigational Medicinal Product Dossier (IMPD)36.  


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The sponsor will provide to HMR a certificate of analysis (CoA), and a Certificate of 
GMP Compliance (CoC) for the test product for 
batches of IMP.   
13.2 
Packaging and labelling 
The trial medication will be packaged and labelled by the HMR Pharmacy, in 
accordance with The Rules Governing Medicinal Products in the European Union, 
Volume 4:  Good Manufacturing Practice (GMP), and with 
 
Authorisation for IMPs (MIA(IMP)).  The IMP labels will include all the information 
required by Annex 13 to GMP37.   
13.3 
Storage and accountability of IMP 
The IMP will be stored and accounted for according to GMP and HMR SOPs. 
At the end of the trial, all unused IMP supplies will be returned to the sponsor or 
 
14 
Adverse events 
14.1 
Definitions of adverse events 
Adverse event (AE) 
Any untoward medical occurrence in a patient or clinical trial subject administered a 
medicinal product and which does not necessarily have a causal relationship with 
that treatment.   
Adverse drug reaction (AR) 
All untoward and unintended responses to an IMP related to any dose administered. 
Note that, according to the ICH Guideline for Good Clinical Practice (ICH GCP), the 
a causal relationship between the medicinal 
product and an AE is at least a reasonable possibility, ie a relationship cannot be 
ruled out. 
Unexpected AR 
An AR, the nature or severity of which is not consistent with the applicable product 
information (eg IB for an unauthorised investigational product, or summary of 
product characteristics for an authorised product). 
Serious adverse event (SAE) or serious adverse drug reaction (SAR) 
An AE or AR that: 
 is fatal; 
 is life-threatening;  


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 requires inpatient hospitalisation, or prolongs existing hospitalisation;  
 results in persistent or significant disability or incapacity; or 
 is a congenital anomaly or birth defect. 
Note that: 
 
-
reaction in which the patient was at risk of death at the time of the event; it does 
not refer to an event or reaction which hypothetically might have caused death 
had it been more severe; and  
 in accordance with the ICH Guideline on Clinical Safety Data Management:  
Definitions and Standards of Expedited Reporting, events or reactions that are 
not immediately life-threatening or may not result in death or hospitalisation, but 
might jeopardise the subject or require intervention to prevent one of the other 
outcomes listed above, should usually be considered serious. 
Significant AE or AR 
Any SAE or SAR, or an AE or AR which is not serious but is otherwise significant.  
The following should normally be considered significant:  
 a marked haematological or other laboratory abnormality;  
 an AE or AR that leads to an intervention, including withdrawal of drug 
treatment, dose reduction or significant additional concomitant therapy; or 
 any AE or AR that the investigator considers to be significant. 
14.2 
Procedures for recording adverse events 
Subjects will be carefully monitored for AEs. The investigator or delegate will 
question the subjects about AEs using a non-
AEs reported spontaneously by the 
subjects.  Clinically significant changes in the findings of physical examination, and 
clinically significant abnormalities in the results of objective tests (eg laboratory 
variables, x-ray, ECG) may also be recorded as AEs.  The investigator will use the 
following criteria when deciding whether to report an abnormal result as an AE. 
1. 
The test result is associated with accompanying symptoms. 
2. 
Results of additional diagnostic tests cause concern or necessitate medical 
intervention. 
3. 
As a consequence of the test result, the dose administered to the subject is 
changed, the subject is withdrawn, or the subject is given concomitant treatment. 
4. 
The investigator considers the result to constitute an AE. 
If any of the above criteria are met, the investigator will report the result as an AE. 


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A record will be kept in the source documents of all AEs as reported, whether 
believed to be related or unrelated to the treatment.  The record will include the 
following. 
 Clinical symptoms: a simple, brief description. 
 Date and time of onset and end of clinical symptoms. 
 Frequency:  constant or intermittent. 
 Severity.  The following categories will be used: 
Mild:  the AE 
require intervention; it causes slight discomfort. 
Moderate:  the AE 
requires intervention, but is not damaging to health; it causes moderate 
discomfort. 
Severe:  the AE results in alteration, discomfort or disability which is clearly 
damaging to health. 
 Relationship to treatment:  The assessment of relationship of AEs to the 
administration of IMP is a clinical decision based on all available information at 
the time of the completion of the case report form.  The following categories will 
be used. 
Possibly related 
 An event for which, after careful medical evaluation, a connection with trial 
medication cannot be ruled out with certainty. The event occurs after exposure to 
trial medication.  The event may occur at a reasonable time in relation to the time 
of administration of the trial medication, but might also be attributable to a 
commonly occurring alternative cause.  Alternatively, the event may not occur at 
a reasonable time in relation to the time of administration of trial medication, but 
may not be attributable to an alternative cause. 
Unlikely to be related 
 An event which occurs before exposure to the trial medication, or which does not 
occur at a reasonable time in relation to the time of administration of trial 
medication, and can be attributed to a commonly occurring alternative cause.  
Alternatively, the event is unrelated to the trial (eg road traffic accident), unless it 
can be demonstrated that the treatment could have caused the event. 
 Action taken:  none, drug treatment, subject withdrawn, other (specified). 
 Outcome:  recovered/resolved, recovering/resolving, not recovered/not resolved, 
or unknown. 


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14.3 
Procedures for dealing with serious adverse events 
In the event of any SAE which, in 
modification of the trial (see section 8.4), dosing will be stopped and the sponsor
medical monitor will be informed immediately (within 24 h of the investigator 
becoming aware of the event) by telephone or email, as follows.   
Medical monitor: 
Arpeat Kaviya 
Tel: 
07753 828 096 
Email: 
arpeat.kaviya@benevolent.ai 
All SAEs occurring after the signing of the ICF until the follow up visit, regardless 
provider, with as much information as possible, within 24 h of the investigator 
becoming aware of the event.   The investigator will complete an SAE form and 
provider, via the following contact 
details. 
QbD Group Ltd 
Email (primary): 
pv@qbdgroup.com 
Tel (back-up): 
+44 (0) 1865 893 290 
The sponsor will also be notified by email (adepeju.oshisanya@benevolent.ai). 
The investigator will notify the REC of SAEs that occur during this trial, if 
applicable, in accordance with the SOPs issued by the Research Ethics Service 
(RES)38. 
The sponsor is responsible for determining the expectedness of the event, using the 
reference safety information in the IB29.  The sponsor will notify the MHRA of all 
suspected unexpected serious adverse reactions (SUSARs), and will be responsible 
for ensuring that the REC is notified of SUSARs, if applicable.  SUSARs that are 
fatal or life-threatening must be notified to the MHRA and REC within 7 days after 
the sponsor has learned of them.  Other SUSARs must be reported to the REC and 
MHRA within 15 days after the sponsor has learned of them. 
14.4 
Procedures for handling withdrawals due to adverse events 
The investigator will assess the reason for withdrawal as far as possible and will fully 
record the circumstances and medical details.  Provided that subjects give written 
informed consent, they will undergo the standard medical examination and 
laboratory tests at withdrawal from the trial which they would have undergone had 
they completed it (see also section 9.4). 


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14.5 
Procedures for reporting pregnancies 
Subjects will be asked to follow the contraception guidance in section 11. 
If, during the study, the investigator becomes aware of a pregnancy in a subject or 
vigilance provider immediately 
(within 24 h of the investigator becoming aware of the event), as follows. 
QbD Group Ltd  
Email (primary): 
pv@qbdgroup.com 
Tel (back-up): 
+44 (0) 1865 893 290 
The investigator will follow-up the pregnancy according to HMR SOPs, provided the 
subject (or their partner) consents to that.  A pregnancy will not constitute an SAE 
unless it meets one of the criteria in section 14.1. 
15 
Data management and quality assurance 
Paper source documents will be securely stored within HMR.  Data collected in 
source documents (see section 18.2) will be transcribed into an electronic CRF 
(eCRF). 
The investigator is responsible for ensuring the accuracy and completeness of the 
data entered into the eCRF, and the timeliness of data entry.  Clinical data (including 
AEs, concomitant medication, etc) will be entered into a 21 CFR Part 11-compliant 
Medrio M-1 database.  The Medrio M-1 system includes password protection and 
internal quality checks, such as automatic range checks, to identify data that appear 
inconsistent, incomplete, or inaccurate.  Data reported in the eCRF, derived from 
source documents, should be consistent with the source documents or the 
discrepancies should be explained.  Where the data violate data validation checks, 
queries will be generated for resolution by clinical staff.  All edits made to the 
database upon resolution of queries will be recorded in an electronic audit trail. 
The database will be locked after the following have been completed:  all expected 
eCRF data have been entered and accounted for; all discrepancies have been 
resolved; data have been coded as appropriate; SAEs have been reconciled; all site 
audit findings impacting the database have been closed; and QC inspection has been 
completed. 
Data in source documents will be checked by the HMR Quality Assurance (QA) 
Department.  In addition, the HMR QA Department will audit the trial report; that 
audit will include checks to ensure that statistical output is correctly reproduced in 
the report. If requested, the investigator will provide the sponsor, MHRA, and REC 
with direct access to the original source documents. 


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16 
Statistical methods 
16.1 
Pharmacokinetic methods 
The pharmacokinetic analysis will be done by the Statistics and Data Management 
Department at HMR, using WinNonlin 8.3 or higher. 
Actual times will be used to derive pharmacokinetic parameters.  Missing data will 
not be imputed. 
For calculation of all PK parameters, and for individual concentration time plots, 
plasma concentrations below the limit of quantification of the assay (BLQ) will be 
treated as follows:  values that occur before tmax will be taken as zero; all other values 
will be taken as missing. 
For calculation of plasma concentration summary statistics, BLQ values will be 
taken as zero, unless they fall between two quantifiable concentrations, in which case 
they will be treated as missing. 
For urine concentrations reported as BLQ, it is not possible to impute a value.  The 
amount excreted will be set to zero when the concentration is BLQ. 
The pharmacokinetic parameters listed in sections 16.1.1 and 16.1.2 will be derived. 
16.1.1 Plasma parameters 
Part A and B (single dose) 
Text symbol 
Definition 
Calculation 
Concentrations and times 
Cmax 
Maximum (peak) plasma 
concentration 
Obtained directly from the 
concentration time data. 
tmax 
Time to reach maximum 
(peak) plasma concentration
Obtained directly from the 
concentration time data.
Half-life 
z 
Terminal rate constant 
Estimated by linear regression of 
logarithmically transformed 
concentration versus time data.
t½ 
Terminal half-life 
Calculated from the terminal slope of 
the log concentration time curve, as 
follows:
 
Areas under the curve 
AUClast 
Area under the plasma 
concentration time curve 
from time zero to time of last 
measurable concentration 
Calculated using the trapezoidal 
method.  
AUCinf 
Area under the plasma 
concentration time curve 
from time zero to infinity 
Calculated using the trapezoidal method 
for the interval 0 to tlast (time tlast is the 
time at which the last non-zero level 
was recorded), plus the area under the 


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Text symbol 
Definition 
Calculation 
exponential curve from tlast to infinity, 
calculated as follows: 
z
t
t
C
AUC
inf
 where 
t
C is the 
predicted value of the concentration at 
tlast.  
AUC24 
Area under the plasma 
concentration time curve 
from time zero to time 24 h 
Calculated using the trapezoidal 
method.  
 
If 
z is not estimable, a partial AUC is 
not calculated (when tlast<t). 
AUC72 
Area under the plasma 
concentration time curve 
from time zero to time 72 h 
Calculated using the trapezoidal 
method.  
 
If 
z is not estimable, a partial AUC is 
not calculated (when tlast<t). 
%AUCextrap 
Percentage of AUC  
extrapolated from tlast to 
infinity 
inf
inf
100
%
AUC
AUC
AUC
t
extrap
 
Clearance, volume of distribution and mean residence time 
CL/F 
Apparent total clearance from 
plasma after oral 
administration 
Calculated using the following formula: 
inf
/
AUC
Dose
F
CL
Vz/F 
Apparent volume of 
distribution during terminal 
phase after non-intravenous 
administration 
Calculated using the following formula: 
inf
/
AUC
Dose
F
V
z
z
Part C (multiple dose) 
Day 1  
Text symbol 
Definition 
Calculation 
Concentrations and times 
Cmax 
Maximum (peak) plasma 
concentration
Obtained directly from the 
concentration time data.
tmax 
Time to reach maximum (peak) 
plasma concentration 
Obtained directly from the 
concentration time data. 
Areas under the curve 
z 
Terminal rate constant 
Estimated by linear regression of 
logarithmically transformed 
concentration versus time data. 
 
t½ 
Terminal half-life 
Calculated from the terminal slope of 
the log concentration time curve, as 
follows:
 


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Text symbol 
Definition 
Calculation 
Areas under the curve (after final dose) 
AUCtau 
Area under the plasma 
concentration time curve 
during a dosing interval (tau) 
Calculated using the trapezoidal method. 
AUClast 
Area under the plasma 
concentration time curve from 
time zero to time of last 
measurable concentration 
Calculated using the trapezoidal method. 
AUC72 
Area under the plasma 
concentration time curve from 
time zero to time 72 h  
Calculated using the trapezoidal method. 
AUCinf 
Area under the plasma 
concentration time curve from 
time zero to infinity  
Calculated using the trapezoidal method 
for the interval 0 to tlast (time tlast is the 
time at which the last non-zero level was 
recorded), plus the area under the 
exponential curve from tlast to infinity, 
calculated as follows: 
z
t
t
C
AUC
inf
 where 
t
C is the 
predicted value of the concentration at 
tlast.    
%AUCextrap 
Percentage of AUC  
extrapolated from tlast to infinity 
inf
inf
100
%
AUC
AUC
AUC
t
extrap
 
Days 2 14 
Text symbol 
Definition 
Calculation 
Concentrations during and after multiple dosing 
Ctrough 
Trough plasma concentration 
Trough plasma concentration (measured 
concentration at the end of a dosing 
interval at steady state [taken 
directly before next administration]) 
obtained directly from the 
concentration time data.
Final dosing day 
Text symbol 
Definition 
Calculation 
Concentrations and times (after final dose) 
Cmax 
Maximum (peak) plasma 
concentration 
Obtained directly from the 
concentration time data. 
tmax 
Time to reach maximum (peak) 
plasma concentration  
Obtained directly from the 
concentration time data. 
Half-life (after final dose) 
z 
Terminal rate constant 
Estimated by linear regression of 
logarithmically transformed 
concentration versus time data. 
t½ 
Terminal half-life 
Calculated from the terminal slope of 
the log concentration time curve, as 
follows:
 


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Text symbol 
Definition 
Calculation 
Areas under the curve (after final dose) 
AUCtau 
Area under the plasma 
concentration time curve during 
a dosing interval (tau) 
Calculated using the trapezoidal method. 
AUClast 
Area under the plasma 
concentration time curve from 
time zero to time of last 
measurable concentration
Calculated using the trapezoidal method. 
AUC72 
Area under the plasma 
concentration time curve from 
time zero to time 72 h 
Calculated using the trapezoidal method. 
AUCinf 
Area under the plasma 
concentration time curve from 
time zero to infinity 
Calculated using the trapezoidal method 
for the interval 0 to tlast (time tlast is the 
time at which the last non-zero level was 
recorded), plus the area under the 
exponential curve from tlast to infinity, 
calculated as follows: 
z
t
t
C
AUC
inf
 where 
t
C is the 
predicted value of the concentration at 
tlast.  
%AUCextrap 
Percentage of AUC  
extrapolated from tlast to infinity 
inf
inf
100
%
AUC
AUC
AUC
t
extrap
 
Clearance, volume of distribution and mean residence time (after final dose) 
CLSS/F 
Apparent total clearance from 
plasma at steady state after 
non-intravenous administration 
Calculated using the following formula: 
tau
SS
AUC
Dose
F
CL
/
Vz/F 
apparent volume of distribution 
after non-intravenous 
administration calculated at 
steady state 
Calculated using the following formula: 
tau
z
z
AUC
Dose
F
V /
Accumulation and time invariance ratios 
Rac(AUC) 
Accumulation ratio for AUC 
Calculated from AUCtau at steady state 
and AUCtau after a single dose
Rac(Cmax) 
Accumulation ratio for Cmax 
Calculated from Cmax at steady state and 
Cmax after a single dose
SR(AUC) 
Stationarity ratio for AUC 
Stationarity ratio will be calculated from 
AUCt at steady state and AUC  after 
single dose 
AUC
AUC
SRAUC
 


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16.1.2 Urine sample parameters (Parts B and C) 
Text Symbol Definition 
Calculation 
Urinary recovery 
Ae72 
Cumulative amount of 
unchanged drug excreted into 
the urine at 72 h 
Calculated as the sum of the products of 
concentration and urine volume over the 
appropriate collection intervals 
fe F  
Fraction of non-intravenously 
administered drug excreted into 
the urine
Calculated as Ae24/Dose administered 
Renal clearance 
CLR 
Renal clearance of drug from 
plasma 
Calculated from the ratio of the 
appropriate values for urinary recovery 
and area under the plasma 
concentration time curve, using the 
following formula: 
 
16.2 
Statistical methods 
16.2.1 Planned analyses 
Final statistical analysis, including analysis of PK parameters, will be done by HMR.  
A statistical analysis plan will be prepared by the HMR Statistics and Data 
Management Department after completion of the final protocol and before database 
lock. 
All statistical analysis and reporting will be done using SAS 9.4 or higher. 
16.2.2 Statistical hypotheses 
The trial is an exploratory one, and there are no null hypotheses to be tested.   
16.2.3 Analysis populations 
The following populations will be identified: 
Safety population: 
All subjects who received at least one dose of study 
drug.   
PK concentration population: All subjects who received at least one dose of study 
drug and for whom a pharmacokinetic sample has 
been analysed.   
PK parameter population: 
All subjects in the PK concentration population for 
whom pharmacokinetic parameters can be derived.   
In all populations, treatment will be assigned based upon the treatment subjects 
actually received, regardless of the treatment to which they were randomised. 


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The primary endpoint will be analysed using the safety and PK populations. 
16.2.4 General considerations for data analyses 
The minimum set of summary statistics for numeric variables will be:  n, mean, 
standard deviation (or standard error), median, minimum, and maximum.  95% 
confidence intervals (CI) will be presented where appropriate for data interpretation.  
Categorical data will be summarised in frequency tables with n and percentage.  
Summaries of a categorical variable will include all recorded values. 
The minimum and maximum values will be presented to the same number of decimal 
places as the raw data collected on the CRF (or to 3 significant figures for derived 
parameters).  The mean, median and percentiles (eg Q1, and Q3) will be presented to 
one additional decimal place.  The standard deviation and standard error will be 
presented to 2 additional decimal places.  
Day 1, or Day 1 if not recorded at predose, or screening if not recorded at predose 
or on Day 1.  Out-of-range laboratory tests may be repeated.  If a test is out of-range 
at baseline and repeated before dosing, the latest repeat value before dosing will be 
used as baseline.  However, if a test is out-of-range and repeated at any other time 
during the study, the out-of-range value (not the repeat value) will be included in 
statistical summaries. 
16.2.5 Study population analyses 
16.2.5.1 Disposition of subjects 
The disposition of all subjects in the enrolled population will be summarised 
including:  number of subjects randomised; number completing the study, by 
treatment; and number discontinued from the study. 
All subjects who withdraw or are withdrawn from the study will be listed, by 
treatment, with the reason for withdrawal. 
16.2.5.2 Demographic and baseline characteristics 
Demographic and baseline characteristics (eg physical examination, vital signs and 
ECGs) will be summarised.  
Subjects who take concomitant medication will be listed.  All non-trial medication 
will be coded using the latest version of the World Health Organisation Drug 
Dictionary Enhanced (WHO DDE) current at the time of database lock. 
16.2.5.3 Treatment compliance 
Dates and times of dosing will be listed.  


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16.2.6 Safety data analyses 
Summaries and listings of safety data will use the safety population.  
16.2.6.1 Adverse events 
AEs will be coded using the version of the Medical Dictionary for Regulatory 
Activities (MedDRA) current at the time of database lock.   
All AEs will be listed. 
A treatment-emergent adverse event (TEAE) is an AE that emerges during treatment 
(having been absent before treatment) or that worsens after treatment39.  
The number of subjects with at least one TEAE will be tabulated by actual treatment 
and MedDRA system organ class and preferred term.   
For each of the following, the number of TEAEs and subjects with TEAEs will be 
summarised by actual treatment as follows: 
 TEAEs, by system organ class and preferred term 
 drug-related TEAEs, by system organ class and preferred term 
Subjects with more than one TEAE will be counted only once, at the maximum 
causality, for each system organ class and preferred term.  AEs with missing severity 
and/or causality will be treated as severe and possibly related, respectively. 
AEs leading to withdrawal, deaths and other SAEs will be listed separately (fatal 
events will be listed separately from non-fatal events).   
16.2.6.2 Clinical laboratory evaluations 
Data from haematology and clinical chemistry will be summarised by treatment.  
Any laboratory value outside the reference interval for that variable will be flagged 
Additionally, if, during the course of the trial, a variable changes from baseline by 
more than a predetermined amount (as defined by the principal investigator), that 
both falls outside the reference interval and alters from the baseline value by more 
than the predetermined amount, it will attract a double flag and will be considered to 
be potentially clinically important. 
All laboratory values of potential clinical importance will be listed.  In a separate 
listing, laboratory values of potential clinical importance will be listed with all 
related laboratory results (ie haematology or clinical chemistry).  Frequencies of 
laboratory values of potential clinical importance will be summarised. 


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16.2.6.3 Other safety measures  
Vital signs at each planned assessment, and change in vital signs from baseline at 
each planned post-baseline assessment, will be summarised by actual treatment.  
Vital signs of potential clinical importance will be listed separately.  
QT interval will be corrected using Fridericia's (QTcF) formulae.   
ECG variables will be summarised by treatment and timepoint.  Differences from 
baseline will be summarised by treatment and timepoint. 
QTcF > 450 msec and increases in QTcF from baseline (Day 1 predose) of 
> 30 msec will be considered to be potentially clinically important.  The number of 
subjects with a potentially clinically important QTcF will be summarised by actual 
treatment and timepoint, giving the numbers of subjects with QTcF > 450 msec, 
> 480 msec and > 500 msec, and the numbers of subjects with increases in QTcF 
from baseline of > 30 msec and > 60 msec40.  A supporting listing of all subjects with 
a QTcF value of potential clinical importance, and a separate listing of ECG findings 
classified as abnormal by the investigator, will also be provided. 
Abnormal physical examination findings will be listed. 
Positive C-SSRS data will be listed (Part C only). 
16.2.7 Pharmacokinetic data analyses 
PK concentration data will be summarised using the PK concentration population. 
PK parameters will be summarised using the PK parameter population.  
For log-transformed parameters, the primary measure of central tendency will be the 
geometric mean41; for untransformed parameters, it will be the arithmetic mean or 
median. 
For all variables, N (number of subjects in receiving the treatment/formulation in the 
population), n (number of observations), arithmetic mean, median, minimum, 
maximum, SD, %CV (coefficient of variation), and the 95% CI of the arithmetic 
mean will be derived.  For log-transformed variables, all of the above plus the 
geometric mean, its 95% CI, and the SD of the log-transformed variables, will be 
provided. 
Plasma concentrations and PK parameters will be listed and summarised, by 
treatment, using descriptive statistics.  Individual and mean plasma 
concentration time profiles will be presented graphically.  All available data will be 
used to derive PK parameters in individual subjects. 
In Parts B and C, urine concentrations, and urine PK parameters will be listed and 
summarised, by treatment, using descriptive statistics. 


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Food effect analysis 
To assess the effect of food in Part B, analysis of variance (ANOVA) models will be 
fitted with the logarithm of the PK parameters (AUCinf, AUClast and Cmax) as the 
dependent variables, and formulation as a fixed effect.  The estimated least square 
means and residual variance from the model will be used to construct 90% CIs for 
the difference in means on the log scale for the comparison of fed versus fasted 
solutions.  Food effect will be concluded if the 90% CI of the ratio (fed:fasted) is not 
included within the range 80 125%. 
For tmax, the Hodges Lehmann estimator of the difference between fed and fasted 
solutions in median values and the 90% CI generated with the Moses method will be 
presented. 
16.3 
Determination of sample size 
Since this is a Phase 1 study, no formal sample size determination is appropriate.  
17 
Ethical and regulatory requirements 
The trial proposal will be reviewed by a recognised REC, and by the MHRA.  The 
trial will not proceed unless the sponsor obtains from the MHRA a clinical trial 
authorisation (CTA), and the REC approves the trial.   
The trial will be done at HMR, in compliance with The Medicines for Human Use 
(Clinical Trials) Regulations 2004 and current amendments42, The Medicines for 
Human Use (Clinical Trials) (Amendment) (EU Exit) Regulations 201943, The 
Human Medicines (Amendment etc) (EU Exit) Regulations of 2019 and 202044,45, 
GMP37, the SOPs issued by RES for RECs in the UK38, and Good Clinical Practice, 
which has its origins in the Declaration of Helsinki.  
All subjects must give written consent to participate in this trial.  Consent for 
screening evaluations may be obtained using the information and consent form for 
the HMR healthy volunteer panel, which has been approved by the Health Research 
-specific information and consent 
form will be signed by the subject either before any screening evaluation or after the 
investigator confirms the eligibility of the subject for the trial and before the subject 
is randomised to receive the first administration of IMP.  Before giving consent, 
subjects must read the information sheet about the trial.  They must also read the 
consent form.  They will then discuss the trial with the investigator or his deputy and 
be given the opportunity to ask questions.  The trial-specific information sheet and 
the consent form must be approved by the REC. 
Each subject is free to withdraw from the trial at any time, without giving a reason.  
If a subject withdraws, the investigator will ask the subject to consent to a follow-up 
examination.  For withdrawn subjects, the investigator will use a special information 
and consent form which has been ethically approved.  If the subject consents to the 


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follow-up examination but asks the investigator to destroy all identifiable samples 
taken from the subject and/or not enter into the eCRF results of the follow-up 
 
The sponsor will ensure that the MHRA and the REC, are informed promptly of 
SUSARs (see section 14.3), and that any new reports of SUSARs from other ongoing 
trials of the IMPs under investigation in this trial are notified to the MHRA, and to 
the REC, if applicable.  The sponsor will provide the investigator, the REC and the 
MHRA with annual safety reports of each IMP under investigation, and listings of all 
suspected serious adverse reaction (SSAR) reports.  The sponsor will also inform the 
investigator promptly of any new safety or toxicology data that might affect the 
safety of the subjects in this study.   
The investigator will promptly inform the sponsor and, if applicable, the REC of any 
SAE that occurs during this trial (see section 14.3).  The investigator will provide the 
REC with annual progress reports of the trial, if the trial lasts longer than a year.   
The investigator will report to the REC any protocol deviation that is, in his opinion, 
of clinical significance.  The investigator will also inform the REC in the event of 
several deviations which, although of no clinical significance, cause inconvenience 
and/or discomfort to the volunteers.  The sponsor will notify the MHRA and REC of 
any serious breach of good clinical practice (for example, the investigator puts 
 
or good clinical practice).  
Within 90 days after the end of the trial, the sponsor will ensure that the REC and the 
MHRA are notified that the trial has finished.  If the trial is terminated prematurely, 
those reports will be made within 15 days after the end of the trial. 
The sponsor will supply a summary of the clinical trial report to the MHRA and REC 
within 1 year after the end of the trial.  
Trial procedures at HMR will be subject to audits by the HMR QA Department, to 
ensure compliance with the protocol and applicable regulatory requirements. 
18 
Trial documentation 
18.1 
Protocol amendments 
After the protocol has been approved by the REC and the MHRA, no changes may 
be made without the agreement of both the investigator and the sponsor.   
The MHRA and REC do not need to approve any substantial change to the protocol 
that needs to be implemented urgently to avoid an immediate hazard to trial subjects.  
The sponsor will ensure that the MHRA and REC are informed of urgent 
amendments or a temporary halt to the trial in accordance with The Medicines for 
Human Use (Clinical Trials) Regulations 2004 (and current amendments)42 and the 
SOPs issued by RES for NHS RECs38. 


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All agreed protocol amendments will be recorded on a written agreement which will 
be signed and dated by the investigator and sponsor, and attached to the original 
protocol.  The REC and/or MHRA must approve substantial amendments before they 
are implemented.  
The standard text in our information and consent form template explains that the 
planned doses for Part A may change during the trial, and that we may give the 
subjects any dose that has been approved by the MHRA and REC in Part A.  
However, if we want to reduce the planned dose, we consider it essential to fully 
inform the subject of our reasons, because a reduction in dose might be due to poor 
Wherever possible, we will obtain prior approval from the REC for the information 
and consent form that we give to subjects before we reduce the dose.  But, owing to 
the nature of trials on healthy volunteers, it is likely that we will sometimes have to 
implement an urgent amendment to lower the planned dose, to avoid immediate 
hazard to the subjects.  We will fully inform the subjects of the reason for reducing 
the dose, and will notify the REC and MHRA promptly of the urgent amendment, in 
accordance with statutory requirements. 
18.2 
Case report forms 
The eCRF will be designed and produced by HMR.   
number and/or HMR volunteer number will be used for identification. 
The investigator is responsible for ensuring the accuracy and completeness of the 
data entered into the eCRF, and the timeliness of data entry.  Clinical data (including 
AEs, concomitant medication, etc) will be entered into a 21 CFR Part 11-compliant 
Medrio database.  The Medrio system includes password protection and internal 
quality checks, such as automatic range checks, to identify data that appear 
inconsistent, incomplete, or inaccurate.  Data reported in the eCRF, derived from 
source documents, should be consistent with the source documents or the 
discrepancies should be explained.  Where the data violate validation checks, queries 
will be generated for resolution by clinical staff.  All edits made to the database upon 
resolution of queries will be recorded in an electronic audit trail. 
Source documents 
Before the start of the study, the sponsor and investigator will sign an agreement 
listing the source documents to be used in this trial.  
18.3 
Reporting of results 
HMR will prepare a draft report for discussion with the sponsor.  The report will 
contain results and discussion of the trial, to which will be attached tables, figures 
and listings in compliance with ICH E346. 


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Completed eCRFs will be supplied separately to the sponsor by HMR. 
19 
Obligations of the sponsor and investigator 
19.1 
Monitoring, auditing and inspection 
The trial will be monitored by the sponsor.   
A sample of documents generated by HMR which form part of this trial, and the 
ensuing data, will be audited by the HMR Quality Assurance Department to assess 
compliance with the quality management system of HMR.  That system incorporates 
the requirements of The Medicines for Human Use (Clinical Trials) Regulations 
2004 (and current amendments)42, ICH GCP, GMP37, and the SOPs issued by RES 
for RECs in the UK38, and is based on ISO 9001.   
The sponsor may do a quality assurance audit, and regulatory authorities may inspect 
this study, at any time during or after the study.  The sponsor and investigator agree 
to allow auditors and inspectors direct access to all relevant documents, and to 
allocate time to discuss findings with the auditors or inspectors. 
19.2 
Compensation of volunteers 
The sponsor agrees to abide by the Association of the British Pharmaceutical 
Industry (ABPI) Guidelines for medical experiments in non-patient human 
volunteers (2018 edition)47, and undertakes to compensate the subjects for injuries 
which are considered, on the balance of probabilities, to have arisen as a result of 
their participation in the trial. 
19.3 
Confidentiality 
All personal details of the participating subjects and the results of the trial will be 
informed of the nature and timing of the trial. 
All unpublished documents including the protocol, the CRF, and the IB are 
confidential.  Those documents cannot be disclosed to a third party without the 
written consent of the sponsor.  However, submission of those documents to a REC 
is expressly permitted. 
The investigator agrees that the sponsor maintains the right to use the results of this 
trial, in their original form and/or in a global report, for submission to governmental 
and regulatory authorities of any country. 
19.4 
Publication 
If the data merit, the investigator and the sponsor will discuss the preparation of a 
manuscript for publication in a peer-reviewed professional journal or an abstract for 


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presentation, oral or written, to a learned society or symposium.  Either party may 
undertake the task but both must agree to the strategy before the work is started.  
Each party will allow the other 30 days to comment before any results are submitted 
for publication or presentation.  Authorship should reflect work done by the 
investigators and personnel of the sponsor, in accordance with generally recognised 
principles of scientific collaboration.  
19.5 
Archiving 
The sponsor and HMR will keep in a trial master file all the essential documents 
generated during the trial, will be archived in a secure place for at least 25 years.  
Documents will be stored such that they are readily available for inspection at the 
request of the sponsor or a regulatory authority.  Any transfer of ownership of the 
informed.   
20 
Premature termination of the trial 
The sponsor and investigator reserve the right to terminate this trial should severe 
AEs, SAEs or any other safety issue occur during the trial.  If the trial is terminated 
prematurely, and the sponsor or investigator, as appropriate, will provide a written 
statement of the reasons for termination.  The sponsor will ensure that the MHRA 
and REC are notified, as described in section 17. 
 
 


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21 
References 
1. Burisch J, Jess T, Martinato M, Lakatos PL, EpiCom E.  The burden of 
inflammatory bowel disease in Europe. J Crohns Colitis.  2013;7(4):322-37. 
2. Collaborators GBDIBD.  The global, regional, and national burden of 
inflammatory bowel disease in 195 countries and territories, 1990-2017:  a 
systematic analysis for the Global Burden of Disease Study 2017.  Lancet 
Gastroenterol Hepatol.  2020;5(1):17-30. 
3. Ng SC, Shi HY, Hamidi N, Underwood FE, Tang W, Benchimol EI, et al. 
Worldwide incidence and prevalence of inflammatory bowel disease in the 21st 
century: a systematic review of population-based studies.  Lancet. 
2017;390(10114):2769-78. 
4. Freeman K, Ryan R, Parsons N, Taylor-Phillips S, Willis BH, Clarke A.  The 
incidence and prevalence of inflammatory bowel disease in UK primary care: a 
retrospective cohort study of the IQVIA Medical Research Database.  BMC 
Gastroenterol. 2021;21(1):139. 
5. Pasvol TJ, Horsfall L, Bloom S, Segal AW, Sabin C, Field N, et al.  Incidence 
and prevalence of inflammatory bowel disease in UK primary care: a 
population-based cohort study. BMJ Open. 2020;10(7):e036584. 
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