An Open-Label, Single-Dose, Single-Period Study Designed to Assess the Mass Balance Recovery, Metabolite Profile and Metabolite Identification of [14C]-MD1003 in Healthy Male Subjects
Phase: PHASE1
Conditions: Healthy Volunteers
Sponsor: MedDay Pharmaceuticals SA

 
 
CLINICAL STUDY PROTOCOL 
An Open-Label, Single-Dose, Single-Period Study Designed to 
Assess the Mass Balance Recovery, Metabolite Profile and 
Metabolite Identification of [14C]-MD1003 in Healthy Male 
Subjects 
Quotient Study Number: 
QSC201639 
Sponsor Study Number: 
MD1003CT2019-03MB 
EudraCT Number: 
2019-003122-24 
Clinical Study Site: 
Quotient Sciences 
Mere Way 
Ruddington Fields 
Ruddington 
Nottingham NG11 6JS, UK 
Tel: +44 (0)115 974 9000 
Sponsor: 
MedDay Pharmaceuticals 
24-26 Rue de la Pépinière 
75008 
Paris 
France 
Tel: +33 (0)1 80 40 14 00 
Date of Protocol: 
12 SEP 2019 
Status of Protocol: 
Version 1.0 
SPONSOR/QUOTIENT SCIENCES CONFIDENTIAL 
This clinical protocol may not be reproduced or communicated to a third party 
without the written permission of MedDay Pharmaceuticals. 
 
 

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Study Contacts 
Principal Investigator: 
Somasekhara Menakuru MBBS, MS, MRCS, 
Dip Pharm Med 
Quotient Sciences 
Mere Way 
Ruddington Fields 
Ruddington 
Nottingham NG11 6JS, UK 
Tel: +44 (0)115 974 9000 (day) 
Tel: +44 (0)7774 017236 (out of hours emergency) 
Sub-Investigators: 
 
Sharan Sidhu MBChB, BAO, MRCS, MFPM 
Philip Evans MBChB, MRCS (Ed) 
Stuart Mair MBChB, DRCOG, DCPSA, FFPM 
Nand Singh BSc, MD, DPM, MFPM 
Litza McKenzie MBChB, BScMedSci 
Martina Fieldingova MD 
Dan Hamzea MD 
Elizabeth Maria van Niekerk MBChB, DipPalMed 
Jonathan Whitton BMBS, BSc, MRCS, PGcert  
David Everton BSc, MBBS 
Jeyanthi Rangaraj MBBS, MRCPH, MRCP, DCH, 
MRCGP 
Quotient Sciences 
Tel: +44 (0)115 974 9000 (day) 
Tel: +44 (0)7774 017236 (out of hours emergency) 
Project Manager: 
Michelle Lawton BSc (Hons), PhD 
Quotient Sciences 
Tel: +44 (0)115 931 3210 
Study Monitor: 
Mat Dawson 
Stoneygate Clinical Research Ltd 
260 Kimberley Road 
Leicester 
LE2 1LJ 
Medical Monitor: 
Marie-Pierre Caby-Tosi, PharmD, PhD 
Global Head of Drug Safety 
MedDay Pharmaceuticals 
24-26 Rue de la Pépinière 
75008 
Paris 
France 
Tel : +33 (0)6 30 43 40 80 

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Pharmacovigilance 
Provider: 
MedDay Pharmaceuticals 
24-26 Rue de la Pépinière 
75008 
Paris 
France 
Tel : +33 (0)6 30 43 40 80 
Email: pharmacovigilance@medday-pharma.com 
ARSAC Practitioner 
Stuart Mair MBChB, DRCOG, DCPSA, FFPM 
Tel: +44 (0)115 974 9000  
Email: stuart.mair@quotientsciences.com 
 
Central Laboratory: 
The Doctors Laboratory 
The Halo Building 
1 Mabledon Place 
London WC1H 9AX 
Bioanalytical, Mass 
Balance and 
Metabolite Profiling 
and Identification 
Laboratory: 
Pharmaron 
Pegasus Way 
Crown Business Park 
Rushden  
Northamptonshire 
NN10 6ER 
UK 
Tel:+44 (0)1933 319 970 
Bioanalytical 
Laboratory for 
MD1003, Bisnorbiotin 
and Biotin Sulfoxide 
Atlanbio 
1 Rue Graham Bell 
Z.I de Brais 
44600 Saint-Nazaire 
France 
Tel: +33 (0)2 51 10 10 89 
Fax: +33 (0)2 51 10 01 09 

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1 
Table of Contents 
1 
Table of Contents ............................................................................................ 6 
2 
List of Tables and Figures ............................................................................... 9 
2.1 
Table of In-Text Tables ...................................................................... 9 
2.2 
Table of In-Text Figures ..................................................................... 9 
3 
Synopsis ....................................................................................................... 10 
4 
List of Abbreviations ...................................................................................... 14 
5 
Background Information ................................................................................ 16 
5.1 
Introduction ...................................................................................... 16 
5.2 
Investigational Medicinal Product .................................................... 17 
5.3 
Previous Study Findings .................................................................. 17 
5.3.1 
Non-clinical Findings ....................................................................... 17 
5.3.2 
Clinical Findings .............................................................................. 18 
5.3.3 
Efficacy ............................................................................................ 20 
5.3.4 
Pharmacokinetics and Product Metabolism in Animals .................... 21 
6 
Rationale ....................................................................................................... 22 
6.1 
Study Rationale ............................................................................... 22 
6.2 
Dose Rationale ................................................................................ 22 
6.3 
Population Rationale ....................................................................... 22 
6.4 
Risks and Benefits ........................................................................... 23 
7 
Objectives and Endpoints .............................................................................. 24 
8 
Study Design ................................................................................................. 24 
8.1 
Study Plan ....................................................................................... 24 
8.2 
Criteria for In-Study Decisions ......................................................... 25 
8.3 
Subject Withdrawal .......................................................................... 25 
8.4 
Subject Replacement ...................................................................... 26 
8.5 
Stopping Criteria .............................................................................. 26 
8.6 
Study Termination ........................................................................... 27 
8.7 
Treatment Allocation ........................................................................ 28 
8.7.1 
Subject Numbers ............................................................................. 28 
8.7.2 
Blinding ........................................................................................... 28 
9 
Selection of Subjects ..................................................................................... 28 
9.1 
Informed Consent ............................................................................ 28 
9.2 
Inclusion Criteria .............................................................................. 28 
9.3 
Exclusion Criteria ............................................................................. 29 
9.4 
Contraception .................................................................................. 30 
9.4.1 
Exposure to Sexual Partners During the Study ................................ 30 
9.4.2 
Sperm Donation............................................................................... 30 
9.5 
Pregnancy ....................................................................................... 31 
9.6 
Additional Study Restrictions ........................................................... 31 

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10 
Study Procedures .......................................................................................... 31 
10.1 
Screening ........................................................................................ 31 
10.1.1 Subject Re-Screening ...................................................................... 32 
10.2 
Admission and Pre-dose Procedures ............................................... 32 
10.3 
Study Day Procedures ..................................................................... 32 
10.3.1 Blood Volume .................................................................................. 32 
10.3.2 Timing of Procedures ...................................................................... 32 
10.3.3 Discharge from the Clinical Unit ....................................................... 33 
10.3.4 Medical Supervision ........................................................................ 33 
11 
Dosing of Subjects ........................................................................................ 33 
11.1 
Food and Fluid Intake ...................................................................... 33 
11.2 
Administration of Test Preparations ................................................. 34 
11.3 
Dosing Compliance ......................................................................... 34 
11.4 
Prior and Concomitant Medications ................................................. 34 
12 
Assessment of Efficacy ................................................................................. 34 
13 
Assessment of Mass Balance, Pharmacokinetics, Metabolite Profiling 
and Identification, and Pharmacodynamics ................................................... 35 
13.1 
Assessment of Mass Balance, Pharmacokinetics and 
Metabolite Profiling and Identification .............................................. 35 
13.1.1 Blood Sampling ............................................................................... 35 
13.1.2 Urine Sampling ................................................................................ 35 
13.1.3 Faecal Sampling .............................................................................. 36 
13.1.4 Unexpected Sources of Elimination ................................................. 36 
13.2 
Assessment of Pharmacodynamics ................................................. 36 
14 
Assessment of Safety ................................................................................... 36 
14.1 
Definition and Classification of Adverse Events ............................... 36 
14.2 
Assessment of Causality ................................................................. 37 
14.3 
Recording Adverse Events .............................................................. 37 
14.4 
Serious Adverse Events .................................................................. 38 
14.4.1 Definition of Serious Adverse Events ............................................... 38 
14.4.2 Definition of Suspected Unexpected Serious Adverse 
Reactions ........................................................................................ 38 
14.5 
Laboratory Measurements ............................................................... 38 
14.5.1 Haematology and Clinical Chemistry ............................................... 38 
14.5.2 Urinalysis ......................................................................................... 39 
14.5.3 Drug Screen .................................................................................... 39 
14.5.4 Alcohol Breath Test ......................................................................... 39 
14.5.5 Carbon Monoxide Breath Test ......................................................... 39 
14.5.6 Abnormal Laboratory Findings ......................................................... 39 
14.6 
Vital Signs Measurements ............................................................... 40 
14.7 
ECG Measurements ........................................................................ 40 
14.8 
Body Weight and Height .................................................................. 40 
14.9 
Physical Examination ...................................................................... 41 
14.10 
Additional Safety Procedures........................................................... 41 
15 
Statistics and Data Analysis .......................................................................... 41 

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15.1 
Sample Size Justification ................................................................. 41 
15.2 
Data Management ........................................................................... 41 
15.3 
Mass Balance Data Analysis ........................................................... 41 
15.4 
Pharmacokinetic Data Analysis ....................................................... 42 
15.5 
Metabolite Profiling and Identification .............................................. 43 
15.6 
Statistical Data Analysis .................................................................. 43 
15.7 
Interim Analysis ............................................................................... 43 
16 
Safety Reporting to Ethics Committees and Regulatory Authorities............... 44 
16.1 
Events Requiring Expedited Reporting ............................................ 44 
16.2 
Urgent Safety Measures .................................................................. 44 
16.3 
Reporting ......................................................................................... 45 
16.3.1 Reporting Serious Adverse Events .................................................. 45 
16.3.2 Reporting of Suspected Unexpected Serious Adverse 
Reactions (SUSARs) ....................................................................... 45 
16.3.3 Expedited Reporting of Events ........................................................ 45 
16.3.4 Reporting of Urgent Safety Issues ................................................... 45 
16.4 
Serious Breaches ............................................................................ 46 
17 
Protocol Amendments and Deviations ........................................................... 46 
17.1 
Amendments ................................................................................... 46 
17.2 
Protocol Deviations .......................................................................... 46 
18 
Regulatory ..................................................................................................... 46 
18.1 
Compliance ..................................................................................... 46 
18.2 
Ethical Approval............................................................................... 47 
18.3 
MHRA Approval ............................................................................... 47 
18.4 
Administration of Radiation .............................................................. 47 
18.5 
Source Data .................................................................................... 47 
18.6 
Declaration of the End of the Study ................................................. 48 
18.7 
Document Storage and Archiving .................................................... 48 
18.8 
Protection of Personal Data and Confidentiality ............................... 48 
18.9 
Data Security Breach ....................................................................... 49 
19 
Quality Control and Quality Assurance .......................................................... 49 
19.1 
Monitoring........................................................................................ 49 
20 
Finance and Insurance .................................................................................. 50 
21 
Publication .................................................................................................... 50 
22 
References .................................................................................................... 50 
Appendix 1 
Clinical Laboratory Parameters ........................................................ 52 
Appendix 2 
Study Flow Chart ............................................................................. 53 
 

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2 
List of Tables and Figures  
2.1 
Table of In-Text Tables 
Table 1 
Investigational Medicinal Product .............................................................. 17 
Table 2 
Tabulated List of Adverse Reactions ........................................................ 20 
 
2.2 
Table of In-Text Figures 
Figure 1 
Study Sequence ....................................................................................... 25 
 
 

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3 
Synopsis 
Sponsor: 
MedDay Pharmaceuticals 
Drug Substance: 
[14C]-MD1003 
EudraCT No.: 
2019-003122-24 
Title of Study: 
An Open-Label, Single-Dose, Single-Period Study Designed to Assess the Mass Balance 
Recovery, Metabolite Profile and Metabolite Identification of [14C]-MD1003 in Healthy Male 
Subjects 
Principal Investigator:  
Somasekhara Menakuru MBBS, MS, MRCS, Dip Pharm Med 
Study Centre: 
Quotient Sciences, Mere Way, Ruddington Fields, Nottingham, NG11 6JS, UK 
Objectives and Endpoints: 
Objectives 
Endpoints 
Primary 
 
To determine the mass balance recovery after a 
single oral dose of carbon-14 [14C]-MD1003 
 
To perform metabolite profiling and structural 
identification of MD1003 metabolites from plasma, 
urine and faecal samples 
 
 
Mass balance recovery of total radioactivity in all 
excreta (urine and faeces): Ae, %Ae, Cum Ae and 
Cum %Ae 
 
Metabolite profiling, structural identification, and 
quantification of [14C]-MD1003 metabolites in 
plasma, urine and faeces 
Secondary 
 
To determine the routes and rates of elimination of 
[14C]-MD1003 
 
To identify the chemical structure of each 
metabolite accounting for more than 10% of 
circulating total radioactivity 
 
To further explore the oral pharmacokinetics (PK) 
of MD1003 and its metabolites bisnorbiotin and 
biotin sulfoxide 
 
To evaluate the extent of distribution of total 
radioactivity into blood cells 
 
To provide additional safety and tolerability 
information for MD1003 
 
 
Amount of total radioactivity excreted and amount 
of total radioactivity excreted as a percentage of 
the administered dose in urine and faeces at each 
time interval 
 
Identification of the chemical structure of each 
metabolite accounting for more than 10% by AUC 
of circulating total radioactivity 
 
Assessment of the oral PK profile for MD1003, 
bisnorbiotin, biotin sulfoxide and total radioactivity 
based on: Tlag, Tmax, Cmax, AUC(0-last), 
AUC(0-inf), AUCextrap, T1/2, Lambda-z, CL/F 
(MD1003 only), Vz/F (MD1003 only), MPR Cmax 
and MPR AUC(0-inf) 
 
Evaluation of whole blood:plasma concentration 
ratios for total radioactivity 
 
To provide additional safety and tolerability 
information for MD1003 by assessing: adverse 
events (AEs), vital signs, electrocardiograms 
(ECGs), physical examinations and laboratory 
safety  
The metabolite profile and structural identification objectives will be reported separately. 
Methodology: 
This is a single-centre, open-label, non-randomised, single oral dose study in healthy male 
subjects. It is planned to enrol 6 subjects to ensure 4 evaluable subjects. 
Each subject will receive a single oral administration of a capsule containing 100 mg MD1003 
and not more than 2.22 MBq (approximately 60.0 µCi) [14C], in the fasted state. 
Study Design: 
Subjects will be screened to participate in the study up to 28 days before dosing. Subjects will 
be admitted to the clinical unit on the evening of Day -1 prior to investigational medicinal product 
(IMP) administration.  

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Subjects will be dosed on the morning of Day 1 following an overnight fast and will remain 
resident in the clinical unit until up to 168 h after dosing (up to Day 8). It is planned that subjects 
will be released as a group when all subjects have achieved a mass balance cumulative 
recovery of >90% or if <1% of the dose administered has been collected in urine and faeces 
within 2 separate consecutive 24 h periods. This may result in the subjects being discharged as 
a group prior to completion of the planned residency period. Once the discharge criteria or the 
planned residency period have been achieved, collection of all samples (blood, urine and 
faeces) will be stopped and the subjects will undergo discharge assessments. If the mass 
balance criteria have not been met by all subjects by Day 8, the residency period for the 
subjects not achieving the release criteria may be extended up to a maximum of an additional 
48 h (up to Day 10) for further collection of urine and/or faeces. If the release criteria have still 
not been met by Day 10, or if any additional residency is not considered appropriate or 
necessary, then home collections of urine and/or faeces may be requested at the discretion of 
the investigator for individual subjects.  
Number of Subjects Planned: 
It is planned to enrol 6 healthy male subjects to ensure data in 4 evaluable subjects. A subject 
will be considered evaluable if they have provided mass balance and PK samples for up to 72 h 
(up to Day 4) after IMP administration, or have demonstrated >90% mass balance recovery, or 
have <1% of the administered dose eliminated in excreta for 2 consecutive days, whichever is 
sooner. No replacement subjects are to be used in this study. 
Duration of Study: 
Single oral dose administration on a single occasion. The estimated time from screening until 
the end of the study is approximately up to 6 weeks. 
Main Inclusion Criteria: 
Healthy males aged 30 to 65 years. 
Body mass index (BMI) 18.0 to 30.0 kg/ m2. 
Investigational Medicinal Product, Dose and Mode of Administration: 
The following IMP will be used in this clinical study. 
Treatment 
IMP Name 
Dose 
Route of Administration 
Single dose 
[14C]-MD1003 Capsule 
100 mg (NMT 2.22 MBq; 
60.0 µCi 14C) 
Oral, fasted 
14C: carbon 14, NMT: not more than 
All doses will be administered orally with 240 mL water, following an overnight fast. 

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Mass Balance Assessments: 
Mass balance of total radioactivity in urine and faeces will be calculated as follows: 
Parameter 
Definition 
Ae(urine) 
amount of total radioactivity excreted in urine 
%Ae(urine) 
amount of total radioactivity excreted in urine expressed as a percentage of the radioactive 
dose administered 
CumAe(urine) 
cumulative amount of total radioactivity excreted in urine 
Cum%Ae(urine) 
cumulative amount of total radioactivity excreted in urine expressed as a percentage of the 
radioactive dose administered 
Ae(faeces) 
amount of total radioactivity eliminated in faeces 
%Ae(faeces) 
amount of total radioactivity eliminated in faeces expressed as a percentage of the 
radioactive dose administered 
CumAe(faeces) 
cumulative amount of total radioactivity eliminated in faeces 
Cum%Ae(faeces) 
cumulative amount of total radioactivity eliminated  in faeces expressed as a percentage of 
the radioactive dose administered 
Ae(total) 
amount of total radioactivity excreted in urine and faeces combined 
%Ae(total) 
amount of total radioactivity excreted in urine and faeces combined expressed as a 
percentage of the radioactive dose administered 
CumAe(total) 
cumulative amount of total radioactivity excreted in urine and faeces combined 
Cum%Ae(total) 
cumulative amount of total radioactivity excreted in urine and faeces combined expressed 
as a percentage of the radioactive dose administered 
Pharmacokinetic Assessments: 
The plasma concentration data for MD1003, bisnorbiotin and biotin sulfoxide, and plasma and 
whole blood total radioactivity concentrations provided by Pharmaron will be analysed by 
Quotient Sciences using appropriate non-compartmental techniques to obtain estimates of the 
following PK parameters: 
Parameter 
Definition 
Tlag 
Time prior to the first measurable (non-zero) concentration 
Tmax 
Time of maximum observed concentration 
Cmax 
Maximum observed concentration 
AUC(0-last) 
Area under the curve from 0 time to the last measurable concentration 
AUC(0-inf) 
Area under the curve from 0 time extrapolated to infinity 
AUCextrap 
Percentage of AUC(0–inf) extrapolated beyond the last measurable concentration 
T1/2  
Apparent elimination half-life 
Lambda-z 
Slope of the apparent elimination phase 
CL/F (MD1003 only) 
Apparent total body clearance calculated after a single extravascular administration 
where F (fraction of dose bioavailable) is unknown  
Vz/F (MD1003 only) 
Apparent volume of distribution based on the terminal phase calculated after a single 
extravascular administration where F (fraction of dose absorbed) is unknown  
MPR Cmax 
Metabolite to parent ratio based on Cmax 
MPR 
AUC(0-inf) 
Metabolite to parent ratio based on AUC(0-inf) 
Metabolite Profiling and Identification 
Metabolite profiling of plasma, urine and faeces will be performed using liquid 
chromatography-radio-detection with subsequent mass spectrometry where appropriate. 
Identification of the chemical structure of each metabolite accounting for greater than 10% of 
circulating radioactivity in plasma (“AUC pool”) and accounting for greater than 10% of the 
administered dose in urine and faeces (from urine pools and faeces homogenate pools) will be 
performed. These aspects will be reported separately from the clinical study report as a 
standalone document.  

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Safety Assessments: 
The safety assessments to be conducted are: 
 
Adverse Events 
 
12-lead ECGs 
 
Vital Signs 
 
Clinical laboratory tests (clinical chemistry, haematology and urinalysis) 
 
Physical examinations 
Statistical Methodology: 
No formal statistical analysis will be performed for the safety, mass balance or PK data. 
Descriptive statistics (eg mean, standard deviation, median, minimum, maximum and number of 
subjects with an observation) are considered adequate for a study of this type. 
Sample Size and Power: 
The study is exploratory and no formal sample size calculation has been made. Based on 
experience from previous studies of a similar design, a total of 6 subjects is to be enrolled and a 
minimum of 4 evaluable subjects is considered sufficient.  

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4 
List of Abbreviations 
Abbreviation 
Definition 
14C 
carbon-14 
ACC 
acetyl-CoA carboxylase 
ADME 
absorption, metabolism, distribution and elimination 
AE 
adverse event 
ALT 
alanine aminotransferase 
ARSAC 
Administration of Radioactive Substances Advisory 
Committee 
ATP 
adenosine triphosphate 
ATUc 
Autorisation Temporaire d’Utilisation de cohorte 
BMI 
body mass index 
CA 
colon arrival 
CHMP 
Committee for Medicinal Products for Human Use 
CNS 
central nervous system 
CV% 
coefficient of variation 
DMP 
data management plan 
EC 
ethics committee 
ECG 
electrocardiogram 
eCRF 
electronic case report form  
EDSS 
Expanded Disability Scale Status 
EMA 
European Medicines Agency 
GCP 
good clinical practice 
GGT 
gamma glutamyl transferase 
GP 
general practitioner 
HBsAg 
hepatitis B surface antigen 
HCV Ab 
hepatitis C virus antibody 
HIV 
human immunodeficiency virus 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IMP 
investigational medicinal product 
MCC 
3-methylcrotonyl-CoA carboxylase 
MedDRA 
Medical Dictionary for Regulatory Activities 
MHRA 
Medicines and Healthcare products Regulatory Agency 
MS 
multiple sclerosis  
NMT 
not more than 

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ON 
optic neuritis 
PC 
pyruvate carboxylase 
PCC 
propionyl-CoA carboxylase 
PHE 
Public Health England 
PIS 
Participant Information Sheet 
PK 
pharmacokinetic(s) 
QA 
quality assurance 
QTcF 
Corrected QT interval by Fridericia’s formula 
RAP 
Reporting and Analysis Plan 
SAE 
serious adverse event 
SMVT 
sodium multivitamin transporter 
SOP 
standard operating procedure 
SUSAR 
suspected unexpected serious adverse reaction 
TCA 
tricarboxylic acid 
TID 
three times daily 
WHO 
World Health Organisation 
 

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5 
Background Information 
5.1 
Introduction  
MD1003 is the code name for high doses of pharmaceutical-grade biotin being 
developed by MedDay Pharmaceuticals as a treatment for patients with primary and 
secondary progressive multiple sclerosis (MS). 
MD1003 is a powder of biotin in hard capsule (100 mg per capsule). The therapeutic 
dose of MD1003 is 300 mg/day (ie between 3 and 6 mg/kg/day) [1]. 
Biotin is a water-soluble vitamin acting as a carboxyl (CO2) transporter in carboxylation 
reactions. In mammals, biotin serves as a cofactor for four carboxylases involved in the 
metabolism of carbohydrates, amino acids and fatty acids: (1) pyruvate carboxylase 
(PC), (2) 3-methylcrotonyl-CoA carboxylase (MCC), (3) propionyl-CoA carboxylase 
(PCC) and (4) acetyl-CoA carboxylase (ACC) [2]. These carboxylases play a critical 
role in the intermediate metabolism of gluconeogenesis, fatty acid synthesis, and 
amino acid catabolism 
Of note, in the nervous system, ACC1 and ACC2 are detected exclusively in 
oligodendrocytes, the cells responsible for myelin synthesis, and are found in purified 
myelin, suggesting that these enzymes are key regulators of myelin synthesis [3]. 
Besides its role as a co-factor, biotin may regulate genes encoding enzymes or 
transporters involved in its own metabolism or other cell function [4]. However, this 
physiological role of biotin remains unclear. 
MD1003 is expected to be the first therapeutic approach having an impact on not active 
progressive MS by reversing the “virtual hypoxia” phenomenon and triggering 
remyelination [5],[6]. 
It was hypothesised that the positive effects of MD1003 that are seen in demyelinating 
diseases such as multiple sclerosis are linked to: (1) increased energy production 
through feeding the tricarboxylic acid (TCA) cycle in demyelinated neurons and in 
oligodendrocytes, and (2) stimulation of myelin repair through activation of the 
acetyl-CoA carboxylase in oligodendrocytes [6]. 
It is hypothesised that the treatment with MD1003 reverses the state of energy deficit 
through its role as a cofactor for PC, MCC, and PCC. All 3 of these enzymes are 
expressed in central nervous system (CNS) cells. These three biotin-dependent 
carboxylases generate intermediates for the TCA cycle at three different entry points: 
oxaloacetate, succinate and acetyl-CoA, and could be expected to increase the levels 
of cellular adenosine triphosphate (ATP). By increasing the available intraneuronal pool 
of ATP, high-dose biotin may reduce demyelinated neural dysfunction and the adverse 
effects of hypoxia. 
A second biotin-dependent pathway that occurs in the cytoplasm through the 
biotin-dependent ACC1 and ACC2 may play a role in myelin repair. This pathway is 
key in the regulation of fatty acid synthesis [2]. ACC1 and ACC2 are key regulators of 
membrane lipid synthesis including myelin synthesis [3]. In the CNS, ACC1 and ACC2 
are mostly expressed in oligodendrocytes [3]. Furthermore, ACC can be detected in 
purified myelin [3]. 

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As 
other 
chronic 
demyelinating 
diseases 
and 
neuropathies 
share 
the 
pathophysiological mechanisms that are thought to be targeted by MD1003, it is 
expected that MD1003 would be beneficial in these diseases such as some 
demyelinating neuropathies and adrenomyeloneuropathy. 
5.2 
Investigational Medicinal Product 
The following investigational medicinal product (IMP) will be used in this clinical study 
(Table 1). 
Table 1 
Investigational Medicinal Product 
Treatment 
IMP Name 
Dose 
Route of 
Administration 
Single dose 
[14C]-MD1003 Capsule 
100 mg (NMT 2.22 MBq; 
60.0 µCi 14C) 
Oral, fasted 
14C: carbon 14, NMT: not more than 
[14C]-MD1003 is an un-licensed medicinal product for use only in the proposed clinical 
trial.  
Only subjects enrolled in the study may receive study treatment and only authorised 
site staff may supply or administer study treatment. All study treatments will be stored 
in a secure, environmentally-controlled, and monitored (manual or automated) area in 
accordance with the labelled storage conditions with access limited to the investigator 
and authorised site staff. 
Where Quotient Sciences is manufacturing the IMP(s), suitability of the manufacturing 
process will be documented in a Pharmaceutical Development and Control Strategy 
Report. 
IMPs will be reconciled and destroyed in accordance with the study-specific quality 
agreement and technical addendum. 
5.3 
Previous Study Findings 
The non-clinical and clinical studies conducted for MD1003 are summarised below; 
further details are provided in the Investigator’s Brochure [1]. 
5.3.1 Non-clinical Findings 
The hypothesised positive effects of MD1003 that may be seen in demyelinating or 
dysmyelinating diseases such as MS are thought to be linked to: (1) increased energy 
production through augmenting the TCA cycle in demyelinated neurons, and 
(2) stimulation of myelin repair through activation of the acetyl-CoA carboxylase in 
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Following oral administration, biotin is absorbed in the intestine via the sodium 
multivitamin transporter (SMVT). At the therapeutic dose level, biotin has good oral 
bioavailability (~50%) and is largely not bound to plasma proteins. Following an oral 
administration of MD1003 in rats, the highest concentrations were found in the 
stomach, bladder, and kidneys with a rapid elimination with very low concentrations 
after 24 h and no storage of biotin observed. Biotin uptake into the CNS, liver, and 
most peripheral tissues also involves the SMVT. No saturation of the SMVT at the 
blood-brain barrier is expected at the therapeutic dose. Biotin may accumulate in the 
placenta and is excreted in milk in animals. Biotin is catabolized mostly in the liver via 
2 pathways leading to 2 main metabolites, bisnorbiotin and biotin sulfoxide. Biotin 
metabolites are inactive. Following an intravenous administration of MD1003 in rats, 
biotin and its metabolites are rapidly excreted in the urine (>80% of elimination) with 
biotin being the major form excreted. Urinary clearance data obtained following 
administration of MD1003 in healthy volunteers suggest that biotin is actively secreted 
by the kidneys. 
Drug interaction with MD1003 treatment involving cytochrome P450 enzymes or 
transporters commonly involved in the absorption, metabolism and elimination of other 
drugs are not expected. The expected risk of drug interaction with MD1003 
administration in humans resides mainly from pharmacodynamic interaction with insulin 
and pharmacokinetic (PK) interactions with other substrates of the biotin transporter 
(SMVT) and some antiepileptic drugs (carbamazepine, oxcarbazepine, primidone, and 
valproate semisodium). 
Based on the safety profiles of MD1003 in rats and dogs following repeated 
administrations, there is no identified toxicity associated with MD1003 using doses 
resulting in up to 8-fold the plasmatic exposure corresponding to the MS trial doses of 
100 mg orally 3 times daily (TID). MD1003 did not reveal any untoward effect on the 
CNS, respiratory, cardiovascular, hepatic or renal functions. In several studies, 
MD1003 did not demonstrate genotoxic potential. This combined with the absence of 
genotoxicity or carcinogenicity in literature reports suggest that biotin is unlikely to 
present a risk for carcinogenicity. No carcinogenicity studies have been conducted with 
MD1003, but a 2-year study in rats and a 6-month study in transgenic rasH2 mice are 
ongoing. A teratogenic effect of MD1003 was observed in pregnant rabbits at a dose 
equivalent to twice the exposure in humans in the absence of maternal toxicity. No 
teratogenic effect was observed in rats. However, the risk of teratogenicity observed in 
rabbits cannot be excluded in humans at the MD1003 therapeutic dose. Oral doses of 
MD1003 did not result in epithelial irritation and is not expected to have allergic 
potential. 
5.3.2 Clinical Findings 
MD1003 is currently in Phase III of clinical development for the treatment of 
progressive MS. At the date of the last update of the Investigator’s Brochure (cut-off 
date 18 Jan 2019), a total of 1,145 patients or healthy volunteers had been randomised 
in 11 studies (ongoing or completed) in the MD1003 clinical program. Of the 
1,145 subjects/patients, a total of 493 had been exposed to MD1003 and for 
642 patients with progressive MS (Phase III study), treatment groups are still blinded. 
In addition, an early access program for MD1003 (ATUc; Autorisation Temporaire 
d’Utilisation de cohorte) is ongoing in France since July 2016 with MD1003 
administered in patients with progressive MS. 

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A total of 9,661 patients were included in the ATUc between 13 Jul 2016 and 
12 Jan 2019 representing 12,241 patients-years of exposure. 
A Phase I program with 4 studies assessing the safety and PK profile of MD1003 has 
been completed. A total of 124 healthy volunteers have been randomised to date. 
MD1003 daily doses ranged from 100 to 600 mg, with treatment duration of up to 
8 days. No deaths, adverse events (AEs) or serious adverse events (SAEs) leading to 
treatment discontinuation with MD1003 were reported in these 4 healthy volunteer 
studies. 
Two Phase II studies were conducted in which 30 patients with amyotrophic lateral 
sclerosis and 15 patients with demyelinating neuropathies were included with a daily 
dose of 300 mg (100 mg TID) MD1003. 
A total of 5 Phase IIb-III or Phase III studies are ongoing or completed with MD1003 in 
Europe and Lebanon at the dose of 300 mg per day (100 mg TID) in patients with 
progressive MS (830 patients) and adrenomyeloneuropathy (60 patients). Further 
details can be found in the Investigator’s Brochure [1]. 
5.3.2.1 
Safety 
Two large randomised, double blind, placebo-controlled Phase IIb-III studies have been 
conducted in patients with MS; 65 patients in study MS-ON for up to 6 months and 
103 patients in study MS-SPI received 100 mg MD1003 TID for up to 12 months. Both 
studies have open label extension phases which are ongoing. The most commonly 
reported adverse events (>5% of patients) after treatment with MD1003 in these 2 
completed randomised, double-blind, placebo-controlled studies, regardless of 
assessment of relationship to study treatment were nasopharyngitis, urinary tract 
infection, worsening of signs and symptoms of MS and MS relapse. The majority of 
reported adverse events were mild to moderate. Reported SAEs are consistent with the 
conduct of a trial in an MS patient population.  
In completed studies with MD1003, a total of 4 serious adverse events (SAEs), 
reported in 4 patients and considered by investigators as being related to the study 
drug were reported. These SAEs included mucocutaneous rash, hypoglycaemia, 
transient myopathy and laboratory test interference. 
In ongoing studies, one SAE (rash maculo-papular) in one patient with amyotrophic 
lateral sclerosis was considered as related to MD1003 by the investigator. 
No deaths, SAEs, or AEs leading to treatment discontinuation with MD1003 were 
reported in the 4 healthy volunteer studies with MD1003 administered at doses up to 
600 mg. 
Based on MD1003 clinical and non-clinical data available, as well as the corpus of 
scientific and medical literature related to biotin, the following safety issues have been 
identified in patients treated with MD1003: interference with laboratory tests based on a 
biotin/streptavidin interaction, for which minimisation measures are in place (trial 
participation card and referral letter to general practitioner/hospital stating the subject 
has received a high biotin dose if a subject if withdrawn early), and a potential risk of 
teratogenicity observed in animal studies (rabbits). Since this study involves a single 
dose of biotin and subjects are planned to be discharged only after the administered 
dose has been eliminated, risk due to interference with laboratory results is considered 

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to be very low and will be considered only if subjects are withdrawn early. In the case 
of early withdrawal, the risk minimisation measures above will be applied In addition, 
some local allergic skin reactions have been observed. A single case of hypoglycaemia 
in an insulin-dependent patient and a single case of transient myopathy have also been 
reported in clinical trials. Adverse drug reactions reported in clinical trials to date are 
provided in Table 2. 
Table 2 
Tabulated List of Adverse Reactions 
MedDRA System Organ Class 
Adverse Reaction 
(Preferred Term) 
Frequency 
Category 
Metabolism and nutrition disorders 
Hypoglycaemiaa 
Uncommond 
Skin and subcutaneous tissue disorders 
Mucocutaneous rashb 
Uncommond 
Blisterb 
Uncommond 
Eczemab 
Uncommond 
Musculoskeletal and connective tissue disorders 
Myopathyc 
Uncommond 
MedDRA: Medical Dictionary for Regulatory Activities 
a One patient (0.4%) with insulin-dependent diabetes experienced hypoglycaemic episodes, which 
occurred in the open-label phase of the studies approximately 1 year after initiation of MD1003. Episodes 
ceased when MD1003 was stopped and recurred on re-challenge. 
b During treatment with MD1003 in the double-blind placebo-controlled phases of the clinical studies, 
1 (0.6%) patient developed a mucocutaneous rash, 1 (0.6%) patient cutaneous blisters and 
1 (0.6%) patient eczema. No patients in the placebo group reported these events. 
c One (0.4%) patient developed transient myopathy, which occurred in the open-label phase of the studies 
5 months after initiation of MD1003. The patient fully recovered when MD1003 was stopped. 
d Uncommon frequency category defined as ≥1/1000 to <1/100. 
No serious adverse reactions have been listed as expected so far [1]. 
The safety profile of MD1003 is favourable, supporting the continuation of the clinical 
investigations program for the treatment of MS as planned. 
5.3.3 Efficacy 
An open label pilot study was conducted in MS patients (n=23) using high doses of 
biotin and demonstrated that biotin could favourably effect disease progression in 
patients with progressive MS [5]. 
MS-SPI Trial: The Multiple Sclerosis-Spinal (MS-SPI) study (randomised double-blind 
study) was conducted to demonstrate the superiority of MD1003 300 mg/day over 
placebo in patients with progressive MS (n=154). The primary outcome measure was 
the proportion of patients who demonstrated improvement in a composite measure of 
Expanded Disability Scale Status (EDSS) and timed 25-foot walk. The primary 
endpoint was reached with 13 (12.6%) patients treated with MD1003 who achieved 
clinical improvement in MS-related disability at month 9, confirmed at month 12, 
compared with none of the placebo-treated patients (p=0.0051). Results of clinician 
and patient global impression of change measure (CGI/SGI) also showed statistically 
significant differences in favour of the MD1003 group. The mean change EDSS was 
stable in MD1003 treated patients while it progressively worsened in placebo active 
arms and compared to previous published studies (p=0.69) [7]. An open label 
extension study continues. 

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MS-ON Trial: The effect of MD1003 in MS patients with permanent visual loss 
following optic neuritis (ON) was assessed in another controlled clinical study, MS-ON, 
enrolling 93 patients. Following a 6-month treatment, there was no clinically significant 
difference between the MD1003 group and the placebo group, with no increase in the 
mean change of visual acuity in all groups. A positive trend was observed in the 
progressive optic neuropathy subgroup (n=31), which is consistent with findings of 
Study MS-SPI, where MD1003 showed efficacy in patients with a progressive form of 
MS [8]. 
These results support that targeting neuron/oligodendrocyte metabolism represents a 
novel disease modifying therapy approach in progressive MS. 
Overall, results of the double-blind and extension phases of MS-SPI and MS-ON 
studies showed a benign safety profile and suggest a durable treatment effect of 
MD1003 in patients with progressive MS. 
A larger international randomised placebo-controlled trial (SPI2) is ongoing in patients 
with progressive MS. 
5.3.4 
Pharmacokinetics and Product Metabolism in Animals 
Full details of PK and absorption, metabolism, distribution and elimination (ADME) data 
can be found in the Investigator’s Brochure [1]. 
In the GLP Study MD1003-ADME-RAT, the radioactivity was rapidly eliminated from 
plasma after intravenous administration of 10 mg/kg 
14C-MD1003. After oral 
administration of 30 mg/kg 14C-MD1003 (human equivalent therapeutic dose), the 
radioactivity was rapidly absorbed and after a first phase of rapid elimination from the 
plasma, the radioactivity was then slowly eliminated. 
At physiological doses of [14C] biotin (88 nmol/kg body weight) given orally to pigs, the 
plasma concentration profile best fitted a tri-exponential equation [9], which 
corresponds to a tricompartmental open model. Disappearance curves of total 14C and 
of [14C] biotin were similar. Biotin pharmacokinetics after intravenous injection of [14C] 
biotin was marked by a very short half-life of the initial distribution phase (7 min), 
followed by a slower plasma elimination phase (T1/2, β of 1.43 h) and a long apparent 
terminal half-life T1/2, γ estimated at 22 h. The rapid initial distribution phase was 
shown to correspond to the disappearance of biotin from the plasma (central 
compartment) to the peripheral compartments, such as the total body water pool or 
tissue pools [9]. 
The retention over many days of a substantial portion of the administered dose may 
occur as a consequence of the metabolic trapping of biotin into cells: conversion of 
biotin to intermediates such as biotinyl-adenosine monophosphate and biotinyl-CoA, or 
binding of biotin to proteins such as carboxylases and histones [9]. The half-life of 
pyruvate carboxylase was determined to be 28 h and 4.6 days for acetyl-CoA 
carboxylase [10]. 
Overall, PK data obtained with MD1003 confirmed the literature data and completed 
the PK properties of biotin: 
 
Biotin is rapidly absorbed by the oral route in animals  

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 
At the equivalent therapeutic dose in rats (30 mg/kg), biotin is not completely 
absorbed 
 
At very high doses (up to 3000 mg/kg), plasma exposure does not significantly 
increase, suggesting that the transport is saturated 
 
The major route of elimination is urinary and most of the biotin is excreted 
unchanged 
 
There was no evidence of accumulation after once daily repeated dosing in animals 
6 
Rationale 
6.1 
Study Rationale 
This study is being conducted to investigate the oral PK, mass balance and metabolite 
profiling and identification of [14C]-MD1003. 
6.2 
Dose Rationale 
The therapeutic daily dose of biotin is 300 mg given as 100 mg TID; therefore, a 
100 mg single does is considered the appropriate dose to investigate in an ADME 
study. This dose is not expected to result in any significant adverse effects in a healthy 
volunteer population.  
The dose of radioactivity has been determined following review of human dosimetry 
calculations provided by Public Health England (PHE). The associated radiation 
exposure will fall within International Commission on Radiological Protection (1992) 
Guidelines for Category IIa studies (0.1 to 1 mSv). The dose of radioactivity will be no 
more than 2.22 MBq (60.0 µCi). 
To ensure that the [14C] drug product(s) does not exceed the limit for radioactive dose 
approved by the Administration of Radioactive Substances Advisory Committee 
(ARSAC), the target specific activity of the drug substance will be set at 95% of 90% of 
the threshold radioactive dosing limit. This takes into account the allowed tolerances 
during the manufacture of the drug product (± 5% range and drug substance ± 10% 
range). This provides continued assurance for compliance with the ARSAC-approved 
limit for drug product radioactivity dose. 
6.3 
Population Rationale 
As this is a Phase I study assessing the mass balance, PK and safety of MD1003, the 
most relevant population is healthy volunteers. Subjects who are non-smokers without 
a history of alcohol or drug abuse are proposed to avoid interaction on drug 
metabolism and to avoid non-compliance.  
We acknowledge the ARSAC Notes for Guidance recommend that wherever possible, 
healthy subjects selected for research projects should be aged over 50 years [11]. 
However, the current study is designed to generate data for supporting the 
investigation of the human ADME of a drug, as well as generating samples for 
metabolite profiling and structural identification. 

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There are 2 main reasons for generating these data within a clinical development 
programme. The first is to provide human metabolite data that can be used to interpret 
the metabolism profiles seen in the preclinical species employed in the longer term 
toxicity studies, to ensure that there is adequate toxicology coverage for the safe 
development of the drug in patients. The second is to provide data to understand how 
the drug is processed in physiologically normal subjects, because understanding the 
routes of metabolism and elimination in a healthy population generates the appropriate 
data to guide the clinical pharmacology package required to fulfil the regulatory 
requirements of a New Drug Application.  
In order to address these 2 main aims of an ADME study, investigation of the drug 
under development is required in a population with normal physiological function, as it 
is recognised that certain physiological processes eg renal function, deteriorate with 
age and therefore it is preferable to use as healthy as possible population, to mitigate 
against factors which may make interpretation of the data difficult. Also, healthy 
subjects as a trial population are ideal since they have a relatively stable physiological, 
biochemical and hormonal status, which removes any disease-related variations and 
variations due to concomitant medications. Therefore given the aims of this ADME 
study our target age range for this study will be 30 to 65 years. 
Based on the above considerations, including the risk of teratogenicity (see 
Section 5.3.1) in rabbits that cannot be excluded in humans and risks associated with 
radiation exposure, and to ensure homogeneity of the population, healthy male 
subjects, aged 30 to 65 years are considered suitable for this study. 
6.4 
Risks and Benefits 
Adverse drug reactions from the MS-SPI and MS-ON studies in MS patients reported in 
the Investigator’s Brochure [1] are listed in Table 2. There are no expected serious 
adverse reactions for either healthy volunteers or patients administered MD1003. It is 
unlikely that healthy volunteers administered a single 100 mg dose of MD1003 will 
experience an adverse reaction. Adverse events will be treated symptomatically, if 
required. 
The dosage form will contain a radionuclide (NMT 2.22 MBq [60.0 µCi] 14C), so 
subjects will be exposed to ionising radiation. The effective dose that each subject will 
receive from one administration will not exceed 1 mSv. This is approximately 4.5 
months of the average radiation exposure received in the UK each year (2.7 mSv; data 
obtained from PHE Ionising Radiation Exposure of the UK Population: 2010 Review). 
This equates to slightly more than the radiation dose that would result from 2 X-rays of 
the abdomen. It is believed that any increase in the amount of radiation that is received 
above natural radiation carries a risk of later developing serious and possibly fatal 
conditions. The risk associated with the maximum possible dose of radiation in this 
study is very small indeed and is considered to be acceptable.  
Collecting a blood sample from a vein may cause pain, swelling, bruising, 
light-headedness, fainting, and very rarely, clot formation, nerve damage and/or 
infection at the site of the needle stick. 
During cannulation, more than one attempt may be needed to insert the cannula in a 
vein of a subject and it is possible that bruising and/or inflammation may be 
experienced at the site of cannulation.  

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Electrocardiogram stickers on the subjects' chests and limbs may cause some local 
irritation and may be uncomfortable to remove but subjects will be closely monitored to 
ensure any local irritation does not persist. 
There is no benefit to the subjects from taking part in this study. The development of a 
product to treat MS will be of benefit to the wider community/patients with this disease. 
The overall risk benefit balance is therefore considered to be acceptable. 
7 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
 
To determine the mass balance recovery 
after a single oral dose of [14C]-MD1003 
 
To perform metabolite profiling and structural 
identification of MD1003 metabolites from 
plasma, urine and faecal samples 
 
 
Mass balance recovery of total radioactivity in 
all excreta (urine and faeces): Ae, %Ae, Cum 
Ae and Cum %Ae 
 
Metabolite profiling, structural identification, 
and quantification of [14C]-MD1003 metabolites 
in plasma, urine and faeces 
Secondary 
 
To determine the routes and rates of 
elimination of [14C]-MD1003 
 
To identify the chemical structure of each 
metabolite accounting for more than 10% of 
circulating total radioactivity 
 
To further explore the oral PK of MD1003 and 
its 
metabolites 
bisnorbiotin 
and 
biotin 
sulfoxide 
 
To evaluate the extent of distribution of total 
radioactivity into blood cells 
 
To provide additional safety and tolerability 
information for MD1003 
 
 
Amount of total radioactivity excreted and 
amount of total radioactivity excreted as a 
percentage of the administered dose in urine 
and faeces at each time interval 
 
Identification of the chemical structure of each 
metabolite accounting for more than 10% by 
AUC of circulating total radioactivity 
 
Assessment of the oral PK profile for MD1003, 
bisnorbiotin, 
biotin 
sulfoxide 
and 
total 
radioactivity based on: Tlag, Tmax, Cmax, 
AUC(0-last), AUC(0-inf), AUCextrap, T1/2, 
Lambda-z, CL/F (MD1003 only), Vz/F (MD1003 
only), MPR Cmax and MPR AUC(0-inf) 
 
Evaluation 
of 
whole 
blood:plasma 
concentration ratios for total radioactivity 
 
To provide additional safety and tolerability 
information for MD1003 by assessing: AEs, 
vital 
signs, 
electrocardiograms 
(ECGs), 
physical examinations and laboratory safety  
8 
Study Design 
8.1 
Study Plan 
This is a single-centre, open-label, non-randomised, single oral dose study in healthy 
male subjects. It is planned to enrol 6 subjects to ensure 4 evaluable subjects. 
Each subject will receive a single oral administration of a capsule containing 100 mg 
MD1003 and NMT 2.22 MBq (approximately 60.0 µCi) [14C], in the fasted state. 
The study design is presented in Figure 1. Subjects will be screened to participate in 
the study up to 28 days before dosing. Subjects will be admitted to the clinical unit on 
the evening of Day -1 prior to IMP administration.  

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Subjects will be dosed on the morning of Day 1 following an overnight fast and will 
remain resident in the clinical unit until up to 168 h after dosing (up to Day 8). It is 
planned that subjects will be released as a group when all subjects have achieved a 
mass balance cumulative recovery of >90% or if <1% of the dose administered has 
been collected in urine and faeces within 2 separate consecutive 24 h periods. This 
may result in the subjects being discharged as a group prior to completion of the 
planned residency period. Once the discharge criteria or the planned residency period 
has been achieved, collection of all samples (blood, urine and faeces) will be stopped 
and the subjects will undergo discharge assessments. If the mass balance criteria have 
not been met by all subjects by Day 8, the residency period for the subjects not 
achieving the release criteria may be extended up to a maximum of an additional 48 h 
(up to Day 10) for further collection of urine and/or faeces. If the release criteria have 
still not been met by Day 10, or if any additional residency is not considered 
appropriate or necessary, then home collections of urine and/or faeces may be 
requested at the discretion of the investigator for individual subjects. 
Figure 1 
Study Sequence 
Screening 
Day -28 to Day -2 
 
Admission 
Day -1 
 
Dose 
Day 1 
 
Discharge 
Day 8a 
a Subject may be discharged as a group earlier if a cumulative recovery of >90% has been achieved or if 
<1% of the dose administered has been collected in urine and faeces within 2 separate consecutive 24 h 
periods. If the criteria are not met by Day 8, this may result in the extension of the residency period for the 
subjects not achieving the release criteria up to a maximum of an additional 48 h (up to Day 10) for further 
collection of urine and/or faeces. If the criteria are still not met by Day 10, or if additional residency is not 
considered appropriate or necessary, then home collections of urine and/or faeces may be requested at 
the discretion of the investigator for individual subjects.  
8.2 
Criteria for In-Study Decisions 
Not applicable for this study. 
8.3 
Subject Withdrawal 
If a subject wishes to leave the study at any time, they will be permitted to do so. Every 
reasonable effort will be made by Quotient Sciences to complete a final 
assessment/discharge procedures. Quotient Sciences will advise the sponsor of the 
withdrawal of any subject from the study. 

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Early withdrawal is defined as the date of the decision to withdraw the subject from the 
study. Subject completion is defined as the date of the last procedure conducted or last 
contact (ie phone call) for that subject. 
If a subject requests to leave the clinical unit earlier than the planned discharge time 
eg due to unforeseen personal circumstances, but aims to return to the clinical unit to 
complete the study, this will be documented as a subject self-discharge and a protocol 
deviation. The subject must complete the planned assessments/discharge procedures 
before discharge from the clinical unit and will return for the next study 
period/assessments, as planned.  
Subjects will be withdrawn from the study drug(s) for the following reasons: 
 
Experiencing a serious or severe AE including but not limited to: 
− corrected QT interval by Fridericia’s formula (QTcF) of >500 msec or 
increase in QTcF interval of >60 msec from baseline (confirmed following 
a repeat ECG) 
− alanine aminotransferase (ALT) concentration >3 × the upper limit of the 
reference range (confirmed following a repeat ALT blood test) 
 
Experiencing a 25% decrease in creatinine clearance (CLcr) 
 
Termination of the study 
 
Upon the subject’s request (withdrawal of consent) 
 
Significant deviation from the protocol 
 
Concurrent illness that would compromise subject safety of study data 
interpretation or requirement for prohibited medication 
 
At the discretion of the investigator 
For the purpose of withdrawal criteria, baseline will be considered as pre-dose Day 1 
measurement. 
For a subject who withdraws because of an IMP-related AE, every effort will be made 
to ensure the subject completes follow-up procedures.  
Early termination of the study will be distinguished from withdrawal of consent by the 
subject to participate in any further activities. 
8.4 
Subject Replacement 
No replacement subjects are to be used in this study. 
A subject will be considered evaluable if they have provided mass balance and PK 
samples for up to 72 h (up to Day 4) after IMP administration, or have demonstrated 
>90% mass balance recovery, or have <1% of the administered dose eliminated in 
excreta for 2 consecutive days, whichever is sooner. 
8.5 
Stopping Criteria 
The study will be halted, and the risk to other subjects evaluated if any of the following 
criteria are met:  
 
A serious adverse reaction (ie a serious AE considered at least possibly related to 
the IMP administration) in one subject. 

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 
Severe non-serious adverse reactions (ie severe non-serious AE considered as, at 
least possibly related to the IMP administration) in two subjects in the same cohort, 
independent of within or not within the same system organ class. 
Relatedness will be determined by the investigator.  
If the study is halted, a temporary halt will be submitted to the Medicines and 
Healthcare products Regulatory Agency (MHRA) and ethics committee (EC) in the form 
of a substantial amendment. The study may be resumed or terminated; however, it will 
not be resumed until a further substantial amendment to resume the study is submitted 
and approved by MHRA and EC. 
The ARSAC Practitioner will also be informed of the temporary halt. 
8.6 
Study Termination 
After the start of protocol activities but prior to the commencement of dosing, the study 
may be terminated by the sponsor and investigator without consultation with the 
MHRA, EC and ARSAC practitioner or ARSAC. The end of the trial must be notified to 
the MHRA and EC immediately and at the latest within 15 days after the study is 
terminated, clearly explaining the reasons. A description of any follow-up measures 
taken for safety reasons if applicable, will also be provided. The ARSAC Practitioner 
and ARSAC will also be notified within an appropriate timeframe. 
If the study is abandoned prior to commencement of any protocol activities, the PI or 
sponsor must notify the EC, MHRA, ARSAC practitioner and ARSAC (if ARSAC 
research application has been submitted or approved) in writing outlining the reasons 
for abandonment of the trial. 
Once exposure to ionising radiation has begun, the study will be completed as planned 
unless the following criteria are satisfied that require a temporary halt or early 
termination of the study. 
 
The occurrence of serious or severe adverse event(s), as defined in Section 8.5, if 
considered to be related to the IMP, as defined in Section 14.2. 
 
New information regarding the safety of the IMP that indicates a change in the 
risk/benefit profile for the compound, such that the risk/benefit is no longer 
acceptable for subjects participating in the study. 
 
Significant violation of Good Clinical Practice (GCP) that compromises the ability to 
achieve the primary study objectives or compromises subject safety. 
If any of the above occurs, the study will be terminated if careful review of the overall 
risk/benefit analysis described in Section 6.4 demonstrates that the assumptions have 
changed and that the overall balance is no longer acceptable. In these circumstances 
termination can only take place with the agreement of the investigator and sponsor. 
The MHRA, EC, ARSAC practitioner and ARSAC will be informed of study termination. 
If it becomes necessary to consider termination of the study on the dosing day, dosing 
may be suspended pending discussion between the investigator, sponsor and ARSAC 
practitioner. Dosing will be stopped immediately on safety grounds. 
The study may be terminated or suspended at the request of the MHRA or EC. 

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8.7 
Treatment Allocation 
This is an open-label, non-randomised study, therefore a randomisation schedule will 
not be produced. A treatment allocation will be produced prior to dosing with IMP, 
which will dictate the order in which the treatments should be administered to each 
subject. The treatment allocation will be retained in the Investigator Site File. 
8.7.1 Subject Numbers 
Subject numbers will be allocated on the morning of dosing according to the code 001 
to 006 using the lowest number available.  
8.7.2 Blinding  
This is an open-label, non-randomised study and therefore blinding is not required. 
9 
Selection of Subjects 
Quotient Sciences must have a full medical history from each subject’s general 
practitioner (GP) within the last 12 months, prior to enrolment for the study.  
Subjects will be recruited from the Quotient Sciences panel or by direct advertising to 
the public.  
Before subjects are admitted to the clinical unit, The Over Volunteering Prevention 
System will be checked to ensure that each subject has not participated in a study at 
another site within at least 90 days of the dosing date. 
9.1 
Informed Consent 
Subjects will be provided with a written explanation of the study at least the day before 
the screening visit. A physician or nurse will explain to each subject the nature of the 
study, its purpose, expected duration and the benefits and risks involved in study 
participation. Subjects will be informed that, for safety reasons, brief details of their 
involvement in the study may be revealed to other units and companies that carry out 
clinical studies in the local area. Subjects will then be given the opportunity to ask 
questions and will be informed of their right to withdraw from the study without 
prejudice. After this explanation and before entering the study, the subject will 
voluntarily sign an informed consent form (ICF). Until written consent has been 
obtained from the subject no study specific procedure or investigation will be 
performed. If an amendment is made to the participant information sheet (PIS), 
participants will be re-consented to the most current version of the ICF(s) where 
appropriate. 
9.2 
Inclusion Criteria 
1. Healthy males 
2. Age 30 to 65 years of age at the time of signing informed consent 
3. Body mass index (BMI) of 18.0 to 30.0 kg/m2 as measured at screening  
4. Must be willing and able to communicate and participate in the whole study 
5. Must have regular bowel movements (ie average stool production of ≥1 and 
≤3 stools per day) 
6. Must provide written informed consent 
7. Must agree to adhere to the contraception requirements defined in Section 9.4 

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Inclusion criteria 1, 4, 5, 6 and 7 from the list above will be re-assessed at 
admission/pre-dose. 
9.3 
Exclusion Criteria 
1. Subjects who have received any IMP in a clinical research study within the 90 days 
prior to Day 1  
2. Subjects who are study site employees, or immediate family members of a study 
site or sponsor employee 
3. Subjects who have previously been enrolled in this study 
4. History of any drug or alcohol abuse in the past 2 years 
5. Regular alcohol consumption in males >21 units per week (1 unit = ½ pint beer, or 
a 25 mL shot of 40% spirit, 1.5 to 2 Units = 125 mL glass of wine, depending on 
type) 
6. A confirmed positive alcohol breath test at screening or admission 
7. Current smokers and those who have smoked within the last 12 months. A 
confirmed breath carbon monoxide reading of greater than 10 ppm at screening or 
admission 
8. Current users of e-cigarettes and nicotine replacement products and those who 
have used these products within the last 12 months  
9. Subjects with pregnant or lactating partners 
10. Radiation exposure, including that from the present study, excluding background 
radiation but including diagnostic X-rays and other medical exposures, exceeding 
5 mSv in the last 12 months or 10 mSv in the last 5 years. No occupationally 
exposed worker, as defined in the Ionising Radiation Regulations 2017, shall 
participate in the study  
11. Subjects who do not have suitable veins for multiple venepunctures/cannulation as 
assessed by the investigator or delegate at screening 
12. Clinically significant abnormal clinical chemistry, haematology or urinalysis as 
judged by the investigator (laboratory parameters are listed in Appendix 1). 
Subjects with Gilbert’s Syndrome are allowed 
13. Confirmed positive drugs of abuse test result (drugs of abuse tests are listed in 
Appendix 1) 
14. Positive hepatitis B surface antigen (HBsAg), hepatitis C virus antibody (HCV Ab) 
or human immunodeficiency virus (HIV) results 
15. Evidence of renal impairment at screening, as indicated by an estimated creatinine 
clearance of <80 mL/min using the Cockcroft-Gault equation 
16. History of clinically significant cardiovascular, renal, hepatic, chronic respiratory or 
gastrointestinal disease, neurological or psychiatric disorder, as judged by the 
investigator 
17. Serious adverse reaction or serious hypersensitivity to any drug or the formulation 
excipients 
18. Presence or history of clinically significant allergy requiring treatment, as judged by 
the investigator. Hay fever is allowed unless it is active 
19. Donation or loss of greater than 400 mL of blood within the previous 3 months 
20. Subjects who are taking, or have taken, any prescribed or over-the-counter drug 
(other than 4 g of paracetamol per day), herbal remedies, vitamin B5 or dietary 
supplements containing lipoic acid in the 14 days before IMP administration (see 
Section 11.4). Exceptions may apply on a case by case basis, if considered not to 
interfere with the objectives of the study, as determined by the PI 
21. Subjects who have had any intake of biotin (including as a nutritional supplement) 
in the 14 days before IMP administration 
22. Failure to satisfy the investigator of fitness to participate for any other reason 

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Exclusion criteria 6, 7, 9, 10, 12, 13, 18, 19, 20, 21 and 22 from the list above will be 
re-assessed at admission/pre-dose. 
Healthy subjects who do not meet the inclusion/exclusion criteria for the study will not 
be enrolled. 
9.4 
Contraception 
Male subjects who are sexually active with a partner of child bearing potential must 
use, with their partner, a condom plus an approved method of effective contraception 
from the time of informed consent until 90 days after IMP administration. 
The following methods are acceptable: 
 
Partner’s use of combined (oestrogen and progestogen-containing) hormonal 
contraception associated with inhibition of ovulation:  
− oral  
− intravaginal  
− transdermal  
 
Partner’s use of progestogen-only hormonal contraception:  
− oral  
− injectable/implantable 
− intrauterine hormone-releasing system  
 
Partner’s use of intrauterine device  
 
Surgical sterilisation (for example, vasectomy or partner’s bilateral tubal occlusion) 
 
Partner’s use of female cap or diaphragm or sponge with spermicide (double 
barrier) 
Alternatively, sexual abstinence is considered a highly effective method only if defined 
as refraining from heterosexual intercourse during the entire period of risk associated 
with the study treatments. The reliability of sexual abstinence needs to be evaluated in 
relation to the duration of the clinical trial and the preferred and usual lifestyle of the 
subject. 
These contraception requirements are aligned with guidance issued by the Heads of 
Medicines Agency: Clinical Trials Facilitation Group [12]. 
9.4.1 Exposure to Sexual Partners During the Study 
There is a significant risk of drug exposure through the ejaculate (which also applies to 
vasectomised males) that might be harmful to sexual partners (both male and female), 
including pregnant partners of male subjects. Therefore, a condom should be used by 
all male subjects throughout the study and for 90 days after IMP administration.  
9.4.2 Sperm Donation 
Male subjects should not donate sperm for the duration of the study and for 90 days 
after IMP administration. 

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9.5 
Pregnancy 
Subjects will be instructed that if their partner becomes pregnant during the study this 
should be reported to the investigator. The investigator should also be notified of 
pregnancy occurring during the study but confirmed after completion of the study. In 
the event that a subject’s partner is subsequently found to be pregnant after the subject 
is included in the study, then consent will be sought from the partner and, if granted, 
any pregnancy will be followed and the status of mother and/or child will be reported to 
the sponsor after delivery.  
A pregnancy notification form and follow-up will be completed. 
9.6 
Additional Study Restrictions 
The following additional restrictions will be in place for the duration of the study: 
1. Subjects must abstain from alcohol during the 24 h prior to screening and the 24 h 
prior to admission until discharge from the study 
2. Subjects must not drink liquids or eat food containing grapefruit, cranberry, caffeine 
or other xanthines from 24 h prior to admission until discharge from the study 
3. Subjects should refrain from eating food containing poppy seeds for 48 h prior to 
screening and for 48 h prior to admission until discharge from the study 
4. Subjects must not take part in any unaccustomed strenuous exercise from the 72 h 
before the screening visit and then from 72 h prior to admission until discharge from 
the study 
The additional restrictions above are not exclusion criteria; if non-compliance occurs, a 
protocol deviation will be completed.  
10 Study Procedures 
Study procedures will be performed as detailed in the study schedule of assessments 
in Appendix 2, and in accordance with Quotient Sciences standard operating 
procedures (SOPs) unless otherwise stated in this protocol. 
10.1 Screening 
Within the 28 days preceding first dose, all subjects will be required to undergo a 
screening visit. Screening procedures will be carried out in accordance with the study 
flow chart in Appendix 2. 
If the start of the study is delayed for any reason so that the interval between screening 
and first dose exceeds 28 days, all or part of the screening procedures may be 
repeated at the discretion of the investigator. 
Subjects previously screened generically may participate in this study provided they 
meet the subject selection criteria. Procedures required by this protocol will only be 
done if they were not performed during generic screening. All screening data must be 
obtained within 28 days prior to administration of study medication, as stipulated 
above. 
Screening safety procedures such as safety bloods, ECGs, vital signs, carbon 
monoxide breath tests, alcohol breath tests and urinalysis can be repeated as clinically 
indicated under the discretion of the investigator or sub-investigator if there is a 
concern regarding a subject’s safety or eligibility to participate in the trial. 

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10.1.1 Subject Re-Screening 
This study permits the re-screening of a subject who has discontinued the study as a 
pre-treatment failure (ie subject has not been treated); the reason for failure must be 
temporary and expected to resolve. If re-screened, the subject must be re-consented. 
10.2 Admission and Pre-dose Procedures 
The admission and pre-dose procedures are presented in Appendix 2.  
The identity of the subjects will be confirmed at admission and pre-dose.  
In 
addition, 
the 
ongoing 
eligibility 
of 
subjects 
will 
be 
re-assessed 
at 
admission/pre-dose, as described in Sections 9.2 and 9.3.  
Admission safety procedures such as safety bloods, ECGs, vital signs, urinalysis and 
drugs of abuse tests can be repeated as clinically indicated under the discretion of 
investigator or sub-investigator if there is a concern regarding a subject’s safety or 
eligibility to participate in the clinical trial. 
The subjects will be admitted to the clinical unit on the evening before dosing (Day -1).  
10.3 Study Day Procedures 
10.3.1 Blood Volume 
The total blood volume for each subject will not exceed 550 mL in a 4 week period.  
The first 0.5 mL of blood withdrawn via cannula will be discarded. 
10.3.2 Timing of Procedures 
There are times where the protocol requires more than one procedure to be completed 
at the same time point. In these instances the following will apply to post-dose time 
points: 
PK samples should take priority over other procedures scheduled at the same time 
point.  
As guidance, the preferred order of assessments is: 
ECGs 
 
Vitals 
 
PK blood 
sampling 
 
Other assessments 
eg physical 
examinations 
ECGs should be taken prior to vital signs when both measurements are scheduled at 
the same time point. Other assessments, eg physical examinations, will be performed 
within the required time windows. 
All safety assessments will be timed and performed relative to the start of dosing. 

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10.3.3 Discharge from the Clinical Unit 
A subject will be allowed to leave the premises without additional investigator or 
delegate review, following completion of study-specific procedures at discharge, 
providing that: 
 
no AEs have been reported during the study visit  
 
the subject responds in the affirmative when asked if they are feeling well 
Subjects will be dosed on the morning of Day 1 following an overnight fast and will 
remain resident in the clinical unit until up to 168 h after dosing (Day 8). It is planned 
that subjects will be released as a group when all subjects have achieved a mass 
balance cumulative recovery of >90% or if <1% of the dose administered has been 
collected in urine and faeces within 2 separate, consecutive 24 h periods. This may 
result in the subjects being discharged as a group prior to completion of the planned 
residency period. Once the discharge criteria or the planned residency period has been 
achieved, subjects will undergo discharge assessments and collection of all samples 
(blood, urine and faeces) will be stopped. If mass balance criteria have not been met 
by all subjects on Day 8, the residency period for the subjects not achieving the release 
criteria may be extended up to a maximum of 48 h post-dose (Day 10) for further 
collection of urine and/or faeces. If the criterion is still not met by Day 10, or if additional 
residency is not considered appropriate or necessary, then home collections of urine 
and/or faeces may be requested at the discretion of the investigator for individual 
subjects. 
If any of these conditions are not met, then the subject will only be allowed to leave the 
clinical unit with the authorisation of the investigator or appropriately qualified delegate. 
There will be no continued provision of the study intervention or treatment for subjects 
as this study involves healthy volunteers only. 
10.3.4 Medical Supervision 
A physician will be responsible for the clinical aspects of the study and will be available 
at all times during the study. In accordance with the current Association of the British 
Pharmaceutical Industry guidelines [13], each subject will receive a card stating the 
telephone number of the investigator and the 24/7 contact details of the Quotient 
on-call physician. 
11 Dosing of Subjects 
11.1 Food and Fluid Intake 
The calorie/fat content of meals is not required to be controlled during this study, with 
the exception of meals on Day 1. Meals on subsequent days will be provided at 
nominal times. 
Subjects will be allowed water up to 1 h before the scheduled dosing time and will be 
provided with 240 mL of water at 1 h post-dose. Water will be allowed ad libitum after 
1 h post-dose. Decaffeinated fluids will be allowed ad libitum from lunch time on the 
day of dosing.  
If, for technical reasons, dosing is delayed for more than 2 h beyond the expected 
dosing time, subjects will receive 200 mL of Lucozade Sport at the originally scheduled 
dosing time, or earlier if possible. 

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Subjects will be provided with a light snack and then fast from all food and drink 
(except water) for a minimum of 8 h the day prior to dosing until approximately 4 h 
post-dose, at which time lunch will be provided. An evening meal will be provided at 
approximately 10 h post-dose and an evening snack at approximately 14 h post-dose. 
On subsequent days, meals will be provided at appropriate times. 
If an individual subject has not experienced a bowel movement in any 36-h period 
post-dose, fluid intake should be increased and administration of a mild laxative 
(eg prune juice or a mild stool softener) should be implemented. 
11.2 Administration of Test Preparations 
Specific details of IMP(s) and doses to be administered are provided in Section 5.2 and 
Section 8.1, respectively. Subjects will be dosed on the morning of Day 1.  
The exact time of dosing will be decided based on logistics and will be documented in 
the source.  
Each subject will receive a single oral administration of a capsule containing 100 mg 
[14C]-MD1003 and NMT 2.22 MBq (60.0 µCi) on a single occasion in the fasted state. 
11.3 Dosing Compliance 
During all clinical phases of the study, subjects will be observed by study staff to 
assure compliance to all study procedures, including dose administration.  
Mouth and hand checks will be conducted after dosing to ensure the capsule has been 
swallowed.  
The date and time that each subject is dosed will be recorded in the subject’s source 
data. Any violation of compliance will require evaluation by the investigator and 
sponsor to determine if the subject can continue in the study. 
11.4 Prior and Concomitant Medications 
No prescribed, over-the-counter medication, herbal remedies, vitamin B5 or dietary 
supplements containing lipoic acid will be permitted from 14 days before IMP 
administration until discharge from the study except 4 g per day of paracetamol and 
those deemed necessary by the investigator to treat AEs (see also Section 9.3). Any 
medications used will be recorded in the source. 
Emergency equipment and drugs will be available within the clinical unit as per current 
standard procedures. In the unlikely event that they are required, their use will be 
documented. 
12 Assessment of Efficacy 
Not applicable for this Phase I study.  

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13 Assessment 
of 
Mass 
Balance, 
Pharmacokinetics, 
Metabolite 
Profiling 
and 
Identification, 
and 
Pharmacodynamics 
13.1 Assessment of Mass Balance, Pharmacokinetics and Metabolite Profiling 
and Identification 
13.1.1 Blood Sampling 
Venous blood samples will be collected from the subjects by a trained member of the 
clinical team. Consent will be collected from the subjects for use of these samples for 
the purposes of the proposed study.  
Plasma and whole blood samples are sent for laboratory testing in linked anonymised 
form (subject number only). This information is able to be linked directly to the 
volunteer by the Quotient research team and study monitor, however not by the 
laboratory staff or Sponsor. 
Venous blood samples will be withdrawn via an indwelling cannula or by venepuncture 
according to the time schedule presented in Appendix 2. 
The acceptable deviations from the nominal blood sampling times are as follows: 
 
The pre-dose samples will be taken ≤1 h before dosing 
 
0 to 1 h post-dose samples will be taken within ± 2 min of the nominal post-dose 
sampling time  
 
>1 to 12 h post-dose samples will be taken within ± 10 min of the nominal 
post-dose sampling time 
 
>12 h post-dose samples will be taken within ± 30 min of the nominal post-dose 
sampling time  
Samples will be collected into appropriate tubes as specified by the bioanalytical 
laboratory. Details of sample tubes and processing will be contained in the 
Clinical Sample Processing Manual. 
Samples will be shipped to Pharmaron for the analysis of total radioactivity in plasma 
and whole blood, and for metabolite profiling and identification in plasma. Samples will 
be shipped to Atlanbio for the analysis of MD1003, bisnorbiotin and biotin sulfoxide in 
plasma. 
13.1.2 Urine Sampling 
Urine samples will be collected according to the time schedule presented in 
Appendix 2. 
A single urine sample will be taken at pre-dose (the first void of the day). Where a 
sample is not provided, this will not be considered a deviation. All individual urine voids 
will be collected and shipped to the metabolism laboratory for analysis, according to 
Quotient Sciences SOPs, unless indicated otherwise by the sponsor. 
Samples will be collected into appropriate containers as specified by the metabolism 
laboratory. Details of sample containers and processing will be contained in the Clinical 
Sample Processing Manual. 

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Samples will be shipped to Pharmaron for the analysis of total radioactivity and for 
metabolite profiling and identification. 
13.1.3 Faecal Sampling 
Faecal samples will be collected according to the time schedule presented in 
Appendix 2. 
The pre-dose faecal sample will be taken from admission until pre-dose. If a pre-dose 
faecal sample cannot be obtained, the subject will still be dosed. Where a sample is not 
provided, this will not be considered a deviation. 
Samples and toilet paper will be collected into appropriate pots/containers as specified 
by the metabolism laboratory. Details of sample containers and processing will be 
contained in the Clinical Sample Processing Manual. 
Samples will be shipped to Pharmaron for the analysis of total radioactivity and for 
metabolite profiling and identification. 
13.1.4 Unexpected Sources of Elimination  
During the study, other accidental sources of elimination will be collected as voided 
(eg emesis). 
Samples will be shipped to Pharmaron for the analysis of total radioactivity. 
13.2 Assessment of Pharmacodynamics 
Not applicable for this Phase I study. 
14 Assessment of Safety 
14.1 Definition and Classification of Adverse Events 
An AE is any untoward medical occurrence in a subject that occurs either before 
dosing (referred to as a pre-dose AE) or once a medicinal product has been 
administered, including occurrences which are not necessarily caused by or related to 
that product.  
An adverse drug reaction is any AE where a causal relationship with the IMP is at least 
a reasonable possibility (possibly related or related). 
AEs will be monitored from the time the subject signs the ICF until discharge from the 
study. The severity of AEs should be assessed as follows: 
Mild 
An AE that is easily tolerated by the subject, causes minimal discomfort 
and does not interfere with everyday activities 
Moderate An AE that is sufficiently discomforting to interfere with normal everyday 
activities; intervention may be needed 
Severe 
An AE that prevents normal everyday activities; treatment or other 
intervention usually needed 

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14.2 Assessment of Causality 
Every effort should be made by the investigator to try to explain each AE and assess its 
relationship, if any, to the IMP. The temporal relationship of the event to IMP 
administration should be considered in the causality assessment (ie if the event starts 
soon after IMP administration and resolves when the IMP is stopped). 
Causality should be assessed using the following categories:  
Unrelated: 
Clinical event with an incompatible time relationship to IMP 
administration, and that could be explained by underlying 
disease or other drugs or chemicals or is incontrovertibly not 
related to the IMP 
Possibly related: 
Clinical event with a reasonable time relationship to IMP 
administration, and that is unlikely to be attributed to 
concurrent disease or other drugs or chemicals 
Related: 
Clinical event with plausible time relationship to IMP 
administration and that cannot be explained by concurrent 
disease or other drugs or chemicals 
The degree of certainty with which an AE is attributed to IMP administration (or 
alternative causes, eg natural history of the underlying disease, concomitant therapy) 
will be determined by how well the experience can be understood in terms of one or 
more of the following: 
 
known pharmacology of the IMP 
 
reactions of a similar nature have been previously observed with the IMP or this 
class of drug 
 
the experience being related by time to IMP administration, terminating with IMP 
withdrawal or recurring on re-challenge 
 
alternative cause 
14.3 Recording Adverse Events 
AEs will be recorded from the time of providing written informed consent until discharge 
from the study. During each study visit the subject will be questioned directly regarding 
the occurrence of any adverse medical event according to the schedule in the source. 
All AEs, whether ascribed to study procedures or not, will be documented immediately 
in the source. This will include the date and time of onset, a description of the AE, 
severity, duration, actions taken, outcome and an investigator’s current opinion on the 
relationship between the study drug and the event. A diagnosis and final opinion on the 
relationship between the study drug and the event will be provided at the end of the 
study by the investigator.  
Any subject who withdraws from the study due to an AE will be followed up until the 
outcome is determined and written reports provided by the investigator. 

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14.4 Serious Adverse Events 
14.4.1 Definition of Serious Adverse Events 
A serious adverse event (SAE) is defined as any untoward medical occurrence that at 
any dose:  
 
results in death 
 
is life-threatening 
 
requires hospitalisation or prolongation of existing hospitalisation 
 
results in persistent or significant disability or incapacity 
 
consists of a congenital anomaly or birth defect 
 
an important medical event as recognised by the PI 
SAEs must be immediately (without any delay) reported to the sponsor and in any case 
no later than 24 h of becoming aware of the event. 
14.4.2 Definition of Suspected Unexpected Serious Adverse Reactions 
Suspected unexpected serious adverse reactions (SUSARs) are AEs that are believed 
to be related to an IMP and are both unexpected (ie the nature or severity is not 
expected from the information provided in the Reference Safety Information (RSI) 
section of the Investigator’s Brochure Edition No 10) and serious. SUSARs are subject 
to expedited reporting to the MHRA, European Medicines Agency (EMA) and EC (see 
Section 16.3.2 for details on reporting SUSARs). 
14.5 Laboratory Measurements 
Venous blood, urine and faecal samples will be collected from the subjects by a trained 
member of the clinical team. Consent will be collected from the subjects for use of 
these samples for the purposes of the proposed study. 
Blood, urine and faecal samples are sent for laboratory testing in linked anonymised 
form (subject number, initials and the subjects’ gender and date of birth for analytical 
reasons). This information is able to be linked directly to the volunteer by the Quotient 
research team and study monitor, however not by the laboratory staff or sponsor. 
Safety laboratory tests and virology will be carried out on blood samples, and drugs of 
abuse tests and urinalysis will be carried out on urine samples. The research will not 
involve analysis or use of human DNA. 
Blood and urine samples results will be reviewed by a physician and acted upon before 
the subject is dosed or receives their next dose, or is released from the study, as is 
appropriate. A list of the laboratory parameters measured is presented in Appendix 1. 
14.5.1 Haematology and Clinical Chemistry 
Laboratory tests will be performed by The Doctors Laboratory according to the time 
schedule presented in Appendix 2. Blood samples will be collected and processed as 
detailed in the Clinical Sample Processing Manual. Scheduled blood samples will be 
taken following an 8 h fast. 
The acceptable deviations from the nominal blood sampling time points for laboratory 
assessments are: 

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 
The pre-dose blood sample will be taken ≤2 h before dosing 
 
Post-dose blood samples will be taken ± 1 h from the nominal blood sampling time  
Creatinine clearance (CLcr) will be calculated at screening by The Doctors Laboratory 
using the Cockcroft-Gault equation and body weight for eligibility purposes: 
CLcr (mL/min) = (140-age [years]) x (body weight [kg]) (× 1.23) 
 
serum creatinine (µmol/L) 
14.5.2 Urinalysis 
Urinalysis will be performed on-site using a dipstick according to the time schedule 
presented in Appendix 2. Urine samples will be collected and processed as detailed in 
the Clinical Sample Processing Manual. If microscopy is required, a urine sample will 
be sent to The Doctors Laboratory. Any urine used for urinalysis will be added back to 
the full sample for total radioactivity analysis. If microscopy is required, a urine sample 
(approximately 20 mL) will be taken from the urine collection, and sent to The Doctors 
Laboratory after the void has been weighed. 
The acceptable deviations from the nominal urine sampling time points for urinalysis 
are: 
 
The pre-dose urine sample will be taken ≤3 h before dosing or the first void of the 
day 
 
Post-dose urine samples will be taken ± 2 h from the nominal urine sampling time 
14.5.3 Drug Screen 
A urine drug screen will be performed on-site using a dipstick method according to the 
time schedule presented in Appendix 2. The sample will be collected and processed as 
detailed in the Clinical Sample Processing Manual. Subjects will be screened for the 
drugs of abuse listed in Appendix 1.  
14.5.4 Alcohol Breath Test 
An alcohol breath test will be performed according to the time schedule presented in 
Appendix 2. A positive result will exclude the subject from dosing during that 
admission. 
14.5.5 Carbon Monoxide Breath Test 
A carbon monoxide breath test will be performed according to the time schedule 
presented in Appendix 2. A result of greater than 10 ppm will exclude the subject from 
the study. 
14.5.6 Abnormal Laboratory Findings 
In cases where laboratory findings are outside the normal range and the investigator 
believes that the results may be of clinical significance, repeat sampling may be 
requested as clinically indicated. If the abnormal finding is clinically significant, 
appropriate actions will be taken eg the subject will not be entered into the study or the 
subject may be withdrawn from the study. The subject will be referred to their GP or 
other appropriate provider for further care. The same will apply if the results of the 
HBsAg, HCV Ab or HIV test are positive and in addition the investigator will ensure that 
adequate counselling is available if requested. 

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Abnormal results at follow-up assessments will also require repeat testing if the 
investigator believes the results may be of clinical significance. 
Any clinically significant abnormality, including changes from baseline, must be 
reported as an AE. 
Additional blood and/or urine samples may be taken for safety tests. Furthermore, 
additional assays outside those specified in the protocol may be performed for safety 
reasons as requested by the investigator or sub-investigator. 
14.6 Vital Signs Measurements 
Blood pressure and heart rate will be measured by an automated recorder after the 
subject has been in a supine position for a minimum of 5 min according to the time 
schedule presented in Appendix 2. Oral temperature will also be measured. The 
acceptable deviations from the nominal vital signs measurement time points are: 
 
The pre-dose vital signs measurements will be taken ≤2 h before dosing. 
 
Post-dose vital signs measurements will be taken ± 15 min from the nominal 
post-dose time points. 
 
Discharge vital signs measurements will be taken ± 1 h from the nominal time point. 
If a subject shows an abnormal assessment at any stage, repeat measurements may 
be made and the abnormality followed to resolution if required. Additional 
measurements may be taken as deemed necessary by the investigator or sub-
investigator. 
Any clinically significant abnormality, including changes from baseline, must be 
reported as an AE. 
14.7 ECG Measurements 
Single 12-lead ECGs will be measured after the subject has been in the supine position 
for a minimum of 5 min according to the time schedule presented in Appendix 2. The 
acceptable deviations from the nominal ECG measurement time points are: 
 
The pre-dose ECG measurements will be taken ≤2 h before dosing 
 
Post-dose ECG measurements will be taken ± 15 min from the nominal post-dose 
time point. 
 
Discharge ECG measurements will be taken ± 1 h from the nominal time point.  
If a subject shows an abnormal assessment at any stage, repeat measurements may 
be made and the abnormality followed to resolution if required. Additional 
measurements may be taken as deemed necessary by the investigator or sub-
investigator. 
Any clinically significant abnormality, including changes from baseline, will be reported 
as an AE. 
14.8 Body Weight and Height 
The subject’s body weight and height will be measured as detailed in Appendix 2. 

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14.9 Physical Examination 
Subjects will undergo a physical examination as detailed in Appendix 2. 
14.10 Additional Safety Procedures 
Additional non-invasive procedures that are already specified in the protocol may be 
performed, if it is believed that an important effect of the IMP(s) is occurring or may 
occur at a time when no measurements are scheduled, or if extra procedures are 
needed in the interests of safety. 
Additional blood samples for safety assessments may be taken if required by the 
investigator at any point. 
15 Statistics and Data Analysis 
15.1 Sample Size Justification 
The study is exploratory and no formal sample size calculation has been made. Based 
on experience from previous studies of a similar design, a total of 6 subjects is to be 
enrolled and a minimum of 4 evaluable subjects is considered sufficient. 
15.2 Data Management 
Data management will be performed by Quotient Sciences. 
Study data will be managed using a validated electronic case report form (eCRF) 
database system and subjected to data consistency and validation checks. Data 
queries will be raised within the study eCRF database by data management staff and 
resolved with the assistance of clinical staff. 
AEs and medications will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA) (v22.0 or a more recent version) and the World Health 
Organisation (WHO) Drug Dictionary Global Drug Reference (2019 or a more recent 
version), respectively. An independent coding review will also be performed within the 
Data Sciences department. 
Clinical chemistry and haematology data (and other safety laboratory data) will be 
collected by a central laboratory (The Doctors Laboratory) and stored electronically in 
their clinical pathology system. The data will be transferred electronically to Quotient 
Sciences and all demographic details and sample dates will be cross-referenced with 
the corresponding data on the study database. All queries will be resolved with the 
assistance of laboratory staff, or if necessary, clinical staff.  
The database will be closed after all queries have been resolved. The database will be 
locked when all criteria listed in the Data Management Plan (DMP) are met.  
Further details are addressed in the DMP. 
15.3 Mass Balance Data Analysis 
Urine and faeces will be collected for the analysis of total radioactivity. Graphical and 
tabular representation of whole blood and plasma total radioactivity concentrations and 
ratios at selected time points will be presented. The following mass balance 
parameters will be calculated by Quotient Sciences for urine, faeces and combined 
urine and faeces (ie total radioactivity from all excreta). 

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Parameter 
Definition 
Ae(urine) 
Amount of total radioactivity excreted in urine 
%Ae(urine) 
Amount of total radioactivity excreted in urine expressed as a percentage of the 
radioactive dose administered 
CumAe(urine) 
Cumulative amount of total radioactivity excreted in urine 
Cum%Ae(urine) 
Cumulative amount of total radioactivity excreted in urine expressed as a 
percentage of the radioactive dose administered 
Ae(faeces) 
Amount of total radioactivity eliminated in faeces 
%Ae(faeces) 
Amount of total radioactivity eliminated in faeces expressed as a percentage of the 
radioactive dose administered 
CumAe(faeces) 
Cumulative amount of total radioactivity eliminated in faeces 
Cum%Ae(faeces) 
Cumulative amount of total radioactivity eliminated  in faeces expressed as a 
percentage of the radioactive dose administered 
Ae(total) 
Amount of total radioactivity excreted in urine and faeces combined 
%Ae(total) 
Amount of total radioactivity excreted in urine and faeces combined expressed as a 
percentage of the radioactive dose administered 
CumAe(total) 
Cumulative amount of total radioactivity excreted in urine and faeces combined 
Cum%Ae(total) 
Cumulative amount of total radioactivity excreted in urine and faeces combined 
expressed as a percentage of the radioactive dose administered 
15.4 
Pharmacokinetic Data Analysis 
The plasma concentration data for MD1003, bisnorbiotin and biotin sulfoxide, and 
plasma and whole blood total radioactivity concentrations provided by Pharmaron will 
be analysed by Quotient Sciences using Phoenix WinNonlin v8.0 or a more recent 
version (Certara USA, Inc., USA). 
Calculated MD1003 concentrations may be corrected for specific activity of the 
administered radiolabelled oral dose by the Data Sciences department at Quotient 
Sciences. 
Plasma concentration data will be tabulated and plotted for each subject for whom 
concentrations are quantifiable. PK analysis of the concentration time data obtained will 
be performed using appropriate non-compartmental techniques to obtain estimates of 
the following PK parameters: 
Parameter 
Definition 
Tlag 
Time prior to the first measurable (non-zero) concentration 
Tmax 
Time of maximum observed concentration 
Cmax 
Maximum observed concentration 
AUC(0-last) 
Area under the curve from 0 time to the last measurable concentration 
AUC(0-inf) 
Area under the curve from 0 time extrapolated to infinity 
AUCextrap 
Percentage of AUC(0–inf) extrapolated beyond the last measurable concentration 
T1/2  
Apparent elimination half-life 
Lambda-z 
Slope of the apparent elimination phase 
CL/F 
 (MD1003 only) 
Apparent total body clearance calculated after a single extravascular 
administration where F (fraction of dose bioavailable) is unknown  
Vz/F 
 (MD1003 only) 
Apparent volume of distribution based on the terminal phase calculated after a 
single extravascular administration where F (fraction of dose absorbed) is 
unknown  
MPR Cmax 
Metabolite to parent ratio based on Cmax 
MPR 
AUC(0-inf) 
Metabolite to parent ratio based on AUC(0-inf) 

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Further details of the PK data analysis will be included in the Reporting and Analysis 
Plan (RAP). 
15.5 Metabolite Profiling and Identification 
Metabolite profiling of plasma, urine and faeces will be performed using liquid 
chromatography-radio-detection 
with 
subsequent 
mass 
spectrometry 
where 
appropriate.  
Identification of the chemical structure of each metabolite accounting for greater than 
10% of circulating radioactivity in plasma (“AUC pool”) and accounting for greater than 
10% of the administered dose in urine and faeces (from urine pools and faeces 
homogenate pools) will be performed.  
These aspects will be reported separately from the clinical study report as a standalone 
document. 
15.6 Statistical Data Analysis  
Production of summary tables, figures and listings for this study will be performed by 
Quotient Sciences using the statistical package SAS (v9.4 or more recent version).  
No formal statistical analysis will be performed for this study. Descriptive statistics 
(eg mean, median, standard deviation, minimum, maximum and number of subjects 
with an observation [n]) are considered adequate for a study of this type. Additional 
statistics will be provided for PK-related data, including coefficient of variation (CV%), 
geometric mean, geometric CV% and geometric n (ie number of subjects with an 
observation that are included in the natural logarithmic transformation).  
Populations and analysis sets will be determined for safety, mass balance and PK data 
after database lock using the criteria defined in the RAP; the RAP will be signed off 
prior to database lock. 
Further details relating to the statistical analysis will be included in the RAP including 
the following: 
 
Criteria to be used to define each of the populations and analysis sets 
 
Additional detail covering the analyses and/or description of primary and secondary 
analyses and safety data 
 
Handling of missing data, unused or spurious data 
 
Handling of data from withdrawn subjects 
All safety, mass balance recovery and PK data will be listed. 
15.7 Interim Analysis 
No formal interim analyses are planned for this study.  

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16 Safety Reporting to Ethics Committees and Regulatory 
Authorities 
16.1 Events Requiring Expedited Reporting 
SUSARs (Section 14.4.2) are subject to expedited reporting to the MHRA, EMA and 
EC. 
In addition to SUSARs, other safety issues may qualify for expedited reporting where 
they might materially alter the current benefit-risk assessment of an IMP or that would 
be sufficient to consider changes in the IMPs administration or in the overall conduct of 
the study, for instance: 
 
an increase in the rate of occurrence or a qualitative change of an expected serious 
adverse reaction, which is judged to be clinically important 
 
SAEs that occur after the subject has completed the clinical study where the 
sponsor considers them to be a SUSAR 
 
new events related to the conduct of the study or the development of the IMPs and 
likely to affect the safety of the subjects, such as: 
− an SAE which could be associated with the study procedures and which 
could modify the conduct of the study 
− a major safety finding from a newly completed animal study (such as 
carcinogenicity) 
− any anticipated end or temporary halt of a study for safety reasons and 
conducted with the same IMPs in another country by the same sponsor 
16.2 Urgent Safety Measures 
If Quotient Sciences or any of its staff or contractors becomes aware of an actual or 
potential urgent safety issue, then the sponsor must be immediately contacted so that 
appropriate urgent safety measures can be agreed. An urgent safety issue is defined 
as:  
 
An immediate hazard to the health or safety of subjects participating in a clinical 
study 
 
A serious risk to human health or potentially a serious risk to human health 
An urgent safety issue may include issues with an investigational drug or comparators, 
study procedures, inter-current illness (including pandemic infections), concomitant 
medications, concurrent medical conditions or any other issues related to the safe 
conduct of the study or that pose a risk to study subjects. 
In exceptional circumstances of imminent hazard and in order to safeguard the health 
or safety of individuals, Quotient Sciences may take urgent safety measures before 
informing the sponsor, but the sponsor must be informed immediately after the hazard 
has resolved.  
Quotient Sciences will take responsibility for informing appropriate competent 
authorities, and the EC. 

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16.3 Reporting 
16.3.1 Reporting Serious Adverse Events 
The investigator is required to notify the study sponsor if appropriate immediately and 
not later than 24 h of becoming aware of the occurrence of an SAE or serious adverse 
reaction. A copy of the written report of the event should promptly be sent to the study 
sponsor for information purposes, in accordance with International Council for 
Harmonisation (ICH) guidelines for GCP. 
16.3.2 Reporting 
of 
Suspected 
Unexpected 
Serious 
Adverse 
Reactions 
(SUSARs) 
It is the responsibility of the sponsor to determine whether a reported SAE fits the 
classification of a SUSAR and to notify the investigator of their decision as soon as 
possible. 
16.3.3 Expedited Reporting of Events 
It is the responsibility of the sponsor to determine whether an event requires expedited 
reporting and to notify the investigator of their decision as soon as possible. 
Where expedited reporting is required, the following procedures should be followed. 
Fatal or life-threatening SUSARs 
It is the responsibility of the sponsor to report fatal or life-threatening SUSARs to the 
MHRA and EMA as soon as possible, but no later than 7 calendar days after they first 
became aware of the reaction. Any additional relevant information should be sent 
within 8 days of the report. This responsibility may be delegated to the 
pharmacovigilance provider.  
The investigator is required to notify the EC of any SUSAR as soon as possible, but no 
later than 7 calendar days after they first became aware of the reaction. Any additional 
relevant information should be sent within 8 days of the report.  
The ARSAC Practitioner will be notified of any SUSAR that is considered related to the 
exposure to radioactivity. 
Other SUSARs 
It is the responsibility of the sponsor to report other SUSARs to the MHRA and EMA as 
soon as possible, but no later than 15 calendar days after they first became aware of 
the reaction. This responsibility may be delegated to the pharmacovigilance provider. 
The investigator is required to notify the EC of other SUSARs as soon as possible, but 
no later than 15 calendar days after they first became aware of the reaction.  
The ARSAC Practitioner will be notified of any SUSAR that is considered related to the 
exposure to radioactivity 
16.3.4 Reporting of Urgent Safety Issues 
Quotient Sciences is required to inform the appropriate competent authorities and the 
EC within 3 calendar days of the urgent safety issue. 

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16.4 Serious Breaches 
It is the responsibility of the sponsor to notify the licensing authority of any serious 
breach, which is likely to affect, to a significant degree, the safety or mental integrity of 
the subjects of the study or the scientific value of the study.  
All serious breaches will be notified to the MHRA within 7 days. The reporting will be 
performed by the party who suspects the serious breach. 
17 Protocol Amendments and Deviations 
17.1 Amendments 
After the protocol has been submitted to the MHRA and/or EC, any amendment must 
be agreed by the investigator after discussion with the sponsor and will be formally 
documented. 
All substantial amendments will be submitted to the MHRA and/or EC for an opinion as 
required by current regulations. Any amendments relating to the administration of 
radioactive substances will be reviewed by the ARSAC practitioner prior to submission 
to ARSAC as required by the current ARSAC Notes for Guidance. The ARSAC 
practitioner will also be notified of any substantial amendments to the PIS and ICF 
and/or protocol. 
If the PIS and ICF are updated as a result of the substantial amendment, the new 
approved versions will be used to re-consent currently enrolled subjects and must be 
provided to additional/replacement subjects prior to their entry into the study. 
17.2 Protocol Deviations 
The study must be conducted in accordance with the Clinical Protocol. Should a 
protocol deviation occur, it must be promptly assessed in order to decide whether any 
of these non-compliances should be reported to the MHRA as a serious breach of GCP 
and the Clinical Protocol. 
Protocol waivers are not acceptable. 
Deviations from the protocol will be recorded in the source as noted by the clinical staff. 
If necessary, the sponsor will be informed of the deviation. 
Any protocol deviations assessed as major will be discussed with the sponsor in order 
to determine if the withdrawal criteria stated in Section 8.3 have been met. 
18 Regulatory 
18.1 Compliance 
This study will be conducted in accordance with the protocol and with the following 
legislation: 
 
International Council for Harmonisation Good Clinical Practice (GCP) Guidelines 
approved by the Committee for Medicinal Products for Human Use (CHMP) on 
17 Jul 1996, which came into force on 17 Jan 1997, updated Jul 2002, Integrated 
Addendum E6 (R2) dated 09 Nov 2016 [14] 
 
The Medicines for Human Use (Clinical Trials) Regulations. Statutory Instruments 
2004 No. 1031 [15] 

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 
The Medicines for Human Use (Clinical Trials) Amendment Regulations. Statutory 
Instruments 2006 No. 1928 [16] 
 
The Medicines for Human Use (Clinical Trials) Amendment (No. 2) Regulations. 
Statutory Instruments 2006 No. 2984 [17] 
 
The Medicines for Human Use (Clinical Trials) Amendment Regulations. Statutory 
Instruments 2008 No. 941 [18] 
 
Health and Safety. The Ionising Radiations Regulations 2017. Statutory Instrument 
2017 No. 1075 [19]  
 
Health and Safety. Ionising Radiation (Medical Exposure) Regulations 2017. 
Statutory Instrument 2017 No. 1322 [20] 
In addition, the study will be performed according to the ethical principles outlined in 
the World Medical Association Declaration of Helsinki and its amendments [21]. 
18.2 Ethical Approval 
Prior to the initiation of the study, the protocol and associated documentation must be 
given a favourable opinion by an EC. A copy of this written approval and any 
correspondence with the EC will be provided to the sponsor.  
18.3 MHRA Approval 
Prior to the initiation of the study, the Clinical Trial Authorisation application must be 
approved by the MHRA. A copy of this approval and any correspondence with the 
MHRA will be available at the clinical and sponsor sites. A copy of the MHRA approval 
will be provided to the EC. 
18.4 Administration of Radiation 
Dr Stuart Mair will be the ARSAC practitioner for this study, which includes the 
administration of radiation at Quotient Sciences. Administration will be conducted in 
accordance with Dr Mair’s current ARSAC practitioner licence and Quotient’s current 
ARSAC Employer licence. Additionally a research application will be submitted to 
ARSAC to obtain approval for the conduct of the study before dosing. 
Before submitting to the ARSAC, a summary of available nonclinical tissue distribution 
and excretion information on [14C]-MD1003 will be submitted to the Radiation 
Protection Division of PHE for human dosimetry calculations in order to facilitate the 
selection of the dose of radioactivity to be administered. The final report from the PHE 
will be included in the application to the ARSAC. 
The protocol will be reviewed and the final version will be approved by the ARSAC 
practitioner, Dr Stuart Mair. 
18.5 Source Data 
A study-specific source document identification list will be finalised with the sponsor 
prior to the start of the clinical phase of the study. The document will identify what data 
should be considered source data for this study.  
For this study, electronic data capture will be used where possible and data will be 
automatically recorded into an eCRF. In instances where paper source documents are 
used, data to be transcribed into the eCRF will be identified using a Source Document 
Identification List, as governed by Quotient Sciences SOPs. 

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18.6 Declaration of the End of the Study 
The end of the study is defined as the last visit of the last subject (eg discharge). Any 
changes to this definition will be notified as a substantial amendment (see 
Section 17.1). 
The EC and MHRA should be notified in writing of the conclusion of the study within 
90 days of the end of the study, or within 15 days if the study is terminated early, 
clearly explaining the reasons for the termination. 
ARSAC and the ARSAC Practitioner will also be notified of the end of trial or early 
termination of the trial in writing within an appropriate timeframe. 
18.7 Document Storage and Archiving 
All documentation and correspondence pertaining to the study (source data, raw data, 
letters etc) will be kept in accordance with the ICH guidelines for Good Clinical Practice 
1996, updated 2002, Integrated Addendum E6 (R2) dated 09 Nov 2016 (ICH GCP 
Section 4.9.5) [14], The Medicines for Human Use (Clinical Trials) Regulations 2004 
[15] and The Medicines for Human Use (Clinical Trials) Amendment Regulations 2006 
[16],[17]. 
All study related documents will be retained for a minimum period of 25 years. After this 
time, the sponsor will be contacted to ascertain whether continued storage or 
destruction is required in accordance with current regulations. 
18.8 Protection of Personal Data and Confidentiality 
Personal data are securely stored to prevent unauthorised access, disclosure, 
dissemination, alteration or loss of information and unauthorised personal data 
processing. Access to personal information is restricted so that only personnel who are 
required to access personal data as part of their job role can do so. All personnel who 
access personal information are bound by a duty of confidentiality. 
Technical arrangements surrounding the electronic storage and use of data are as 
follows: 
 
Computers storing electronic personal data are protected by antivirus software and 
the network on which computers are linked are protected by industry grade firewalls 
 
Off-site personnel can only access networked computers through a virtual private 
network 
 
Electronic access of data is limited according to user roles 
 
All data are stored on password protected computers 
Organisational arrangements are as follows: 
 
All buildings are secured by key-card access 
Manual files of personal data are stored within locked cabinets that can only be 
accessed by authorised personnel 
 
Data security and/or confidentiality provisions are utilised in agreements with third 
parties 
 
Documented Back-up and disaster recovery procedures are in place 
 
Internal audit and compliance functions provide regulatory oversight 

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The personal data of volunteers will be pseudonymised in that they will only include 
health, initials, date of birth and demographics (gender and ethnicity) and cannot be 
linked back to the individual by the recipient. The sponsor shall be the data controller in 
respect of the personal data of the study subjects collected in connection with the 
study, and shall act in accordance with the relevant data protection laws in relation to 
the collection and processing of those personal data. The study subjects’ 
pseudonymised personal data shall be collected and processed for the purposes of the 
study and may also be added to research databases and used in the future by the 
sponsor and its affiliates for certain additional clinical research, for product regulation 
and safety reporting purposes and for ensuring compliance with legal requirements. 
The study subjects’ pseudonymised personal data may be processed for such 
purposes by other parties including: the sponsor’s affiliates and licensing partners, its 
business partners, regulatory agencies and other health authorities, and ECs. The 
study subjects’ authorisation for such use and disclosure shall be obtained by the study 
subjects signing the ICF for the study. 
Additionally, Quotient personnel are contractually bound by a duty of confidentiality and 
receive training in this matter. 
18.9 Data Security Breach 
Quotient has a comprehensive process in place for identifying, assessing, resolving 
and reporting any potential data security breach. All staff are trained in the identification 
of potential data security breaches. Potential breaches are managed by appropriately 
trained quality assurance personnel in accordance with Quotient Sciences standard 
operating procedures. After robust assessment of data breaches, those deemed 
serious will be reported to the sponsor and Information Commissioner’s Office, as 
applicable. 
19 Quality Control and Quality Assurance 
Quality control of all data collected from this study will be performed in accordance with 
Quotient SOPs. This study (or elements thereof) may be subject to Quotient quality 
assurance (QA) audit, in line with current internal auditing procedures. Similarly, the 
study (or elements thereof) may be subject to sponsor QA audit. 
19.1 Monitoring 
GCP requires that studies are adequately monitored. The sponsor should determine 
the appropriate extent and nature of monitoring. A study monitor, independent of 
Quotient Sciences, will be appointed to verify that the study is conducted in accordance 
with current GCP, regulatory requirements, the protocol and that the data are authentic, 
accurate and complete.  
The investigator agrees to receive visits from a study monitor and provide assistance to 
verify protocol implementation, source completion and transcription of data into the 
eCRF, document storage and AE reporting. 
Quotient Sciences will extend the professional privilege of access to the subjects’ 
clinical source documents to the study monitor, EC, regulatory bodies or other 
authorised personnel (eg auditor) for the purposes of source data verification. 

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Following completion of the study both study related documents and subject data may 
be sent to the sponsor at a location outside of the UK where data protection laws differ. 
In the interests of confidentiality, subjects will not be identified on any such documents 
or data, and specific subject consent for such a disposition will be obtained. 
20 Finance and Insurance 
The sponsor (MedDay Pharmaceuticals) has funded this study. A no-fault clinical trials 
insurance has been obtained by the sponsor. The sponsor insurance will compensate 
subjects in accordance with the Association of the British Pharmaceutical Industry 
Guidelines for Phase I Clinical Trials 2018 edition [13]. 
21 Publication 
Please refer to the Master Services Agreement for information on publication.  
Quotient Sciences shall have the right to publish the results of the research, subject to 
the sponsor’s prior written consent, which shall not be unreasonably withheld or 
delayed. Following the receipt of such consent, Quotient Sciences shall submit a copy 
of the proposed publication to the sponsor who shall have 30 days in which to request 
amendments thereto which, to the extent that such proposed amendments are 
reasonable, Quotient shall be obliged to incorporate prior to such publication. 
The sponsor undertakes that, prior to publication of any information, article, paper, 
report or other material concerning the research, it will submit a copy of such 
publication to Quotient Sciences who shall have 90 days in which to request 
amendments thereto which, to the extent that such proposed amendment are 
reasonable, the sponsor shall be obliged to incorporate prior to such publication. 
22 References 
[1] 
Investigator’s Brochure for MD1003 (Biotin). Edition No 10. 13 May 2019. 
[2] 
Tong L.. Structure and function of biotin-dependent carboxylases. Cell Mol Life 
Sci. 2013. 70(50): 863-91. 
[3] 
Chakraborty G, Ledeen R. Fatty acid synthesizing enzymes intrinsic to myelin. 
Brain Res Mol Brain Res. 2003. 112(1-2): 46-52. 
[4] 
Zempleni J, Wijeratne SS, Hassan YI. Biotin. Biofactors. 2009. 35(1): 36-46. 
[5] 
Sedel F, Papeix C, Bellanger A, et al. High doses of biotin in chronic 
progressive multiple sclerosis: a pilot study. Mult Scler Relat Disord. 2015. 
4(2): 159-69. 
[6] 
Sedel F, Bernard D, Mock DM, et al. Targeting demyelination and virtual 
hypoxia with high-dose biotin as a treatment for progressive multiple sclerosis. 
Neuropharmacology. 2016. 110(Pt B): 644-53. 
[7] 
Tourbah A, Lebrun-Frenay C, Edan G, et al. MD1003 (high-dose biotin) for the 
treatment of progressive multiple sclerosis: A randomised, double-blind, 
placebo-controlled study. Mult Scler. 2016. 22(13): 1719-31. 

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[8] 
Tourbah 
A, 
Gout 
O, 
Vighetto 
A, 
et 
al. 
MD1003 
(High-Dose 
Pharmaceutical-Grade Biotin) for the Treatment of Chronic Visual Loss Related 
to Optic Neuritis in Multiple Sclerosis: A Randomized, Double-Blind, 
Placebo-Controlled Study/ CNS Drugs. 2018. 32 (7): 661-72. 
[9] 
Wang KS, Kearns GL, Mock DM. The clearance and metabolism of biotin  
administered intravenously to pigs in tracer and physiologic amounts is much 
more rapid than previously appreciated. 2001. J Nutr. 131(4): 1271-8. 
[10] 
Zempleni J, Mock DM. The efflux of biotin from human peripheral blood 
mononuclear cells. J Nutr Biochem. 1999b. 10(2): 105-9. 
[11] 
Notes for guidance on the clinical administration of radiopharmaceuticals and 
use of sealed radioactive sources. Administration of Radioactive Substances 
Advisory Committee. January 2019. 
[12] 
Heads 
of 
Medicines 
Agency: 
Clinical 
Trials 
Facilitation 
Group. 
Recommendations related to contraception and pregnancy testing in clinical 
trials. 15 Sep 2014 http://www.hma.eu/fileadmin/dateien/Human_Medicines/01-
About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf 
[13] 
Guidelines for Phase I Clinical Trials. Association of the British Pharmaceutical 
Industry Guidelines. London, UK; 2018 Edition (publication date 29 May 2018). 
[14] 
International Council for Harmonisation Good Clinical Practice (GCP) 
Guidelines approved by the Committee for Medicinal Products for Human Use 
(CHMP) on 17 Jul 1996, which came into force on 17 Jan 1997, updated 
Jul 2002, Integrated Addendum E6 (R2) dated 09 Nov 2016. 
[15] 
The Medicines for Human Use (Clinical Trials) Regulations. Statutory 
Instruments 2004 No. 1031. 
[16] 
The Medicines for Human Use (Clinical Trials) Amendment Regulations. 
Statutory Instruments 2006 No. 1928. 
[17] 
The Medicines for Human Use (Clinical Trials) Amendment (No. 2) Regulations. 
Statutory Instruments 2006 No. 2984. 
[18] 
The Medicines for Human Use (Clinical Trials) Amendment Regulations. 
Statutory Instruments 2008 No. 941. 
[19] 
Health and Safety. The Ionising Radiations Regulations 2017. Statutory 
Instrument 2017 No. 1075. 
[20] 
Health and Safety. Ionising Radiation (Medical Exposure) Regulations 2017. 
Statutory Instrument 2017 No. 1322. 
[21] 
World Medical Association, Declaration of Helsinki. Ethical Principles for 
Medical 
Research 
Involving 
Human 
Subjects 
(and 
all 
subsequent 
amendments). 
 

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Appendix 1 
Clinical Laboratory Parameters 
Haematology 
Clinical Chemistry 
Virology 
Urinalysis 
Drugs of Abuse 
Basophils 
Eosinophils 
Haematocrit  
(Packed Cell Volume- PCV) 
Haemoglobin 
Lymphocytes 
Mean Cell Haemoglobin (MCH) 
Mean Cell Haemoglobin Concentration 
(MCHC) 
Mean Cell Volume (MCV) 
Monocytes 
Neutrophils 
Platelet Count 
Red Blood Cell (RBC) Count  
White Blood Cell (WBC) Count 
 
Alanine Aminotransferase 
(ALT) 
Albumin 
Alkaline Phosphatase 
Aspartate 
Aminotransferase (AST) 
Bicarbonate 
Bilirubin (Total) 
Bilirubin (Direct) (only if 
Total is elevated) 
Calcium 
Chloride 
Creatine Kinase (CK) 
Creatininea 
Gamma Glutamyl 
Transferase (GGT) 
Glucose 
Glucose (Fasting) 
Potassium 
Phosphate (Inorganic) 
Protein (Total) 
Sodium 
Urea  
Hepatitis B Surface 
Antigen 
Hepatitis C Antibody 
HIV Antibody 
Bilirubin 
Blood 
Glucose 
Ketones 
Leukocytes 
Nitrites 
pH 
Protein 
Specific gravity 
Urobilinogen 
At discretion of 
investigator based on 
urinalysis results 
Microbiology  
Urine Microscopy 
Amphetamines 
Barbiturates 
Benzodiazepines 
Cocaine 
Marijuana/Cannabis 
Methadone 
Methamphetamine/ 
Ecstasy 
Morphine/Opiates 
Phencyclidine 
Tricyclic 
Antidepressants 
a Creatinine clearance will be calculated at screening using the Cockcroft-Gault equation for eligibility purposes 
 

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Protocol MD1003CT2019-03MB (QSC201639) Version 1.0 
12 SEP 2019 
Page 53 of 54  
 
Appendix 2 
Study Flow Chart 
Study Day 
-28 to -2 
-1 
1 
2 
3 
4 
5 
6 
7 
8 
 
Times After Dosing (h) 
Screening Admission 
Pre-
dose 
0 0.5 1 1.5 2 
3 4 6 8 12 18 
24 
36 48 
72 
96 120 144 168a 
General Assessments 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight and Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vein Assessment 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Carbon Monoxide Breath Test 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Drug Screen 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Alcohol Breath Test 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IMP Administration 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Safety Assessments 
Physical Examination 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xb 
 
 
 
 
 
 
Xb 
Safety Labsc 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
Urinalysis 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
ECG 
X 
 
X 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
X 
Vital Signsd 
X 
 
X 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
 
X 
Adverse Events 
 
Prior and Concomitant Medication  
 
Mass Balance and PK Assessments 
Plasma Samples for MD1003, bisnorbiotin 
and biotin sulfoxide 
 
 
X 
 
X 
X X X X X X X X X 
X 
X 
X 
X 
X X 
X 
X 
Plasma Samples for TR 
 
 
X 
 
X 
X X X X X X X X X 
X 
X 
X 
X 
X X 
X 
X 
Whole Blood Samples for TR 
 
 
X 
 
 
X 
 
 
 
X 
 
X X 
 
X 
 
X 
X 
X 
 
 
X 
Plasma Samples for Metabolite Profiling 
and ID 
 
 
X 
 
 
X 
 
X 
 
X 
 
X X 
 
 
 
 
 
 
 
 
 
Urine Samples for TR and Metabolite 
Profiling and Identificatione 
 
 
 
 
Faecal Samples for TR and Metabolite 
Profiling and Identificationf 
 
 
 
 
ECG: Electrocardiogram; ID: Identification; IMP: Investigational Medicinal Product; TR: total radioactivity  

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Protocol MD1003CT2019-03MB (QSC201639) Version 1.0 
12 SEP 2019 
Page 54 of 54  
 
a Discharge from clinical unit; subjects may be discharged earlier if a cumulative mass balance recovery of 90% % has been achieved or if <1% of the dose 
administered has been collected in urine and faeces within 2 separate consecutive 24 h periods. If the criteria are not met by Day 8, this may result in the 
extension of the residency period for the subjects not achieving the release criteria up to a maximum of an additional 48 h (up to Day 10) for further collection of 
urine and/or faeces. If the criteria are still not met by Day 10, or if additional residency is not considered appropriate or necessary, then home collections of urine 
and/or faeces may be requested at the discretion of the investigator for individual subjects 
b Targeted (symptom driven) physical examination  
c Haematology and clinical chemistry at each time point including virology at screening (see Appendix 1 for a full list of clinical laboratory parameters). Creatinine 
clearance will be estimated at screening from plasma creatinine using the Cockcroft-Gault equation for eligibility purposes 
d Blood pressure and heart rate. Oral temperature will be measured at screening, pre-dose and any unscheduled assessments as required 
e A single urine sample will be collected at pre-dose (the first void of the day) and then at the following collection periods: 0 to 12 h, 12 to 24 h, and then daily 
(24 h intervals) until discharge  
f Faeces will be collected pre-dose (sample to be taken between admission and pre-dose) and then daily (24 h intervals) until discharge