Conditions: Healthy Volunteers
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 6
Healthy volunteers: yes

Brief summary:
This single-center, open-label, non randomized Phase I study is being conducted to investigate the pharmacokinetics, mass balance and metabolite profiling and identification after a single oral dose of 100mg of \[14C\]-MD1003 in 6 healthy males subjects. The radioactivity will be followed in the blood, urine and faeces to study MD1003 metabolism.

Detailed description:

Arms:
arm 1: radiolabeled 14C MD1003 (High Dose Biotin) 100mg

Interventions: intervention 1: [14C]-MD1003
Intervention descriptions: intervention 1: single oral dose of 100mg \[14C\]-MD1003

Protocol document:
Prot_000.pdf: 
 
 
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 
oligodendrocytes. 


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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 
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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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12 SEP 2019 
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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 

SAP_001.pdf: 
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REPORTING AND ANALYSIS PLAN 
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 Males 
Subjects 
Quotient Study Number: 
QSC201639 
Sponsor Study Number: 
MD1003CT2019-03MB 
Sponsor: 
MedDay Pharmaceuticals 
24-26 Rue de la Pépinière 
75008 
Paris 
France 
Date of RAP: 
02 Dec 2019 
Status of RAP: 
Final v1.0 
Document Version History 
Version 
Number 
Reason for Update 
Updated By: 
Date 
v1.0 
Issued for finalisation 
Amy Cotterill 
02 Dec 2019 
SPONSOR/QUOTIENT SCIENCES CONFIDENTIAL 
This Reporting and Analysis Plan may not be reproduced or communicated to a third 
party without the written permission of MedDay Pharmaceuticals.






    
 
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1 
Table of Contents 
1 
Table of Contents ............................................................................................ 3 
2 
List of Abbreviations ........................................................................................ 6 
3 
Introduction ..................................................................................................... 9 
3.1 
Responsibilities ................................................................................. 9 
3.2 
Definitions.......................................................................................... 9 
3.2.1 
Subject Definitions ............................................................................. 9 
3.2.2 
Definition of Treatment .................................................................... 10 
3.2.3 
Definition of Visits ............................................................................ 10 
4 
Objectives ..................................................................................................... 10 
4.1 
Primary Objectives .......................................................................... 10 
4.2 
Secondary Objectives ...................................................................... 10 
4.3 
Study Endpoints .............................................................................. 10 
4.3.1 
Primary Endpoints ........................................................................... 10 
4.3.2 
Secondary Endpoints ...................................................................... 11 
5 
Study Design ................................................................................................. 11 
5.1 
Brief Description .............................................................................. 11 
5.2 
Criteria for In-Study Decisions ......................................................... 12 
5.3 
Study Sample Size .......................................................................... 12 
5.4 
Subject Numbers ............................................................................. 12 
5.5 
Blinding Issues ................................................................................ 12 
6 
Populations and Analysis Sets ...................................................................... 12 
6.1 
Safety Population and Safety Analysis Set ...................................... 12 
6.2 
Mass Balance Population and Mass Balance Analysis Set .............. 13 
6.3 
Pharmacokinetic Population and Pharmacokinetic Analysis 
Set ................................................................................................... 13 
7 
Subject Disposition, Demographics and Baseline Characteristics ................. 14 
7.1 
Screening Failures ........................................................................... 14 
7.2 
Subject Disposition and Withdrawals ............................................... 14 
7.3 
Analysis Populations ....................................................................... 14 
7.4 
Analysis Sets ................................................................................... 14 
7.5 
Demographic Characteristics and Lifestyle Details .......................... 15 
7.6 
Medical/Surgical History .................................................................. 15 
7.7 
Prior and Concomitant Medication ................................................... 15 
7.8 
Other Baseline Characteristics ........................................................ 16 
8 
Efficacy ......................................................................................................... 16 
9 
Mass Balance and Pharmacokinetics ............................................................ 16 


    
 
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9.1 
Mass Balance Parameter Estimation and Reporting ........................ 16 
9.1.1 
Definition of Mass Balance Parameters ........................................... 17 
9.1.2 
Rules for Mass Balance Parameter Estimation ................................ 18 
9.1.3 
Mass Balance Summary Tables ...................................................... 20 
9.1.4 
Mass Balance Figures ..................................................................... 21 
9.1.5 
Mass Balance Listings ..................................................................... 21 
9.1.6 
Statistical Analysis of Mass Balance Parameters............................. 21 
9.2 
Pharmacokinetic Parameter Estimation and Reporting .................... 21 
9.2.1 
Definition of Pharmacokinetic Parameters ....................................... 21 
9.2.2 
Rules for Pharmacokinetic Parameter Estimation using 
WinNonlin ........................................................................................ 22 
9.2.3 
Bioanalytical and Pharmacokinetic Reporting Specifications ........... 24 
9.2.4 
Bioanalytical and Pharmacokinetic Summary Tables ....................... 25 
9.2.5 
Bioanalytical and Pharmacokinetic Figures...................................... 25 
9.2.6 
Bioanalytical and Pharmacokinetic Listings ..................................... 26 
9.2.7 
Statistical Analysis of Pharmacokinetic Parameters ......................... 26 
10 
Safety Assessments ...................................................................................... 26 
10.1 
Extent of Exposure and Treatment Compliance ............................... 26 
10.2 
Meal Details ..................................................................................... 27 
10.3 
Adverse Events ............................................................................... 27 
10.3.1 
Summary Tables for Adverse Events ............................................... 27 
10.3.2 
Listings for Adverse Events ............................................................. 30 
10.4 
Laboratory Evaluations .................................................................... 30 
10.4.1 
Summary Tables for Laboratory Evaluations ................................... 30 
10.4.2 
Listings for Laboratory Evaluations .................................................. 30 
10.5 
Vital Signs ....................................................................................... 31 
10.5.1 
Summary Tables for Vital Signs ....................................................... 31 
10.5.2 
Listings for Vital Signs ..................................................................... 31 
10.6 
ECGs ............................................................................................... 32 
10.6.1 
Summary Tables for ECGs .............................................................. 32 
10.6.2 
Listings for ECGs ............................................................................. 32 
10.7 
Physical Examination ...................................................................... 33 
11 
Interim Statistical Analyses ........................................................................... 33 
12 
Changes in the Conduct of the Study or Planned Analysis ............................ 33 
12.1 
Changes in the Conduct of the Study .............................................. 33 
12.2 
Changes to the Planned Analyses ................................................... 33 
12.3 
Any Other Relevant Changes .......................................................... 33 
13 
Overall Considerations .................................................................................. 33 
13.1 
Statistical Programming and Analysis .............................................. 33 
13.2 
Quality Control of Summary Tables, Figures and Listings and 
Statistical Analysis ........................................................................... 35 
13.2.1 
Quality Control - Summary Tables ................................................... 35 
13.2.2 
Quality Control - Figures .................................................................. 36 


    
 
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13.2.3 
Quality Control - Data Listings ......................................................... 36 
14 
SAS Data Transfer ........................................................................................ 36 
15 
Programming Conventions ............................................................................ 36 
16 
Reference List ............................................................................................... 37 
17 
Index of Tables ............................................................................................. 38 
18 
Index of Figures ............................................................................................ 42 
19 
Index of Listings ............................................................................................ 45 
20 
Mock Tables .................................................................................................. 49 
Appendix 1: Study Flow Chart ..................................................................................... 72 
 
 


    
 
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2 
List of Abbreviations 
14C 
carbon-14 
ADaM 
analysis data model  
ADR 
adverse drug reaction 
AE 
adverse event 
Ae 
amount of total radioactivity excreted 
ATC 
anatomical therapeutic chemical 
AUC 
area under the curve  
BLQ 
below the limit of quantification 
BMI 
body mass index 
BP 
blood pressure 
CDISC 
Clinical Data Interchange Standards Consortium 
CHMP 
Committee for Medicinal Products for Human Use 
CSR 
clinical study report 
CumAe 
cumulative amount of total radioactivity excreted  
Cum%Ae 
cumulative amount of total radioactivity excreted, expressed as a 
percentage of the radioactive dose administered 
CV% 
coefficient of variation 
D 
‘substantial’ decrease from baseline for vital signs parameters 
DP 
decimal place 
ECG 
electrocardiogram 
h 
hour 
H 
flag used for value that is above normal reference range 
HR 
heart rate 
I 
‘substantial’ increase from baseline for vital signs parameters / 
increase in QTcF interval from baseline 


    
 
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ICH 
International Council on Harmonisation 
IP 
investigational product 
L 
flag used for value that is below normal reference range 
LLOQ 
lower limit of quantification 
LOCF 
last observation carried forward 
LOD 
limit of detection 
Max 
maximum 
MBq 
megabecquerel 
MedDRA 
Medical Dictionary for Regulatory Activities 
µCi 
microcurie 
Min 
minimum 
MPR 
metabolite to parent ratio 
MW 
molecular weight 
n 
number of subjects with an observation 
N 
number of subjects in the dataset 
NA 
not applicable 
NC 
not calculated 
ND 
not detected 
NMT 
not more than 
NR 
no result 
NS 
no sample 
PI 
principal investigator 
PK 
pharmacokinetic 
PT 
preferred term 
QC 
quality control 


    
 
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QTcF 
QT interval corrected for heart rate using Fridericia’s correction 
RAP 
reporting analysis plan 
SAE 
serious adverse event 
SD 
standard deviation 
SDTM 
study data tabulation model 
SF 
significant figure 
SI 
substantial increase in QTcF interval from baseline 
SOC 
system organ class 
SOP 
standard operating procedure 
TEAE 
treatment-emergent adverse events 
TER 
total exposure ratio 
TFL 
tables, figures and listings 
WHO  
World Health Organisation  
%Ae 
amount of total radioactivity excreted, expressed as a percentage 
of the radioactive dose administered 
Abbreviations and flags used in reporting of mass balance and pharmacokinetic data are 
defined in Section 9. 


    
 
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3 
Introduction 
This document details the following for Quotient Sciences (Quotient) Study QSC201639 
(MD1003CT2019-03MB): 
 
criteria to be used for the definition of the populations and analysis sets relating to 
safety, mass balance and pharmacokinetic (PK) data 
 
handling of missing data 
 
proposed tables, figures and listings (TFLs) for demographic, dosing, mass balance, 
PK and safety data  
 
methods for mass balance and PK parameter estimation 
 
This document has been compiled according to the Quotient standard operating 
procedure (SOP) “Production of Reporting and Analysis Plans” and has been written 
based on information contained in the final study protocol (version 1.0) dated 
12 Sep 2019. 
3.1 
Responsibilities 
The Data Sciences Department at Quotient will be responsible for the production of the 
following items using Quotient SOPs: Clinical Data Interchange Standards Consortium 
(CDISC) study data tabulation model (SDTM) and analysis data model (ADaM) datasets, 
mass balance parameter estimation and output, PK parameter estimation and output; 
including all TFLs; and the clinical study report (CSR). 
Quotient will provide two sets of TFLs during the study: 
 
post database lock TFLs (draft) for MedDay Pharmaceuticals review, and  
 
post-review TFLs (final) for inclusion into the CSR 
Quotient will be responsible for the quality control (QC) of all deliverables prior to the 
client review (Section 13.2). 
Metabolite profiling and structural identification will be the responsibility of Pharmaron, 
and will be the subject of a separate Analytical Work Plan. These aspects will be reported 
separately from the CSR as a standalone document. 
3.2 
Definitions 
3.2.1 
Subject Definitions 
During the clinical phase of the study, an evaluable subject is defined as a subject who 
has provided mass balance and PK samples for up to 72 h (Day 4) after IP 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. This will be 
monitored during the clinical phase but will not be used during the reporting phase 
including the identification of analysis populations and datasets. 
An enrolled subject is defined a subject who signed the informed consent, qualified per 
the inclusion/exclusion criteria and were allocated a subject number. 


    
 
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3.2.2 
Definition of Treatment 
A single oral administration of a capsule containing 100 mg MD1003 and not more than 
(NMT) 2.22 MBq (approximately 60 µCi) [14C] will be administered to each subject and 
labelled as 100 mg [14C]-MD1003 in TFLs. 
3.2.3 
Definition of Visits 
For clinical data, visits will be referred to as Day throughout this document and will be 
referred to as Screening, Day -1 (Admission) and Day 1 through to Day 8 (planned 
discharge). Time points within these days are detailed in the study flow chart in 
Appendix 1. 
Baseline is defined as nominally the last measurement recorded prior to the first dose of 
investigational product (IP). 
4 
Objectives 
4.1 
Primary Objectives 
The primary objectives of this study are: 
 
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 
4.2 
Secondary Objectives 
The secondary objectives of this study are: 
 
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 
4.3 
Study Endpoints 
4.3.1 
Primary Endpoints 
The primary endpoints of the study are: 
 
mass balance recovery of total radioactivity in all excreta (urine and faeces): Ae, 
%Ae, CumAe and Cum%Ae 
 
metabolite profiling, structural identification, and quantification of [14C]-MD1003 
metabolites in plasma, urine and faeces 


    
 
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4.3.2 
Secondary Endpoints 
The secondary endpoints of the study are: 
 
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 
5 
Study Design 
5.1 
Brief Description 
This is a single-centre, open-label, non-randomised, single oral dose study in healthy 
male subjects. It is planned to enrol 6 subjects. 
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 IP administration. 
Subjects will be dosed in the morning of Day 1 following an overnight fast with a single 
oral administration of a capsule containing 100 mg MD1003 and NMT 2.22 MBq 
(approximately 60.0 µCi) [14C]-MD1003. 
Subjects 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 subject 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 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 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 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. 


    
 
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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.  
5.2 
Criteria for In-Study Decisions 
Not applicable for this study. 
5.3 
Study Sample Size 
This 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. 
5.4 
Subject Numbers 
This is an open-label, non-randomised study, therefore a randomisation schedule will not 
be produced.  
Subject numbers will be allocated on the morning of dosing according to the code 001 to 
006 using the lowest number available. 
No replacement subjects are to be used in this study. 
5.5 
Blinding Issues 
This is an open-label, non-randomised study and, therefore, blinding is not required. 
6 
Populations and Analysis Sets 
6.1 
Safety Population and Safety Analysis Set 
The safety population will include all subjects who have received any amount of IP. 
The safety analysis set will include all relevant data from the subjects included in the 
safety population. 


    
 
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The safety population will be confirmed by Quotient with approval from MedDay 
Pharmaceuticals after database lock and will be used for the populations table and to 
determine the subjects to be included in the safety analysis set. 
The safety analysis set will be confirmed by Quotient with approval from MedDay 
Pharmaceuticals at the same time as the safety population and will be used for the 
analysis of demographic and baseline characteristics, and all safety data. 
6.2 
Mass Balance Population and Mass Balance Analysis Set 
The mass balance population will include all subjects who have received IP, who have 
evaluable total radioactivity concentration (urinary and faecal) data and who have no 
protocol deviations that affect the mass balance analysis. Such protocol deviations would 
include anything that affects the accurate measurement of amount of urine/faeces 
collected or any AEs that may affect the mass balance analysis, for example: 
 
spillage of urine and/or faeces 
 
missing collections 
 
AEs that may affect the mass balance analysis, such as vomiting of the dose 
The mass balance analysis set will include all relevant data from the subjects included 
in the mass balance population.  
The mass balance population will be confirmed by Quotient with approval from MedDay 
Pharmaceuticals once all urinary and faecal data have been received and will be used 
for the populations table and to determine the subjects to be included in the mass 
balance analysis set. 
The mass balance analysis set will be confirmed by Quotient with approval from MedDay 
Pharmaceuticals at the same time as the mass balance population and will be used for 
the provision of mass balance summary tables and figures.  
6.3 
Pharmacokinetic Population and Pharmacokinetic Analysis Set 
The PK population will include all subjects who have received IP and who satisfy the 
following criteria for at least 1 profile: 
 
no missing samples or invalid post-dose analytical results at critical time points eg 
around the Tmax 
 
no relevant protocol deviations which may impact the study objectives with respect 
to the PK endpoints 
 
no relevant AEs such as vomiting after dosing which suggest that the whole dose 
was not available for absorption for a particular subject 
The PK analysis set will include all relevant data from the subjects included in the PK 
population. 
The PK population will be confirmed by Quotient with approval from MedDay 
Pharmaceuticals following derivation of all PK parameter estimates and will be used for 
the populations table and to determine the subjects to be included in the PK analysis set.  


    
 
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The PK analysis set will be confirmed by Quotient with approval from MedDay 
Pharmaceuticals at the same time as the PK population and will be used for the provision 
of PK summary tables and figures. 
7 
Subject 
Disposition, 
Demographics 
and 
Baseline 
Characteristics 
No formal statistical testing will be performed on subject disposition, or on demographic 
or baseline data. Summaries of subject disposition and analysis populations will be 
based on all enrolled subjects and summaries of all other data described in this section 
will be based on the safety analysis set, unless otherwise stated. 
7.1 
Screening Failures 
Data for subjects who have failed screening will be databased but will not be cleaned 
and therefore will not be included in the SAS extracts, SDTM or ADaM datasets or any 
of the TFLs. 
7.2 
Subject Disposition and Withdrawals 
The number and percentage of subjects enrolled, dosed, completed and discontinued 
will be presented. If any subjects discontinued from the study early then the number of 
subjects for each reason for discontinuation will be presented. However, if none of the 
subjects discontinued from the study early, then the reasons for discontinuation will not 
be populated in the summary table. 
Subject disposition and withdrawal data will be listed including details of informed 
consent. 
Protocol deviations and any violations of the inclusion/exclusion criteria will also be listed. 
7.3 
Analysis Populations 
A summary table will be produced detailing the number and percentage of subjects in 
each safety, mass balance and PK population. The reasons for exclusion from each 
population will also be included in the summary.  
Details of subjects included in and excluded from the different analysis populations will 
be listed. 
7.4 
Analysis Sets 
A summary table will be produced detailing the number and percentage of subjects in 
each safety/mass balance/PK analysis set. The table will be based on the relevant 
population the analysis set is a subset of (ie the safety/mass balance/PK population). 
The reasons for exclusion from each analysis set will also be included in the summary.  
Details of subjects included and excluded in the different analysis sets will be listed. 


    
 
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7.5 
Demographic Characteristics and Lifestyle Details 
Demographic data (date of birth, ethnicity, race, sex, height [cm], weight [kg] and body 
mass index [BMI; kg/m2]) will be recorded at screening. Age will be calculated using the 
following formula: 
Age (years) = 
Date of Informed Consent – Date of Birth 
365.25 
and will be rounded down to the nearest year (using the SAS Software floor function). 
Summary statistics (ie number of subjects with an observation [n], mean, standard 
deviation [SD], median, minimum and maximum) will be presented for age, height, weight 
and BMI at screening. The number and percentage of subjects will be presented for 
ethnicity, race and sex. The denominator for the percentage is all subjects in the safety 
analysis set. If any values are missing, a “missing” row will be presented on the table. 
Lifestyle details (ie smoking history [does the subject smoke, use e-cigarettes or any 
nicotine replacement products?] and alcohol consumption) will be summarised as 
categorical variables. 
Demographic and lifestyle data will be listed by subject for all enrolled subjects. 
7.6 
Medical/Surgical History 
Medical/surgical history will be recorded for each subject at the screening visit and 
updated at admission. All medical/surgical history data will be listed by subject for all 
enrolled subjects. 
7.7 
Prior and Concomitant Medication 
Medications (product name) will be coded using the World Health Organization (WHO) 
Drug Dictionary Global Drug Reference (2019 September version or more recent 
version) using the following Anatomical Therapeutic Chemical (ATC) classification 
codes: 
 
product name 
 
preferred name  
 
drug code 
 
therapeutic subgroup (ATC 2nd level code) 
 
chemical subgroup (ATC 4th level code) 
Prior medications are defined as medications that start and stop prior to the dosing of IP. 
All other medications will be defined as concomitant medications including those that 
start prior to the first dose of IP and continue thereafter. Any medications with an 
unknown start or stop date will be assumed to be concomitant medications unless a 
partial start or stop date indicates otherwise.  


    
 
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7.7.1 
Summary Table for Prior and Concomitant Medication 
If 2 or more subjects receive concomitant medications, a table will be presented to 
summarise concomitant medications data.  
All subjects taking concomitant medications will be summarised. Counts will be given for 
total number (and percentage) of subjects who received concomitant medications and 
total number of occasions in which medications were taken. 
Additionally, concomitant medication will be summarised by therapeutic subgroup, 
chemical subgroup and preferred name. Counts will be given for the number (and 
percentage) of subjects and total number of occasions in which medications were taken. 
No summary table will be presented for prior medication. 
7.7.2 
Listing for Prior and Concomitant Medication 
All medications, including coded terms and the underlying indication for which the 
medication was given, will be listed. One combined data listing of prior and concomitant 
medications will be provided. All prior medications as defined above will be flagged with 
a “#” symbol. Within this flagged group, medications that started after screening and 
stopped before dosing of IP will also be flagged using a “*” symbol. 
7.8 
Other Baseline Characteristics 
All other baseline characteristics, as listed below, at screening and on admission (unless 
otherwise stated) will be listed by subject for all enrolled subjects: 
 
carbon monoxide breath test 
 
urine drug screen 
 
alcohol breath test  
 
virology (screening only) 
 
creatinine clearance (screening only) 
8 
Efficacy 
Not applicable. 
9 
Mass Balance and Pharmacokinetics 
9.1 
Mass Balance Parameter Estimation and Reporting  
Pharmaron will provide the following concentration and weight data on a per subject 
basis for each collection period as specified in the clinical protocol: 
 
amount of dose received (mg) and radioactive dose received (µCi and MBq) 
 
total radioactivity concentration (mass unit equivalents/g) 
 
weight of urine (g)  
 
faeces weight (g) ie not faecal homogenate weight 


    
 
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Concentration values will be expressed in terms of mass unit equivalents of the free base 
form. Quotient Data Sciences will be responsible for the calculation of excretion and 
recovery of total radioactivity in urine, faeces and urine and faeces combined for 
inclusion into the CSR.  
For the purposes of this document, “excretion” will be used when describing the amount 
of total radioactivity excreted and “recovery” will be used when describing the amount of 
total radioactivity expressed as a percentage of the radioactive dose administered. 
9.1.1 
Definition of Mass Balance Parameters 
A list of mass balance parameter definitions are provided in Table 1. 
Table 1 
Mass Balance Parameters and Reporting Specifications 
Parameter 
Definition 
Units 
DP or SF 
No. of 
DP/SF 
Ae(urine) 
Amount of total radioactivity excreted 
in urine 
Mass unit equiv 
SF 
3 
%Ae(urine) 
Amount of total radioactivity excreted 
in urine expressed as a percentage 
of the radioactive dose administered 
% 
DP 
2 
CumAe(urine) 
Cumulative amount of total 
radioactivity excreted in urine 
Mass unit equiv 
SF 
3 
Cum%Ae(urine) 
Cumulative amount of total 
radioactivity excreted in urine 
expressed as a percentage of the 
radioactive dose administered 
% 
DP 
2 
Ae(faeces) 
Amount of total radioactivity excreted 
in faeces 
Mass unit equiv 
SF 
3 
%Ae(faeces) 
Amount of total radioactivity excreted 
in faeces expressed as a percentage 
of the radioactive dose administered 
% 
DP 
2 
CumAe(faeces) 
Cumulative amount of total 
radioactivity excreted in faeces 
Mass unit equiv 
SF 
3 
Cum%Ae(faeces) 
Cumulative amount of total 
radioactivity excreted in faeces 
expressed as a percentage of the 
radioactive dose administered 
% 
DP 
2 
Ae(total) 
Amount of total radioactivity excreted 
in urine and faeces combined 
Mass unit equiv 
SF 
3 
%Ae(total) 
Amount of total radioactivity excreted 
in urine and faeces combined 
expressed as a percentage of the 
radioactive dose administered 
% 
DP 
2 
CumAe(total) 
Cumulative amount of total 
radioactivity excreted in urine and 
faeces combined 
Mass unit equiv 
SF 
3 


    
 
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Parameter 
Definition 
Units 
DP or SF 
No. of 
DP/SF 
Cum%Ae(total) 
Cumulative amount of total 
radioactivity excreted in urine and 
faeces combined expressed as a 
percentage of the radioactive dose 
administered 
% 
DP 
2 
DP = decimal place 
SF = significant figure 
Home collections of urine and/or faeces may be requested at the discretion of the 
investigator for individual subjects. All mass balance parameters will be calculated for all 
collection periods including home collections, if applicable. 
9.1.2 
Rules for Mass Balance Parameter Estimation  
The following will be calculated for total radioactivity in urine, faeces and total (ie urine 
and faeces combined) by Quotient Data Sciences (note that the amount excreted in pre-
dose samples will not be included in the calculation of the cumulative amount excreted 
or in the calculation of the cumulative percentage of the radioactive dose excreted): 
 
The amount excreted in urine, ie Ae(urine), and the amount excreted in faeces, ie 
Ae(faeces), will be calculated for each collection period using the following formula 
(where matrix is either urine or faeces): 
Ae(<matrix>) = concentration * weight 
 
 
The total amount excreted in urine and faeces combined, ie Ae(total), will be 
calculated for each collection period using the following formula: 
Ae(total) = Ae(urine) + Ae (faeces) 
 
 
The cumulative amount excreted in urine, ie CumAe(urine), and the cumulative 
amount excreted in faeces, ie CumAe(faeces), will be calculated by the incremental 
summation of the Ae(<matrix>) across all collection periods (where matrix is either 
urine or faeces).  
 
The cumulative amount excreted in urine and faeces combined, ie CumAe(total), will 
be calculated across all collection periods using the following formula: 
CumAe(total) = CumAe(urine) + CumAe(faeces) 
 
The % amount of the total radioactive dose excreted in urine, ie %Ae(urine), and 
the % amount of the total radioactive dose excreted in faeces, ie %Ae(faeces), will 
be calculated for each collection period using the following formula (where matrix is 
either urine or faeces): 
%Ae(<matrix>) = 100 * Ae(<matrix>) / Total Radioactive Dose Administered 


    
 
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 
The % amount of the total radioactive dose excreted in urine and faeces combined, 
ie %Ae(total), will be calculated for each collection period using the following 
formula: 
%Ae(total) = %Ae(urine) + %Ae(faeces) 
 
The cumulative % amount of the total radioactive dose excreted in urine, ie 
Cum%Ae(urine), and the cumulative % amount of the total radioactive dose 
excreted in faeces, ie Cum%Ae(faeces), will be calculated by the incremental 
summation of the %Ae(<matrix>) across all collection periods (where matrix is 
either urine or faeces). 
 
The cumulative % amount of the total radioactive dose excreted in urine and faeces 
combined, ie Cum%Ae(total), will be calculated for each collection period using the 
following formula: 
Cum%Ae(total) = Cum%Ae(urine) + Cum%Ae(faeces) 
Where the collection periods for urine and faeces differ (ie, on Day 1 urine collected at 
12 h intervals while faeces collected over 24 h), the total excretion and recovery (ie, urine 
and faeces combined) will be calculated over the larger of the intervals. 
For urine and faeces, where a subject has failed to void over a particular collection period 
the Amount excreted (Ae) will be set to zero. 
If part of a void over a particular collection period is missing due to spillage or accidental 
discarding, the Ae will still be calculated providing other samples have be collected within 
the interval. Where no other samples are collected within the interval the data will be set 
to missing for the purposes of the calculation of Ae, %Ae, CumAe and Cum%Ae. In both 
scenarios the data will be flagged to highlight a missing void. 
Non-numerical values reported in the urine and faecal data set (ie concentrations that 
are ND) will be entered as zero for calculation of mass balance parameters. 
When converting urine collection weights to urine volume (if required), the following 
conversion factor will be used: 
1.02 g of urine = 1 mL of urine 
This will be calculated in SAS as follows: 
Urine weight (g) / 1.02 = Urine volume (mL) 
If total radioactivity concentrations in urine have been provided in mass unit/g units the 
following conversion (if required) will be performed using SAS: 
Concentration (mass units/g) * 1.02 = Concentration (mass units/mL) 


    
 
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The radioactivity associated with toilet paper may be determined at the request of the 
sponsor. The results will be reported for each subject as a single value for the whole 
collection period and included in the calculation of amount excreted and % of dose 
recovered. 
Other unexpected sources of elimination will be collected as voided (ie, emesis) and 
samples will be shipped to Pharmaron for the analysis of total radioactivity. Such cases 
will be discussed with Med Day and details regarding the reporting will be documented. 
The actual dose, as received from Pharmaron, will be used for mass balance analysis. 
9.1.3 
Mass Balance Summary Tables 
Summary statistics (ie n, mean, SD, coefficient of variation [CV%], median, minimum 
and maximum) will be presented for amount excreted (Ae) and recovery (%Ae) by 
collection period for the following: 
 
urine [ie Ae(urine) and %Ae(urine)] for total radioactivity 
 
faeces [ie Ae(faeces) and %Ae(faeces)] for total radioactivity 
 
urine and faeces combined [ie Ae(total) and %Ae(total)] for total radioactivity 
In addition, summary statistics (ie n, mean, SD, CV%, median, minimum and maximum) 
will be presented for the cumulative excretion (CumAe) and cumulative recovery 
(Cum%Ae) by collection period for each of the following:  
 
urine [ie CumAe(urine) and Cum%Ae(urine)] for total radioactivity 
 
faeces [ie CumAe(faeces) and Cum%Ae(faeces)] for total radioactivity 
 
urine and faeces combined [ie CumAe(total) and Cum%Ae(total)] for total 
radioactivity 
Finally, summary statistics (ie n, mean, SD, CV%, median, minimum and maximum) will 
be presented for the cumulative excretion (CumAe) and cumulative recovery (Cum%Ae) 
for the study as a whole for each of the following: 
 
urine [ie CumAe(urine) and Cum%Ae(urine)] for total radioactivity 
 
faeces [ie CumAe(faeces) and Cum%Ae(faeces)] for total radioactivity 
 
urine and faeces combined [ie CumAe(total) and Cum%Ae(total)] for total 
radioactivity 
If any subject withdraws prior to the end of a study visit or if subjects have differing 
collection periods (eg Day 8 for some subjects and Day 10 for others) then a last 
observation carried forward (LOCF) approach will also be used whilst calculating 
cumulative Ae and %Ae (ie CumAe and Cum%Ae), where the last observed value will 
be carried forward to the subsequent collection period. If this is the case, then 2 tables 
will be presented. The first table will have the observed values without the use of LOCF 
so the number of subjects may reduce over time and the second table will have the LOCF 
values included so that the number of subjects will remain constant over time. Table 
numbering will be revised as applicable. 


    
 
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9.1.4 
Mass Balance Figures 
Arithmetic mean cumulative excretion (ie CumAe) and cumulative recovery (ie Cum%Ae) 
vs time curves will be produced on a linear/linear scale and will include ± SD bars. These 
plots will be produced for CumAe and Cum%Ae, separately, with urine, faeces and total 
overlaid. 
In addition, individual cumulative excretion (ie, CumAe) and cumulative recovery (ie, 
Cum%Ae) vs time curves will be produced on a linear/linear scale. These plots will be 
produced for CumAe and Cum%Ae, separately, with urine, faeces and total overlaid. 
A legend identifying each profile (ie urine, faeces and total) will be displayed on the mean 
plots. Mean figures will be produced using the LOCF imputation strategy (see 
Section 9.1.3) if summary tables are produced using this method. 
9.1.5 
Mass Balance Listings 
The sample collection data (eg collection times) for all urine and faecal samples will be 
listed by subject for enrolled subjects. In addition, all total radioactivity concentrations, 
urine and faecal weights and all mass balance parameters will be listed per subject. 
For urine and feces, where a subject has failed to void over a particular collection interval, 
the amount excreted (Ae) will be listed as “NS” in the data listings. 
Concentrations that are not detected (ie, < limit of detection (LOD)), will be listed as “ND” 
in the data listings. 
9.1.6 
Statistical Analysis of Mass Balance Parameters 
No formal statistical analysis is required for the mass balance data in this study. 
Descriptive statistics are considered adequate for a study of this type. 
9.2 
Pharmacokinetic Parameter Estimation and Reporting 
Charles River will provide plasma concentration data for MD1003, bisnorbiotin and biotin 
sulfoxide. Pharmaron will provide plasma and whole blood concentration data for total 
radioactivity. 
The PK parameters for MD1003, bisnorbiotin, biotin sulfoxide and total radioactivity in 
plasma (only) will be estimated by Quotient, where possible and appropriate for each 
subject using Phoenix WinNonlin software (v8.0 or a more recent version, Certara USA, 
Inc., USA). 
9.2.1 
Definition of Pharmacokinetic Parameters 
Plasma PK parameter definitions are provided in Table 2 and will be calculated for 
MD1003, bisnorbiotin, biotin sulfoxide and total radioactivity unless otherwise stated. 


    
 
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Table 2 
Plasma Pharmacokinetic Parameters and Rounding Specifications  
Parameter 
Definition 
Unit 
DP or 
SF 
No. of 
DP/SF 
Tlag 
Time prior to the first measurable 
concentration 
h 
DP 
2 
Tmax 
Time of maximum observed 
concentration 
h 
DP 
2 
Cmax 
Maximum observed concentration 
mass unit/mL 
SF 
3 
AUC(0-last) 
Area under the curve from 0 time to the 
last measurable concentration 
mass unit.h/mL 
SF 
3 
AUC(0-inf) 
Area under the curve from 0 time 
extrapolated to infinity 
mass unit.h/mL 
SF 
3 
AUCextrap 
Percentage of AUC(0–inf) extrapolated 
beyond the last measurable 
concentration 
% 
DP 
2 
T1/2  
Apparent elimination half-life 
h 
DP 
2 
lambda-z 
Slope of the apparent elimination phase 
1/h 
DP 
4 
CL/F 
(MD1003 only) 
Apparent total body clearance 
calculated after a single extravascular 
administration, where F (fraction of 
dose bioavailable) is unknown  
mL/min 
SF 
3 
Vz/F 
(MD1003 only) 
Apparent volume of distribution based 
on the terminal phase calculated after a 
single extravascular administration, 
where F (fraction of dose bioavailable) 
is unknown 
L 
SF 
3 
MPR Cmax 
Metabolite to parent ratio based on 
Cmax 
NA 
DP 
2 
MPR 
AUC(0-last) 
Metabolite to parent ratio based on 
AUC(0-last) 
NA 
DP 
2 
MPR 
AUC(0-inf) 
Metabolite to parent ratio based on 
AUC(0-inf) 
NA 
DP 
2 
TER Cmax 
Total exposure ratio based on Cmax 
NA 
DP 
2 
TER 
AUC(0-last) 
Total exposure ratio based on 
AUC(0-last) 
NA 
DP 
2 
TER AUC(0-inf) 
Total exposure ratio based on 
AUC(0-inf) 
NA 
DP 
2 
lambda-z lower* 
Lower limit on time for values to be 
included in the calculation of lambda-z 
h 
DP 
2 
lambda-z upper* 
Upper limit on time for values to be 
included in the calculation of lambda-z 
h 
DP 
2 
DP=decimal places 
SF=significant figures 
*=these values should be listed but omitted from the descriptive statistics 
NA=not applicable 
9.2.2 
Rules for Pharmacokinetic Parameter Estimation using WinNonlin 
The imputation of non-numerical or negative values reported in the input data set will be 
performed as follows: 
 
pre-dose sample times will be entered as zero 
 
values that are below the limit of quantification (BLQ) or not detected (ND) will be 
entered as zero 


    
 
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 
should partial AUCs be required then values that are BLQ or ND after Cmax may be 
imputed as zero for these partial areas if lambda-z cannot be determined 
 
values that are quantifiable after at least 2 consecutive BLQ or ND values after Cmax 
will be treated as missing for the calculation of PK parameters 
 
values that are reported as “No Result” (NR) or “No Sample” (NS) etc. will be treated 
as missing 
PK parameters will be estimated using standard Phoenix WinNonlin methods, details of 
which may be found in the documentation accompanying the WinNonlin software 
package. The following constraints will apply: 
Parameter Estimation 
Constraint 
Sampling times 
Actual 
Trapezoidal method 
Linear trapezoidal rule  
Number of points used for lambda-z 
At least 3, not including Cmax 
Minimum requirements for AUC  
At least 3 consecutive quantifiable concentrations 
Dose 
Actual 
Rounded dose level   
3 significant figures  
 
Prior to PK parameter estimation the bioanalytical data may be corrected to account for 
the proportion of administered [14C] material not measured due to the use of a [12C] LC-
MS/MS analysis method. Data correction will only be performed if the [14C]-contribution 
exceeds 1 % of the dose administered. If required, MD1003 bioanalytical data will be 
multiplied by the determined data correction factor in SAS by the lead statistical 
programmer (or designee). 
Where possible, the terminal elimination rate constant (lambda-z) will be calculated for 
all subjects. The value of lambda-z will be determined by the slope of the regression line 
of the natural log transformed concentrations vs time.  
The WinNonlin determined choice of data points for determination of lambda-z will be 
reviewed by the pharmacokineticist who may adjust the selection in order to provide a 
more appropriate fit. The choice of data points for determination of lambda-z for each 
profile will be confirmed following a documented peer review.  
Total radioactivity whole blood to plasma ratios will be determined using SAS by the Lead 
Statistical Programmer (or designee) at the time points: 1, 4, 8, 12, 24, 48, 72, 96 and 
168 h. If either the blood or plasma concentration values are ND (ie <LOD) at any given 
time point the ratio will not be calculated. 
When converting blood collection weights to blood volume (if required) for the calculation 
of the whole blood to plasma ratios, the following conversion factor will be used: 
1.06 g of blood = 1 mL of blood 
This will be calculated in SAS as follows: 
Blood weight (g) / 1.06 = Blood volume (mL) 


    
 
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Alternatively, where total radioactivity concentrations in blood have been provided in 
mass unit/g units the following conversion will be performed using SAS: 
Concentration (mass units/g) * 1.06 = Concentration (mass units/mL) 
Metabolite to parent ratios (MPR) after a single dose administration will be calculated as 
follows using Cmax, AUC(0-last) and AUC(0-inf). If for any reason the AUC(0-inf) is not 
calculable then an alternative AUC such as AUC(0-t) over a partial area may be used 
and will be agreed with MedDay:  
MPR = AUC or Cmax (metabolite)
AUC or Cmax (parent)
×
MW (parent)
MW(metabolite) 
 
Correcting for molecular weight (MW): 
 
parent (MD1003) MW = 244.31 g/mol 
 
metabolite (bisnorbiotin) MW = 216.26 g/mol 
 
metabolite (biotin sulfoxide) MW = 260.31 g/mol 
In addition, total exposure ratios (TER) will be calculated for MD1003, bisnorbiotin and 
biotin sulfoxide as follows using Cmax, AUC(0-last) and AUC(0-inf):  
TER(parent) =
AUC or Cmax (parent)
AUC or Cmax (parent + metabolites) 
TER(metabolite) =
AUC or Cmax (metabolite)
AUC or Cmax (parent + metabolites) 
 
Note that each analyte will be corrected by it’s own MW (as given above) for calculation 
of TER. 
9.2.3 
Bioanalytical and Pharmacokinetic Reporting Specifications 
PK parameters for each subject will be reported according to the definitions and rounding 
specifications provided in Table 2. The following flags/footnotes may be applied to the 
PK parameters: 
Flag 
Footnote 
a 
Rsq of regression was <0.9 
b 
Period used for regression analysis was less than 2-fold the calculated half-life 
c 
Extrapolated portion of AUC(0-inf) >20% 
d 
Insufficient post-Cmax data points for estimation of lambda-z 
e 
Entire profile BLQ, no pharmacokinetic parameters could be calculated 


    
 
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In the event that the Rsq of regression was <0.9 (“a” flag) or the extrapolated portion of 
AUC(0-inf) >20% (“c” flag), then lambda-z, AUC(0-inf) and the parameter estimates 
derived using lambda-z and/or AUC(0-inf) will be deemed unreliable and will be listed 
but excluded from the summary statistics. 
In the event that the period used for regression analysis was less than 2-fold the 
calculated half-life (“b” flag) parameter estimates derived using lambda-z will be listed, 
flagged and included in summary statistics. 
Additional flags may be applied based on emerging data. 
9.2.4 
Bioanalytical and Pharmacokinetic Summary Tables 
Summary statistics (ie n, mean, SD, CV%, median, minimum, maximum, geometric n, 
geometric mean, geometric SD and geometric CV%) will be calculated for the following 
concentration data where possible: 
 
plasma concentrations of MD1003 by time point  
 
plasma concentrations of bisnorbiotin by time point  
 
plasma concentrations of biotin sulfoxide by time point  
 
plasma concentrations of total radioactivity by time point  
 
whole blood concentrations of total radioactivity by time point  
 
whole blood:plasma concentration ratio of total radioactivity by time point  
Values reported in the plasma and whole blood concentration data (ie values that are 
BLQ or ND) will be entered as zero for the determination of summary statistics with the 
exception of geometric mean parameters where BLQ or ND values will be imputed as 
half the LLOQ or LOD value. Data recorded as NR or NS will be handled as missing, ie 
no assumption will be made about the actual concentration. 
Summary statistics (ie n, mean, SD, CV%, median, minimum and maximum) will be 
calculated for all plasma PK parameters. Geometric n, geometric mean, geometric SD 
and geometric CV% will be presented for all PK parameters except Tlag and Tmax. 
These summary statistics will be calculated for relevant plasma PK parameters relating 
to the following: 
 
MD1003 
 
bisnorbiotin 
 
biotin sulfoxide 
 
total radioactivity  
If applicable, data recorded as “Not Calculated” (NC) will be handled as missing.  
9.2.5 
Bioanalytical and Pharmacokinetic Figures 
Mean and individual concentration plots will be produced for each of the following: 
 
plasma concentrations of MD1003, bisnorbiotin, biotin sulfoxide and total 
radioactivity on same plot  
 
plasma and whole blood concentrations of total radioactivity on the same plot 


    
 
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Individual concentration vs time plots (using actual sampling times after dosing) will be 
produced on the linear/linear and the log10/linear scale for each individual subject. 
Mean concentration vs time (using nominal times) plots will be produced on the following: 
 
linear/linear scale using arithmetic mean concentrations (error bars ± arithmetic SD) 
 
log10/linear scale using geometric mean concentrations (error bars x/÷ geometric 
SD) 
Separate concentration vs time (using actual sampling time) plots displaying 1 line per 
subject will be produced on the linear/linear and the log10/linear for each of the following: 
 
plasma MD1003 
 
plasma bisnorbiotin 
 
plasma biotin sulfoxide 
 
plasma total radioactivity  
 
whole blood total radioactivity 
Where curves from multiple analytes or subjects are overlaid on the same plot, symbols 
will be used to identify different analytes/subjects. A legend will be included on these 
plots to define the symbols used in identifying different profiles. 
For all plots on a linear/linear scale, concentration values reported as BLQ or ND will be 
set to zero. For all plots on a log 10/linear scale then concentration values reported as 
BLQ will be set to ½ x LLOQ or LOD and pre-dose samples on Day 1 will not be plotted. 
9.2.6 
Bioanalytical and Pharmacokinetic Listings 
The sample collection data (eg collection times) for PK samples will be listed by subject. 
In addition, all concentration data including individual ratios (total radioactivity whole 
blood:plasma) and PK parameters will be listed on a per subject basis. Any flags used 
will be provided in listings with the appropriate definition. 
9.2.7 
Statistical Analysis of Pharmacokinetic Parameters 
No formal statistical analysis will be performed for the PK data in this study. Descriptive 
statistics are considered adequate for a study of this type. 
10 Safety Assessments 
Safety data summaries will be presented using the safety analysis set, throughout. 
10.1 
Extent of Exposure and Treatment Compliance 
The total dose given, including the dose of MD1003 (in mg) and radioactivity in µCi and 
MBq, will be summarised (ie n, mean, SD, median, minimum and maximum). 
Dosing details (including the date and time of IP administration and any comments) will 
be listed for all enrolled subjects. Dose will be reported to 3 significant figures in listings. 
Any recorded deviations from the planned dosing regimen will be listed as protocol 
deviations.  


    
 
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10.2 
Meal Details 
Meal details as recorded on the eCRF as sponsor data will be listed. Any recorded 
deviations from the planned meal times will be listed as protocol deviations. 
10.3 
Adverse Events 
Throughout the study, all AEs will be evaluated by the principal investigator (PI) and 
noted in the AE section of the eCRF. 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 (referred as TEAEs), including occurrences 
which are not necessarily caused by or related to that product. 
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA v22.1, 
or most recent version), and reported by system organ class (SOC) and preferred term 
(PT). 
AEs will be classified into the following categories: 
 
pre-dose AEs: AEs recorded at screening or with a start date and time prior to the 
dose of IP  
 
treatment-emergent adverse events (TEAEs): AEs that commence during/after the 
dose of IP or commence before dose of IP (ie a pre-dose AE or existing medical 
condition) but worsen in intensity during exposure to IP 
Where the severity of a pre-dose AE intensifies during/after dosing this will be defined 
as a new AE and classified as a TEAE. 
Adverse events will be classified as “unrelated”, “possibly related” and “related” when 
considering their relationship to IP. Adverse drug reactions (ADRs) are any AE where a 
causal relationship with the IP is at least reasonable possibility ie “possibly related” or 
“related”. Pre-dose AEs will always have the classification of “unrelated”.  
Adverse events will be classified as “mild,” “moderate” or “severe” when considering their 
severity. 
If the severity or relationship to IP of a TEAE is missing, the severity/relationship will be 
tabulated as “severe”/”related” in the summary tables ie a worst case scenario will be 
assumed. 
Where the start date of an AE is missing and the stop date is on or after the day of dosing 
of IP or both the start and stop dates are missing then a “worst-case” scenario will be 
assumed, ie the AE is assumed to have occurred post-dose and is therefore considered 
treatment-emergent. If a partial start date/time is available then the event will be 
considered as treatment-emergent unless the partial information suggests otherwise. 
10.3.1 
Summary Tables for Adverse Events 
All pre-dose AEs (as defined in Section 10.3) will be excluded from the summary tables 
but will be listed for all enrolled subjects.  
Descriptive statistical methods will be used to summarise the TEAE data.  


    
 
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The number and percentage of subjects reporting each TEAE will be summarised for 
both SOC and PT. For summaries by SOC and PT, the number of subjects and the 
number of events will be summarised.  
For counts of subjects experiencing events the following will apply: 
 
a subject with a TEAE in more than one body system will be counted once in the 
total number of subjects with TEAEs; 
 
a subject with more than 1 TEAE in the same SOC counts only once at the SOC 
level; 
 
a subject with more than 1 TEAE in the same PT counts only once at the PT level. 
For event counts, all events are included. 
When it is necessary to calculate percentages, the denominator will be the total number 
of subjects in the safety analysis set and the numerator will be the total number of 
subjects reporting a TEAE within the relevant category. 
Summaries presented for SOC and PT will be presented in descending order of 
frequency overall ie most frequently reported SOC in the study and then by most 
frequently reported PT in the study within each SOC. 
10.3.1.1 
Overall Summary of Adverse Events 
The following will be summarised for the safety analysis set: 
 
number and percentage of subjects reporting at least one TEAE 
 
number and percentage of subjects reporting severe TEAEs 
 
number and percentage of subjects reporting ADRs 
 
number and percentage of subjects reporting serious TEAEs 
 
number and percentage of subjects reporting TEAEs leading to death 
 
total number of TEAEs  
 
total number of severe TEAEs 
 
total number of ADRs 
 
total number of serious TEAEs 
 
total number of TEAEs leading to death 
10.3.1.2 
Summary of Treatment-Emergent Adverse Events by System Organ 
Class and Preferred Term 
All subjects reporting TEAEs will be summarised. Counts will be given for number of 
subjects and number of events. Subjects experiencing more than 1 TEAE will be counted 
only once for number of subjects but will be counted more than once for number of 
events.  


    
 
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Additionally, subjects reporting TEAEs will be summarised for SOC and PT. Counts will 
be given for number of subjects and number of events. For programming purposes 
counts of number of subjects will be by maximum severity ie subjects experiencing more 
than 1 episode of a TEAE will be counted only once within each SOC and PT using the 
most severe episode.  
10.3.1.3 
Summary of Treatment-Emergent Adverse Events by Severity 
All subjects reporting TEAEs will be summarised by severity (“mild”, “moderate” or 
“severe”). Counts will be given for number of subjects and number of events. Counts for 
number of subjects will be given by severity category (ie subjects experiencing more than 
1 TEAE across severity categories will be counted only once by severity category). 
Additionally, subjects reporting TEAEs will be summarised for SOC and PT by severity 
(ie “mild”, “moderate” or “severe”). Counts will be given for total number of subjects and 
number of events. Counts for number of subjects will be given by severity category (ie 
subjects experiencing more than 1 TEAE across severity categories will be counted only 
once within each SOC and PT by severity category). 
10.3.1.4 
Summary of Treatment-Emergent Adverse Events by Relationship to 
IP 
All subjects reporting TEAEs will be summarised by relationship to IP (ie “unrelated”, 
“possibly related” or “related”). Counts will be given for number of subjects and number 
of events. Counts for number of subjects will be given by level of relationship to IP (ie 
subjects experiencing more than 1 TEAE across relationship to IP categories will be 
counted only once by level of relationship). 
Additionally, subjects reporting TEAEs will be summarised for SOC and PT by level of 
relationship to IP (ie “unrelated”, “possibly related” or “related”). Counts will be given for 
total number of subjects and number of events. Counts for number of subjects will be 
given by level of relationship (ie subjects experiencing more than 1 TEAE across 
relationship to IP categories will be counted only once within each SOC and PT by level 
of relationship). 
10.3.1.5 
Summary of Adverse Drug Reactions 
All subjects reporting ADRs will be summarised. Counts will be given for number of 
subjects and number of events. Subjects experiencing more than 1 ADR will be counted 
only once for number of subjects but will be counted more than once for number of 
events.  
Additionally, subjects reporting ADRs will be summarised for SOC and PT. Counts will 
be given for number of subjects and number of events. For programming purposes 
counts of number of subjects will be by maximum severity ie subjects experiencing more 
than 1 episode of an ADR will be counted only once within each SOC and PT using the 
most severe episode.  


    
 
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10.3.1.6 
Summary of Serious Adverse Events 
All subjects reporting serious adverse events (SAEs) will be summarised. Counts will be 
given for number of subjects and number of events. Subjects experiencing more than 1 
SAE will be counted only once for number of subjects but will be counted more than once 
for number of events.  
Additionally, subjects reporting SAEs will be summarised for SOC and PT. Counts will 
be given for number of subjects and number of events. For programming purposes 
counts of number of subjects will be by maximum severity ie subjects experiencing more 
than 1 episode of a SAE will be counted only once within each SOC and PT using the 
most severe episode.  
10.3.2 
Listings for Adverse Events 
All pre-dose AEs (as defined in Section 10.3) will be listed including SOC and PT. 
A separate data listing of all TEAEs will be provided including the SOC and PT. In 
addition separate listings of all TEAEs leading to deaths and SAEs will be provided. 
10.4 
Laboratory Evaluations 
The details of sample collection for laboratory safety analysis are described in the study 
protocol. 
Where a value is provided by the safety laboratory as either above or below the LOD this 
will be set to the respective LOD itself for descriptive summaries. No imputations will be 
made in the individual listings. 
10.4.1 
Summary Tables for Laboratory Evaluations 
Haematology and clinical chemistry data will be summarised (ie n, mean, SD, median, 
minimum and maximum) for each laboratory parameter at each time point, including 
changes from baseline (pre-dose, Day 1) at the 24 h and discharge (planned to be 168 
h) post-baseline time point. 
Shift tables from baseline to 24 h and discharge post-baseline time point (with respect to 
the number and percentage of subjects with values below, within or above the reference 
range) will be presented. Percentages will be based on the number of subjects with 
measurements at baseline and the 24 h and discharge post-baseline time points. 
Note that the clinical chemistry parameters glucose (fasting) and glucose (random) are 
treated as separate parameters. Glucose (fasting) will be presented in the summary 
statistic and shift tables if there is pre-dose and post-dose readings for subjects. Glucose 
(random) will be listed only. 
Reference ranges for each laboratory parameter will be presented for the relevant 
parameter in each summary table. 
10.4.2 
Listings for Laboratory Evaluations 
The sample collection data (eg collection times) for laboratory analysis and urinalysis 
data will be listed. 


    
 
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All individual subject data, for planned haematology, clinical chemistry and urinalysis 
data including derivations such as change from baseline will be listed. If applicable, data 
from unscheduled laboratory tests will also be listed and flagged with a “#” to indicate it 
will not be used in the summary statistics. In these listings, individual data will be flagged 
with an “H” or an “L” for values that are higher or lower than their reference ranges, 
respectively. 
Separate listings of haematology, clinical chemistry and urinalysis values outside their 
reference ranges by subject will also be provided. References ranges will be supplied by 
the safety laboratory for haematology and clinical chemistry and per the eCRF for 
urinalysis (ie a positive or negative result) with the exception of the following reference 
ranges for urinalysis: 
 
pH: 5.0 to 8.0 
 
Specific gravity: 1.005 to 1.035 
10.5 
Vital Signs 
The details of measurement of supine vital signs are described in the study protocol. 
10.5.1 
Summary Tables for Vital Signs 
Vital signs data (ie systolic and diastolic blood pressure [BP] and heart rate), including 
change from baseline (pre-dose, Day 1), will be summarised (ie n, mean, SD, median, 
minimum and maximum) at each post-baseline time point. 
In addition, the number of subjects with ‘substantial’ increases or decreases or no 
substantial change from baseline in systolic BP (>20 mmHg), diastolic BP (>10 mmHg) 
and heart rate (>15 bpm) will be summarised. 
10.5.2 
Listings for Vital Signs 
All individual vital signs data (ie systolic and diastolic BP, heart rate and oral temperature) 
including derivations such as change from baseline will be listed. Individual data will be 
flagged with an “H” or an “L” for values that are higher or lower than their reference 
ranges (see Table 3), respectively, and subjects with ‘substantial’ increases or decreases 
from baseline (as defined in Section 10.5.1) in systolic BP, diastolic BP and heart rate 
will be flagged with an ‘I’ (increase) or ‘D’ (decrease), respectively. If applicable, data 
from unscheduled vital signs assessments will also be listed and flagged with a “#” to 
indicate it will not be used in the summary statistics. 
In addition, a separate listing of all vital signs data outside their reference ranges by 
subject will be provided.  
The reference ranges (from Quotient SOP “The Interpretation of the Electrocardiogram, 
Vital Signs and Clinical Laboratory Data During Phase I / II Clinical Trials) defined in 
Table 3 will be used.  


    
 
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Table 3 
Vital Signs Reference Ranges 
Parameter 
Split 
Lower limit 
Upper limit 
Systolic BP 
18-45 years 
90 mmHg 
140 mmHg 
Systolic BP 
>45 years 
90 mmHg 
160 mmHg 
Diastolic BP 
NA 
40 mmHg 
90 mmHg 
Heart rate 
NA 
40 bpm 
100 bpm 
Oral Body Temperature 
NA 
35.5ºC 
37.5ºC 
NA=Not applicable 
10.6 
ECGs 
The details of measurement of supine ECG parameters (ie ventricular rate, QT interval, 
QTcF interval, PR interval, QRS duration, QRS axis, rhythm and interpretation) are 
described in the study protocol. ECG parameters will be reported in the order given 
above in both summary tables and data listings. 
10.6.1 
Summary Tables for ECGs 
ECG data, including change from baseline (pre-dose, Day 1), will be summarised (ie n, 
mean, SD, median, minimum and maximum) at each post-baseline time point. 
The number and percentage of subjects with normal and prolonged QT intervals 
corrected for heart rate using Fridericia’s correction (ie QTcF) and increases in QTcF 
intervals from baseline within the categories defined in Table 4 (based on the 
International Council on Harmonisation [ICH] E14 guideline [1]) will be summarised by 
time point. Percentages will be based on the number of subjects with measurements at 
the relevant time point. 
Table 4 
ICH E14 Ranges for QTcF Intervals 
Parameter 
ICH E14 Range 
QTcF intervals 
≤450 msec (normal) 
451-480 msec 
481-500 msec 
>500 msec 
Increase in QTcF interval from 
baseline 
<30 msec 
30-60 msec 
>60 msec 
10.6.2 
Listings for ECGs 
All ECG measurements (ie single readings) including derivations such as change from 
baseline will be listed by subject for all enrolled subjects.  
Individual ECG measurements will be flagged with an “H” or an “L” for values that are 
higher or lower than their reference ranges, respectively. If applicable, data from 
unscheduled ECG assessments will also be listed and flagged with a # to indicate it will 
not be used in the summary statistics. 


    
 
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In addition, measurements with increase in QTcF interval from baseline (30-60 msec) 
and with ‘substantial increases’ (>60 msec) will be flagged with ‘I’ and ‘SI’, respectively. 
A separate listing of all ECG parameters outside their reference range by subject will 
also be provided. 
The reference ranges (from Quotient SOP “The Interpretation of the Electrocardiogram, 
Vital Signs and Clinical Laboratory Data During Phase I / II Clinical Trials”) and defined 
in Table 5 will be used. Note that QT interval will not be presented with a respective 
reference range. 
Table 5 
ECG Reference Ranges 
Parameter 
Lower limit 
Upper limit 
Ventricular Rate (HR) 
40 
100 
QTcF Interval 
NA 
450 msec 
PR Interval 
120 msec 
220 msec 
QRS Duration 
NA 
120 msec 
QRS Axis 
-30º 
100º 
HR=heart rate 
NA=Not applicable 
10.7 
Physical Examination  
All physical examination details and comments on any physical examination findings will 
be listed by subject for all enrolled subjects. 
11 Interim Statistical Analyses 
No interim statistical analysis is planned for this study. 
12 Changes in the Conduct of the Study or Planned Analysis 
12.1 
Changes in the Conduct of the Study 
No changes in the conduct of the study had been reported at the time this document was 
written. 
12.2 
Changes to the Planned Analyses 
No changes to planned analysis. 
12.3 
Any Other Relevant Changes 
Not applicable. 
13 Overall Considerations 
13.1 
Statistical Programming and Analysis 
The Data Sciences Department at Quotient will perform the statistical programming and 
analysis to produce all analysis datasets and TFLs using the statistical SAS Software 
v9.4. 


    
 
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In general terms, categorical data will be presented using counts and percentages, whilst 
continuous variables will be presented using n, mean, SD, median, minimum and 
maximum. For PK data additional statistics including CV%, geometric n, geometric 
mean, geometric SD and geometric CV% will be presented, as appropriate. The 
geometric n is the number of subjects included in the calculation of the geometric mean, 
geometric SD and geometric CV%. 
The geometric mean is obtained by applying a natural log transformation to the raw data, 
calculating the arithmetic mean of the transformed values and then back transforming 
the arithmetic mean. 
The following formula will be used to calculate the geometric SD: 
 
ie a natural log transformation is applied to the raw data, the arithmetic SD of the 
transformed values is calculated, and then the arithmetic SD of the transformed values 
is back transformed. 
The following formula will be used to calculate the geometric CV%: 
 
ie a natural log transformation is applied to the raw data, the arithmetic SD of the 
transformed values is calculated. This value is then squared. The square value is back 
transformed and a value of 1 is subtracted from the back transformed value. A square 
root is then applied and the resulting value is multiplied by 100. 
In general summary statistics will be presented as detailed in Table 6 below, unless 
otherwise stated: 
Table 6 
Reporting Conventions for Summary Statistics  
Data Type 
Statistic 
Number of decimal places for reporting (i) 
Frequency 
Counts (n) 
None 
Percentages (%) 
1 decimal place 
Summary statistic 
n 
None 
Mean 
i + 1 decimal place 
SD 
i + 1 decimal place 
CV% 
1 decimal place 
Median 
i + 1 decimal place 
Min 
i decimal places 
Max 
i decimal places 
Geometric n 
None 
Geometric Mean 
i + 1 decimal place 
Geometric SD 
i + 1 decimal place 
Geometric CV% 
1 decimal place 
i refers to the number of decimal places reported in the eCRF or other appropriate source data for the original 
data. Where bioanalytical or PK data are received rounded in significant figures rather than decimal places, 
summary statistics will be supplied to the same precision. 
Details of how the individual mass balance and PK parameters will be presented are 
detailed in Section 9.1.1 and Section 9.2.1, respectively. Where data requires rounding, 


    
 
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values ending with 1 to 4 will be rounded down and values ending with 5 to 9 will be 
rounded up. 
All data listings will be based on all enrolled subjects (see Section 3.2.1). Details of age 
and sex will be included on all data listings. 
If any baseline measurements are found to be missing then consideration will be given 
to imputation using the preceding time point (eg Screening, Admission, if applicable). 
Unscheduled assessment may be used if appropriate. Details of any such imputations 
will be documented as part of the safety population. 
There will be no other imputations for the safety data with regard to missing values or 
study discontinuation (ie subjects who do not complete the study). Imputation for mass 
balance parameter estimation using SAS Software is described in Section 9.1.2 and for 
PK parameter estimation using WinNonlin is described in Section 9.2.2. 
If partial dates are available for smoking history, prior medications or medical/surgical 
history, there will be no date imputations. The data listings will only show the date 
information for the date part that is available eg if only the year part of the date is available 
then YYYY will be presented in the listing. If the full date information is missing, then this 
will be presented as missing on the data listing. 
13.2 
Quality Control of Summary Tables, Figures and Listings and Statistical 
Analysis 
Isolated data errors detected as a result of the QC checks that are deemed significant 
(ie errors that would impact the interpretation of the results in relation to the study 
objectives) will be corrected as per the data management plan. Systematic data errors 
will be investigated further. The data will be corrected if necessary, and the appropriate 
table, figure, and/or listing re-generated and then re-checked. 
In addition to QC checks, a documented peer review will be performed of all SAS 
Software-generated report standard summary tables, figures and data listings, including 
a review of SAS Software code and program log files. 
13.2.1 
Quality Control - Summary Tables 
Manual QC methods (ie comparison of results in the table to results calculated by a 
calculator or spreadsheet) will be used for all summary tables. All summary tables will 
be QC’d as follows: 
 
for tables with no time points, all summary statistics will be QC’d 
 
for tables with time points, at least one time point in each table will be QC’d – different 
combinations of time point will be selected across tables 
 
where tables are produced using a macro for multiple parameters, a minimum of 3 
tables, using treatment and time point as appropriate, will be QC’d 
 
for AEs, the treatment details will be 100% QC’d against the treatment allocation list 
for all subjects 
 
AE summary tables will be 100% checked using the relevant data listing 


    
 
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13.2.2 
Quality Control - Figures 
All figures will be QC’d manually using the corresponding/appropriate summary table or 
data listing, as follows: 
 
all data points for treatment will be checked 
 
where figures are produced using a macro for individual subjects and/or multiple 
parameters, a minimum of 3 figures will be QC’d 
 
mean figures will be QC’d using the corresponding summary table 
13.2.3 
Quality Control - Data Listings 
All data listings will be subjected to a 100% manual check against the eCRF or other 
appropriate source data for a minimum of 2 subjects. If appropriate, the subjects checked 
will include at least one subject who withdrew early from the study. 
14 SAS Data Transfer 
All study data used for analysis and reporting will be transferred to MedDay on issue of 
the final CSR. Datasets will be provided in SAS transport file format (XPT), each dataset 
will be in an individual transport file and will be performed in compliance with SDTM 
(IG v3.2) and ADaM (IG v1.1). This will include define.xml (v2.0) output as well as a Data 
Reviewers Guide (one for SDTM and one for ADaM) in PDF which will be linked to the 
ADaM define.xml. The define.xml will be issued on finalisation of the CSR. 
In addition, copies of reporting SAS programs will be provided with the final data transfer 
(as executable files). This transfer will also include SDTM/ADaM specs, ‘raw’ database 
extract datasets, external vendor datasets (with transfer specs) and the database and 
dataset annotated eCRFs. 
15 Programming Conventions 
Quotient standards for layout of tables, figures and data listings and programming 
conventions will be used as follows: 
 
courier new, font size 8 
 
landscape 
 
A4 paper 
Tables and listings will be produced as MS Word 2016 documents and figures will be 
produced as RTF and PDF files. Listings will be sorted by subject ID number. 
The mock tables (Section 20) presented are a representation of Quotient reporting 
standards. However these are provided for illustrative purposes only. The numbering 
and titles of all TFLs and the formatting, labelling, footnotes and cosmetic appearance of 
tables may be modified or additional labelling/footnotes may need to be added during 
analysis and reporting, for clarification purposes. Any such changes will not be regarded 
as changes to planned analyses. 


    
 
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16 Reference List 
[1] International Council for Harmonisation (ICH) Topic E 14, The Clinical Evaluation of 
QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic 
Drugs Guidelines approved by the Committee for Medicinal Products for Human Use 
(CHMP) in May 2005 which came into force November 2005. 
 
 
 


    
 
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17 Index of Tables 
Table 
Number 
Table Title 
 
Subject Disposition, Populations and Datasets 
14.1.1 
Subject Disposition by Reason 
Summary Statistics: All Enrolled Subjects 
14.1.2.1 
Analysis Populations 
Summary Statistics: All Enrolled Subjects 
14.1.2.2.1 
Safety Analysis Set 
Summary Statistics: Safety Population 
14.1.2.2.2 
Mass Balance Analysis Set 
Summary Statistics: Mass Balance Population 
14.1.2.2.3 
PK Analysis Set 
Summary Statistics: PK Population 
 
Demographic and Baseline Characteristics 
14.1.3 
Demographic and Baseline Characteristics 
Summary Statistics: Safety Analysis Set 
14.1.4 
Lifestyle Details: Smoking History and Alcohol Consumption at Baseline 
Summary Statistics: Safety Analysis Set 
 
Concomitant Medications 
14.1.5 
Concomitant Medications 
Summary Statistics: Safety Analysis Set 
 
Dosing Details 
14.1.6 
Extent of Exposure 
Summary Statistics: Safety Analysis Set 
 
Excretion and Recovery – Urine  
14.2.1.1.1 
Excretion: Total Radioactivity 
Ae(Urine) by Collection Period <(units)> 
Summary Statistics: Mass Balance Analysis Set 
14.2.1.1.2 
Excretion: Total Radioactivity 
Cumulative Ae(Urine) <(units)> 
Summary Statistics: Mass Balance Analysis Set 
14.2.1.1.3 
Recovery: Total Radioactivity 
%Ae(Urine) by Collection Period <(units)> 
Summary Statistics: Mass Balance Analysis Set 
14.2.1.1.4 
Recovery: Total Radioactivity 
Cumulative %Ae(Urine) <(units)> 
Summary Statistics: Mass Balance Analysis Set 


    
 
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Table 
Number 
Table Title 
 
Excretion and Recovery – Faeces  
14.2.1.2.1 
Excretion: Total Radioactivity 
Ae(Faeces) by Collection Period <(units)> 
Summary Statistics: Mass Balance Analysis Set 
14.2.1.2.2 
Excretion: Total Radioactivity 
Cumulative Ae(Faeces) <(units)> 
Summary Statistics: Mass Balance Analysis Set 
14.2.1.2.3 
Recovery: Total Radioactivity  
%Ae(Faeces) by Collection Period <(units)> 
Summary Statistics: Mass Balance Analysis Set 
14.2.1.2.4 
Recovery: Total Radioactivity 
Cumulative %Ae(Faeces) <(units)> 
Summary Statistics: Mass Balance Analysis Set 
 
Excretion and Recovery – Urine and Faeces Combined 
14.2.1.3.1 
Excretion: Total Radioactivity 
Ae(Total) by Collection Period <(units)> 
Summary Statistics: Mass Balance Analysis Set 
14.2.1.3.2 
Excretion: Total Radioactivity 
Cumulative Ae(Total) <(units)> 
Summary Statistics: Mass Balance Analysis Set 
14.2.1.3.3 
Recovery: Total Radioactivity  
%Ae(Total) by Collection Period <(units)> 
Summary Statistics: Mass Balance Analysis Set 
14.2.1.3.4 
Recovery: Total Radioactivity 
Cumulative %Ae(Total) <(units)> 
Summary Statistics: Mass Balance Analysis Set 
 
Cumulative Excretion and Recovery Parameters 
14.2.1.4 
Excretion and Recovery: Total Radioactivity 
Cumulative Excretion and Recovery Parameters 
Summary Statistics: Mass Balance Analysis Set 
 
Plasma and Whole Blood Pharmacokinetic Concentrations 
14.2.1.5.1 
Plasma Pharmacokinetic Concentrations: MD1003 <(units)> 
Summary Statistics: PK Analysis Set 
14.2.1.5.2 
Plasma Pharmacokinetic Concentrations: Bisnorbiotin <(units)> 
Summary Statistics: PK Analysis Set 
14.2.1.5.3 
Plasma Pharmacokinetic Concentrations: Biotin Sulfoxide <(units)> 
Summary Statistics: PK Analysis Set 


    
 
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Table 
Number 
Table Title 
14.2.1.5.4 
Plasma Pharmacokinetic Concentrations: Total Radioactivity <(units)> 
Summary Statistics: PK Analysis Set 
14.2.1.5.5 
Whole Blood Pharmacokinetic Concentrations: Total Radioactivity <(units)> 
Summary Statistics: PK Analysis Set 
14.2.1.5.6 
Whole Blood: Plasma Pharmacokinetic Concentrations Ratios: Total 
Radioactivity 
Summary Statistics: PK Analysis Set 
 
Plasma Pharmacokinetic Parameters 
14.2.2.1 
Plasma Pharmacokinetic Parameters: MD1003 
Summary Statistics: PK Analysis Set 
14.2.2.2 
Plasma Pharmacokinetic Parameters: Bisnorbiotin 
Summary Statistics: PK Analysis Set 
14.2.2.3 
Plasma Pharmacokinetic Parameters: Biotin Sulfoxide 
Summary Statistics: PK Analysis Set 
14.2.2.4 
Plasma Pharmacokinetic Parameters: Total Radioactivity 
Summary Statistics: PK Analysis Set 
 
Adverse Events 
14.3.1 
Overall Summary of Treatment-Emergent Adverse Events 
Summary Statistics: Safety Analysis Set 
14.3.2 
Treatment-Emergent Adverse Events 
By MedDRA System Organ Class and Preferred Term 
Summary Statistics: Safety Analysis Set 
14.3.3 
Treatment-Emergent Adverse Events 
By MedDRA System Organ Class, Preferred Term and Severity 
Summary Statistics: Safety Analysis Set 
14.3.4 
Treatment-Emergent Adverse Events 
By MedDRA System Organ Class, Preferred Term and Relationship to IP 
Summary Statistics: Safety Analysis Set 
14.3.5 
Adverse Drug Reactions 
By MedDRA System Organ Class and Preferred Term  
Summary Statistics: Safety Analysis Set 
14.3.6 
Serious Adverse Events 
By MedDRA System Organ Class and Preferred Term  
Summary Statistics: Safety Analysis Set 
 
Laboratory Results 
14.4.1 
Haematology 
Summary Statistics: Safety Analysis Set 
Parameter <(units)> 


    
 
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Table 
Number 
Table Title 
14.4.2 
Haematology 
Shift Analysis: Safety Analysis Set 
Parameter <(units)> 
14.4.3 
Clinical Chemistry 
Summary Statistics: Safety Analysis Set 
Parameter <(units)> 
14.4.4 
Clinical Chemistry 
Shift Analysis: Safety Analysis Set 
Parameter <(units)> 
 
Vital Signs and ECG Results 
14.5.1 
Vital Signs 
Summary Statistics: Safety Analysis Set 
Parameter <(units)> 
14.5.2.1 
ECGs  
Summary Statistics: Safety Analysis Set 
Parameter <(units)> 
(Programming note: The order of ECG parameters is to be as per Section 
10.5) 
14.5.2.2 
ECGs 
QTcF Categorical Data 
Summary Statistics: Safety Analysis Set 


    
 
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18 Index of Figures 
Figure 
Number 
Figure Title 
 
Cumulative Excretion and Recovery 
14.2.1.1 
Mean Cumulative Excretion of Total Radioactivity 
CumAe(Urine), CumAe(Faeces) and CumAe(Total) 
Linear/Linear Scale 
Arithmetic Mean (± Arithmetic SD) Values: Mass Balance Analysis Set  
14.2.1.2 
Mean Cumulative Recovery of Total Radioactivity 
Cum%Ae(Urine), Cum%Ae(Faeces) and Cum%Ae(Total) 
Linear/Linear Scale 
Arithmetic Mean (± Arithmetic SD) Values: Mass Balance Analysis Set  
14.2.1.3 
Cumulative Excretion of Total Radioactivity 
CumAe(Urine), CumAe(Faeces) and CumAe(Total) 
Linear/Linear Scale 
Individual Values for Subject <xxx>: Mass Balance Analysis Set 
 
(Programming note: Subjects will be plotted on separate pages) 
14.2.1.4 
Cumulative Recovery of Total Radioactivity 
Cum%Ae(Urine), Cum%Ae(Faeces) and Cum%Ae(Total) 
Linear/Linear Scale 
Individual Values for Subject <xxx>: Mass Balance Analysis Set 
 
(Programming note: Subjects will be plotted on separate pages) 
 
Plasma and Whole Blood Pharmacokinetic Concentrations 
14.2.2.1 
Plasma Pharmacokinetic Concentrations: MD1003, Bisnorbiotin, Biotin 
Sulfoxide and Total Radioactivity <(units)> 
Linear/Linear Scale 
Arithmetic Mean (±Arithmetic SD) Values: PK Analysis Set 
14.2.2.2 
Plasma Pharmacokinetic Concentrations: MD1003, Bisnorbiotin, Biotin 
Sulfoxide and Total Radioactivity <(units)> 
Log10/Linear Scale 
Geometric Mean (×/÷ Geometric SD) Values: PK Analysis Set 
14.2.3.1 
Plasma and Whole Blood Pharmacokinetic Concentrations: Total 
Radioactivity <(units)> 
Linear/Linear Scale 
Arithmetic Mean (±Arithmetic SD) Values: PK Analysis Set 
14.2.3.2 
Plasma and Whole Blood Pharmacokinetic Concentrations: Total 
Radioactivity <(units)> 
Log10/Linear Scale 
Geometric Mean (×/÷ Geometric SD) Values: PK Analysis Set 


    
 
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Figure 
Number 
Figure Title 
14.2.4.1 
Plasma Pharmcokinetic Concentrations: MD1003 <(units)> 
Linear/Linear 
Spaghetti Plot of All Individual Values: PK Analysis Set 
14.2.4.2 
Plasma Pharmcokinetic Concentrations: MD1003 <(units)> 
Log10/Linear 
Spaghetti Plot of All Individual Values: PK Analysis Set 
14.2.5.1 
Plasma Pharmcokinetic Concentrations: Bisnorbiotin <(units)> 
Linear/Linear 
Spaghetti Plot of All Individual Values: PK Analysis Set 
14.2.5.2 
Plasma Pharmcokinetic Concentrations: Bisnorbiotin <(units)> 
Log10/Linear 
Spaghetti Plot of All Individual Values: PK Analysis Set 
14.2.6.1 
Plasma Pharmcokinetic Concentrations: Biotin Sulfoxide <(units)> 
Linear/Linear 
Spaghetti Plot of All Individual Values: PK Analysis Set 
14.2.6.2 
Plasma Pharmcokinetic Concentrations: Biotin Sulfoxide <(units)> 
Log10/Linear 
Spaghetti Plot of All Individual Values: PK Analysis Set 
14.2.7.1 
Plasma Pharmcokinetic Concentrations: Total Radioactivity <(units)> 
Linear/Linear 
Spaghetti Plot of All Individual Values: PK Analysis Set 
14.2.7.2 
Plasma Pharmcokinetic Concentrations: Total Radioactivity <(units)> 
Log10/Linear 
Spaghetti Plot of All Individual Values: PK Analysis Set 
14.2.8.1 
Whole Blood Pharmcokinetic Concentrations: Total Radioactivity 
<(units)> 
Linear/Linear 
Spaghetti Plot of All Individual Values: PK Analysis Set 
14.2.8.2 
Whole Blood Pharmcokinetic Concentrations: Total Radioactivity 
<(units)> 
Log10/Linear 
Spaghetti Plot of All Individual Values: PK Analysis Set 
14.2.9.1 
Plasma Pharmacokinetic Concentrations: MD1003, Bisnorbiotin, Biotin 
Sulfoxide and Total Radioactivity <(units)> 
Linear/Linear Scale 
Individual Values for Subject <xxx>: PK Analysis Set 
14.2.9.2 
Plasma Pharmacokinetic Concentrations: MD1003, Bisnorbiotin, Biotin 
Sulfoxide and Total Radioactivity <(units)> 
Log10/Linear Scale 
Individual Values for Subject <xxx>: PK Analysis Set 


    
 
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Figure 
Number 
Figure Title 
14.2.10.1 
Plasma and Whole Blood Pharmacokinetic Concentrations: Total 
Radioactivity <(units)> 
Linear/Linear Scale 
Individual Values for Subject <xxx>: PK Analysis Set 
14.2.10.2 
Plasma and Whole Blood Pharmacokinetic Concentrations: Total 
Radioactivity <(units)> 
Log10/Linear Scale 
Individual Values for Subject <xxx>: PK Analysis Set 
 
 


    
 
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19 Index of Listings 
Listing 
Number 
Listing Title 
 
Subject Informed Consent and Completion/Withdrawal 
16.2.1 
Subject Informed Consent and Completion/Withdrawal 
Individual Values: All Enrolled Subjects 
 
Protocol Deviations and Inclusion/Exclusion Criteria 
16.2.2.1 
Protocol Deviations  
Individual Values: All Enrolled Subjects 
16.2.2.2 
Inclusion/Exclusion Criteria  
Individual Values: All Enrolled Subjects 
 
Analysis Populations and Reasons for Exclusion 
16.2.3.1 
Analysis Populations and Reasons for Exclusion  
Individual Values: All Enrolled Subjects 
16.2.3.2 
Analysis Sets and Reasons for Exclusion  
Individual Values: All Enrolled Subjects 
 
Demographic and Baseline Characteristics 
16.2.4.1 
Demographics and Baseline Characteristics 
Individual Values: All Enrolled Subjects 
16.2.4.2 
Lifestyle Details: Smoking History and Alcohol Consumption  
Individual Values: All Enrolled Subjects 
16.2.4.3 
Medical/Surgical History  
Individual Values: All Enrolled Subjects 
16.2.4.4 
Prior and Concomitant Medication 
Individual Values: All Enrolled Subjects 
16.2.4.5 
Carbon Monoxide and Alcohol Breath Test 
Individual Values: All Enrolled Subjects 
16.2.4.6 
Urine Drug Screen 
Individual Values: All Enrolled Subjects 
16.2.4.7 
Virology  
Individual Values: All Enrolled Subjects 
16.2.4.8 
Creatinine Clearance 
Individual Values: All Enrolled Subjects 
 
Dosing Details and Meal Details 
16.2.5.1.1 
Dosing Details 
Individual Values: All Enrolled Subjects 


    
 
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Listing 
Number 
Listing Title 
16.2.5.1.2 
Meal Details 
Individual Values: All Enrolled Subjects 
 
Urine and Faecal Concentration Data 
16.2.5.2.1 
Urine Collection Details 
Individual Values: All Enrolled Subjects 
16.2.5.2.2 
Urine Concentrations and Excretion: Total Radioactivity <(units)> 
Individual Values: All Enrolled Subjects 
16.2.5.2.3 
Faecal Collection Details 
Individual Values: All Enrolled Subjects 
16.2.5.2.4 
Faecal Concentrations and Excretion: Total Radioactivity <(units)> 
Individual Values: All Enrolled Subjects 
16.2.5.2.5 
Urine and Faecal Concentrations and Excretion Combined: Total 
Radioactivity <(units)> 
Individual Values: All Enrolled Subjects 
 
Plasma and Whole Blood Pharmacokinetic Concentration Data 
16.2.5.3.1 
Blood Sample Collection Details Pharmacokinetic 
Individual Values: All Enrolled Subjects 
16.2.5.3.2 
Plasma Pharmacokinetic Concentrations: MD1003 <(units)> 
Individual Values: All Enrolled Subjects 
16.2.5.3.3 
Plasma Pharmacokinetic Concentrations: Bisnorbiotin <(units)> 
Individual Values: All Enrolled Subjects 
16.2.5.3.4 
Plasma Pharmacokinetic Concentrations: Biotin Sulfoxide <(units)> 
Individual Values: All Enrolled Subjects 
16.2.5.3.5 
Plasma and Whole Blood Pharmacokinetic Concentrations: Total 
Radioactivity <(units)> 
Individual Values: All Enrolled Subjects 
 
Plasma Pharmacokinetic Parameter Data 
16.2.6.1 
Plasma Pharmacokinetic Parameters: MD1003 
Individual Values: All Enrolled Subjects 
16.2.6.2 
Plasma Pharmacokinetic Parameters: Bisnorbiotin 
Individual Values: All Enrolled Subjects 
16.2.6.3 
Plasma Pharmacokinetic Parameters: Biotin Sulfoxide 
Individual Values: All Enrolled Subjects 
16.2.6.4 
Plasma Pharmacokinetic Parameters: Total Radioactivity 
Individual Values: All Enrolled Subjects 


    
 
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Listing 
Number 
Listing Title 
16.2.6.5 
Pharmacokinetic Parameter Flags 
 
(Programming note: Details of the PK parameter flags will be added to 
listing 16.2.6.1, 16.2.6.2, 16.2.6.3 and 16.2.6.4 as footnotes if length of 
these details allows – in which case do not produce this listing. 
Otherwise display PK parameter flags in this listing). 
 
Adverse Events 
16.2.7.1 
Pre-dose Adverse Events 
Individual Values: All Enrolled Subjects 
16.2.7.2 
All Treatment-Emergent Adverse Events  
Individual Values: All Enrolled Subjects 
16.2.7.3 
Serious Adverse Events  
Individual Values: All Enrolled Subjects 
16.2.7.4 
TEAEs Leading to Death 
Individual Values: All Enrolled Subjects 
 
Laboratory Data 
16.2.8.1 
Blood Sample Collection Details for Laboratory Analysis 
Individual Values: All Enrolled Subjects 
16.2.8.2 
Haematology 
Individual Values: All Enrolled Subjects 
16.2.8.3 
Haematology 
Individual Values Outside the Reference Range: All Enrolled Subjects 
16.2.8.4 
Clinical Chemistry 
Individual Values: All Enrolled Subjects 
16.2.8.5 
Clinical Chemistry 
Individual Values Outside the Reference Range: All Enrolled Subjects 
16.2.8.6 
Urinalysis Sample Collection 
Individual Values: All Enrolled Subjects 
16.2.8.7 
Urinalysis 
Individual Values: All Enrolled Subjects 
16.2.8.8 
Urinalysis 
Individual Values Outside the Reference Range: All Enrolled Subjects 
 
Vital Signs and ECGs 
16.2.9.1.1 
Vital Signs  
Individual Values: All Enrolled Subjects 
16.2.9.1.2 
Vital Signs 
Individual Values Outside the Reference Range: All Enrolled Subjects 


    
 
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Listing 
Number 
Listing Title 
16.2.9.2.1 
ECGs 
Individual Values: All Enrolled Subjects 
 
(Programming note: The order of ECG parameters is to be as per 
Section 10.5) 
16.2.9.2.2 
ECGs 
Individual Values Outside the Reference Range: All Enrolled Subjects 
 
Other Data 
16.2.9.4 
Physical Examination Data 
Individual Values: All Enrolled Subjects 


    
 
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20 Mock Tables 


    
 
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MedDay Pharmaceuticals                                                                                                     Page x of y 
Protocol: MD1003CT2019-03MB 
 
TABLE 14.1.1 
Subject Disposition by Reason 
Summary Statistics: All Enrolled Subjects 
 
                                          100 mg [14C]-MD1003  
                                                 (N=XX)        
                                                 n (%)         
 _____________________________________________________________ 
                                                               
 Subjects enrolled (1)                         xx (xx.x)       
 Subjects dosed                                xx (xx.x)       
 Subjects completed                            xx (xx.x)       
 Subjects discontinued                         xx (xx.x)       
                                                               
 Reason for discontinuation                                    
   REASON 1                                    xx (xx.x)       
   REASON 2                                    xx (xx.x)       
   REASON 3                                    xx (xx.x)       
   …                                               …           
   <All categories on source>                  xx (xx.x)       
                                                               
                                                               
                                                               
____________________________________________________________________________________________________________________________                                  
Note: The data in this table are presented in listing x.x                                                                                                     
      (1) An enrolled subject is defined as a subject who signed the informed consent, qualified per the inclusion/exclusion criteria                         
      and was allocated a subject number.                                                                                                                     
      A subject may be discontinued for one reason only.                                                                                                      
      Percentages are based on the number of subjects enrolled.                                                                                               
                                                                                                                                                              
                                                                                                                                                              
PROGRAM PATH: X:\~\QSC201639\~\TFLS\PRODUCTION\TAB-XX                                                   DDMMMYYYY HH:MM                                       
                                                                                                                                                              
(Programming note: This table will be continued for all reasons for discontinuation as recorded on the eCRF. If none of the subjects                          
                   discontinued from the study early then reasons for discontinuation will not be populated in the summary table.)                            


    
 
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MedDay Pharmaceuticals                                                                                                     Page x of y 
Protocol: MD1003CT2019-03MB 
 
TABLE 14.1.2.1 
Analysis Populations 
Summary Statistics: All Enrolled Subjects 
 
                                                              100 mg [14C]-MD1003  
                                                                     (N=XX)        
 _________________________________________________________________________________ 
                                                                                   
 Number (%) of subjects in Safety Population                       xx (xx.x)       
 Reasons for exclusion from Safety Population                                      
   <All categories on source listing>                              xx (xx.x)       
                                                                       …           
                                                                                   
 Number (%) of subjects in Mass Balance Population                 xx (xx.x)       
 Reasons for exclusion from Mass Balance Population                                
   <All categories on source listing>                              xx (xx.x)       
                                                                       …           
                                                                                   
 Number (%) of subjects in PK Population                           xx (xx.x)       
 Reasons for exclusion from PK Population                                          
   <All categories on source listing>                              xx (xx.x)       
                                                                       …           
                                                                                   
                                                                                   
____________________________________________________________________________________________________________________________                                  
Note: The data in this table are presented in listing x.x                                                                    
      A subject may be excluded for more than one reason.                                                                                                     
      Percentages are based on the number of subjects enrolled.                                                                                               
                                                                                                                                                              
                                                                                                                                                              
PROGRAM PATH: X:\~\QSC201639\~\TFLS\PRODUCTION\TAB-XX                                                   DDMMMYYYY HH:MM                                       
                                                                                                                                                              
(Programming note: This table will be continued for all reasons for exclusion. If none of the subjects were excluded from a 
                   population, then reasons for exclusion will not be populated in the summary table.)                                                        


    
 
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MedDay Pharmaceuticals                                                                                                     Page x of y 
Protocol: MD1003CT2019-03MB 
 
TABLE 14.1.2.2.1 
Safety Analysis Set 
Summary Statistics: Safety Population 
 
                                                              100 mg [14C]-MD1003  
                                                                     (N=XX)        
 _________________________________________________________________________________ 
                                                                                   
 Number (%) of subjects in Safety Analysis Set                     xx (xx.x)       
 Reasons for exclusion from Safety Analysis Set                                    
   <All categories from source>                                    xx (xx.x)       
                                                                       …           
                                                                                   
                                                                                   
                                                                                   
                                                                                   
                                                                                   
                                                                                   
                                                                                   
____________________________________________________________________________________________________________________________                                  
Note: The data in this table are presented in listing x.x                                                                          
      A subject may be excluded for more than one reason.                                                                                                     
                                                                                                                                                              
                                                                                                                                                              
PROGRAM PATH: X:\~\QSC201639\~\TFLS\PRODUCTION\TAB-XX                                                   DDMMMYYYY HH:MM                                       
                                                                                                                                                              
(Programming note: This table will be continued for all reasons for exclusion. If none of the subjects were excluded from the safety                          
                   analysis set, then reasons for exclusion will not be populated in the summary table. Similar tables will be 
                   produced for:                     
                   • PK Analysis Set, ie Table [14.1.2.3] and                                                                                                 
                   • Mass Balance Analysis Set, ie Table [14.1.2.4].                                                                                          
                   Each analysis set will be a subset of their respective populations and percentages will be based on number of  
                   subjects in each population.)                                                                                                              


    
 
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MedDay Pharmaceuticals                                                                                                     Page x of y 
Protocol: MD1003CT2019-03MB 
 
TABLE 14.1.3 
Demographic and Baseline Characteristics 
Summary Statistics: Safety Analysis Set 
 
                                                                  100 mg [14C]-MD1003  
                                                                         (N=XX)        
______________________________________________________________________________________ 
                                                                                       
Age (years)              n                                                 xx          
                         Mean                                            xx.xx         
                         SD                                              xx.xx         
                         Median                                          xx.xx         
                         Min                                              xx.x         
                         Max                                              xx.x         
                                                                                       
Ethnicity n (%)          <All categories on source>                    xx (xx.x)       
                                                                                       
Race n (%)               <All categories on source>                    xx (xx.x)       
                                                                                       
Sex n (%)                Male                                          xx (xx.x)       
                                                                                       
Height (cm)              …                                                 …           
                                                                                       
Weight (kg)              …                                                 …           
                                                                                       
BMI (kg/m^2)             …                                                 …           
                                                                                       
____________________________________________________________________________________________________________________________                                  
Note: The data in this table are presented in listing x.x                                                                          
                                                                                                                                                              
                                                                                                                                                              
PROGRAM PATH: X:\~\QSC201639\~\TFLS\PRODUCTION\TAB-XX                                                   DDMMMYYYY HH:MM                                       
                                                                                                                                                              
(Programming note: This table will continue for all categories of ethnicity and race. Height, Weight and BMI will be summarised using 
                   the same descriptive statistics as Age, If any values are missing, then a ‘missing’ row will be presented in 
                   the table.)                       


    
 
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MedDay Pharmaceuticals                                                                                                     Page x of y 
Protocol: MD1003CT2019-03MB 
 
TABLE 14.1.4 
Lifestyle Details: Smoking History and Alcohol Consumption 
Summary Statistics: Safety Analysis Set 
 
                                                          100 mg [14C]-MD1003  
                                                                 (N=XX)        
                                                                 n (%)         
______________________________________________________________________________ 
                                                                               
Does subject smoke (1)          NO: NEVER                      xx (xx.x)       
                                PREVIOUSLY                     xx (xx.x)       
                                                                               
                                                                               
Alcohol Consumption (2)         NONE                           xx (xx.x)       
                                YES: <21 UNITS                 xx (xx.x)       
                                                                               
                                                                               
                                                                               
____________________________________________________________________________________________________________________________                                  
Note: The data in this table are presented in listing x.x                                                                         
      (1) Anyone who smoked, used e-cigarettes or any nicotine replacement products in the last 12 months is excluded from the study.                         
      (2) Anyone who regularly consumes alcohol (>21 units/week in males) is excluded from the study.                                                         
      1 unit = 1/2 pint beer, or a 25 mL shot of 40% spirit, 1.5 to 2 units = 125 mL glass of wine, depending on type.                                        
                                                                                                                                                              
                                                                                                                                                              
PROGRAM PATH: X:\~\QSC201639\~\TFLS\PRODUCTION\TAB-XX                                                   DDMMMYYYY HH:MM   
 
 


    
 
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MedDay Pharmaceuticals                                                                                                     Page x of y 
Protocol: MD1003CT2019-03MB 
                                        
TABLE 14.1.5 
Concomitant Medications 
Summary Statistics: Safety Analysis Set 
 
                                                              100 mg [14C]-MD1003  (N=XX)   
                                                          ____________________________________      
                                                                 n (%)           Number of  
Medications                                                                      Occasions 
______________________________________________________________________________________________ 
                                                                 
Any Concomitant Medication                                      xx (xx.x)           xx                      
  
Therapeutic subgroup 1                                          xx (xx.x)           xx                                                    
   Chemical subgroup 1                                          xx (xx.x)           xx                                                    
      preferred name 1                                          xx (xx.x)           xx                    
      preferred name 2                                          xx (xx.x)           xx                    
      …                                                            …                … 
   Chemical subgroup 2                                          xx (xx.x)           xx                                                    
      preferred name 1                                          xx (xx.x)           xx                    
      preferred name 2                                          xx (xx.x)           xx                    
      …                                                            …                … 
                                                                 
Therapeutic subgroup 1                                          xx (xx.x)           xx                                                    
   Chemical subgroup 1                                          xx (xx.x)           xx                                                    
      preferred name 1                                          xx (xx.x)           xx 
      preferred name 2                                          xx (xx.x)           xx                                       
      …                                                            …                … 
                                                                 
____________________________________________________________________________________________________________________________                                  
Note: The data in this table are presented in listing x.x                                                                         
      Medications are coded using WHODrug 2019 September version.   
      n is the number of subjects reporting at least one concomitant medication.                                                                              
      Counts are given for number of subjects and total number of occasions in which medications were taken.                                                  
      Abbreviations: WHODrug=World health organisation drug dictionary global drug reference                                                     
                                                     


    
 
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MedDay Pharmaceuticals                                                                                                     Page x of y 
Protocol: MD1003CT2019-03MB 
 
TABLE 14.1.6 
Extent of Exposure 
Summary Statistics: Safety Analysis Set 
 
                                   100 mg [14C]-MD1003               
                                         (N=XX)                      
                     _______________________________________________ 
                           mg              MBq             µCi       
____________________________________________________________________ 
                                                                     
n                          xx              xx              xx        
Mean                      xx.xx           xx.xx           xx.xx      
SD                        xx.xx           xx.xx           xx.xx      
Median                    xx.xx           xx.xx           xx.xx      
Min                       xx.x            xx.x            xx.x       
Max                       xx.x            xx.x            xx.x       
                                                                     
                                                                     
                                                                     
                                                                     
____________________________________________________________________________________________________________________________                                  
Note: The data in this table are presented in listing x.x                                                                          
                                                                                                                                                              
                                                                                                                                                              
PROGRAM PATH: X:\~\QSC201639\~\TFLS\PRODUCTION\TAB-XX                                                   DDMMMYYYY HH:MM                                       


    
 
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MedDay Pharmaceuticals                                                                                                     Page x of y 
Protocol: MD1003CT2019-03MB 
 
TABLE 14.2.1.1.1 
Excretion: Total Radioactivity 
Ae(Urine) by Collection Period <(units)> 
Summary Statistics: Mass Balance Analysis Set 
  
100 mg [14C]-MD1003 (N=XX) 
 
Collection Period               n     Mean      SD      CV%   Median    Min     Max   
_____________________________________________________________________________________ 
                                                                                      
PRE-DOSE                        xx   xx.xx    xx.xx    xx.x    xx.xx   xx.x    xx.x   
TIME0 - TIME1                   xx   xx.xx    xx.xx    xx.x    xx.xx   xx.x    xx.x   
TIME1 - TIME2                   xx   xx.xx    xx.xx    xx.x    xx.xx   xx.x    xx.x   
TIME2 - TIME3                   xx   xx.xx    xx.xx    xx.x    xx.xx   xx.x    xx.x   
…                               …      …        …        …       …       …       …    
<All other time intervals>      xx   xx.xx    xx.xx    xx.x    xx.xx   xx.x    xx.x   
                                                                                      
____________________________________________________________________________________________________________________________                                  
Note: The data in this table are presented in listing x.x                                                                         
      Where a subject has failed to void or has a ND concentration over a particular collection interval, the amount excreted (Ae)                            
      has been set to zero.                                                                                                                                   
                                                                                                                                                              
                                                                                                                                                              
PROGRAM PATH: X:\~\QSC201639\~\TFLS\PRODUCTION\TAB-XX                                                   DDMMMYYYY HH:MM                                       
                                                                                                                                                              
(Programming note: This table will be continued for all collection periods. Similar tables will be produced for                                               
                   • %Ae(Urine) (Recovery), ie Table [14.2.1.1.3]                                                                                             
                   • Ae(Faeces), ie Table [14.2.1.2.1]                                                                                                        
                   • %Ae(Faeces) (Recovery), ie Table [14.2.1.2.3]                                                                                            
                   • Ae(total), ie Table [14.2.1.3.1] and                                                                                             
                   • %Ae(total) (Recovery), ie Table [14.2.1.3.3].)  
(Programming note: Tables 14.2.1.2.1, 14.2.1.2.3, 14.2.1.3.1 and 14.2.1.3.3 will have ‘ADIMISSON – 0 H’ for ‘PRE-DOSE’.)                                      


    
 
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MedDay Pharmaceuticals                                                                                                     Page x of y 
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TABLE 14.2.1.1.2 
Excretion: Total Radioactivity 
Cumulative Ae(Urine) <(units)> 
Summary Statistics: Mass Balance Analysis Set 
  
100 mg [14C]-MD1003 (N=XX) 
 
Collection Period               n     Mean      SD      CV%   Median    Min     Max   
_____________________________________________________________________________________ 
                                                                                      
PRE-DOSE                        xx   xx.xx    xx.xx    xx.x    xx.xx   xx.x    xx.x   
TIME0 - TIME1                   xx   xx.xx    xx.xx    xx.x    xx.xx   xx.x    xx.x   
TIME0 - TIME2                   xx   xx.xx    xx.xx    xx.x    xx.xx   xx.x    xx.x   
TIME0 - TIME3                   xx   xx.xx    xx.xx    xx.x    xx.xx   xx.x    xx.x   
…                               …      …        …        …       …       …       …    
<All other time intervals>      xx   xx.xx    xx.xx    xx.x    xx.xx   xx.x    xx.x   
                                                                                      
____________________________________________________________________________________________________________________________                                  
Note: The data in this table are presented in listing x.x                                                                          
                                                                                                                                                              
                                                                                                                                                              
PROGRAM PATH: X:\~\QSC201639\~\TFLS\PRODUCTION\TAB-XX                                                   DDMMMYYYY HH:MM                                       
                                                                                                                                                              
(Programming note: This table will be continued for all collection periods. If required, as a result of early withdrawal or varying                           
                   follow-up periods, a further set of tables will be produced for LOCF values. Table numbers will be incremented                             
                   by .1 for observed values and .2 for LOCF. Similar tables will be produced for                                                             
                   • Cumulative %Ae(Urine) (Recovery), ie Table [14.2.1.1.4]                                                                                  
                   • Cumulative Ae(Faeces), ie Table [14.2.1.2.2]                                                                                             
                   • Cumulative %Ae(Faeces) (Recovery), ie Table [14.2.1.2.4]                                                                                 
                   • Cumulative Ae(total), ie Table [14.2.1.3.2] and                                                                                  
                   • Cumulative %Ae(total) (Recovery), ie Table [14.2.1.3.4].)                                                                        
(Programming note: Tables 14.2.1.2.2, 14.2.1.2.4, 14.2.1.3.2 and 14.2.1.3.4 will have ‘ADIMISSON – 0 H’ for ‘PRE-DOSE’.)                                      
                                                                    


    
 
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MedDay Pharmaceuticals                                                                                                     Page x of y 
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TABLE 14.2.1.4 
Excretion and Recovery: Total Radioactivity 
Cumulative Excretion and Recovery Parameters 
Summary Statistics: Mass Balance Analysis Set 
  
100 mg [14C]-MD1003 (N=XX) 
 
                        Urine                Faeces                 Total         
                _____________________ _____________________ _____________________ 
                  CumAe      Cum%Ae     CumAe      Cum%Ae     CumAe      Cum%Ae   
                 (units)      (%)      (units)      (%)      (units)      (%)     
_________________________________________________________________________________ 
                                                                                  
n                   xx         xx         xx         xx         xx         xx     
Mean              xx.xx      xx.xx      xx.xx      xx.xx      xx.xx      xx.xx    
SD                xx.xx      xx.xx      xx.xx      xx.xx      xx.xx      xx.xx    
CV%                xx.x       xx.x       xx.x       xx.x       xx.x       xx.x    
Median            xx.xx      xx.xx      xx.xx      xx.xx      xx.xx      xx.xx    
Min                xx.x       xx.x       xx.x       xx.x       xx.x       xx.x    
Max                xx.x       xx.x       xx.x       xx.x       xx.x       xx.x    
                                                                                  
                                                                                  
____________________________________________________________________________________________________________________________                                  
Note: The data in this table are presented in listing x.x                                                                          
      CumAe represents the cumulative excretion. Cum%Ae represents the cumulative recovery as a percentage of the radioactive dose                            
      administered.                                                                                                                                           
                                                                                                                                                              
                                                                                                                                                              
PROGRAM PATH: X:\~\QSC201639\~\TFLS\PRODUCTION\TAB-XX                                                   DDMMMYYYY HH:MM                                       


    
 
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MedDay Pharmaceuticals                                                                                                     Page x of y 
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TABLE 14.2.1.5.1 
Plasma Pharmacokinetic Concentrations: Total Radioactivity <(units)> 
Summary Statistics: PK Analysis Set 
  
100 mg [14C]-MD1003 (N=XX) 
 
                                          Arithmetic (1)                        Geometric (2)       
                          _______________________________________________ _________________________ 
Time Point                 n   Mean     SD     CV%   Median  Min    Max    n   Mean     SD    CV%   
___________________________________________________________________________________________________ 
                                                                                                    
PRE-DOSE                  xx   xx.xx  xx.xx   xx.x   xx.xx   xx.x   xx.x  NC    NC      NC     NC   
0.5 H                     xx   xx.xx  xx.xx   xx.x   xx.xx   xx.x   xx.x  xx   xx.xx  xx.xx   xx.x  
1 H                       xx   xx.xx  xx.xx   xx.x   xx.xx   xx.x   xx.x  xx   xx.xx  xx.xx   xx.x  
1.5 H                     xx   xx.xx  xx.xx   xx.x   xx.xx   xx.x   xx.x  xx   xx.xx  xx.xx   xx.x  
…                          …     …      …       …      …      …      …     …     …      …      …    
<All other time points>   xx   xx.xx  xx.xx   xx.x   xx.xx   xx.x   xx.x  xx   xx.xx  xx.xx   xx.x  
                                                                                                    
                                                                                                    
____________________________________________________________________________________________________________________________                                  
Note: The data in this table are presented in listing x.x                                                                         
      (1) For arithmetic summary statistics, concentration values reported as BLQ are set to zero.                                                          
      (2) For calculation of geometric summary statistics, values reported as BLQ are set to ½ × LLOQ, except for pre-dose                            
      values which will not be summarised. The LLOQ value was <value, units>.                                                                              
                                                                                                                                                              
                                                                                                                                                              
PROGRAM PATH: X:\~\QSC201639\~\TFLS\PRODUCTION\TAB-XX                                                   DDMMMYYYY HH:MM                                       
                                                                                                                                                              
(Programming note: This table will be continued for all time points. Similar tables will be produced for                                                      
                   • Plasma Pharmacokinetic Concentrations: Bisnorbiotin, ie Table [14.2.1.5.2]       
                   • Plasma Pharmacokinetic Concentrations: Biotin Sulfoxide, ie Table [14.2.1.5.3]                                                           
                   • Plasma Pharmacokinetic Concentrations: Total Radioactivity, ie Table [14.2.1.5.4]                                                        
                   • Whole Blood Concentrations: Total Radioactivity, ie Table [14.2.1.5.5]                                                                 
                   • Whole Blood: Plasma Concentration Ratio, ie Table [14.2.1.5.6].)                                                                         


    
 
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TABLE 14.2.2.1 
Plasma Pharmacokinetic Parameters: Total Radioactivity 
Summary Statistics: PK Analysis Set 
  
100 mg [14C]-MD1003 (N=XX) 
 
                                                PK Parameter                               
                   _______________________________________________________________________ 
                   Parameter 1  Parameter 2  Parameter 3          All Other PK Parameters  
Statistic            (units)      (units)      (units)    ......          (units)          
__________________________________________________________________________________________ 
                                                                                           
n                       xx           xx           xx        …               xx             
Mean                  xx.xx        xx.xx        xx.xx       …              xx.xx           
SD                    xx.xx        xx.xx        xx.xx       …              xx.xx           
CV%                    xx.x         xx.x         xx.x       …              xx.x            
Median                xx.xx        xx.xx        xx.xx       …              xx.xx           
Min                    xx.x         xx.x         xx.x       …              xx.x            
Max                    xx.x         xx.x         xx.x       …              xx.x            
Geometric n             xx           xx           xx        …               xx             
Geometric Mean        xx.xx        xx.xx        xx.xx       …              xx.xx           
Geometric SD          xx.xx        xx.xx        xx.xx       …              xx.xx           
Geometric CV%          xx.x         xx.x         xx.x       …              xx.x            
____________________________________________________________________________________________________________________________                                  
Note: The data in this table are presented in listing x.x                                                                         
      For concentration parameters, BLQ values will be set to 0 for arithmetic statistics and to ½ × LLOQ for geometric statistics.                           
      The LLOQ value was <value, units>                                                                                                                       
                                                                                                                                                              
                                                                                                                                                              
PROGRAM PATH: X:\~\QSC201639\~\TFLS\PRODUCTION\TAB-XX                                                   DDMMMYYYY HH:MM                                       
                                                                                                                                                              
(Programming note: A similar table will be produced for                                                                                                       
                   • Plasma Pharmacokinetic Parameters: Bisnorbiotin, ie Table [14.2.2.2])     
                   • Plasma Pharmacokinetic Parameters: Biotin Sulfoxide, ie Table [14.2.2.3])                                                                
                   • Plasma Pharmacokinetic Parameters: Total Radioactivity, ie Table [14.2.2.4].)                                                            


    
 
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TABLE 14.3.1 
Overall Summary of Treatment-Emergent Adverse Events 
Summary Statistics: Safety Analysis Set 
 
                                                      100 mg [14C]-MD1003          
                                                            (N=XX)                 
                                             _____________________________________    
Event                                              n (%)             Events n      
__________________________________________________________________________________ 
                                                                                   
TEAEs                                            xx (xx.x)              xx         
                                                                                   
Severe TEAEs                                     xx (xx.x)              xx         
                                                                                   
ADRs (1)                                         xx (xx.x)              xx         
                                                                                   
Serious TEAEs                                    xx (xx.x)              xx         
                                                                                   
TEAEs leading to death                           xx (xx.x)              xx         
____________________________________________________________________________________________________________________________                                  
Note: The data in this table are presented in listing x.x                                                                          
      TEAEs are coded using MedDRA vXX.X                                                                                                                      
      (1) ADR is any AE where a causal relationship with the IP is classified as ‘possibly related’ or ‘related’.                                             
      n is the number of subjects reporting at least one event.                                                                                               
                                                                                                                                                              
                                                                                                                                                              
PROGRAM PATH: X:\~\QSC201639\~\TFLS\PRODUCTION\TAB-XX                                                   DDMMMYYYY HH:MM                                       


    
 
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MedDay Pharmaceuticals                                                                                                     Page x of y 
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TABLE 14.3.2 
Treatment-Emergent Adverse Events 
By MedDRA System Organ Class and Preferred Term 
Summary Statistics: Safety Analysis Set 
 
                                             100 mg [14C]-MD1003          
                                                   (N=XX)                 
                                    _____________________________________ 
System Organ Class                                         
   Preferred Term                         n (%)             Events n      
_________________________________________________________________________ 
                                                                          
TEAEs                                   xx (xx.x)              xx         
                                                                          
SYSTEM ORGAN CLASS 1                    xx (xx.x)              xx         
   PREFERRED TERM 1                     xx (xx.x)              xx         
   PREFERRED TERM 2                     xx (xx.x)              xx         
   etc                                      …                  …          
                                                                          
SYSTEM ORGAN CLASS 2                    xx (xx.x)              xx         
   PREFERRED TERM 1                     xx (xx.x)              xx         
   PREFERRED TERM 2                     xx (xx.x)              xx         
   etc                                      …                  …          
                                                                          
…                                           …                  …          
____________________________________________________________________________________________________________________________                                  
Note: The data in this table are presented in listing x.x                                                                          
      TEAEs are coded using MedDRA vXX.X and are presented in descending order of frequency.                                                                  
      Subjects experiencing more than one episode of a TEAE are counted only once within each SOC and PT.                                                     
                                                                                                                                                              
                                                                                                                                                              
PROGRAM PATH: X:\~\QSC201639\~\TFLS\PRODUCTION\TAB-XX                                                   DDMMMYYYY HH:MM                                       
                                                                                                                                                              
(Programming note: This table will be continued for all SOC and PT.)    
(Programming note: Counts of number of subjects are by maximum severity, ie subjects experiencing more than one episode of TEAE 
                   are only counted once within each SOC and PT using the most severe episode.)                                                               


    
 
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TABLE 14.3.3 
Treatment-Emergent Adverse Events 
By MedDRA System Organ Class, Preferred Term and Severity 
Summary Statistics: Safety Analysis Set 
 
                                              100 mg [14C]-MD1003               
                                                    (N=XX)                      
                            ______________________________________________________  
                                  Mild             Moderate            Severe             
                            ________________   ________________   ________________  
System Organ Class                    Events             Events             Events            
  Preferred Term              n (%)     n       n (%)      n       n (%)      n       
__________________________________________________________________________________ 
                                                                                                                             
TEAEs                       xx (xx.x)   xx     xx (xx.x)   xx     xx (xx.x)   xx    
                                                                                                                             
SYSTEM ORGAN CLASS 1        xx (xx.x)   xx     xx (xx.x)   xx     xx (xx.x)   xx    
  PREFERRED TERM 1          xx (xx.x)   xx     xx (xx.x)   xx     xx (xx.x)   xx    
  PREFERRED TERM 2          xx (xx.x)   xx     xx (xx.x)   xx     xx (xx.x)   xx    
etc                         xx (xx.x)   xx     xx (xx.x)   xx     xx (xx.x)   xx    
                                                                                                                             
SYSTEM ORGAN CLASS 2        xx (xx.x)   xx     xx (xx.x)   xx     xx (xx.x)   xx      
  PREFERRED TERM 1          xx (xx.x)   xx     xx (xx.x)   xx     xx (xx.x)   xx    
  PREFERRED TERM 2          xx (xx.x)   xx     xx (xx.x)   xx     xx (xx.x)   xx    
etc                         xx (xx.x)   xx     xx (xx.x)   xx     xx (xx.x)   xx    
                                                                                                             
                                                                                                             
____________________________________________________________________________________________________________________________                                  
Note: The data in this table are presented in listing x.x                                                                          
      TEAEs are coded using MedDRA vXX.X and are presented in descending order of frequency.                                                                  
      Counts are given for number of subjects and number of events  
      Counts for number of subjects are given by severity category (ie subject experiencing TEAEs across different  
      severity categories will be counted once for each severity category).                                                                                   
                                                                                                                                                              
                                                                                                                                                              
PROGRAM PATH: X:\~\QSC201639\~\TFLS\PRODUCTION\TAB-XX                                                   DDMMMYYYY HH:MM                                       
                                                                                                                                                              
(Programming note: This table will be continued for all SOC and PT.)       
(Programming note: Counts of number of subjects are by severity i.e. subjects experiencing more than 1 episode of a TEAE  
                   at the same level of severity will be counted only once within each SOC and PT for that level of severity,  
                   subjects experiencing at least 2 TEAEs at different levels of severity will be counted once in each  
                   level of severity.)                                                                                                                        


    
 
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MedDay Pharmaceuticals                                                                                                     Page x of y 
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TABLE 14.3.4 
Treatment-Emergent Adverse Events 
By MedDRA System Organ Class, Preferred Term and Relationship to IP 
Summary Statistics: Safety Analysis Set 
 
                                              100 mg [14C]-MD1003               
                                                    (N=XX)                      
                            ______________________________________________________  
                               Unrelated       Possibly Related       Related             
                            ________________   ________________   ________________  
System Organ Class                    Events             Events             Events            
  Preferred Term              n (%)     n        n (%)     n        n (%)     n       
__________________________________________________________________________________ 
                                                                                                                             
TEAEs                       xx (xx.x)   xx     xx (xx.x)   xx     xx (xx.x)   xx    
                                                                                                                             
SYSTEM ORGAN CLASS 1        xx (xx.x)   xx     xx (xx.x)   xx     xx (xx.x)   xx    
  PREFERRED TERM 1          xx (xx.x)   xx     xx (xx.x)   xx     xx (xx.x)   xx    
  PREFERRED TERM 2          xx (xx.x)   xx     xx (xx.x)   xx     xx (xx.x)   xx    
etc                         xx (xx.x)   xx     xx (xx.x)   xx     xx (xx.x)   xx    
                                                                                                                             
SYSTEM ORGAN CLASS 2        xx (xx.x)   xx     xx (xx.x)   xx     xx (xx.x)   xx      
  PREFERRED TERM 1          xx (xx.x)   xx     xx (xx.x)   xx     xx (xx.x)   xx    
  PREFERRED TERM 2          xx (xx.x)   xx     xx (xx.x)   xx     xx (xx.x)   xx    
etc                         xx (xx.x)   xx     xx (xx.x)   xx     xx (xx.x)   xx    
                                                                                                             
                                                                                                             
____________________________________________________________________________________________________________________________                                  
Note: The data in this table are presented in listing x.x                                                                          
      TEAEs are coded using MedDRA vXX.X and are presented in descending order of frequency.                                                                  
      Counts are given for total number of subjects and number of events.                                                                                     
      Counts for number of subjects are given by relationship to IP category (ie subject experiencing TEAEs across different  
      relationship categories will be counted once for each relationship category).                                                                           
                                                                                                                                                              
                                                                                                                                                              
PROGRAM PATH: X:\~\QSC201639\~\TFLS\PRODUCTION\TAB-XX                                                   DDMMMYYYY HH:MM                                       
                                                                                                                                                              
(Programming note: This table will be continued for all SOC and PT.)  
(Programming note: Counts of number of subjects are given by closest relationship i.e. subjects experiencing more than 1 
                   episode of a TEAE at the same level of relationship to IP will be counted only once within each SOC and  
                   PT for that level of relationship to IP,subjects experiencing at least 2 TEAEs at different levels of  
                   relationship to IP will be counted once in each level of relationship to IP.)   


    
 
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TABLE 14.3.5 
Adverse Drug Reactions 
By MedDRA System Organ Class and Preferred Term 
Summary Statistics: Safety Analysis Set 
 
                                        100 mg [14C]-MD1003          
                                              (N=XX)                 
                               _____________________________________ 
System Organ Class                                    
   Preferred Term                    n (%)             Events n     
____________________________________________________________________ 
                                                                     
ADRs (1)                           xx (xx.x)              xx         
                                                                     
SYSTEM ORGAN CLASS 1               xx (xx.x)              xx         
   PREFERRED TERM 1                xx (xx.x)              xx         
   PREFERRED TERM 2                xx (xx.x)              xx         
   etc                                 …                  …          
                                                                     
SYSTEM ORGAN CLASS 2               xx (xx.x)              xx         
   PREFERRED TERM 1                xx (xx.x)              xx         
   PREFERRED TERM 2                xx (xx.x)              xx         
   etc                                 …                  …          
                                                                     
…                                      …                  …          
____________________________________________________________________________________________________________________________                                  
Note: The data in this table are presented in listing x.x                                                                          
      (1) An ADR is any AE where a causal relationship with the IP is classified as ‘possibly related’ or ‘related’.                                          
      TEAEs are coded using MedDRA vXX.X and are presented in descending order of frequency.                                                                  
      Counts are given for total number of subjects and number of events.                                                                  
                                                                                                                                                              
                                                                                                                                                              
PROGRAM PATH: X:\~\QSC201639\~\TFLS\PRODUCTION\TAB-XX                                                   DDMMMYYYY HH:MM                                       
                                                                                                                                                              
(Programming note: A similar table will be produced for                                                                                                       
                   • Serious Adverse Events, ie Table [14.3.6].)  
(Programming note: Subjects experiencing more than one episode of an ADR/SAE are counted only once within each SOC and PT.)                                   


    
 
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MedDay Pharmaceuticals                                                                                                     Page x of y 
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TABLE 14.4.1 
Haematology 
Summary Statistics: Safety Analysis Set 
  
100 mg [14C]-MD1003 (N=XX) 
<Parameter> (<units>) [ref range xxx - xxx (male)] 
 
                                            Result                                 Change from Baseline              
                         _____________________________________________ _____________________________________________ 
Time Point                 n    Mean     SD    Median    Min     Max     n    Mean     SD    Median    Min     Max   
____________________________________________________________________________________________________________________ 
                                                                                                                     
BASELINE                  xx    xx.xx   xx.xx   xx.xx   xx.x    xx.x                                                 
24 H                      xx    xx.xx   xx.xx   xx.xx   xx.x    xx.x    xx    xx.xx   xx.xx   xx.xx   xx.x    xx.x   
DISCHARGE                 xx    xx.xx   xx.xx   xx.xx   xx.x    xx.x    xx    xx.xx   xx.xx   xx.xx   xx.x    xx.x   
                                                                                                                     
                                                                                                                     
____________________________________________________________________________________________________________________________                                  
Note: The data in this table are presented in listing x.x                                                                          
      BASELINE is defined as Day 1, Pre-dose. DISCHARGE is planned to be 168 h.                                                                               
                                                                                                                                                              
                                                                                                                                                              
PROGRAM PATH: X:\~\QSC201639\~\TFLS\PRODUCTION\TAB-XX                                                   DDMMMYYYY HH:MM                                       
                                                                                                                                                              
(Programming note: This table will be continued for all haematology parameters and all time points.                                            
                   A similar table will be produced for                                                                                                       
                   • Clinical Chemistry, ie Table [14.4.3].                                                                                                   
                   Parameter may be added as the first column in this table.)                                                                                 


    
 
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MedDay Pharmaceuticals                                                                                                     Page x of y 
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TABLE 14.4.2 
Haematology 
Shift Analysis: Safety Analysis Set 
  
100 mg [14C]-MD1003 (N=XX) 
<Parameter> (<units>) [ref range xxx - xxx (male)] 
 
                                                Baseline                   
                              ____________________________________________ 
Time Point                        Below          Within         Above      
   Assessment            N#        n(%)           n(%)           n(%)      
__________________________________________________________________________ 
                                                                           
24 H                     xx                                                
   Below                        xx (xx.x)      xx (xx.x)      xx (xx.x)    
   Within                       xx (xx.x)      xx (xx.x)      xx (xx.x)    
   Above                        xx (xx.x)      xx (xx.x)      xx (xx.x)    
                                                                           
DISCHARGE                xx                                                
   Below                        xx (xx.x)      xx (xx.x)      xx (xx.x)    
   Within                       xx (xx.x)      xx (xx.x)      xx (xx.x)    
   Above                        xx (xx.x)      xx (xx.x)      xx (xx.x)    
                                                                           
                                                                           
____________________________________________________________________________________________________________________________                                  
Note: The data in this table are presented in listing x.x                                                                          
      BASELINE is defined as Day 1, Pre-dose. DISCHARGE is planned to be 168 h.                                                                               
      N# is the total number of subjects that have a value at baseline and each given time-point and is used in the denominator for                           
      calculating the percentages of subjects, n indicates the number of subjects with a baseline and a post baseline assessment at                           
      the time point indicated. Below/within/above indicate the number (%) of subjects with assessments below/within/above the normal                         
      reference range.                                                                                                                                        
                                                                                                                                                              
                                                                                                                                                              
PROGRAM PATH: X:\~\QSC201639\~\TFLS\PRODUCTION\TAB-XX                                                   DDMMMYYYY HH:MM                                       
                                                                                                                                                              
(Programming note: This table will be continued for all haematology parameters and all time points.                                            
                   A similar table will be produced for                                                                                                       
                   • Clinical Chemistry, ie Table [14.4.4].                                                                                                   
                   Parameter may be added as the first column in this table 


    
 
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MedDay Pharmaceuticals                                                                                                     Page x of y 
Protocol: MD1003CT2019-03MB 
 
TABLE 14.5.1 
Vital Signs 
Summary Statistics: Safety Analysis Set 
  
100 mg [14C]-MD1003 (N=XX) 
<Parameter> (<units>) [ref range xxx - xxx (age xx - xx), xxx - xxx (age > xx)] 
 
                                                                            Change from                Substantial   
                                        Result                               Baseline                    Change      
                         _____________________________________ _____________________________________ _______________ 
Time Point                n   Mean    SD   Median   Min   Max   n   Mean    SD   Median   Min   Max  DEC  NONE  INC  
____________________________________________________________________________________________________________________ 
                                                                                                                     
BASELINE                 xx  xx.xx  xx.xx   xx.xx  xx.x  xx.x                                                        
1 H                      xx  xx.xx  xx.xx   xx.xx  xx.x  xx.x  xx  xx.xx  xx.xx   xx.xx  xx.x  xx.x   xx   xx    xx  
4 H                      xx  xx.xx  xx.xx   xx.xx  xx.x  xx.x  xx  xx.xx  xx.xx   xx.xx  xx.x  xx.x   xx   xx    xx  
24 H                     xx  xx.xx  xx.xx   xx.xx  xx.x  xx.x  xx  xx.xx  xx.xx   xx.xx  xx.x  xx.x   xx   xx    xx  
72 H                     xx  xx.xx  xx.xx   xx.xx  xx.x  xx.x  xx  xx.xx  xx.xx   xx.xx  xx.x  xx.x   xx   xx    xx  
DISCHARGE                xx  xx.xx  xx.xx   xx.xx  xx.x  xx.x  xx  xx.xx  xx.xx   xx.xx  xx.x  xx.x   xx   xx    xx  
                                                                                                                     
____________________________________________________________________________________________________________________________                                  
Note: The data in this table are presented in listing x.x                                                                          
      BASELINE is defined as Day 1, Pre-dose. DISCHARGE is planned to be 168 h.                                                                               
      Substantial change is defined as: > ± 20 mmHg Systolic BP, > ± 10 mmHg Diastolic BP and > ± 15 bpm HR.   
      DEC: number of subjects with substantial decrease from baseline, NONE: number of subjects with no substantial change from  
      baseline, INC: number of subjects with substantial increase from baseline.                                                   
                                                                                                                                                              
                                                                                                                                                              
PROGRAM PATH: X:\~\QSC201639\~\TFLS\PRODUCTION\TAB-XX                                                   DDMMMYYYY HH:MM                                       
                                                                                                                                                              
(Programming note: This table will be continued for all vital signs parameters.                                                                               
                   Parameter may be added as the first column in this table.)                                                                                 


    
 
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MedDay Pharmaceuticals                                                                                                     Page x of y 
Protocol: MD1003CT2019-03MB 
 
TABLE 14.5.2.1 
ECGs 
Summary Statistics: Safety Analysis Set 
  
100 mg [14C]-MD1003 (N=XX) 
<Parameter> (<units>) [<ref range xxx - xxx (age xx - xx), xxx - xxx (age > xx)> / <ref range xxx - xxx (male)>] 
 
                                            Result                                 Change from Baseline              
                         _____________________________________________ _____________________________________________ 
Time Point                 n    Mean     SD    Median    Min     Max     n    Mean     SD    Median    Min     Max   
____________________________________________________________________________________________________________________ 
                                                                                                                     
BASELINE                  xx    xx.xx   xx.xx   xx.xx   xx.x    xx.x                                                 
1 H                       xx    xx.xx   xx.xx   xx.xx   xx.x    xx.x    xx    xx.xx   xx.xx   xx.xx   xx.x    xx.x   
4 H                       xx    xx.xx   xx.xx   xx.xx   xx.x    xx.x    xx    xx.xx   xx.xx   xx.xx   xx.x    xx.x   
24 H                      xx    xx.xx   xx.xx   xx.xx   xx.x    xx.x    xx    xx.xx   xx.xx   xx.xx   xx.x    xx.x   
DISCHARGE                 xx    xx.xx   xx.xx   xx.xx   xx.x    xx.x    xx    xx.xx   xx.xx   xx.xx   xx.x    xx.x   
                                                                                                                     
____________________________________________________________________________________________________________________________                                  
Note: The data in this table are presented in listing x.x                                                                           
      BASELINE is defined as Day 1, Pre-dose. DISCHARGE is planned to be 168 h.                                                                               
                                                                                                                                                              
                                                                                                                                                              
PROGRAM PATH: X:\~\QSC201639\~\TFLS\PRODUCTION\TAB-XX                                                   DDMMMYYYY HH:MM                                       
                                                                                                                                                              
(Programming note: This table will be continued for all ECG parameters, which will follow the order given in the RAP text.                                    
                   Parameter may be added as the first column in this table.)                                                                                 


    
 
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MedDay Pharmaceuticals                                                                                                     Page x of y 
Protocol: MD1003CT2019-03MB 
 
TABLE 14.5.2.2 
ECGs 
QTcF Categorical Data 
Summary Statistics: Safety Analysis Set 
  
100 mg [14C]-MD1003 (N=XX) 
 
                                                     QTcF                                    QTcF Interval             
                                               Intervals (msec)                             Increase (msec)            
                              ___________________________________________________ ____________________________________ 
                                <=450       451-480        481-500        >500       <30         30-60         >60     
Time Point                N#     n(%)         n(%)           n(%)         n(%)       n(%)         n(%)         n(%)    
______________________________________________________________________________________________________________________ 
                                                                                                                       
BASELINE                  xx  xx (xx.x)    xx (xx.x)      xx (xx.x)    xx (xx.x)                                       
1 H                       xx  xx (xx.x)    xx (xx.x)      xx (xx.x)    xx (xx.x)  xx (xx.x)    xx (xx.x)    xx (xx.x)  
4 H                       xx  xx (xx.x)    xx (xx.x)      xx (xx.x)    xx (xx.x)  xx (xx.x)    xx (xx.x)    xx (xx.x)  
24 H                      xx  xx (xx.x)    xx (xx.x)      xx (xx.x)    xx (xx.x)  xx (xx.x)    xx (xx.x)    xx (xx.x)  
DISCHARGE                 xx  xx (xx.x)    xx (xx.x)      xx (xx.x)    xx (xx.x)  xx (xx.x)    xx (xx.x)    xx (xx.x)  
                                                                                                                       
____________________________________________________________________________________________________________________________                                  
Note: The data in this table are presented in listing x.x                                                                           
      BASELINE is defined as Day 1, Pre-dose. DISCHARGE is planned to be 168 h.                                                                               
      Categories for QTcF interval and QTcF interval increases are based on ICH E14 guidelines.                                                               
      N# is the total number of subjects at the relevant time point and is used in the denominator for calculating the percentages of                         
      subjects, n indicates the number of subjects with observations at the given time point.                                                                 
                                                                                                                                                              
                                                                                                                                                              
PROGRAM PATH: X:\~\QSC201639\~\TFLS\PRODUCTION\TAB-XX                                                   DDMMMYYYY HH:MM                                       
 
 
 


    
 
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Appendix 1: 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 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IP 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; IP: Investigational Product; TR: total radioactivity  


    
 
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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 protocol 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