Clinical trial NCT03930264
Conditions: Therapeutic Equivalency
Sponsor: Nova Laboratories Limited
Start date: 2019-04-11; Completion date: 2019-05-31
Enrollment: 30 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
A single center, single dose, open-label, randomized, two period crossover study to assess the bioequivalence of an oral azathioprine suspension 10 mg/mL (Jayempi™) versus oral azathioprine tablet 50mg (Imurek®, Aspen Pharma Trading Limited, Dublin, Ireland.) in at least 30 healthy adult subjects under fasting conditions.

Detailed description:
This will be a single-dose, open-label, randomised, two-period crossover study with orally administered 1 x 5mL (50 mg) of Jayempi™ Oral Suspension 10mg/mL versus oral azathioprine tablet 50mg (Imurek®, Aspen Pharma Trading Limited, Dublin, Ireland) on two separate occasions conducted under fasting conditions in healthy male and female subjects at a single study centre.

The study will comprise:

* Thiopurine methyltransferase (TPMT) testing;
* Screening period of maximum 28 days
* Two treatment periods (each of which will include a PK profile period of 12 hours) separated by a wash-out period of at least 3 calendar days (minimum number of days based on half-life of the analyte) and maximum of 14 calendar days between consecutive administrations of the IMP
* A post-study visit 7-10 days after the last dose of the last treatment period of the study.

Subjects will be randomly assigned to treatment sequence, prior to the first administration of IMP.

Arms: arm 1: Generic name : Azathioprine Trade name : Imurek® 50mg tablet Dosage form : Tablet containing 50 mg azathioprine Dose : 1 x Imurek 50mg Tablet per treatment period under fasting conditions Mode of administration : Orally Manufacturer : Aspen Pharma Trading Limited, Dublin, Ireland Country of origin : Ireland arm 2: Generic name : Azathioprine

Trade name : (Jayempi™) 10 mg/ mL Oral solution Dosage form : Oral suspension containing 10 mg/mL Azathioprine Dose : 1 x 5mL (50 mg) of Jayempi™ Oral Suspension 10mg/mL per treatment period under fasting conditions Mode of administration : Orally Manufacturer : Nova Laboratories Ltd. Country of origin : Leicester, UK
Interventions: intervention 1: Azathioprine 50Mg Tab intervention 2: Azathioprine 10mg/mL oral suspension
Intervention descriptions: intervention 1: tablet intervention 2: oral suspension

Protocol documents:
Prot_000.pdf: 
Nova Laboratories Ltd., Leicester, UK 
 
Azathioprine Oral Suspension 10mg/mL  
 
 
 
Clinical Study Protocol 
SPONSOR STUDY No.: INV691 
Version 3.0 
Page 1 of 54 
Date: 03 May 2019 
 
Clinical Study Protocol 
A single centre, single dose, open-label, randomised, two period crossover study to assess the 
bioequivalence of an oral azathioprine suspension 10 mg/mL (Jayempi™) versus oral azathioprine 
tablet 50mg (Imurek®, Aspen Pharma Trading Limited, Dublin, Ireland) in at least 30 healthy adult 
subjects under fasting conditions. 
EudraCT:  
2018-004719-28 
SPONSOR STUDY NUMBER: 
INV691 
INVESTIGATIONAL 
MEDICINAL PRODUCTS: 
 
TEST (A): 1 x 5mL (50 mg) of Jayempi™ Oral Suspension 
10mg/mL. Nova Laboratories Ltd., Leicester, UK. 
  
REFERENCE (B):  1 x Imurek 50mg Tablet. Marketing 
Authorisation Holder is Aspen Pharma Trading Limited, Dublin, 
Ireland. 
 
DEVELOPMENT PHASE: 
Bioequivalence Study (Phase I) 
SPONSOR: 
Nova Laboratories Ltd. 
STUDY CENTRE: 
Medicines Evaluation Unit. 
REGION OF SUBMISSION: 
European Medicines Agency 
 
Dates 
Version 3.0:   (03 May 2019) 
Final    
Confidentiality Statement 
This confidential document is the property of Nova Laboratories Ltd., Leicester, United Kingdom.  No 
unpublished information contained herein may be disclosed without prior written approval from Nova 
Laboratories Ltd., Leicester, United Kingdom.  Access to this document must be restricted to relevant parties 
  
 


Nova Laboratories Ltd., Leicester, UK 
 
Azathioprine Oral Suspension 10mg/mL  
 
 
 
Clinical Study Protocol 
SPONSOR STUDY No.: INV691 
Version 3.0 
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Date: 03 May 2019 
 
1. 
TABLE OF CONTENTS 
1. 
TABLE OF CONTENTS ................................................................................................... 2 
2. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS .................................... 5 
3. 
ETHICAL AND REGULATORY REVIEW AND APPROVAL ..................................... 8 
3.1. 
Mandatory Approvals ............................................................................................ 8 
3.2. 
Ethical Conduct of the Study ................................................................................ 8 
3.3. 
Subject Information and Informed Consent .......................................................... 9 
3.3.1. 
Confidentiality .................................................................................................. 9 
3.3.2. 
Remuneration of Subjects ................................................................................. 9 
3.3.3. 
Indemnity ........................................................................................................ 10 
4. 
INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE ....................... 11 
4.1. 
STATEMENT AND SIGNATURE: PRINCIPAL INVESTIGATOR ............... 13 
4.2. 
SIGNATURE: SPONSOR SIGNATORY / SIGNATORIES ............................. 15 
5. 
INTRODUCTION ............................................................................................................ 16 
5.1. 
Background ......................................................................................................... 16 
Risk/Benefit Analysis ....................................................................................................... 17 
5.2. 
Clinical Pharmacokinetics ................................................................................... 19 
5.3. 
Adverse Events, Contraindications and Warnings .............................................. 21 
5.4. 
Rationale for the Study ........................................................................................ 21 
6. 
STUDY OBJECTIVES .................................................................................................... 23 
7. 
INVESTIGATIONAL PLAN .......................................................................................... 24 
7.1. 
Overall Study Plan and Design ........................................................................... 24 
7.1.1. 
Study Design ................................................................................................... 24 
7.1.2.  
Thiopurine Methyltransferase Testing ............................................................ 24 
7.1.3 
Schedule of Study Assessments: ..................................................................... 24 
7.1.4 
Safety and Data Monitoring Committees: ...................................................... 27 
7.2 
Discussion of Study Design ................................................................................ 27 
7.2.1 
Pre-study Evaluation (Screening) ................................................................... 27 
7.2.2 
Expected Duration of Study ............................................................................ 27 
7.2.3 
Treatment Periods (1 and 2) ............................................................................ 27 
7.2.4 
Post-study Evaluations .................................................................................... 28 
7.2.5 
Sampling, Interim Handling and Storage ........................................................ 28 
7.2.5.1 
Safety Blood and Urine Samples ..................................................... 28 
7.2.5.2 
Pharmacokinetic Blood Samples ..................................................... 29 
7.2.6 
Blood Volume ................................................................................................. 29 
7.2.7 
General and Dietary Restrictions .................................................................... 30 
7.2.7.1 
Diet .................................................................................................. 30 
7.2.7.2 
Physical Activity ............................................................................. 31 
7.2.7.3 
Contraception .................................................................................. 31 
7.2.7.4 
Sperm and Oocyte Donation ........................................................... 32 
7.2.7.5 
Receipt of Live Vaccination ............................................................ 32 
7.3 
Selection of Study Population ............................................................................. 32 
7.3.1 
Inclusion Criteria ............................................................................................ 32 
7.3.2 
Exclusion Criteria ........................................................................................... 33 
7.3.3 
Withdrawal Criteria ........................................................................................ 35 


Nova Laboratories Ltd., Leicester, UK 
 
Azathioprine Oral Suspension 10mg/mL  
 
 
 
Clinical Study Protocol 
SPONSOR STUDY No.: INV691 
Version 3.0 
Page 3 of 54 
Date: 03 May 2019 
 
7.3.4 
Replacement of Subjects ................................................................................. 35 
7.3.5 
Premature Termination of the Study ............................................................... 36 
8 
INVESTIGATIONAL MEDICINAL PRODUCTS ......................................................... 37 
8.2 
Products to be administered ................................................................................ 37 
8.3 
Identity of Investigational Medicinal Products ................................................... 37 
Test Product (A) ............................................................................................................. 37 
Reference Product (B) .................................................................................................... 37 
8.3.1 
Supply and Storage ......................................................................................... 38 
8.3.2 
Investigational Medicinal Product Accountability ......................................... 38 
8.3.3 
Retention Samples .......................................................................................... 38 
8.4 
Randomization Schedule ..................................................................................... 38 
8.5 
Selection of Doses in the Study ........................................................................... 39 
8.6 
Administration of Investigational Medicinal Products ....................................... 39 
8.7 
Blinding ............................................................................................................... 39 
8.8 
Prior and Concomitant Medication ..................................................................... 39 
8.9 
Treatment Compliance ........................................................................................ 40 
9 
PHARMACOKINETIC AND SAFETY VARIABLES .................................................. 41 
9.2 
Pharmacokinetic and Safety Measurements ........................................................ 41 
9.3 
Appropriateness of Measurements ...................................................................... 41 
9.4 
Primary Pharmacokinetic Variables .................................................................... 41 
9.5 
Pharmacokinetic Drug Assays ............................................................................ 41 
10 
DATA QUALITY ASSURANCE AND DATA MANAGEMENT ................................ 42 
10.2 
Quality Control and Source Data Verification .................................................... 42 
10.3 
Audit/Inspections ................................................................................................ 42 
10.4 
Study Monitoring ................................................................................................ 42 
10.5 
Data Collection .................................................................................................... 42 
11 
STATISTICAL METHODS ............................................................................................ 44 
11.2 
Statistical Methodology ....................................................................................... 44 
11.2.1 
Pharmacokinetic Population ........................................................................... 44 
11.2.2 
Safety Population ............................................................................................ 44 
11.3 
Sample Size ......................................................................................................... 44 
11.4 
Protocol Deviations and Changes to Planned Analyses ...................................... 45 
11.5 
Pharmacokinetic Variables .................................................................................. 45 
11.5.1 
Primary Variables ........................................................................................... 45 
11.5.2 
Secondary Variables ....................................................................................... 45 
11.6 
Presentation of Data, Descriptive Statistics and PK Assessment ........................ 45 
11.7 
Analysis of Bioequivalence ................................................................................. 46 
11.8 
Analysis of Safety Data ....................................................................................... 47 
12 
ADVERSE EVENTS ....................................................................................................... 48 
12.2 
Definitions ........................................................................................................... 48 
12.2.1 
Adverse Events (or Adverse Experiences) ..................................................... 48 
12.2.2 
Adverse Drug Reaction ................................................................................... 48 
12.2.3 
Unexpected Adverse Drug Reaction ............................................................... 48 
12.2.4 
Serious Adverse Events .................................................................................. 48 
12.3 
Classification of Adverse Events ........................................................................ 49 


Nova Laboratories Ltd., Leicester, UK 
 
Azathioprine Oral Suspension 10mg/mL  
 
 
 
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Version 3.0 
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12.4 
Definition of Adverse Events Relationship. ........................................................ 50 
12.5 
Adverse Events Documentation .......................................................................... 50 
12.6 
Reporting Procedures of Adverse Events/Serious Adverse Events .................... 51 
12.7 
Pregnancy ............................................................................................................ 51 
13 
LEGAL AND ADMINISTRATIVE ASPECTS .............................................................. 53 
13.2 
Documentation .................................................................................................... 53 
13.3 
Publication of Results .......................................................................................... 53 
13.4 
Sponsor’s Obligation ........................................................................................... 53 
13.5 
Clinical Study Report .......................................................................................... 53 
14 
REFERENCES ................................................................................................................. 54 
 
LIST OF TABLES 
Table 7-1 
Schedule of Study Assessments 
Table 7-2  
Total Blood Volume to be collected during the Study 
 
 


Nova Laboratories Ltd., Leicester, UK 
 
Azathioprine Oral Suspension 10mg/mL  
 
 
 
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SPONSOR STUDY No.: INV691 
Version 3.0 
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Date: 03 May 2019 
 
2. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
ABPI 
Association of the British Pharmaceutical Industry 
Adverse event reporting 
Adverse events will be documented as such only from the time that 
the IMP has been administered.  Events experienced before that time 
will be regarded as part of the medical history of the subject. 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
aPTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase 
ATC 
Anatomical-Therapeutic-Chemical classification 
AUC 
Area under the plasma concentration versus time curve 
AUC(0-t) 
Area under the plasma concentration versus time curve, from time 
zero to where t is the time of the last quantifiable concentration 
AUC(0-¥) 
Area under the plasma concentration versus time data pairs, with 
extrapolation to infinity 
AZA 
Azathioprine 
 
BLQ 
Below the lower limit of quantification 
BMI 
Body Mass Index 
 
 
CDER 
Centre for Drug Evaluation and Research 
Citrus fruits 
Any of numerous fruits of the genus Citrus e.g., orange, lemon, lime, 
grapefruit and tangerine 
Clinic day 
Time ranging from the start of the profile period until discharge from 
the clinic 
Cmax 
Maximum observed plasma concentration 
Concomitant medication 
Any medication given in addition to the IMP 
eCRF 
Electronic Case report form 
CTA 
Clinical Trial Authorisation 
CV% 
Coefficient of variation (%) 
 
 
Discontinuer 
Enrolled subject who is withdrawn by the investigator before the 
clinical phase of the study has been completed 
Drop-out 
Enrolled subject who withdraws from the study of the subject's own 
volition before the clinical phase of the study has been completed 
 
 
ECG 
Electrocardiogram 
EDTA 
Ethylenediaminetetraacetic acid 
Enrolled subject 
Subject allocated a subject number which confirms formal entry into 


Nova Laboratories Ltd., Leicester, UK 
 
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SPONSOR STUDY No.: INV691 
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the study 
 
 
FDA 
Food and Drug Administration (United States Department of Health 
and Human Services) 
 
 
GCP 
Good Clinical Practice 
GGT 
Gamma glutamyl transferase (transpeptidase) 
GLP 
Good Laboratory Practice 
GMP 
Good Manufacturing Practice 
 
 
HIV 
Human Immunodeficiency Virus 
 
 
ICH 
International Conference on Harmonisation 
ICH E3 
ICH Guideline for Structure and Content of Clinical Study Reports 
 
 
IMP 
Investigational Medicinal Product 
INR 
International Normalized Ratio 
ISO/IEC 
International Organization for Standardization / International 
Electrotechnical Commission 
 
 
λz 
Terminal elimination rate constant 
LC-MS/MS 
Liquid chromatography with tandem mass spectrometry 
LLOQ 
Lower limit of quantification 
 
 
n 
Number of subjects 
Non-qualifier 
Subject not included in the study due to ineligibility during the 
screening period, or an eligible subject who became ineligible before 
allocation of a subject number (e.g., due to illness and/or use of 
medication) 
Non-smoker 
Subject who has not smoked previously and/or has not used nicotine 
or nicotine-containing products for at least 12 months; subjects who 
have discontinued smoking or the use of nicotine / nicotine-
containing products (including e-cigarettes, snuff and similar 
products) at least 12 months before the first administration of the 
IMP 
 
 
OECD 
Organization for Economic Cooperation and Development 
 
 
 
 
PK 
Pharmacokinetic(s) 
Profile period 
Pharmacokinetic blood sampling period, including clinic stay 


Nova Laboratories Ltd., Leicester, UK 
 
Azathioprine Oral Suspension 10mg/mL  
 
 
 
Clinical Study Protocol 
SPONSOR STUDY No.: INV691 
Version 3.0 
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Date: 03 May 2019 
 
PT 
Prothrombin time 
 
 
Replacement 
Eligible subject who enters the study to replace a drop-out or 
discontinuer 
REC 
Independent Research Ethics Committee 
 
 
SAE 
Serious adverse event (collected and reported from consent) 
Screening period 
Time window during which subjects are evaluated to establish 
eligibility for enrolment into the study 
SOC 
System Organ Class 
SOP 
Standard operating procedure 
SPC 
Summary of Product Characteristics 
SST 
Serum Separator Tube 
Study start 
Study start is defined as administering or giving directions for the 
administration of the IMP to a subject for the purposes of this study 
SUSAR 
Suspected unexpected serious adverse reaction 
 
 
tmax 
Time to maximum observed plasma concentration 
TPMT 
Thiopurine methyltransferase 
Treatment period 
Time between the first and last study-related procedures of a period 
of IMP administration 
t½ 
Apparent terminal elimination half-life 
 
 
UK 
United Kingdom 
USA 
United States of America 
 
 
Wash-out period 
Period between consecutive administrations of IMP 


Nova Laboratories Ltd., Leicester, UK 
 
Azathioprine Oral Suspension 10mg/mL  
 
 
 
Clinical Study Protocol 
SPONSOR STUDY No.: INV691 
Version 3.0 
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Date: 03 May 2019 
 
3. 
ETHICAL AND REGULATORY REVIEW AND APPROVAL 
3.1. 
Mandatory Approvals 
Written approval for the final version of the clinical study protocol and any amendments, as well as 
other applicable documents will be obtained from an independent Research Ethics Committee 
(REC) and the national Competent Authority (by submission or notification of a CTA according to 
local regulations) before performance of any study-related procedures. 
3.2. 
Ethical Conduct of the Study 
The Ethics Committee will be informed that the study is sponsored by Nova Laboratories Ltd. and 
financed by Nova Laboratories Ltd.   
The Ethics Committee should approve the final study protocol, including the final version of the 
Informed Consent Form and any other written information and/or materials to be provided to the 
subjects. The Principal Investigator will ensure the distribution of these documents to the applicable 
Ethics Committee. 
The opinion of the Ethics Committee should be given in writing. The Principal Investigator should 
submit the written approval to Sponsor before enrolment of any subject into the study. 
The Ethics Committee should approve all advertising used to recruit subjects for the study.  The 
Sponsor should approve any modifications to the Informed Consent Form that are needed to meet 
local requirements. 
The Sponsor will provide the Competent Authority, Ethics Committee and investigators at the study 
centres with safety updates and progress reports at least annually and otherwise as appropriate, 
including informing them of any SUSARs (Suspected Unexpected Serious Adverse Reactions) or 
urgent safety measures; completion or termination of the study and providing a final report within 
one year of the end of the study. 
The Chief Investigator shall be responsible for ensuring that the clinical study is performed in 
accordance with the following: 
• Declaration of Helsinki (Brazil, 2013) 
• ICH Harmonised Tripartite Guideline for Good Clinical Practice. 
• The Medicines for Human Use (Clinical Trials) Regulations 2004 (Statutory Instrument 
2004 No. 1031) and subsequent amendments. 
• United States Code of Federal Regulations (CFR) specifically CFR 21 parts 11, 50, 54, 312 
and 314. 


Nova Laboratories Ltd., Leicester, UK 
 
Azathioprine Oral Suspension 10mg/mL  
 
 
 
Clinical Study Protocol 
SPONSOR STUDY No.: INV691 
Version 3.0 
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Date: 03 May 2019 
 
3.3. 
Subject Information and Informed Consent 
Before commencement of the screening procedures, the subjects will be informed verbally by the 
investigator and in writing concerning the nature, purpose and risks involved in the screening 
procedures as well as the purpose, procedures, restrictions, obligations, remuneration, insurance 
coverage and possible adverse drug reactions relevant to the study. 
The purpose of the study, the procedures to be carried out and the potential hazards will be 
described to the subjects in non-technical terms.  Subjects will be required to read, sign and date the 
statement of informed consent summarizing the discussion prior to enrolment.  They will be assured 
that they may withdraw from the study at any time without jeopardizing their medical care.  Each 
subject will be given a signed copy of the subject information sheet and statement of informed 
consent form. Subjects will be given at least 24 hours to consider participation in the study. 
The original as well as any revision of the subject information sheets and statements of informed 
consent provided to the subjects will be submitted for approval as appropriate. 
Representative written information for the subjects and sample consent forms will be kept in the 
Investigator Site File. 
3.3.1. 
Confidentiality 
Study findings will be stored in accordance with local and global data protection laws.  Information 
on confidentiality is also contained in the subject information sheet. 
The subjects will be informed that representatives of the sponsor, REC, regulatory authorities or 
auditors may inspect their medical records to verify the information collected, and that all personal 
information made available for inspection will be handled in strictest confidence and in accordance 
with local data protection laws. 
The investigator will maintain a personal subject identification list (subject numbers with the 
corresponding subject names) to enable records to be identified.  All external communications and 
documents relevant to subjects in the study will identify each subject only by the subjects’ study 
numbers. 
3.3.2. 
Remuneration of Subjects 
Compensation will be reasonable and related to the nature and degree of inconvenience and 
discomfort as a result of participation in the study.  Information on how subjects will be 
compensated is contained in the subject information sheet. 


Nova Laboratories Ltd., Leicester, UK 
 
Azathioprine Oral Suspension 10mg/mL  
 
 
 
Clinical Study Protocol 
SPONSOR STUDY No.: INV691 
Version 3.0 
Page 10 of 54 
Date: 03 May 2019 
 
3.3.3. 
Indemnity 
Insurance cover has been arranged in compliance with the Association of the British Pharmaceutical 
Industry (ABPI) guidelines to indemnify the subjects in the event of death or any deterioration in 
health or well-being caused by participation in the study. 
The certificate of insurance will be kept in the Investigator Site File. 


Nova Laboratories Ltd., Leicester, UK 
 
Azathioprine Oral Suspension 10mg/mL  
 
 
 
Clinical Study Protocol 
SPONSOR STUDY No.: INV691 
Version 3.0 
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Date: 03 May 2019 
 
4. 
INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE 
Principal Investigator and Study Staff: 
Information on the investigators and other persons whose participation will materially affect the 
conduct of the study is contained in the Investigator Site File. 
Principal Investigator: Dr. Naimat Khan 
Study Centre: 
Medicines Evaluation Unit Ltd. 
The Langley Building, Southmoor Road, Wythenshawe, 
Manchester, M23 9QZ 
 
Tel: 
 
Safety Analytical Laboratory: 
The Doctor’s Laboratory (TDL) 
The Halo Building, 1 Mabledon Place, London, 
WC1H 9AX, UK 
 
Tel: 
 
Data Management and Statistics: 
SQN Clinical 
Gostling House, Diss Business Park 
Hopper Way, Diss 
Norfolk, IP22 4GT, UK 
 
Tel: 
 
Pharmacokinetics Analytical Laboratory: 
Alderley Analytical Ltd. Alderley Park,  
Macclesfield,  
Cheshire. SK10 4TG. UK 
Tel: 
 
  
 
Thiopurine methyltransferase (TPMT) phenotyping testing:  
Black Country Pathology Services 
Clinical Skills Services Building, Royal Wolverhampton Hospitals NHS Trust,  
Wednesfield Road,  
Wolverhampton, WV10 0QP  
Tel:  
 
  
 
Pharmacovigilance: 
Diamond Pharma Services 
Suite 2, Ground Floor, Field House, Station Approach, 
Harlow, Essex, CM20 2FB, UK 
 
Tel: 
 


Nova Laboratories Ltd., Leicester, UK 
 
Azathioprine Oral Suspension 10mg/mL  
 
 
 
Clinical Study Protocol 
SPONSOR STUDY No.: INV691 
Version 3.0 
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Date: 03 May 2019 
 
Sponsor: 
Nova Laboratories Ltd. 
 
Martin House, Gloucester Crescent 
 
Wigston, Leicester LE18 4YL 
 
United Kingdom 
 
Tel: 
 
Fax: 
 
Sponsor Medical Expert:
 
Consultant Medical Advisor (Boyd Consultants), / Medical 
Monitor / Research Physician 
Boyd Consultants, 
Unit M South Cambridge Business Park, 
Babraham Road, 
Sawston, 
Cambridgeshire, CB22 3JH 
 
 
Tel: 
 
               
 
Sponsor Contact Person: 
 
 
Head of Clinical Development 
 
Nova Laboratories Ltd. 
 
Martin House, Gloucester Crescent 
 
Wigston, Leicester LE18 4YL 
 
United Kingdom 
 
Tel: 
 
Fax: 
 
Email: 
 
Monitor: 
Information regarding the study monitor will be contained in the Trial Master File. 


Nova Laboratories Ltd., Leicester, UK 
 
Azathioprine Oral Suspension 10mg/mL  
 
 
 
Clinical Study Protocol 
SPONSOR STUDY No.: INV691 
Version 3.0 
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4.1. 
STATEMENT AND SIGNATURE: PRINCIPAL INVESTIGATOR 
A single centre, single dose, open-label, randomised, two period crossover study to assess the 
bioequivalence of an oral azathioprine suspension 10 mg/mL (Jayempi™) versus oral azathioprine 
tablet 50mg (Imurek®, Aspen Pharma Trading Limited, Dublin, Ireland.) in at least 30 healthy adult 
subjects under fasting conditions. 
I, the undersigned, verify that, to the best of my abilities and knowledge: 
1. 
I have reviewed this original clinical study protocol and approve its contents. 
2. 
I am familiar with the properties of the investigational medicinal product (IMP) as described 
in the References.  I am qualified by scientific training and experience to conduct the 
clinical investigational study identified above.  My medical education and experience is 
stated in the curriculum vitae provided. 
3. 
The study centre has adequate staff and appropriate facilities (including laboratories) that 
will be available for the duration of the study to be conducted in conformance with this 
clinical study protocol and Good Clinical Practices (including the national Competent 
Authority guidelines), as assured by an "in-house" quality assurance program. 
4. 
I agree to obtain permission from the sponsor in writing should any changes be required to 
the clinical study protocol.  Should the safety of the study subjects necessitate immediate 
action, which represents a deviation from the clinical study protocol, the sponsor will be 
informed as soon as possible. 
5. 
I shall obtain in writing the necessary approval from the REC and national Competent 
Authority.  I shall ensure communication of any modification, amendment or deviation of 
the clinical study protocol, and also inform the REC and the national Competent Authority 
(where applicable) in the event of discontinuation of the study and the reasons for 
discontinuation. 
6. 
I agree to obtain written informed consent from all subjects prior to performance of any 
study-related activity.  Both oral and written subject study information will be provided in 
the language the subject prefers. Subjects will be given at least 24 hours to consider 
participation in the study. 
7. 
I shall ensure that electronic case report forms (eCRFs) are completed, signed and archived 
at the study centre as applicable. 
8. 
I agree to allow the auditor/inspector/any representatives of regulatory authorities access to 
all relevant documents and be available to discuss any findings/issues. 






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5. 
INTRODUCTION 
5.1. 
Background 
The drug substance azathioprine is a well-established drug and has been used as an 
immunosuppressant post-organ transplant and in autoimmune and inflammatory diseases for almost 
60 years. 
 
Azathioprine is used alone or in combination with other immunosuppressive therapy to prevent 
rejection following organ transplantation, and to treat an array of autoimmune diseases, including 
rheumatoid arthritis, pemphigus, systemic lupus erythematosus, Behçet's disease, and other forms of 
vasculitis, autoimmune hepatitis, atopic dermatitis, myasthenia gravis, neuromyelitis optica (Devic's 
disease), restrictive lung disease, and others. It is also an important therapy and steroid-sparing 
agent for inflammatory bowel disease (such as Crohn's disease and ulcerative colitis) and for 
multiple sclerosis. 
 
In the European Union, azathioprine (Imurek) is currently approved for use in organ transplantation 
from human donors, auto-immune diseases such as rheumatoid arthritis and inflammatory bowel 
disease.  
 
Clinical trial data and evidence collected over the last 50 years demonstrates that azathioprine has 
an important role as an immunosuppressant for organ transplantation and a variety of autoimmune 
and inflammatory diseases in both adults and children. Treatment protocols have evolved during 
this period and necessitate that azathioprine is administered to children at doses related to their body 
size. However, only 25 and 50mg strength tablets are presently marketed across the EU, making 
accurate oral dosing difficult to achieve.  Although the currently approved tablet formulations can 
be halved or quartered to derive an intermediate dose, in most cases this still requires rounding 
doses up or down.  Moreover, young children often find taking tablets very difficult. Acceptability 
of the formulation in children is of paramount importance, especially in post organ transplantation 
and diseases where adherence can significantly impact on outcomes. 
 
As a consequence, unlicensed liquid formulations, prepared extemporaneously or procured as a 
‘Special’ (under the provisions of the UK Medicines Act 1968), are widely prescribed and 


Nova Laboratories Ltd., Leicester, UK 
 
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dispensed. This unlicensed use potentially exposes children to medication errors and the 
consequential higher risk of adverse reactions or inadequate efficacy. 
 
Jayempi administered using an oral syringe will allow the dose of azathioprine to be tailored to 
patient requirements, both accurately and safely. Moreover, improved ease of administration for 
children will enhance medication acceptability and adherence. Jayempi will also be of benefit to 
adolescents and adults who find taking tablets difficult. 
 
The applicant is planning to submit a centralised application to the European Medicines Agency: of 
an alternative formulation to a reference listed drug and as a Hybrid application under Article 10(3) 
regulation. Hence, a bioequivalence study comparing Jayempi to the reference listed drug, Imurek 
50 mg (Aspen Pharma Trading Limited, Ireland) in healthy male and female volunteers is proposed. 
 
Risk/Benefit Analysis 
There is no direct benefit to the study subjects.   
 
Healthy volunteer studies of azathioprine have safetly been done before and have resulted in the 
MHRA granting a marketing authorisation (Public Assessment Report, Azathioprine 50mg Film-
coated Tablets, UK/H/934/01/DC, Relonchem Ltd). 
Nova Laboratories have safely undertaken a similar heatlthy volunteer study with the primary 
metabolite of azathioprine, namely mercaptopurine, for which a European Marketing Authorisation 
has been obtained (European public assessment report (EPAR) for Xaluprine). 
 
The study design reduces the risk to subjects. Specifically: 
 
• Dose and dosing regimen:  A low dose will be used on two occasions only, so the 
immunosuppressive effect of either the investigational medicinal product or the reference 
medication is unlikely to have any clinically relevant or lasting effect in this population of 
healthy volunteers.  
 
• Eligibility:  


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Subjects will be rigorously screened and will be registered on The Over-volunteering 
Prevention System (TOPS) to prevent over volunteering.  Only healthy subjects will be 
enrolled.   
There are individuals with an inherited deficiency of the enzyme thiopurine 
methyltransferase (TPMT) who may be unusually sensitive to the myelosuppressive effect 
of azathioprine and prone to developing rapid bone marrow depression following the 
initiation of treatment with Azathioprine. Also it has been reported that decreased TPMT 
activity increases the risk of secondary leukaemias and myelodysplasia in individuals 
receiving 6-mercaptopurine (the active metabolite of azathioprine) in combination with 
other cytotoxics. All subjects who consent to the study will undergo TPMT phenotyping and 
those with a deficient, low or intermediate TPMT enzyme activity will be excluded from 
taking part. 
Patients with inherited mutated NUDT15 gene are at increased risk of severe azathioprine 
toxicity with the usual doses of thiopurine therapy, such as early leukopenia and alopecia. 
These patients generally require dose reduction, particularly those being NUDT15 variant 
homozygotes . The frequency of NUDT15 c.415C>T has an ethnic variability of 
approximately 10% in East Asians, 4% in Hispanics, 0.2% in Europeans and 0% in 
Africans. In any case, close monitoring of blood counts is necessary. In this study, subjects 
of East Asian and Hispanic ethnicity will be excluded. 
 
• Reproductive Risks: Animal studies have revealed malformations due to azathioprine. In 
embryo-toxicity studies, azathioprine showed teratogenic (affecting the development) or 
lethal effects on embryos in various animal species. In humans, however, there are 
contradictory findings about the teratogenic potential of azathioprine. There have been 
reports of intrauterine growth retardation, prematurity and low birth weight over 
azathioprine, especially in combination with corticosteroids. There are also reports of 
spontaneous abortions after both maternal and paternal exposure. Therefore, the following 
risk mitigation strategies have been put into place: 
o Male and female subjects at reproductive age should use a condom plus one highly 
effective contraceptive measures during the administration of azathioprine and at 
least 6 months after the end of treatment. 
o Subjects who plan to procreate within 6 months after IMP administration will not be 
included in the study. 


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o Male subjects must not have unprotected sexual intercourse with a female who is 
pregnant or breastfeeding during the study and for 6 months after their final dose. 
o Male subjects will be instructed not to donate sperm until 6 months after the last 
dose. 
o Females who are currently pregnant will be excluded 
o Females of child bearing potential will have a pregnancy test carried out at 
screening, at each admission to the clinic prior to dosing and at the follow up visit. 
o Should any pregnancies occur (for a female subject or female partner of a male 
subject, they must be reported immediately and should be followed up to determine 
outcome, including spontaneous or voluntary termination, details of the birth, and the 
presence or absence of any birth defects, congenital abnormalities, or maternal 
and/or new-born complications.  Pregnancy outcomes must be collected for all 
female volunteers and the female partners of any males who took the IMP. Consent 
to report information regarding these pregnancy outcomes would be obtained from 
the mother. 
o In addition to the above, to prevent exposure of any partner (male or female) a 
condom must be used throughout the study and for 6 months after the final dose of 
study drug. 
 
 
5.2. 
Clinical Pharmacokinetics  
Absorption  
Azathioprine is absorbed incompletely and variably.  The median (range) absolute bioavailability of 
6- MP after administration of azathioprine 50 mg is 47% (27 – 80%).  Although there are no food 
effect studies with azathioprine, pharmacokinetic studies with 6-MP have been conducted that are 
relevant to azathioprine.  The mean relative bioavailability of 6-MP was approximately 26% lower 
following administration with food and milk compared to an overnight fast. 6-MP is not stable in 
milk due to the presence of xanthine oxidase (30% degradation within 30 minutes).  Azathioprine 
should be administered at least 1 hour before or 3 hours after food or milk. 
There is no correlation between the plasma levels of azathioprine and 6-mercaptopurine and the 
therapeutic efficacy or toxicity of azathioprine. 
 
Distribution 


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The volume of distribution at steady state (Vdss) of azathioprine is unknown. The mean (± SD) 
apparent Vdss of 6-MP is 0.9 (±0.8) L/kg, although this may be an underestimate because 6-MP is 
cleared throughout the body (and not just in the liver). 
Concentrations of 6-MP in cerebrospinal fluid (CSF) are low or negligible after IV or oral 
administration of 6-MP. 
Azathioprine is rapidly distributed in the body. Only 30% of the substance is bound to plasma 
proteins. 
 
Biotransformation  
Azathioprine is rapidly broken down in vivo by glutathione-S-transferase into 6-MP and a 
methylnitroimidazole moiety.  The 6-MP readily crosses cell membranes and is extensively 
metabolised by many multi-step pathways to active and inactive metabolites, with no one enzyme 
predominating.  Because of the complex metabolism, inhibition of one enzyme does not explain all 
cases of lack of efficacy and/or pronounced myelosuppression.  The predominant enzymes 
responsible for the metabolism of 6-MP or its downstream metabolites are: the polymorphic 
enzyme thiopurine S-methyltransferase (TPMT), xanthine oxidase, inosine monophosphate 
dehydrogenase (IMPDH), and hypoxanthine guanine phosphribosyltransferase (HPRT).  Additional 
enzymes involved in the formation of active and inactive metabolites are: guanosine 
monophosphate synthetase (GMPS, which form TGNs) and inosine triphosphate pyrophosphatase 
(ITPase).  Azathioprine itself is also metabolised by aldehyde oxidase to form 8-hydroxy 
azathioprine, which may be active. 
There are also multiple inactive metabolites formed via other pathways. 
There is evidence that polymorphisms in the genes encoding the different enzyme systems involved 
with metabolism of azathioprine may predict adverse drug reactions to azathioprine therapy. 
 
Thiopurine methyltransferase (TPMT) 
TPMT activity is inversely related to red blood cell 6-MP derived thioguanine nucleotide 
concentration, with higher thioguanine nucleotide concentrations resulting in greater reductions in 
white blood cell and neutrophil counts. Individuals with TPMT deficiency develop very high 
cytotoxic thioguanine nucleotide concentrations. 
Genotypic testing can determine the allelic pattern of a patient. Currently, 3 alleles—TPMT*2, 
TPMT*3A and TPMT*3C—account for about 95% of individuals with reduced levels of TPMT 
activity.  Approximately 0.3% (1:300) of patients have two non-functional alleles (homozygous-
deficient) of the TPMT gene and have little or no detectable enzyme activity.  Approximately 10% 


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of patients have one TPMT non-functional allele (heterozygous) leading to low or intermediate 
TPMT activity and 90% of individuals have normal TPMT activity with two functional alleles. 
There may also be a group of approximately 2% who have very high TPMT activity.  Phenotypic 
testing determines the level of thiopurine nucleotides or TPMT activity in red blood cells and can 
also be informative. 
 
Limited liver function 
In hepatic impairment, the metabolism of azathioprine is altered.  The conversion into the active 
metabolites is limited. Most importantly, degradation to metabolites is reduced. 
 
Elimination   
After oral administration of 100mg 35S-azathioprine, 50% of the radioactivity was excreted in the 
urine and 12% in the faeces after 24 hours.  In the urine, the major compound was the inactive 
oxidised metabolite thiouric acid.  Less than 2% was excreted in the urine as azathioprine or 6-MP.  
Azathioprine has a high extraction ratio with a total clearance greater than 3L/min in normal 
volunteers. The plasma half-life of azathioprine is 3 to 5 hours.  The renal clearance of 6-MP and 
the half-life of 6-MP are 191 mL/min/m2 and 0.9 hr respectively. 
 
6-MP (metabolite of azathioprine) has been detected in colostrum and in breast milk by women 
treated with azathioprine (6MP is excreted in breast milk at concentrations of 3.4 ng / ml to 18 ng / 
ml). 
For more information see Investigators Brochure. 
 
5.3. 
Adverse Events, Contraindications and Warnings 
Refer to the Summaries of Product Characteristics.  As with any medication, the list of adverse 
events will never be exhaustive, and unexpected or very rare adverse events not listed could 
potentially occur. 
5.4. 
Rationale for the Study 
The sponsor has developed a new formulation (test product) of an existing medication (reference 
product) which is intended for marketing authorization (see REGION OF SUBMISSION). 
The proposed study in healthy volunteers is designed to establish a PK profile under fasting 
conditions for the orally administered test and reference products to evaluate bioequivalence in 


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Date: 03 May 2019 
 
accordance 
with 
the 
EMA 
Guideline 
on 
the 
Investigation 
of 
Bioequivalence 
(CPMP/EWP/QWP/1401/98 Rev. 1/ Corr) and the United States Department of Health and Human 
Services, Food and Drug Administration (FDA) Guidance for Industry: Bioavailability and 
Bioequivalence Studies for Orally Administered Drug Products - General Considerations.  Centre 
for Drug Evaluation and Research (CDER) March 2003 BP.  


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6. 
STUDY OBJECTIVES 
Primary Objectives 
• The primary objective of this study is to assess whether Nova’s oral azathioprine suspension 
(Jayempi™) and a marketed tablet formulation (Imurek®) are bioequivalent. 
Secondary Objectives 
• To assess the safety and tolerability of the test product, azathioprine oral 10 mg/ mL 
suspension. 
• To determine the plasma concentrations and pharmacokinetics of the metabolite 
mercaptopurine 


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7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Study Plan and Design 
7.1.1. 
Study Design 
This will be a single-dose, open-label, randomised, two-period crossover study with orally 
administered 1 x 5mL (50 mg) of Jayempi™ Oral Suspension 10mg/mL versus oral azathioprine 
tablet 50mg (Imurek®, Aspen Pharma Trading Limited, Dublin, Ireland) on two separate occasions 
conducted under fasting conditions in healthy male and female subjects at a single study centre. 
The study will comprise: 
• Thiopurine methyltransferase (TPMT) testing; 
• Screening period of maximum 28 days 
• Two treatment periods (each of which will include a PK profile period of 12 hours) separated by 
a wash-out period of at least 3 calendar days (minimum number of days based on half-life of the 
analyte)  and maximum of 14 calendar days between consecutive administrations of the IMP  
• A post-study visit 7-10 days after the last dose of the last treatment period of the study. 
Subjects will be randomly assigned to treatment sequence, prior to the first administration of IMP. 
7.1.2.  
Thiopurine Methyltransferase Testing  
A thiopurine methyltransferase (TPMT) phenotyping test will be performed to confirm if the 
subject is eligible.  
Subjects must consent to having this test done.  The test will be performed at:  
Black County Pathology Services 
Clinical Skills Services Building, Royal Wolverhampton Hospitals NHS Trust,  
Wednesfield Road,  
Wolverhampton, WV10 0QP  
The results of the test will be discussed appropriately with the subject. 
7.1.3 Schedule of Study Assessments: 
The timing of assessments is displayed in Table 7-1. 
The time of dosing commencement may vary for logistical reasons.  Actual clock times will vary 
between subjects, in relation to actual dosing times. 


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Table 7-1  
Schedule of Study Assessments 
Assessment 
Screening* Admission 
1 
Day -1** 
Treatment 
period 1 
Admission 2 
Day -1** 
Treatment 
period 2*** 
Post-
study 
Visit1 
Informed consent 
X 
 
 
 
 
 
Demographic and anthropometric data2 
X 
 
 
 
 
 
Alcohol and tobacco consumption and drug 
use  
X 
 
 
 
 
 
Medical history3 and prior medication 
X 
X 
 
 
 
 
Adverse events and concomitant medication 
 
X$ 
X 
X 
X 
X 
Physical examination4 
X 
 
 
 
 
X 
Vital signs5 
X 
 
X 
 
X 
X 
12-Lead ECG6 
X 
 
 
 
 
X 
Haematology7 
X 
X 
 
X 
 
X 
Clinical chemistry8 
X 
X 
 
X 
 
X 
Blood coagulation9 
X 
X 
 
X 
 
X 
Serology tests10 
X 
 
 
 
 
 
Urinalysis11 
X 
 
 
 
 
 
Urine screen for drugs of abuse12 
X 
X 
 
X 
 
 
Urine screen for tobacco use13 
X 
X 
 
X 
 
 
Pregnancy Test14 
X 
X 
 
X 
 
X 
Eligibility Assessment 
X 
X 
 
X 
 
 
Randomization 
 
 
X 
 
 
 
IMP administration 
 
 
X 
 
X 
 
PK profile15 
 
 
X 
 
X 
 
Palatability questionnaire16 
 
 
X 
 
X 
 
Alcohol breath test17  
X 
X 
 
X 
 
 
Study specific screening test18 
X 
 
 
 
 
 
IMP = investigational medicinal product; ECG = electrocardiogram; PK = pharmacokinetic 
* Screening procedures can be performed over more than one visit 
** Day -1 Safety Labs can be performed within 7 days of dosing. If screening is performed within 7 days of dosing (for treatment 
period 1 only) safety labs do not need to be repeated. Subject will return to the unit in the afternoon/ evening of Day -1 for admission 
and remaining admission tests. 
***Treatment Period 2 to be carried out 3 to 14 days days of Treatment Period 1. 
$ Concomitant Medications only at admission, as only treatment emergent adverse events will be recorded.   
1. Seven (7) to ten (10) days  after the last dose of the last period of the study or, in the case of discontinuers or drop-outs who took 
the IMP, within 72 hours of withdrawal/withdrawing from the study.  
2. Gender, race, date of birth, age, height, weight and BMI.  
3. The recorded medical history will be updated if necessary on pre-profile nights (Day -1 of Admission 1).  
4. A full physical examination will include the following: ear/nose/throat, ophthalmological, dermatological, cardiovascular, 
respiratory, gastrointestinal, central nervous system, lymph nodes and musculoskeletal.; other evaluations may be performed as 
deemed necessary by the investigator. Any other evaluations undertaken will be included in the clinical study report, if applicable. 
The post-study physical examination will only be brief but will include vital signs.  
5. Supine and standing systolic and diastolic blood pressure, pulse and body temperature (tympanic) at screening (supine vital signs 
measured following 5 mins rest in supine position, standing vital signs measured following 2 mins in standing position). Supine 
blood pressure, pulse and body temperature will be recorded before administration of IMP; in addition, supine blood pressure and 
pulse will be recorded at 2, 4 and 6 hours (+/- 10 mins) post-dose and at post study visit.  
6. Standard 12-lead ECG will be performed at screening and post-study following 5 mins rest in supine position.  
7. Haematology (Ethylenediaminetetraacetic acid [EDTA tubes]): leucocytes, erythrocytes, haemoglobin, hematocrit, platelets, 
basophils, monocytes,  neutrophils, eosinophils and lymphocytes (absolute count and percentages).  
8. Screening and post-study: Clinical chemistry (Serum separator tubes [SST]): potassium, sodium, urea, creatinine, uric acid, 
calcium, protein, albumin, total bilirubin, alkaline phosphatase (ALP), gamma glutamyl transferase (GGT), aspartate 
aminotransferase (AST), alanine aminotransferase (ALT) and glucose. The clinical chemistry performed during admission of 
treatment periods 1, 2 and at post treatment will only include the liver function tests GGT, ALP AST and ALT.  
9. Blood coagulation tests (citrated tubes): Prothrombin time (PT), activated partial thromboplastin time (aPTT) and International 
Normalised Ratio (INR).  


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10. Tests for human immunodeficiency virus (HIV) and Hepatitis B and C, performed. Pre- and post-test counselling will be 
provided as appropriate.  
11. Urinalysis (dipstick): protein, bilirubin, blood and urobilinogen.  
12. Using a single urine sample: amphetamines, cannabinoids, cocaine, barbiturates, benzodiazepines, opiates, methadone.  
13. Cotinine testing.  
14. Serum pregnancy testing at screening (where applicable). Urine pregnancy testing at admission 1, 2 and Post-Study Visit for 
women of child bearing potential only. 
15. Blood collections will be made pre-dose within 30 minutes before administration and at 15 mins (±2 mins), 30 mins (±2 mins), 
45 mins(±2 mins), 1hr(±2 mins), 1 hr 20mins(±2 mins),  1 hr 40mins (±2 mins), 2hrs(±5 mins), 2hrs 20 mins(±5 mins), 2hrs 40 mins 
(±5 mins),  3hrs(±5 mins), 4hrs(±5 mins), 5hrs(±5 mins), 6hrs(±5 mins), 8hrs(±5 mins) and 12hrs(±5 mins)) after study drug 
administration. The PK sample should be taken on the scheduled timepoint and other procedures due at the same time scheduled 
around using the applicable windows. 
16. A short palatability questionnaire will be completed after dosing on the day that the subject is given oral liquid only. 
17. Alcohol breath test using a portable breath alcohol measuring device will be performed at screening, on admission to the research 
centre of each treatment period and at random, at any time during the study, if deemed necessary by the principal investigator or 
designee, to detect the presence of alcohol. If any of these tests are positive, subjects will not be allowed further participation in the 
study. 
18. Study-specific screening tests: Thiopurine methyltransferase (TPMT) testing (EDTA tubes) (see Appendix 15.1). 
 
 


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7.1.4 Safety and Data Monitoring Committees: 
Not applicable. 
7.2 Discussion of Study Design 
Bias is prevented by strict adherence to the inclusion and exclusion criteria.  All measurements and 
procedures are clearly defined in advance and will consistently and precisely be applied. 
7.2.1 Pre-study Evaluation (Screening) 
Within 28 days prior to the first administration of IMP and after written informed consent is 
obtained, screening procedures will be performed on each subject (see Table 7-1).  Subjects who 
meet the inclusion criteria (Section 7.3.1) will be considered eligible to participate in the study.  
Subjects who meet one or more of the exclusion criteria (Section 7.3.2) will not be considered 
eligible to participate in the study.  The total screening period will be approximately 28 days. 
At the discretion of the investigator screening procedures may be repeated  
7.2.2 Expected Duration of Study 
The duration of this study is expected to be approximately 2 months per subject (excluding the 
screening period).  The actual overall study duration or subject recruitment may vary. 
7.2.3 Treatment Periods (1 and 2) 
Each treatment period will include a PK profile period of 12 hours, which will commence with 
morning dosing of IMP on a 12-hour clinic stay at the study centre. 
During all treatment periods subjects will have safety laboratory tests performed within 7 days prior 
to dosing (if screening is performed within 7 days of dosing (for treatment period 1 only),  safety 
labs do not need to be repeated). They will be admitted to the study centre on the afternoon/ evening 
of Day -1 for remaining admission tests.  An overnight fast of at least 10 hours (a food and 
beverage-free period with the exception of water) will be observed.  
Before dosing on day 1, an indwelling venous cannula may be inserted.  A member of the clinical 
team will decide when to remove or replace the venous cannula based on the time (since insertion 
of the cannula) or if clotting occurs.  If the cannula is removed, the subsequent blood samples will 
be collected by venepuncture or the cannula will be replaced. 
The IMP will be administered in the sitting position with the volume of water specified in section 
8.6.  Thereafter subjects will be required to  refrain from lying down (except when required for 
clinical procedures e.g. PK sampling) for 4 hours after dosing.   


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Food and beverages on clinic days will be according to Section 7.2.7.1. 
A short palatability questionnaire will be given to the subjects on the day that oral liquid is given 
and will comprise: 
1. What did you think of the taste of the liquid medicine you were given in the study?  
2. Was there an aftertaste to the liquid medicine you were given in the study?  
3. What did you think of the smell of the liquid medicine you were given in the study?  
4. What did you think of the texture of the liquid medicine in the mouth?  
5. If you had to, how easy would it be for you to take the liquid medicine regularly, every 
day?  
Subjects will be allowed to leave the study centre on the treatment days after the last assessments 
have been made. 
7.2.4 Post-study Evaluations 
See Table 7-1. 
If a subject is withdrawn or chooses to withdraw from the study, the investigator will make every 
effort to perform all evaluations described for the post-study visit. 
Post study laboratory investigations with variables outside the reference ranges will not necessarily 
be repeated to establish if and when those variables returned to within the reference ranges.  The 
variables will be reviewed against the clinical background, other relevant investigations and their 
relevance to the administered IMP, before a decision will be taken to repeat the investigations in 
question.  At the discretion of the investigator, the investigations of certain variables outside the 
reference ranges may be repeated until the variables return to within the reference range for the 
particular laboratory test, or until the investigator considers the repeated variable to be at an 
acceptable level in relation to the reference range.  If the investigator has made every effort to 
contact the subject and the subject remains unavailable to attend the clinic for repeat of applicable 
laboratory investigations, the investigator may declare the subject lost to follow-up. 
In cases where results of post-study evaluations are reported after the database has been locked, the 
applicable clinical laboratory reports will be presented in the appendices to the clinical study report. 
All evaluations described for the post-study visit will be performed on all subjects who completed 
the study. 
7.2.5 Sampling, Interim Handling and Storage 
7.2.5.1 Safety Blood and Urine Samples 
Refer to Table 7-1. 
Before starting the study, the investigator (or designee) will supply the sponsor with the reference 
ranges and units of measurement for the laboratory safety variables to be used during the study.  If 


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the reference ranges change during the course of the study, the investigator (or designee) must 
provide the sponsor with a list of the new reference ranges and the effective dates. 
The TPMT deficiency test will be performed by Black County Pathology Services. 
All safety blood and urine sampling will be performed by the study centre, according to their local 
standard operating procedures (SOPs). 
The principal investigator or designee will ensure that all biological fluids collected during the 
study will not be used for purposes other than as directed by the clinical study protocol.  All 
collected biological fluids used for safety investigations will be destroyed within 3 months after the 
clinical execution of the study has been completed. All biological fluids used for the TPMT 
deficiency tests performed at Black County Pathology Services will be destroyed there after the 
clinical execution of the tests required have been completed.  
 
7.2.5.2 Pharmacokinetic Blood Samples 
Pharmacokinetic blood samples will be collected at the following times:  Blood collections will be 
made pre-dose within 30 minutes before administration and at 15 mins (±2 mins), 30 mins 
(±2 mins), 45 mins(±2 mins), 1hr(±2 mins), 1 hr 20mins(±2 mins),  1 hr 40mins (±2 mins), 
2hrs(±5 mins), 2hrs 20 mins(±5 mins), 2hrs 40 (±5 mins), 3hrs(±5 mins), 4hrs(±5 mins), 
5hrs(±5 mins), 6hrs(±5 mins), 8hrs(±5 mins), and 12hrs(±5 mins) after study drug administration.  
The total number of blood collections will be 32, 16 samples per period.  The total volume of blood 
taken (including safety bloods) will be approximately 356.3 ml.  The actual blood sampling times 
will be recorded in the eCRFs. The PK sample should be taken on the scheduled timepoint and 
other procedures due at the same time scheduled around using the applicable windows. 
Venous blood samples, up to 10 mL each, for the determination of azathioprine concentrations will 
be collected. Full details on PK collection, sampling, processing and storage will be provided in a 
study specific lab manual  
Blood samples taken for drug concentration measurements will be analysed by Alderley Analytical 
according to applicable SOPs. 
Unused duplicate plasma PK samples will be stored at Alderley Analytical for up to 1 year after 
completion of the study (defined as last subject last visit).  The sponsor will be required to indicate 
whether additional storage is needed or whether the samples may be discarded. 
7.2.6 Blood Volume 
The total blood volume to be collected from each subject during the study is indicated in Table 7-2. 


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The total volume of blood to be collected from each subject during the study (approximately 
230 mL) is considered acceptable. 
Table 7-2  Total Blood Volume to be Collected during the Study  
Procedure 
Visit 
No. 
Samples 
Blood 
Volume 
per 
Sample 
(mL) 
No. 
Treatment 
Periods 
Blood Volume (mL) 
Clinical 
chemistry 
Screening1 
1 
5 
N/A 
5 
Admission  
1 
2.5 
2 
5 
Post-study 
1 
2.5 
N/A 
2.5 
Full blood 
count 
Screening1 
1 
2 
N/A 
2 
Admission  
1 
2 
2 
4 
Post-study 
1 
2 
N/A 
2 
Blood 
coagulation  
Screening1 
1 
2.7 
N/A 
2.7 
Admission  
1 
2.7 
2 
5.4 
Post-study 
1 
2.7 
N/A 
2.7 
Azathioprine 2 
Treatment Period 
16 
~10 
2 
320 
Study specific 
screening 
Screening 
1 
5ml 
(EDTA) 
N/A 
5 
Total Blood Volume 
356.3 
1 From the screening biochemistry blood samples, virology screen will be conducted.  
2  Note that there will be 1ml waste collected for each post dose timepoint  
 
7.2.7 General and Dietary Restrictions 
7.2.7.1 Diet 
Consumption of grapefruit, grapefruit juice, Seville oranges or orange marmalade, cruciferous 
vegetables (e.g., cabbage, broccoli, sprouts), liquorice, peppermint-containing products, char-grilled 
foods, poppy seeds or cranberry juice will not be allowed from 7 days before the start of the study 
until after completion of the study. 
The ingestion of food and beverages containing pineapple and all other fruit juices will not be 
allowed for 72 hours before the administration of IMP and until the last PK blood sample is 
collected per treatment period. 
The ingestion of food and beverages containing methylxanthines e.g., caffeine (coffee, tea, 
chocolate, energy drinks and cola) will not be allowed for 72 hours before the administration of 
IMP and until the last PK blood sample is collected per treatment period. Decaffeinated alternatives 
are permitted. 
The ingestion of food and beverages containing alcohol will not be allowed for 72 hours prior to 
any safety laboratory samples and for 72 hours before screening and then from 72 hours before the 
first administration of IMP (treatment period 1) until the last PK blood sample (treatment period 2) 
is collected. 
 


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Food and beverage intake during the clinic stay will be as per clinical unit standard practice 
No fluids (apart from water taken with dose) are allowed from 1 h prior to dosing until 1 h 
afterwards.  Water is then allowed ad libitum.  
While resident in the clinic, volunteers will follow a standard meal schedule. After a snack on the 
evening of admission they will be fasted overnight until lunchtime on Study Day 1 
Lunch: Approx 4.5 hours post dosing 
Snack: Approx 7.5 hours post dosing 
Dinner: Approx 10 hours post dosing 
Food and beverage intake will be allowed ad libitum, unless restrictions apply, after the subjects 
have been discharged from the clinic. 
7.2.7.2 Physical Activity 
Strenuous physical activity will not be allowed for 72 hours before the first dose of either treatment 
period until after discharge.  
7.2.7.3 Contraception 
To prevent pregnancy female subjects of child bearing potential and male subjects and their female 
partner must use a condom plus 1 highly effective form of contraception i.e.,  
• Condom + Established use of combined hormonal contraception associated with inhibition 
of ovulation:  
o Oral 
o Intravaginal 
o Transdermal 
• Condom + Established use of progestogen-only hormonal contraception associated with 
inhibition of ovulation: 
o Oral 
o Injectable 
o Implantable 
• Condom + Intrauterine device (IUD). 
• Condom + intrauterine hormone-releasing system (IUS). 
• Vasectomised partner, provided that partner is the sole sexual partner of the female trial 
subject and that the vasectomised partner has received medical assessment of the surgical 
success and this documented evidence is available. 
• 
True abstinence, only if defined as refraining from heterosexual intercourse during the entire 
period of risk associated with the study treatments and up to 6 months after. The reliability 
of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and 


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the preferred and usual lifestyle of the subject. [Periodic abstinence (e.g., calendar, 
ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable 
methods of contraception]. 
The chosen contraception method(s) must be followed from the first dose until at least 6 months 
after the last dose of IMP. 
 
To prevent exposure of any partner (male or female) a condom must be used throughout the study 
and for 6 months after the final dose of study drug 
Male subjects must not have unprotected sexual intercourse with a female who is pregnant or 
breastfeeding during the study and for 6 months after their final dose. 
Contraception advice will be documented in the informed consent form. 
 
7.2.7.4 Sperm and Oocyte Donation 
Subjects must not donate sperm or oocytes from the first dose and for at least 6 months after the last 
dose of IMP. 
7.2.7.5 Receipt of Live Vaccination 
Subjects must not receive live vaccinations 4 weeks prior to first dose and for at least 3 months after 
the last dose of IMP. 
 
7.3 Selection of Study Population 
The criteria are set to ensure a homogeneous subject population without accompanying diseases 
interfering with the conduct and scientific evaluation of the study.  Additionally, the criteria have 
been selected to minimize risk to the subjects' well-being. 
7.3.1 Inclusion Criteria 
1. 
Healthy male and female subjects, 18 years to 55 years inclusive at time of signing the 
informed consent document   
2. 
Females child Bearing potential with a negative pregnancy test at screening and willing to 
use a condom plus 1 highly effective method of contraception from first dose until 6 months 
after last dose of IMP (please see section 7.2.7.3 for contraception details).  
 
3. 
Females of Non child Bearing potential defined as those who have no uterus, ligation of the 
fallopian tubes, or permanent cessation of ovarian function due to ovarian failure or surgical 
removal of the ovaries.( A urine pregnancy test will be required for subjects without Medical 
documentation to support non child bearing status)  or Post-menopausal females defined as  
being at least 45 years of age with history of amenorrhoea for 12 months without an 


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alternative medical reason. A confirmatory follicle-stimulating hormone (FSH) may be 
performed at the discretion of the site Investigator to confirm postmenopausal status. 
 
4. 
Male subject willing to use 2 highly effective methods of contraception from first dose until 
6 months after last dose of IMP (please see section 7.2.7.3 for contraception details).   
5. 
Body Mass Index (BMI) between 18 and 33 kg/m2. 
6. 
Body weight not less than 50 kg. 
7. 
Subject with no clinically significant abnormal serum biochemistry, haematology and urine 
examination values within 28 days before the first dose of IMP.   
8. 
Medical history, physical examination, standard 12-lead electrocardiogram (ECG) and vital 
signs investigations: Findings clinically acceptable or within reference ranges, unless the 
investigator considers the deviation to be irrelevant for the purpose of the study. 
9. 
Non-smokers (subjects using nicotine containing products within 1 year of start of study 
should not be included).  
10. 
Written informed consent given for the participation in the study. 
7.3.2 Exclusion Criteria 
1. 
Evidence of psychiatric disorder, antagonistic personality, poor motivation, emotional or 
intellectual problems likely to limit the validity of consent to participate in the study or limit 
the ability to comply with protocol requirements. 
2. 
Current alcohol use > 21 units of alcohol per week for males and >14 units of alcohol per 
week for females. 
3. 
Regular exposure to substances of abuse (other than alcohol) within the past year. 
4. 
Use of any medication, prescribed or over-the-counter or herbal remedies, within 2 weeks 
prior to the first administration of IMP except if this will not affect the outcome of the study 
in the opinion of the investigator. 
5. 
Participation in a new chemical entity clinical study within the previous 3 months or a 
marketed drug clinical study within the 30 days before first dose of IMP and until the study 
is complete (i.e. the subject has undergone their post study visit).  (Washout period between 
studies is defined as the period of time elapsed between the last dose of the previous study 
and the first dose of the next study). 
6. 
A major illness during the 3 months before commencement of the screening period. 


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7. 
History of hypersensitivity or allergy to the IMP or its excipients or any related medication 
(please refer to azathioprine Oral suspension IMPD and Imurek® SmPC for list of 
excipients). 
8. 
History of bronchial asthma or any other bronchospastic disease, history of epilepsy, history 
of porphyria, history of rheumatoid arthritis, history of pancreatitis, history of any liver 
disease or any other medical condition that in the opinion of the investigator may interfere 
with the study outcome measures or impact upon the safety of the subject. 
9. 
Clinically relevant abnormalities in the coagulation status. 
10. 
Clinically diagnosed peptic ulceration within the past 5 years. 
11. 
History of bleeding disorders. 
12. 
History of any of the following: seizures, diabetes, migraine, cardiovascular (including 
hypertension and hypotension), pulmonary, neurological, hepatic, renal or gastrointestinal 
conditions, hematopoietic abnormalities, blood disorders, gout, leg ulcers, lactose 
intolerance or ongoing infectious diseases at the discretion of the investigator. 
13. 
Subjects with a deficient, low or intermediate TPMT enzyme activity by means of 
phenotyping. 
14. 
Since subjects with inherited mutated NUDT15 gene are at increased risk of severe 
azathioprine toxicity with the usual doses of thiopurine therapy this protocol will exclude 
subjects of East Asian or Hispanic ethnicity (in whom the NUDT15 mutant alleles are most 
common).  
15. 
Subjects who participated in previous thiopurine studies within six months.  
16. 
Relevant history or laboratory or clinical findings indicative of acute or chronic disease, 
likely to influence study outcome. 
17. 
Donation or loss of blood equal to or exceeding 450 mL during the 3 months before the first 
administration of IMP. 
18. 
Subjects with a supine systolic blood pressure >150 mmHg and diastolic BP >90 mmHg. 
19. 
Orthostatic hypotension (fall in blood pressure of at least 20 mmHg systolic or 10 mmHg 
diastolic when standing). 
20. 
Resting supine pulse of >110 beats per minute or <40 beats per minute. 
21. 
Positive testing for HIV and/or Hepatitis B and/or Hepatitis C. 
22. 
Positive urine screen for drugs of abuse. 
23. 
Positive urine screen for tobacco use. 
24. 
Subjects who plan to procreate within 6 months after IMP administration. 


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25. 
Subject with known fertility problems still wanting to procreate.  
26. 
Immunization using a live organism vaccine within 4 weeks prior to the first dosing of IMP. 
27. 
Any specific IMP safety concern. 
28. 
Female subjects who are currently breastfeeding. 
7.3.3 Withdrawal Criteria 
Subjects have the right to withdraw from the study at any time, irrespective of the reason, without 
detriment to their medical care. 
The following are pre-defined incidents that may lead to withdrawal: 
1. 
Adverse events as a result of the IMP, at the discretion of the investigator. 
2. 
Intercurrent illness requiring medication.  The decision whether or not to withdraw the 
subject will be at the discretion of the investigator and will depend on the nature of the 
illness and medication used. 
3. 
Protocol violation by subjects, at the discretion of the investigator.  Protocol violation is 
defined as the wilful disobeying of protocol instructions which have been communicated to 
the subjects verbally and in writing. 
4. 
Pathologically raised body temperature. 
5. 
Positive testing for drugs of abuse. 
6. 
Positive testing for cotinine. 
7. 
Positive alcohol breath test. 
The primary reason for treatment discontinuation will be documented.  
If the investigator withdraws a subject from treatment or if a subject declines further participation, a 
post-study visit will be completed for subjects who were exposed to IMP, within 72 hours of 
withdrawal/withdrawing from the study. 
If a subject's reason for discontinuation is an adverse event, this must be reported in accordance 
with the procedures detailed in Section 12.  The investigator must make every effort to contact a 
subject before he can be regarded as lost to follow-up. 
7.3.4 Replacement of Subjects 
Subjects who withdraw or are withdrawn from the study may be replaced, if fewer complete the 
study than the estimated number of evaluable subjects (see Section 11.2). Replacements will be 
randomised to treatment. 
Subject screening numbers will be allocated at screening. 


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7.3.5 Premature Termination of the Study 
The sponsor or the principal investigator has the right to terminate the study at any time for medical 
and/or administrative reasons.  As far as possible, this should occur after mutual consultation. 
If the study is prematurely terminated for any reason, the investigator will promptly inform the 
subjects and will ensure appropriate therapy and follow-up for the subjects.  The REC and the 
MHRA will be informed as soon as possible after the decision has been made to terminate the study 
and the reasons for termination. 
Should the study be prematurely terminated, the completed and partially completed eCRFs and 
remaining IMP must be returned to the sponsor. 
Medicines Evaluation Unit standard operating procedures (SOPs) governing these actions will be 
followed. 


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8 
INVESTIGATIONAL MEDICINAL PRODUCTS 
8.2 Products to be administered 
Subjects will receive either the test or reference product, according to the randomization schedule, 
under fasting conditions.  Subjects will receive each product once. 
8.3 Identity of Investigational Medicinal Products 
Test Product* (A) 
Generic name 
: Azathioprine 
 
 
 
Trade name 
: (Jayempi™) 10 mg/ mL Oral solution 
Dosage form 
: Oral suspension containing 10 mg/mL Azathioprine 
Dose 
: 1 x 5mL (50 mg) of Jayempi™ Oral Suspension 10mg/mL per treatment 
period under fasting conditions 
Mode of 
administration 
: Orally 
Manufacturer 
: Nova Laboratories Ltd. 
Country of origin 
: Leicester, UK  
Reference Product (B) 
Generic name 
: Azathioprine 
Trade name 
: Imurek® 50mg tablet 
Dosage form 
: Tablet containing 50 mg azathioprine 
Dose 
: 1 x Imurek 50mg Tablet per treatment period under fasting conditions 
Mode of 
administration 
: Orally 
Manufacturer 
: Aspen Pharma Trading Limited, Dublin, Ireland 
Country of origin 
: Ireland   
 
 
 
 
 


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8.3.1 Supply and Storage 
The sponsor will supply sufficient quantities of test and reference products bulk supply packed, 
labelled and released according to Good Manufacturing Practice (GMP) Annex 13 requirements. 
The principal investigator or designee will ensure that the IMPs are stored in a limited access area 
according to the storage instructions of the label, the information in the literature or instructions 
supplied by the sponsor.   
The pharmacy department, as designee of the principal investigator, will dose from the bulk supply 
according to MEU SOPs and also according to the randomization list provided by SQN.  Any 
additional packaging or labelling requirements required at site will be according to Good 
Manufacturing Practice (GMP) Annex 13 requirements.  Accountability records will be prepared 
and maintained and monitored by the sponsor. 
Investigational medicinal product to be administered at the study centre on clinic days will be 
retained in separate containers for each  product. 
8.3.2 Investigational Medicinal Product Accountability 
Medicines Evaluation Unit is fully responsible for Investigational Product accountability according 
to their SOPs.  This must include accurate records for dates and amounts of Investigational Products 
received, dispensed (subject by subject accounting) and that the IMP will not be used for purposes 
other than as directed by the clinical study protocol.  Test product accountability will be performed 
for the liquid by volume of administration being checked and witnessed by two members of staff at  
administration, and for the tablet by tablet count by two members of staff.   
Once the clinical phase of the study has been completed or prematurely terminated, and after drug 
accountability has been performed, used and unused IMPs will be handled in accordance with 
requirements of the Regulatory Authority.  If incinerated, the certificate of incineration will be filed 
in the Investigator Site File. 
8.3.3 Retention Samples 
The sponsor will retain a sufficient quantity for re-testing of the test product and reference product. 
8.4 Randomization Schedule 
The randomisation will be produced by SQN. The treatment will be allocated by staff at the site 
using the randomisation list provided. 
Subjects who withdraw or are withdrawn from the study may be replaced, if fewer complete the 
study than the estimated number of evaluable subjects (see Section 11.2). Replacements will be 
randomised to treatment.  


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8.5 Selection of Doses in the Study 
In compliance with bioequivalence guidelines, the dosage in this study will include a single 50 mg 
oral dose of azathioprine, on each of two separate occasions with a washout period of at least 
3 calendar days, under fasting conditions.  Azathioprine is used in various indications, but the 
starting dosage is usually 1-3mg/kg/body weight/day and adjusted according to the clinical response 
(which may not be evident for weeks or months) and haematological tolerance Thus, in an adult 
male weighing 70 kg the typical dose will typically be between 70 and 200 mg/day. In this study, 
volunteers will be given a single 1 x 50 mg dose of 6-MP (as an oral suspension or tablet) at each of 
the two dosing visits with a washout period of at least 3 days between visits. The relatively low 
dose and the dosing schedule minimises the risk of any short or long term toxicity from two doses 
of azathioprine. 
See Section 5. 
8.6 Administration of Investigational Medicinal Products 
After an overnight fast of at least 10 hours, subjects will receive either the reference or test product 
according to the randomization schedule.  The reference IMPs will be administered with 240 mL of 
water.  
In the case of the solution (Test product), 5 mL of the solution will be prepared by drawing up into 
syringe for oral administration according to the instructions provided by the Sponsor. The syringe 
will be placed directly into the mouth of the subject and the contents gently released. The syringe 
will then be rinsed with 5 mL water immediately after dosing, which the subject will swallow. 
Subjects will then be asked to drink an additional 235 mL of water. See also Section 5 and Section 
7.2.3. 
IMP administration instructions will be provided.  
8.7 Blinding 
The study is open-label.  However, as stated in the EMA guidelines on investigation of 
bioavailability and bioequivalence [6], analysis of the samples should be conducted without 
information on treatment, therefore the laboratory staff responsible for drug concentration analysis 
will be blinded to the treatment. 
8.8 Prior and Concomitant Medication 
Subjects must refrain from using any medication, other than oral contraception, prescribed or 
over-the-counter (including herbal remedies, St. John's wort [Hypericum perforatum]), for 2 weeks 
before the first administration of IMP and for the duration of the study. Occasional use of 
paracetamol ≤2 g/day and/or ibuprofen (≤1200 mg/day) is allowed for pain 


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The administration of concomitant medication will be handled on a case-by-case basis at the 
discretion of the investigator.  If any medication is required during the course of the study, it must 
immediately be reported to the investigator.  Where medication is taken or needs to be taken, a 
decision whether to continue or discontinue the subject's participation in the study will be based on 
subject safety, the time of medication administration and the possible influence of the ingested 
medication on the PK of the IMP and interference with the assay method. 
8.9 Treatment Compliance 
To ensure treatment compliance, the IMP will be administered by the principal investigator or 
designee.  A mouth check will be performed by the principal investigator or designee to ensure that 
the subjects have swallowed the IMP. 


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9 
PHARMACOKINETIC AND SAFETY VARIABLES 
9.2 Pharmacokinetic and Safety Measurements 
Refer to Section 7.1.2. 
9.3 Appropriateness of Measurements 
Standard measures to assess PK and safety apply during the study. 
9.4 Primary Pharmacokinetic Variables 
Refer to Section 11.4. 
9.5 Pharmacokinetic Drug Assays 
Alderley Analytical has been inspected by the MHRA GCP Inspectorate and is included in the 
United Kingdom GLP Compliance Program. The analyses are conducted and reported in 
accordance with the Good Practice regulations and guidelines.  Additionally, the Safety Clinical 
Laboratory, The Doctors Laboratory in London, is accredited according to the requirements of the 
GCP, GLP and CPA inspectorate.  Analytical methods are validated according to internationally 
accepted standards.  The quality and integrity of the analytical work generated in this study will be 
evaluated according to the acceptance criteria, as described in the SOPs of Alderley Analytical. 
Quantitative analysis of azathioprine in the collected plasma samples will be performed by Alderley 
Analytical using liquid chromatography with mass spectrometry (LC-MS/MS). 
All the samples received at Alderley Analytical including samples from drop-outs and 
discontinuers, will be analysed.  Bioanalytical data will be processed according to the relevant SOPs 
of Alderley Analytical. 
Complete method validation and bioanalytical reports will be provided. 
 


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10 DATA QUALITY ASSURANCE AND DATA MANAGEMENT 
A study initiation meeting chaired by the Sponsor or designee will be held prior to study 
commencement. The Principal Investigator or designee will be in attendance at the study initiation 
meeting. 
10.2 Quality Control and Source Data Verification 
Source data verification will be conducted with due regard to subject confidentiality. 
The site will allow the study monitor and sponsor representatives direct access to all study 
documents, medical files, and source documents to enable verification of the study data, whilst 
maintaining the anonymity of the subject and confidentiality of the data.   
Internal quality control will be performed at all stages of the study by the study centre. 
10.3 Audit/Inspections 
The investigator site, facilities and all data and documentation may be audited/inspected by 
independent auditor/inspector/any representatives of regulatory authorities.  The investigator must 
allow the auditor/inspector/any representatives of regulatory authorities access to all relevant 
documents and be available to discuss any findings/issues.  An audit certificate will be included in 
the clinical study report if an audit was performed. 
10.4 Study Monitoring 
The conduct of the study will be monitored by a representative of the sponsor to ensure compliance 
with applicable regulatory requirements and GCP.  The summary documentation of the monitoring 
visits will form part of the study documentation and will be archived as such. 
10.5 Data Collection 
Data Management will design an eCRF to capture all data generated during the study.  
The study centre’s paper source records will be used to capture certain safety data - this will be 
indicated on the Source Document Agreement. 
Designated investigator staff will enter the data required by the protocol into the electronic CRFs 
(eCRFs) using fully validated software that conforms to 21 CFR Part 11 requirements. Staff will not 
be given access to the eCRF until they have been trained. Automatic validation programs check for 
data discrepancies and, by generating appropriate error messages, allow the data to be confirmed or 
corrected before transfer of the data to the Biometrics group. The Investigator must certify that the 
data entered into the eCRF are complete and accurate.  


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Source data will be defined as such in the Source Document Agreement. The responsible study 
monitor will check data at the monitoring visits to the clinical study centre (see Section 10.3).   
All clinical work conducted under this clinical study protocol is subjected to GCP regulations.  This 
includes an inspection by the sponsor and Regulatory Authority representatives at any time.  The 
investigator will agree to the inspection of study-related records by Regulatory Authority 
representatives and the audits of the sponsor or third parties named by the sponsor (also see 
Section 10.2). 


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11 STATISTICAL METHODS 
11.2 Statistical Methodology 
The statistical methodology below describes the statistical analysis as it is foreseen when the study 
is being planned.  If circumstances should arise during the study rendering this analysis 
inappropriate, or if in the meantime improved methods of analysis should come to light, different 
analyses may be made. 
Any deviations from the statistical methods described in this document, reasons for such deviations 
and all alternative or additional statistical analyses that may be performed, will be described in the 
clinical study report. 
11.2.1 Pharmacokinetic Population 
All subjects who complete the study and for whom primary PK variables can be calculated for all 
treatments will be included in the statistical PK analysis for the study. 
In case of events such as vomiting, diarrhoea and use of concomitant medication, which could 
render the plasma concentration-time profile unreliable, such subjects may be excluded from the PK 
population after review of the severity of the event and the start and stop time in relation to dosing.  
When vomiting occurs within 2x the calculated median tmax of the reference product, data from all 
treatments being compared will be excluded from PK and statistical evaluation.  Subjects with 
pre-dose azathioprine concentrations ≥ 5% of Cmax will be excluded from all statistical PK analysis 
(including descriptive statistics).  The available concentration data of the above subjects and those 
who do not complete the study will only be listed, not presented in descriptive statistics or included 
in PK or formal statistical analysis. 
11.2.2 Safety Population 
All subjects who received at least one dose of IMP will be included in the safety analysis for the 
study. 
11.3 Sample Size 
Thirty (30) subjects will be randomised, to allow for dropouts or subjects who otherwise fail to 
complete the study with at least 28 evaluable subjects. The sample size for this study has been 
selected without any formal statistical considerations. However, similar bioequivalence studies 
(AT/H/0270/001-002/DC, UK/H/2846/004/DC and UK/H/934/01/DC) for azathioprine have 
recruited between 24-30 subjects. This figure has been determined adequate to meet the study 
objectives. 


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11.4 Protocol Deviations and Changes to Planned Analyses 
Permission from the sponsor in writing will be obtained should any changes be required to the 
clinical study protocol.  Should the safety of the study subjects necessitate immediate action, which 
represents a deviation from the clinical study protocol, the sponsor will be informed as soon as 
possible. 
Protocol deviations and changes to planned analyses will be described in the clinical study report. 
For protocol amendments, see Section 3.1. 
11.5 Pharmacokinetic Variables 
The following PK variables will be calculated for azathioprine and the metabolite mercaptopurine 
for each subject and treatment using non-compartmental analysis and using the actual sampling 
time intervals (relative to IMP administration): 
11.5.1 Primary Variables 
• Maximum observed plasma concentration (Cmax) 
• AUC Area under the plasma concentration curve from zero to time of the last quantifiable 
concentration (AUC0-t) 
• Area under the plasma concentration curve from zero extrapolated to infinity (AUC0-¥). 
11.5.2 Secondary Variables 
• Time to maximum observed plasma concentration (tmax) 
• Terminal elimination rate constant (λz) 
• Apparent terminal elimination half-life (t½). 
Calculation of the PK variables will be made with Phoenix WinNonlin 6.3. AUCs will be calculated 
using the linear trapezoidal rule.  The version of the software applied will be documented in the 
clinical study report. 
11.6 Presentation of Data, Descriptive Statistics and PK Assessment 
The actual blood sampling times and deviations will be listed for each subject dosed, product and 
scheduled sampling time.  A listing reflecting summary statistics (n, arithmetic mean, geometric 
mean, median, coefficient of variation, standard deviation, minimum and maximum) per product 
will be provided for plasma concentrations of azathioprine. 
Concentrations below LLOQ will be indicated as below the lower limit of quantification (BLQ).  
These BLQ concentrations will be handled as follows: 


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• For PK summaries and analyses , all BLQ values in the absorption phase, prior to the first 
reported concentration, will be substituted by zeros.  The BLQ values between evaluable 
concentrations will be substituted by ½LLOQ, before the calculation of the PK variables.  
The terminal BLQ values will be set to missing.  These measures are taken to prevent an 
over-estimation of AUC. Values reported as ‘NS’ (no sample) will be set to “missing”. 
For PK calculations, missing concentrations will be deleted, resulting in an interpolation between 
the nearest two concentration values. 
A table reflecting summary statistics (n, arithmetic mean, geometric mean, median, coefficient of 
variation, standard deviation, minimum and maximum) per product will be provided for PK 
variables of azathioprine, including the number of points used to calculate λz (λz will, however, not 
be summarised). 
A listing reflecting summary statistics (n, arithmetic mean, geometric mean, median, coefficient of 
variation, standard deviation, minimum and maximum) will be provided for the ratios 
(%test/reference) of the primary PK variables and for the difference (test – reference) of tmax. 
The individual plasma concentration versus actual time profiles of azathioprine for each subject and 
product, as well as the mean plasma (arithmetic and geometric) plasma concentration versus 
scheduled time profiles of azathioprine for each product, will be presented graphically on a linear-
linear and log-linear scale.  Individual plasma concentrations will be presented using actual, rather 
than planned, sampling times.  Combined individual concentration versus time graphs per product 
will also be presented on a linear-linear scale, together with the geometric mean values.  The 
individual log-linear graphs from WinNonlin will be presented. 
The data listings, descriptive statistics, statistical analysis and graphs of this study will be generated 
using SAS® version 9.4 or later. 
11.7 Analysis of Bioequivalence  
The test product (azathioprine only) will be compared to the reference products by means of 
statistical analysis with respect to the primary PK variables using an analysis of variance (ANOVA) 
with sequence, subject(sequence), product and period effects after logarithmic transformation of the 
data.  Point estimates and 90% confidence intervals for the "test/reference" geometric mean ratios of 
these variables will be tabulated. 
Bioequivalence of the test and reference products will be assessed on the basis of the 
90% confidence intervals for the primary PK variables of azathioprine in relation to the 
conventional bioequivalence range of 80.00% to 125.00%. 
In case of outliers present in the data regarding the primary PK parameters, the analyses will be 
performed on both the complete data and on the data excluding the outliers.  Bioequivalence will 
however be assessed on the complete data. 


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Analysis of tmax will be done using Wilcoxon's Signed Rank test.   
The median tmax of the test and reference will be tabulated together with the p-value from 
Wilcoxon's Test. 
11.8 Analysis of Safety Data 
Demographic and anthropometric variables will be listed for all subjects in the safety population.  
Demographic variables will also be tabulated (n, arithmetic mean, median, standard deviation, 
minimum and maximum of continuous variables, and frequency counts and percentages of 
categorical variables, as applicable).  Subject disposition will also be listed and summarised 
Haematology, clinical chemistry and urinalysis values will be listed.  For the full blood count, 
clinical chemistry values and urinalysis, only the abnormal values will be listed and flagged in the 
listings as "L" (for values lower than the lower limit of the reference range) and "H" (for values 
higher than the upper limit of the reference range).  Clinical chemistry and haematology will be 
summarised. 
Vital signs and ECGs will be listed for all subjects in the safety population. 
Adverse events reflecting the System Organ Class (SOC) and preferred term for each AE, 
concomitant medication reflecting Anatomical-Therapeutic-Chemical classification (ATC) will be 
listed.  Adverse events will be summarised as per the following: 
• by treatment 
• by treatment, SOC and preferred term 
• by treatment, SOC, preferred term time and relationship.  
• by treatment, SOC, preferred term and severity.  


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Version 3.0 
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Date: 03 May 2019 
 
12 ADVERSE EVENTS 
Each subject will be carefully monitored by the investigator for AEs.  In addition, information on 
AEs will be obtained from the subjects by regular questioning of each subject by the study staff, 
although no leading questions will be asked.  When an AE occurs, the investigator will decide 
whether to withdraw the subject from the study and/or initiate appropriate treatment.  After 
withdrawal from the study, it will be ensured that the subject is given appropriate medical care, if 
needed, which may take the form of referral to a physician. 
In the case of any event requiring medical intervention occurring during the clinic stay, the 
investigator will institute general supportive measures including, where necessary, respiratory 
assistance and cardiopulmonary resuscitation. 
12.2 Definitions 
12.2.1 Adverse Events (or Adverse Experiences) 
Any untoward medical occurrence in a subject or clinical investigation subject administered a 
pharmaceutical product and which does not necessarily have a causal relationship with this 
treatment.  It can be any unfavourable and unintended sign (e.g., an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of an investigational medicinal product. 
12.2.2 Adverse Drug Reaction 
 
A response to a drug which is noxious and unintended and which occurs at doses normally used in 
man for prophylaxis, diagnosis or therapy of disease or for modification of physiological function. 
12.2.3 Unexpected Adverse Drug Reaction 
An adverse reaction, the nature or severity of which is not consistent with the SPC (or other 
applicable product information such as the Investigator’s Brochure for the test product).  This 
includes class-related reactions that are mentioned in the SPC but which are not specifically 
described as occurring with this product. 
12.2.4 Serious Adverse Events 
Serious adverse event (SAE) means an adverse reaction which: 
• Results in death; 
 
 




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Azathioprine Oral Suspension 10mg/mL  
 
 
 
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SPONSOR STUDY No.: INV691 
Version 3.0 
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Date: 03 May 2019 
 
12.4 Definition of Adverse Events Relationship.  
The investigator will determine the relationship of any adverse event to the IMP according to the 
following criteria: 
• Certain: A clinical event, including laboratory test abnormality, occurring in a plausible time 
relationship to drug administration and which concurrent disease or other drugs or chemicals 
cannot explain and response to withdrawal plausible, and reappearance of the reaction on 
repeated exposure. 
• Probable/Likely: A clinical event, including laboratory test abnormality, with a reasonable 
time sequence to administration of the drug, unlikely to be attributed to concurrent disease or 
other drugs or chemicals and which follows a reasonable response on withdrawal 
(de-challenge). 
• Possible: A clinical event, including laboratory test abnormality, with a reasonable time 
sequence to administration of the drug, but which could also be explained by concurrent disease 
or other drugs or chemicals.  Information on drug withdrawal may be lacking or unclear. 
• Unlikely: A clinical event, including laboratory test abnormality, with a temporal relationship to 
drug administration which makes a causal relationship improbable and in which other drugs, 
chemicals or underlying disease provide plausible explanation. 
• Not related: A clinical event, including laboratory test abnormality, which can be explained by 
any reason excluding the administered drug. 
• Conditional/Unclassified: A clinical event, including laboratory test abnormality, which can / 
cannot be judged because more data for proper assessment needed or additional data under 
examination. 
• Not assessable/Unclassified: A report suggesting an adverse event that cannot be judged 
because information is insufficient or contradictory, and which cannot be supplemented or 
verified. 
12.5 Adverse Events Documentation 
The recording of every single AE/ SAE has to be in line with ICH Topic E2B (M) and has to meet 
the following requirements: 
• Detailed subject data 
• Exact documentation of the event 
• Exact description of temporal sequence to the therapy course 
• Documentation of severity 


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Version 3.0 
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• Documentation of the results of diagnostic and therapeutic measurements 
• Results of a repeated exposure (re-exposure) if possible 
• Details of the development and outcome including medical judgment 
• As much data as possible have to be obtained which are important for judgment concerning the 
relationship of the AE/SAE to IMP 
• Critical examination of the relationship to IMP. 
All AEs have to be charted according to this scheme when spontaneously reported by the subject, 
observed by the principal investigator or designee or elicited by general questioning. 
12.6 Reporting Procedures of Adverse Events/Serious Adverse Events 
The principal investigator or designee is responsible for recording in the eCRF all AEs which have 
occurred during the study (including clinically important deviations of laboratory values from the 
reference ranges), regardless of their relationship to the IMP.  Any AE or SAE reported to site by 
the subject after the end of the study within a reasonable time period and considered to have been 
caused by the IMP must also be recorded.  All recorded AEs will be summarised and reported on in 
the clinical study report. 
All suspected adverse reactions that occur in the concerned study, and that are both unexpected and 
serious are subject to expedited reporting.  A suspected unexpected serious adverse reaction 
(SUSAR) which is fatal or life-threatening will be reported as soon as possible to the authority. 
Occurrence of any SAEs (including death, irrespective of the reason) has to be notified 
immediately (within 24 hours) after becoming aware of the event, to the monitor, sponsor, and the 
Competent Authority (where appropriate i.e. a SUSAR).  The notification must be followed by a 
written report within 48 hours of the initial notification, or at latest on the following working day.  
The first report should contain a detailed description of the observed symptoms and the concomitant 
therapy.  The investigator has to judge the possible causal relationship between the event and the 
IMP and should arrange additional examinations at his/her discretion to clarify if the event is 
connected with the IMP.  He/She should consult a specialist if necessary. 
All AEs and SAEs have to be followed up until an outcome is known.  In the event of an SAE, 
the outcome has to be reported in the eCRF and to the principal investigator, sponsor, 
monitor, the REC and the Competent Authority (where appropriate i.e. a SUSAR). 
12.7 Pregnancy 
Pregnancies must be reported to Diamond PV Ltd immediately (within 24 hours) and should be 
followed up to determine outcome, including spontaneous or voluntary termination, details of the 


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SPONSOR STUDY No.: INV691 
Version 3.0 
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Date: 03 May 2019 
 
birth, and the presence or absence of any birth defects, congenital abnormalities, or maternal and/or 
new-born complications.   
Pregnancy outcomes must be collected for all female volunteers and the female partners of any 
males who took the IMP.  Consent to report information regarding these pregnancy outcomes 
should be obtained from the mother. 


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13 LEGAL AND ADMINISTRATIVE ASPECTS 
13.2 Documentation 
The Investigator site file and associated study documentation will be archived for at least 5 years 
after the end of the study (last subject last visit) as per The Medicines for Human Use (Clinical 
Trials) Amendment Regulations 2006 (No. 1928) The study documentation may be transferred to an 
offsite storage facility during this period but will remain under the control of MEU.   
 
The Sponsor has delegated the set up and maintenance of the Sponsor trial master file (TMF) to 
MEU.  The TMF will checked by the Sponsor’s monitor at monitoring visits and will be 
returned to the Sponsor at the end of the study, who will archive it for at least 25 years after the 
end of the study.   
13.3 Publication of Results 
If a publication based on the results of this study is envisaged, approval from the sponsor will be 
obtained and a draft manuscript will be submitted to the sponsor for scrutiny and comment.  The 
choice of scientific journal will be mutually agreed on by the principal investigator and the sponsor. 
13.4 Sponsor’s Obligation 
The onus rests with the sponsor to ensure that this clinical study protocol complies with all their 
requirements. 
13.5 Clinical Study Report 
An integrated clinical study report (CSR) will be prepared in accordance with the standards of the 
ICH Guideline for Structure and Content of Clinical Study Reports (ICH E3).  The CSR will be 
signed by the investigator in accordance with Annex I of the Directive 2001/83/EC as amended.  
Copies will be provided to the REC in accordance with regulatory requirements and MEU SOPs.  In 
the event of premature termination of the study or other conditions specified in ICH E3, an 
abbreviated CSR may be prepared. 


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Clinical Study Protocol 
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Version 3.0 
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Date: 03 May 2019 
 
14 REFERENCES 
EMA Guideline on the Investigation of Bioequivalence (CPMP/EWP/QWP/1401/98 Rev. 1/ Corr) 
and the United States Department of Health and Human Services, Food and Drug Administration 
(FDA) Guidance for Industry: Bioavailability and Bioequivalence Studies for Orally Administered 
Drug Products - General Considerations.  Centre for Drug Evaluation and Research (CDER) March 
2003 BP. 
Public Assessment Report, Azathioprine 50mg Film-coated Tablets, UK/H/934/01/DC, Relonchem 
Ltd  at: http://www.mhra.gov.uk/home/groups/par/documents/websiteresources/con014182.pdf 
Accessed 11 Jan 2019. 
European public assessment report (EPAR) for Xaluprine, Nova Laboratories Ltd. 
https://www.ema.europa.eu/en/medicines/human/EPAR/xaluprine-previously-mercaptopurine-
nova-laboratories. Accessed 11 Jan 2019 
In accordance with ICH E3, only articles from the literature pertinent to the evaluation of the study 
were cited and will be attached to the appendices of the CSR. 
 
 
 
 

SAP_001.pdf: 
SQN study no: MET18004  
Nova Laboratories study no: INV691
 
Date: 24MAY2019 
Page 1 of 12
Version: Final 
ST/form/010/11 
 
 
 
 
 
 
 
A single centre, single dose, open-label, randomised, two 
period crossover study to assess the bioequivalence of an 
oral azathioprine tablet 50mg (Imurek®, Aspen Pharma 
Trading Limited, Dublin, Ireland) in at least 30 healthy adult 
subjects under fasting conditions. 
 
Nova Laboratories Study No: INV 691 
Medicines Evaluation Unit Study No: MEU 18/372 
SQN Study No:  MET18004 
 
 
Statistical Analysis Plan  
 
 
Version: Final 
Date: 24 May 2019 
 
For Syne qua non Ltd  Lead Statistician 
For Medicines Evaluation Unit 
If signing manually, please include:  Signature + Date + Full Name + Position 
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SQN study no: MET18004  
Nova Laboratories study no: INV691
 
Date: 24MAY2019 
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Contents 
 
1 
INTRODUCTION ............................................................................................................................. 4
2 
STUDY OBJECTIVES AND DESIGN ............................................................................................. 4
2.1 
Study Objectives ......................................................................................................................... 4
2.2 
Study Endpoints .......................................................................................................................... 4
2.3 
Study Design ............................................................................................................................... 4
2.4 
Visit Structure .............................................................................................................................. 5
3 
Sample Size .................................................................................................................................... 5
4 
Randomisation ................................................................................................................................ 5
5 
Interim analysis ............................................................................................................................... 5
6 
Analysis Plan ................................................................................................................................... 6
6.1 
General ....................................................................................................................................... 6
6.2 
General Derivations .................................................................................................................... 6
6.3 
Analysis Sets .............................................................................................................................. 6
6.4 
Data presentations ...................................................................................................................... 7
6.5 
Disposition of subjects ................................................................................................................ 7
6.6 
Protocol Deviations ..................................................................................................................... 7
6.7 
Background and Demographic Characteristics .......................................................................... 8
6.7.1 
Demography ............................................................................................................................ 8
6.7.2 
Medical History ........................................................................................................................ 8
6.7.3 
Thiopurine Methlytransferase Testing ..................................................................................... 8
6.8 
Prior and Concomitant Medications ............................................................................................ 8
6.9 
Study Treatments........................................................................................................................ 9
6.10 
Pharmacokinetics........................................................................................................................ 9
6.11 
SAFETY EVALUATION ............................................................................................................10
6.11.1 
Tolerability .............................................................................................................................10
6.11.2 
Adverse Events ......................................................................................................................10
6.12 
Clinical Laboratory Evaluation ..................................................................................................11
6.13 
Vital Signs .................................................................................................................................12
6.14 
Electrocardiography ..................................................................................................................12
6.15 
Physical Examination ................................................................................................................12
6.16 
Pregnancy Test .........................................................................................................................12
6.17 
Urine Screen and Alcohol Breath Test .....................................................................................12
6.18 
Palatability Questionnaire .........................................................................................................12
6.19 
Changes from the Protocol Planned Analysis ..........................................................................12
 
 
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LIST OF ABBREVIATIONS 
 
AE 
Adverse Event 
AUC0-  
Area Under the Plasma Concentration time curve to the Last 
quantified concentration 
AUC0-  
Area Under the Plasma Concentration time curve from time Zero to 
Infinity 
BLQ 
Below the Lower Limit of Quantification 
BMI 
Body Mass Index 
BP 
Blood Pressure 
Cmax 
Maximum Observed Plasma Concentration 
CI 
Confidence Interval 
ECG 
Electrocardiogram 
z 
Terminal Elimination Rate Constant 
LLOQ 
Lower Limit of Quantification 
MedDRA 
Medical Dictionary for Regulatory Activities 
PK 
Pharmacokinetic 
PT 
Preferred Term 
SAF 
Safety Analysis Set 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SOC 
System Organ Class 
t½ 
Terminal Elimination Half-Life 
TEAE 
Treatment Emergent Adverse Event 
tmax 
Time of the Maximum Observed Plasma Concentration 
WHO Drug World Health Organization Drug Dictionary 
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1 
INTRODUCTION 
This document details the statistical analysis that will be performed for the Nova 
Laboratories study: A single centre, single dose, open-label, randomised, two period 
crossover study to assess the bioequivalence of an oral azathioprine suspension 
Trading Limited, Dublin, Ireland) in at least 30 healthy adult subjects under fasting 
conditions.  
The proposed analysis is based on the contents of the Final Version of the protocol 
(dated 03-May-2019). In the event of future amendments to the protocol, this statistical 
analysis plan (SAP) may be modified to account for changes relevant to the statistical 
analysis.  
The table, listing and figure shells are supplied in a separate document. 
2 
STUDY OBJECTIVES AND DESIGN 
2.1 
Study Objectives 
The primary objective of the study is 
azathioprine tablet formulation (Imurek®) are 
bioequivalent. 
The secondary objectives of the study are 
 To assess the safety and tolerability of the test product, azathioprine 
oral 10mg/mL suspension 
 To determine the plasma concentrations and pharmacokinetics of the 
metabolite mercaptopurine 
2.2 
Study Endpoints 
The primary endpoints of the study are 
 Maximum observed plasma concentration (Cmax) 
 Area under the plasma concentration curve from zero to time of the last 
quantifiable concentration (AUC0-t) 
 Area under the plasma concentration curve from zero extrapolated to infinity 
(AUC0- ) 
The secondary endpoint(s) are 
 Time to maximum observed plasma concentration (tmax) 
 Terminal elimination rate constant ( z) 
 Apparent terminal elimination half-life (t½) 
2.3 
Study Design 
This will be a single-dose, open-label, randomised, two-period crossover study with 
oral azathioprine tablet 50mg (Imurek®, Aspen Pharma Trading Limited, Dublin, 
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Date: 24MAY2019 
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Ireland) on two separate occasions conducted under fasting conditions in healthy male 
and female subjects at a single study centre. 
The study will comprise: 
 Thiopurine methyltransferase (TPMT) testing 
 Screening period of maximum 28 days 
 Two treatment periods (each of which will include a PK profile period of 12 
hours) separated by a wash-out period of at least 3 calendar days (minimum 
number of days based on half-life of the analyte) and maximum of 14 calendar 
days between consecutive administrations of the IMP 
 A post-study visit 7-10 days after the last dose of the last treatment period of 
the study 
Subjects will be randomly assigned to treatment sequence, prior to the first 
administration of IMP. 
2.4 
Visit Structure 
The visit structure and scheduled assessments are detailed in protocol section 7.1.3.  
3 
SAMPLE SIZE 
Thirty (30) subjects will be randomised, to allow for dropouts or subjects who otherwise 
fail to complete the study with at least 28 evaluable subjects. The sample size for this 
study has been selected without any formal statistical considerations. However, similar 
bioequivalence studies 
 AT/H/0270/001-002/DC 
 UK/H/2846/004/DC 
 UK/H/934/01/DC 
for azathioprine have recruited between 24-30 subjects. This figure has been 
determined adequate to meet the study objectives. 
4 
RANDOMISATION 
The randomisation will be produced by SQN. The treatment will be allocated by staff 
at the site using the randomisation list provided. 
Subjects who withdraw or are withdrawn from the study may be replaced (recruitment 
continued), if fewer complete the study than the estimated number of evaluable 
subjects. Replacements will be randomised to treatment (they will not necessarily be 
on the same treatment sequence). 
5 
INTERIM ANALYSIS 
No interim analysis is planned for this study.  
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6 
ANALYSIS PLAN 
6.1 
General 
Summary statistics for continuous variables will consist of number of non-missing 
observations (n), arithmetic mean, standard deviation (SD), minimum, median and 
maximum, unless specified otherwise.  The precision of these variables is defined in 
the table, figure and listing shells document. 
For categorical variables the number and percentage of subjects in each category will 
be presented, based on the number of subjects in the analysis set, unless otherwise 
specified.  
6.2 
General Derivations 
This section provides details of general derivations. Derivations specific to the 
parameter of interest are detailed within the specific SAP section. 
 Definition of baseline 
A within-period baseline is defined as the last non-missing value (including scheduled 
and unscheduled assessments) recorded prior to the subject receiving the respective 
study treatments for the respective period. 
 Incomplete dates 
For calculation purposes, incomplete dates will be completed using worst case. 
Further details are detailed in the relevant sections as required.   
 Non-numeric values 
 
 
 
 
purposes a value of x will be taken. Where a range of values is quoted the midpoint of 
the range will be taken.  
6.3 
Analysis Sets 
The Enrolled set includes all subjects who provide informed consent irrespective of 
whether they were randomised or received study treatment. 
The Safety analysis set (SAF) consists of all subjects who take at least one 
administration of study treatment.  Subjects will be analysed according to the treatment 
actually taken.   
The Pharmacokinetic (PK) set will consist of all subjects who complete the study and 
for whom primary PK variables can be calculated for all treatments. 
In case of events such as vomiting, diarrhoea and use of concomitant medication, 
which could render the plasma concentration time profile unreliable, such subjects 
may be excluded from the PK population after review of the severity of the event and 
the start and stop time in relation to dosing. When vomiting occurs within 2x the 
calculated median tmax of the reference (tablet) product, data from all treatments being 
compared will be excluded from PK and statistical evaluation. Subjects with pre-dose 
max will be excluded from all statistical PK 
analysis (including descriptive statistics). The available concentration data of the 
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above subjects and those who do not complete the study will only be listed, not 
presented in descriptive statistics or included in PK or formal statistical analysis.
The list of subjects included in the PK will be agreed prior to database lock once all 
study data is available. The definitions for the enrolled set and SAF are sufficient to 
determine the subjects included within these analysis sets and so do not require listing 
and agreeing prior to database lock. 
6.4 
Data presentations 
The data will be summarised in tabular form by treatment group (
tablet 50mg  
Oral azathioprine suspension 10mg/mL
exceptions: disposition of subjects, background and demographic characteristics 
which will be summarised by treatment sequence (
Oral azathioprine suspension 10mg/mL
Oral azathioprine suspension 10mg/mL
 
) and overall subjects 
 treatment group.
Only scheduled post-baseline laboratory, vital signs and ECG values will be tabulated, 
post-baseline repeat/unscheduled assessments will be disregarded, although they will 
be listed and in particular all clinically significant values will be noted. 
Analysis sets, protocol deviations and eligibility listing will be summarised using the 
enrolled set, PK outputs will be summarised using the PK set and everything else will 
be summarised using the SAF.  
Listings will be sorted by treatment sequence, subject number and date/time of 
assessment. 
Graphical presentations of the data will also be provided where appropriate. 
6.5 
Disposition of subjects 
The number and percentage of all subjects enrolled, included in the SAF, PK analysis 
set, who completed the study and prematurely discontinued the study, who completed 
study treatment and prematurely discontinued study treatment, study duration and 
treatment duration, will be summarised.  The number and percentage of subjects will 
be summarised by their reasons for withdrawal from the study. 
Study duration will be derived as the number of days between first visit and the date 
of study completion or the date of early study withdrawal. Treatment duration will be 
derived as the number of days between first administration of study treatment in period 
1 and date of study completion or the date of early study withdrawal. 
Eligibility for each of the analysis sets along with reasons for exclusion will be listed. 
Study completion/withdrawal data will be listed. 
6.6 
Protocol Deviations 
Details of all protocol deviations (start and end dates, report type (Full 
report/Procedural), deviation category, specific details and cause) and subject 
eligibility will be listed.   
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6.7 
Background and Demographic Characteristics 
6.7.1 
Demography 
Demographic characteristics (age, sex, ethnicity and race), body measurements 
(height, weight and BMI), average weekly consumption of alcohol and smoking history
collected at Screening will be summarised. 
Body mass index (BMI) in kg/m2 is calculated as 
 
All subject demographic data including informed consent will be listed. 
6.7.2 
Medical History 
Medical history events will be coded using the latest MedDRA dictionary version. The 
version used will be indicated in the data summaries and listings. The number and 
percentage of subjects will be presented for ongoing conditions and previous 
conditions separately by system organ class (SOC), and preferred term (PT), where 
SOC and PT will be presented in decreasing frequency of the total number of subjects 
with medical history events. All events will be listed. 
6.7.3 
Thiopurine Methlytransferase Testing 
The date, time and result in mU/L taken at screening will be listed.  
6.8 
Prior and Concomitant Medications 
Medications will be coded using the latest World Health Organization Drug dictionary 
(WHO Drug) version.  The version used will be indicated in the data summaries and 
listings.  
Prior medications are defined as those that started and ended prior to the first 
administration of study treatment. 
Medications that are ongoing at the first administration of study treatment or started 
after time of first administration will be deemed to be concomitant medications.
Concomitant medications will be reported under each period they were concomitant 
to. For example; a medication starting and ending in period 1 will be assigned to period 
1 only. A treatment starting after the first administration of study treatment in period 2 
will be assigned to period 2 only. A treatment starting before the end of period 1 and 
continuing into period 2 will be reported under period 1 and period 2.   
For the purposes of concomitant medication, period 1 is defined from day of first 
administration of study treatment for period 1 to the day before the first administration 
of study treatment for period 2. If medication dates are incomplete and it is not clear 
whether the medication was concomitant, it will be assumed to be concomitant.
The number and percentage of subjects taking prior and concomitant medications will 
be summarised separately by medication class and standardised medication name, 
where medication class and standardised medication name will be presented in 
decreasing frequency of the total number of subjects with medications.  In summary 
tables, subjects taking multiple medications in the same medication class or having
the same standardised medication recorded multiple times in the study will be counted 
only once for that specific medication class and standardised medication name. 
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Medication data will be listed, where concomitant medications will be flagged. 
6.9 
Study Treatments 
A listing will be provided detailing if the subject received any treatment for the period, 
date and time of administration, the treatment and dose received. 
6.10 
Pharmacokinetics 
Summary statistics for PK outputs will be reported using n, arithmetic mean, geometric 
mean, median, coefficient of variation, standard deviation, minimum and maximum.
For purposes of analysis, the test product is Jayempi 50mg/mL (azathioprine oral 
suspension) and the reference is Imurek 50mg (oral azathioprine tablet). 
Plasma concentrations of azathioprine (both oral and tablet) will be listed and 
summarised over time. Concentrations below the lower limit of quantification (LLOQ)
of 0.2ng/ml will be indicated as below the lower limit of quantification (BLQ). For PK 
summaries and analyses, BLQ concentrations will be handled as follows: 
 All BLQ values in the absorption phase, prior to the first reported 
concentration, will be substituted by zeros. 
 The BLQ values between evaluable concentrations will be substituted by 0.5 × 
LLOQ, before the calculation of the PK variables. 
 Terminal BLQ values will be set to missing. 
These measures are taken to prevent an over-estimation of AUC. Values reported as 
 
For the purposes of PK analysis, missing concentrations will be deleted, resulting in 
an interpolation between the nearest two concentration values. A table reflecting 
summary statistics per product will be provided for PK variables of azathioprine, 
including the number of points used to calculate z 
z will, however, not be 
summarised). 
A table reflecting summary statistics will be provided for the ratios (%test/reference) 
of the primary PK variables (Cmax, AUC0-  and AUC0- ), for t½ and for the difference 
(test  reference) of tmax. 
Analysis of tmax will be done using Wilcoxon's Signed Rank test. The median tmax of 
the test and reference will be tabulated together with the p-value from Wilcoxon's 
Test. 
The test product (azathioprine only) will be compared to the reference product by 
means of statistical analysis with respect to the primary PK variables (Cmax, AUC0-
and AUC0- ) using an analysis of variance (ANOVA) with sequence, 
subject(sequence), product and period effects after logarithmic transformation of the 
data. Point estimates and 90% confidence intervals for the "test/reference" geometric 
mean ratios of these variables will be tabulated. 
Bioequivalence of the test and reference products will be assessed on the basis of 
the 90% confidence intervals for the geometric mean ratio of the primary PK 
variables of azathioprine in relation to the conventional bioequivalence range of 
80.00% to 125.00%. 
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Version: Final 
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In case of outliers present in the data regarding the primary PK parameters, the 
analyses will be performed on both the complete data and on the data excluding the 
outliers. Bioequivalence will however be assessed on the complete data. 
Plots will be produced for plasma concentration versus actual time as follows: 
 Individual subjects plotted together on the same axis per product using a log-
linear and linear-linear scales. 
 Distinct individual subject plots per product using a log-linear and linear-linear 
scales. 
 Arithmetic and geometric mean plots with both products on same axis using 
log-linear and linear-linear scales. 
All PK data will be listed. 
6.11 
SAFETY EVALUATION 
6.11.1 Tolerability 
Tolerability will be evaluated by monitoring adverse event, laboratory, vital signs and 
ECGs performed at protocol-specified visits.  Details regarding summarisation of these 
data are given in the relevant sections below. 
6.11.2 Adverse Events 
Adverse events (AEs) will be coded using the latest MedDRA dictionary version.  The 
version used will be indicated in the data summaries and listings.  
A treatment-emergent adverse event (TEAE) is defined as an AE that started on or 
after the start of the administration study treatment. If adverse event dates and times 
are incomplete and it is not clear whether the adverse event was treatment-emergent, 
it will be assumed to be treatment-emergent. 
Adverse events are treatment-emergent and accountable to period 1 treatment if they 
started on or after the start of the administration study treatment in period 1 up to the 
first administration of study treatment in period 2. However, for period 2, adverse 
events are treatment-emergent and accountable to period 2 treatment if they started 
on or after the start of the administration study treatment period 2 up to the end of the 
follow-up period. If the start date and time, and other data mean that the event could 
have occurred in more than one period, then the event will be recorded under both 
periods. 
A treatment-related TEAE is defined as a TEAE that is certain, probable/likely or 
possibly related to the study treatment. If the TEAE has a missing relationship it is 
assumed to be related to the study treatment for analysis purposes.  
A summary table will present the following:  
 TEAEs (events and subjects).  
 Serious TEAEs (events and subjects).  
 Serious study treatment-related TEAEs (events and subjects). 
 TEAEs by severity (mild/moderate/severe) (events and subjects). 
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SQN study no: MET18004  
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Date: 24MAY2019 
Page 11 of 12
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 TEAEs by relationship to study treatment and the pooled study treatment 
related category (events and subjects). 
 TEAEs leading to withdrawal from study (subjects only). 
 TEAEs leading to discontinuation of study treatment (subjects only). 
 Study treatment-related TEAEs leading to discontinuation of study treatment
(subjects only). 
 TEAEs leading to death (subjects only). 
In the above summaries, if a subject experienced more than one TEAE, the subject 
will be counted once using the most re
study 
treatment  and related to study treatment
 and at the worst severity for the 
 
The following tables will be presented: 
 TEAEs by system Organ Class (SOC) and Preferred Term (PT). 
 TEAEs by SOC, PT and relationship to study treatment and the pooled related 
categories (related/unrelated). 
 TEAEs by SOC, PT and severity (mild/moderate/severe) 
For all of the above, SOC and PT will be presented in decreasing frequency of the 
total number of subjects with TEAEs. 
Further details of the above tables are given below: 
1. If a subject experienced more than one TEAE assigned to the same treatment, 
the subject will be counted once for each SOC and once for each PT within that 
treatment.   
2. If a subject experienced more than one TEAE assigned to the same treatment, 
the subject will be counted once for each PT within that treatment. 
3. If a subject experienced more than one TEAE assigned to the same treatment, 
the subject will be counted once for each SOC and once for each PT using the 
most related event within that treatment. 
4. If a subject experienced more than one TEAE assigned to the same treatment, 
the subject will be counted once for each SOC and once for each PT at the 
worst severity within that treatment. 
Adverse event data will be listed in full and this will also include a treatment emergent 
flag, the treatment the adverse event is assigned to, the time of onset and cessation 
of event relative to first dosing of study treatment and duration of AE. A flag will also 
be used for AEs related to vomiting that occurred within 2 × the calculated median tmax.
6.12 
Clinical Laboratory Evaluation 
Listings of haematology, biochemistry and urinalysis laboratory measurements 
recorded throughout the study will be provided. 
Each haematology, coagulation biochemistry and urinalysis parameter will be classed 
as low, normal, high, missing based on the reference ranges and will be reported in 
separate listings. 
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Observed values in biochemistry and haematology will be summarised by visit. If the 
test results are reported in categorical format, the results will be summarised by 
subject counts and percentage for each category. 
6.13 
Vital Signs 
All vital sign data will be listed. 
6.14 
Electrocardiography 
All ECG data will be listed. 
6.15 
Physical Examination 
Details of timings of physical examinations will be listed.  
6.16 
Pregnancy Test 
Pregnancy test details will be listed. 
6.17 
Urine Screen and Alcohol Breath Test 
Results of urine drugs of abuse, alcohol breath test and urine cotinine test will be listed.
6.18 
Palatability Questionnaire 
Visual analogue scale questions (Questions 1, 3, 4 and 5) captured as lengths in mm 
will be summarised using summary statistics. The categorical question (Question 2) 
will be summarised using number and percent. 
All data related to palatability questionnaire will be listed. 
6.19 
Changes from the Protocol Planned Analysis 
Not applicable. 
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