Clinical trial NCT04004429
Conditions: Rheumatoid Arthritis
Sponsor: SynAct Pharma Aps
Start date: 2019-08-26; Completion date: 2021-11-16
Enrollment: 105 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a multicenter, two-part, randomized, double-blind, placebo-kontrolled, 4-week study with repeated doses of AP1189. The study population will consist of newly diagnosed subjects with severe active Rheumatoid Arthritis, defined with a Clinical Disease Activity score (CDAI) \> 22, who are to start up-titration with methotrexate.

Detailed description:
A multicenter, two-part, randomized, double-blind, placebo-kontrolled, 4-week study with repeated doses of AP1189. The study population will consist of newly diagnosed subjects with severe active Rheumatoid Arthritis, defined with a Clinical Disease Activity score (CDAI) \> 22, who are to start up-titration with methotrexate.

The study will be conducted in two parts separated by an interim analysis.

Part 1: The subjects will be randomized in a 1:1:1 ratio into: .

* AP1189 dose 50 mg
* AP1189 dose 100 mg
* placebo

INTERIM ANALYSIS

Part 2: All subjects will be randomized into either design 1, 2 or 3 based on data from the interim analysis.

* Design 1: AP1189 dose 50 mg or placebo in a 2:1 ratio
* Design 2: AP1189 dose 100 mg or placebo in a 2:1 ratio
* Design 3: Continue with the same doses as in Part 1

The purpose of this study is to determine the safety and efficacy of 2 doses of AP1189 compared with placebo after 4 weeks of treatment.

Arms: arm 1: 50 mg AP1189. The treatment is a 4 week treatment. Each daily dose will be administered as a suspension, i e. the powder will be added 50 ml water. arm 2: 100 mg AP1189. The treatment is a 4 week treatment. Each daily dose will be administered as a suspension, i e. the powder will be added 50 ml water. arm 3: Placebo. The treatment is a 4 week treatment. Each daily dose will be administered as a suspension i e. the powder will be added 50 ml water.
Interventions: intervention 1: 50 mg AP1189 intervention 2: AP1189 intervention 3: Placebo
Intervention descriptions: intervention 1: 50 mg AP1189 powder in bottle intervention 2: 100 mg AP1189 powder in bottle intervention 3: Placebo powder in bottle

Protocol documents:
Prot_000.pdf: 
 
 
  
 
 
 
Protocol Code Number: SynAct-CS002 
 
Version: 9.0 
Date: 14JAN2021 
CONFIDENTIAL 
 
 
 
 
 
 
CLINICAL STUDY PROTOCOL 
 
A double-blind, multi-center, two-part, randomized, placebo-controlled study of the safety, tolerability, and 
efficacy of 4 weeks of treatment with AP1189 in early rheumatoid arthritis (RA) patients with active joint 
disease 
 
Clinical Study Sponsor: 
 
SynAct Pharma ApS 
Clinical Study Phase: 
IIa 
Protocol Code: 
 
SynAct-CS002 
Version: 
9.0 
Version date: 
 
14. January 2021 
EudraCT No: 
2019-001185-15 
 
 
 
 
 
 
 
 
This study document is strictly confidential and is intended as a guideline with information for  
investigators, study staff, the National Competent Authority, and the Ethics Committees.  
It is the property of SynAct Pharma ApS and any copying or distribution is strictly prohibited without prior 
permission is obtained from the sponsor and such persons are bound by a confidentiality agreement with 
SynAct Pharma ApS. 


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Protocol Code Number: SynAct-CS002 
 
 
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1 STUDY ADMINISTRATION 
Sponsor 
SynAct Pharma ApS  
CVR No: 34459975 
Dronninggårds Allé 136 
2840 Holte 
Denmark 
Medically Responsible Person 
SynAct Pharma ApS 
Dronninggårds Allé 136 
2840 Holte 
Denmark 
 
Phone: +45 4547 5020 
Phone: +45 4015 6669   
Fax: +45 4547 5001 
E-Mail: tj@synactpharma.com 
Pharmacovigilance Responsible Person 
 
 
 
 
PharmaLex Denmark A/S 
Agern Allé 24 
2970 Hørsholm 
Denmark 
 
Phone: +45 7879 9529 
Phone: +45 3110 6705 
E-mail: lise.storm@pharmalex.com 
Project Manager 
Irene Sandholdt 
CroxxMed ApS 
Agern Allé 24 
2970 Hørsholm 
Denmark 
 
Phone: +45 2015 7033 
E-mail: isa@croxxmed.com 
Statistician 
Inger Persson 
CroxxMed ApS 
Agern Allé 24 
2970 Hørsholm 
Denmark 
 
E-mail: ipe@croxxmed.com  
Medical Writer/ Regulatory Responsible Person 
 
 
 
 
 
Birgitte Telmer 
CroxxMed ApS 
Agern Allé 24 
2970 Hørsholm 
Denmark 
 
Phone: +45 2015 1221 
E-mail: bte@croxxmed.com 


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Protocol Code Number: SynAct-CS002 
 
 
Version: 9.0 
Date: 14JAN2021 
CONFIDENTIAL 
2 CLINICAL STUDY APPROVAL FORM 
The final clinical study protocol, version 9.0, dated 14. January 2021 has been approved by: 
 
 
Sponsor Medically Responsible Person:  
Thomas Jonassen 
 
 
 
 
 
 
 
 
Date:  
 
 
 
 
 
 
Medical Writer: 
 
Birgitte Telmer 
 
 
 
 
 
 
 
 
Date:  
 
 
 
Statistician:  
Inger Persson  
 
 
 
 
 
 
 
 
 
Date:  
 
 
 
 
21JAN2021
21JAN2021
January 22, 2021


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Protocol Code Number: SynAct-CS002 
 
 
Version: 9.0 
Date: 14JAN2021 
CONFIDENTIAL 
3 COMPLIANCE STATEMENT 
The study will be conducted in accordance with legal and regulatory requirements, as well as the general 
principles set forth in the International Ethical Guidelines for Biomedical Research Involving Human Subjects 
(Council for International Organizations of Medical Sciences 2002), Guidelines for Good Clinical Practices (GCP) 
(ICH GCP Guidelines with Integrated Addendum E6(R2)), and the Declaration of Helsinki (World Medical 
Association 1996 & 2008). 
 
In addition, the study will be conducted in accordance with the protocol, the ICH guideline on GCP, and 
applicable local regulatory requirements and laws. 
 
 
 
 
 


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Protocol Code Number: SynAct-CS002 
 
 
Version: 9.0 
Date: 14JAN2021 
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4 INVESTIGATOR AGREEMENT 
I have read the attached protocol entitled: (“A double-blind, multi-center, two-part, randomized, placebo-
controlled study of the safety, tolerability, and efficacy of 4 weeks of treatment with AP1189 in early 
rheumatoid arthritis (RA) patients with active joint disease”), dated 14 January 2021, and agree to abide by all 
provisions set forth therein.  
I have read the Investigator’s Brochure (IB) for the investigational medicinal product (IMP) including the 
potential risks and adverse drug reactions of the IMP and I agree to report all adverse events which occur during 
the trial.  
I confirm that I am suitably qualified by my education, scientific medical training, and experience to conduct the 
trial. Documentation of my qualifications and professional affiliations are contained in my signed and dated 
curriculum vitae. 
I agree to comply with the International Conference on Harmonization (ICH) Tripartite Guideline on Good 
Clinical Practice (GCP) and applicable national or regional regulations/guidelines. 
I agree to ensure that the study will not be initiated before written approval from the Independent Ethics 
Committee (IEC)/ Institutional Review Board (IRB) and the Competent Authorities (CA), and that any additional 
requirements imposed by the IEC/IRB or CA shall be followed, as appropriate. 
I agree to ensure that the confidential information contained in this document will not be used for any purpose 
other than the evaluation or conduct of the clinical investigation without the prior written consent of the 
sponsor. 
 
 
 
 
Signature 
 
 
 
 
Printed Name of Principal Investigator 
                      
Date (DDMMMYYYY) 
 
 


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CONFIDENTIAL 
5 GLOSSARY OF ABBREVIATIONS 
% 
Percentage 
°C 
Degree Celsius 
αMSH 
Alpha-melanocyte stimulating hormone 
ACR 
American College of Rheumatology 
ACTH 
Adrenocorticotrophic hormone 
ADL 
Activity of Daily Living 
AE 
Adverse Event 
ALAT/ALT 
Alanine aminotransferase/alanine transaminase 
ALP 
Alkaline phosphatase 
ANOVA 
Analysis of variance 
Anti-CCP 
Anti-Cyclic Citrullinated Peptide 
AR 
Adverse Reaction 
ASAT/AST 
Aspartate aminotransferase/aspartate transaminase 
ATC 
Anatomical Therapeutic Chemical (ATC) Classification System 
AUC 
Area under the curve 
bHLH-LZ  
Basic helix-loop-helix leucine zipper 
BLQ 
Below the Limit of Quantification 
BP 
Blood Pressure 
bpm 
Beats per minute 
CA 
Competent Authorities  
Ca2+ 
Calcium 
cAMP 
Cyclic adenosine monophosphate 
CDAI 
Clinical disease activity score 
cDNA 
Complementary deoxyribonucleic acid 
CL/F 
Apparent total clearance 
CLr 
Renal clearance 
Cmax 
Maximum plasma concentration 
COX 
Cyclooxygenase 
CRO 
Clinical Research Organization 
CRP 
C-Reactive Protein 
CSA 
Clinical Study Agreement 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV% 
Coefficient of variation 
CXCL13 
Chemokine ligand 13  
DAS28 
Disease activity score 28 (28 joints are examined) 
DMARD 
Disease-modifying anti-rheumatic drugs 
DMC 
Data Monitoring Committee 
DMP 
Data Management Plan 
DSUR 
Development Safety Update Report 
eCRF 
Electronic Case Report Form 
e.g. 
Exempli gratia (for example) 


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ECG 
Electrocardiogram 
EDC 
Electronic data capture 
EOS 
End of study 
ERK1/2 
Extracellular signal-regulated kinase ½ 
EULAR 
European League Against Rheumatism 
FACIT 
Functional Assessment of Chronic Illness Therapy 
FSH 
Follicle Stimulating Hormone 
GCP 
Good Clinical Practices 
GGT 
Gamma-glutamyl transpeptidase 
HAQ-DI 
Health Assessment Questionnaire – Disability Index 
HbA1c 
Hemoglobin A1c 
HBsAg 
Hepatitis B surface antigen 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 
IB 
Investigator’s Brochure 
IBD 
Inflammatory Bowel Disease 
ICH 
International Conference on Harmonization 
i.e. 
Id est (that is) 
IEC 
Independent Ethics Committee  
IGA 
Investigator Global Assessment 
IL 
Interleukin 
IMP 
Investigational medicinal product 
IP 
Interphalangeal 
IRB 
Institutional review board 
ISF 
Investigator Site File 
IUPAC 
International Union of Pure and Applied Chemistry 
kg 
Kilogram(s) 
LL-R 
Ligand Specific Receptor 
MAD 
Maximum Administered Dose 
MC 
Melanocortin  
MCP 
Metacarpophalangeal 
MCR 
MC receptor 
MCTD 
Mixed Connective Tissue Disease 
MedDRA 
Medical dictionary for regulatory activities 
mg 
Milligram(s) 
MITF 
Microphthalmia-associated transcription factor 
ml 
Millilitre 
mm 
Millimetre(s) 
mmHg 
Millimetre mercury 
mRNA 
Messenger ribonucleic acid 
MTD 
Maximum Tolerated Dose 
MTX 
Methotrexate 
N 
Number of observations 


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ng 
Nanogram 
NFκB 
Nuclear Factor Kappa-B 
NSAID 
Nonsteroidal anti-inflammatory drugs 
PGA 
Patient Global Assessment 
PIP 
Proximal interphalangeal joint 
PK 
Pharmacokinetic 
PRO 
Patient-Reported Outcome questionnaire 
QFG-IT 
QuantiFERON-in-Tube test 
QT 
QT interval 
QTcF 
Corrected QT interval by Fredericia 
RA 
Rheumatoid arthritis 
RBC 
Red blood cell 
RoI 
Resolution of Inflammation 
RF 
Rheumatoid factor 
SAD 
Single Ascending Dose 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SAR 
Serious adverse reaction 
SC 
Steering Committee 
SD 
Standard Deviation 
SDV 
Source data verification 
SJC 
Swollen joint count 
SLE 
Systemic Lupus Erythematosus 
SPC 
Summary of Product Characteristics 
SPM 
Specialized Pro-Resolving Mediators 
Sqrt 
Square 
SSI 
Statens Serum Institut 
SUSAR 
Suspected unexpected serious adverse reaction 
T½ 
Apparent terminal elimination half-life 
TB 
Tuberculosis 
TEAE 
Treatment-emergent adverse event 
TJC 
Tender joint count 
TMF 
Trial Master file 
TNFα 
Tumor necrosis factor alpha 
Tmax 
Time at which the Cmax is observed 
T3 
T4 
TSH 
VAS 
Triiodothyronine 
Thyroxine 
Thyroid stimulation hormone 
Visual Analog Scale 
Vd/F 
Apparent volume of distribution 
WBC 
White blood cell 
WD 
Withdrawn 


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µSV 
Microsivert 
 
 
 


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6 TABLE OF CONTENTS 
1 
Study Administration ......................................................................................................................................... 2 
2 
Clinical Study Approval Form ............................................................................................................................. 3 
3 
Compliance Statement ...................................................................................................................................... 4 
4 
Investigator Agreement ..................................................................................................................................... 5 
5 
Glossary of Abbreviations .................................................................................................................................. 6 
6 
Table of Contents ............................................................................................................................................ 10 
7 
Protocol Synopsis ............................................................................................................................................ 17 
8 
Introduction and Rationale .............................................................................................................................. 22 
8.1 
Introduction ............................................................................................................................................. 22 
8.2 
Resolution of Inflammation ..................................................................................................................... 22 
8.3 
The Melanocortin System ........................................................................................................................ 23 
8.4 
Melanocortin Receptors .......................................................................................................................... 23 
8.4.1 
MC1 Receptor (MC1R) ..................................................................................................................... 23 
8.4.2 
MC2 Receptor (MC2R) ..................................................................................................................... 24 
8.4.3 
MC3 Receptor (MC3R) ..................................................................................................................... 24 
8.4.4 
MC4 Receptor (MC4R) ..................................................................................................................... 24 
8.4.5 
MC5 Receptor (MC5R) ..................................................................................................................... 25 
8.4.6 
Anti-inflammatory Effects of Melanocortins ................................................................................... 25 
9 
Non-clinical Studies ......................................................................................................................................... 26 
9.1 
Summary of pre-clinical Studies .............................................................................................................. 26 
10 
Clinical Studies ............................................................................................................................................. 26 
10.1 
Phase I Study Results ............................................................................................................................... 26 
10.1.1 
Summary of Results from Phase I; Part I, II and III .......................................................................... 26 
10.1.2 
Summary of Result from Part IV ...................................................................................................... 28 
10.1.3 
PK, Part IV Cohort 1 ......................................................................................................................... 28 
10.1.4 
PK, Part IV Cohort 2 ......................................................................................................................... 28 
10.1.5 
PK, Part IV Cohort 3 ......................................................................................................................... 28 
10.1.6 
Safety Conclusion from Part 4 ......................................................................................................... 29 
11 
Indication ..................................................................................................................................................... 30 
11.1 
Rheumatoid Arthritis ............................................................................................................................... 30 
11.2 
AP1189, an anti-inflammatory lead Compound ...................................................................................... 30 


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11.3 
Rationale for the Study ............................................................................................................................ 31 
11.3.1 
Dose Selection ................................................................................................................................. 32 
11.3.2 
Benefits and Risks of Participation .................................................................................................. 32 
12 
Objectives .................................................................................................................................................... 34 
12.1 
Primary safety Objective ......................................................................................................................... 34 
12.2 
Primary efficacy Objective ....................................................................................................................... 34 
12.3 
Secondary efficacy Objectives ................................................................................................................. 34 
12.4 
Tertiary Efficacy Objectives ..................................................................................................................... 34 
12.4.1 
Arthroscopy sub-Study .................................................................................................................... 35 
13 
Safety Endpoints .......................................................................................................................................... 35 
13.1 
Primary Safety Endpoint .......................................................................................................................... 35 
14 
Efficacy Endpoints........................................................................................................................................ 35 
14.1 
Primary Efficacy Endpoint........................................................................................................................ 35 
14.2 
Secondary Efficacy Endpoints .................................................................................................................. 35 
14.3 
Tertiary Efficacy Endpoints ...................................................................................................................... 35 
15 
Experimental Plan ........................................................................................................................................ 36 
15.1 
Study Design ............................................................................................................................................ 36 
15.2 
Sub-study of subjects from Bulgaria/Moldova ........................................................................................ 36 
15.3 
Part 1 (main study only) .......................................................................................................................... 36 
15.3.1 
Number of Subjects in Part 1 ........................................................................................................... 37 
15.4 
Part 2 ....................................................................................................................................................... 37 
15.4.1 
Number of Subjects in Part 2 ........................................................................................................... 37 
15.5 
Estimated Study Duration........................................................................................................................ 37 
15.6 
Number of Investigational Sites .............................................................................................................. 37 
15.7 
Visits during the Study ............................................................................................................................. 37 
15.8 
Steering Committee (SC) ......................................................................................................................... 37 
15.9 
Data Monitoring Committee (DMC) ........................................................................................................ 38 
15.10 
Criteria for Choice of Design for Part 2 ................................................................................................ 38 
15.11 
Stopping Rules ..................................................................................................................................... 39 
16 
Study Population ......................................................................................................................................... 39 
16.1 
Subject Selection Criteria ........................................................................................................................ 39 
16.2 
Inclusion Criteria ...................................................................................................................................... 39 
16.3 
Exclusion Criteria ..................................................................................................................................... 40 


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16.4 
Recruitment of Subjects .......................................................................................................................... 41 
16.4.1 
Subject Participation Card ............................................................................................................... 41 
16.5 
Withdrawal .............................................................................................................................................. 41 
16.5.1 
Subject may decide to withdraw ..................................................................................................... 41 
16.5.2 
Discontinuation of Individual Subjects ............................................................................................ 41 
17 
Treatment Plan and Procedures .................................................................................................................. 42 
17.1 
Subject Identification ............................................................................................................................... 42 
17.2 
Randomization and Treatment Assignment ............................................................................................ 42 
18 
Investigational Product(s) ............................................................................................................................ 42 
18.1 
Description of AP1189 Investigational Product ....................................................................................... 43 
18.1.1 
Nomenclature .................................................................................................................................. 43 
18.1.2 
Drug Substance ................................................................................................................................ 43 
18.1.3 
Basic physical and chemical Characteristics .................................................................................... 43 
18.2 
Packaging and Labeling ............................................................................................................................ 43 
18.3 
Drug Supplies ........................................................................................................................................... 44 
18.3.1 
Drug Accountability ......................................................................................................................... 44 
18.3.2 
Storage and Handling ...................................................................................................................... 45 
18.4 
Administration and handling of Study Drug ............................................................................................ 45 
18.5 
Blinding .................................................................................................................................................... 45 
18.5.1 
Blinding of Investigational Product.................................................................................................. 45 
18.5.2 
Breaking the Blind............................................................................................................................ 46 
19 
Prior and Concomitant Medication ............................................................................................................. 46 
19.1 
Permitted Medicines ............................................................................................................................... 46 
19.1.1 
Methotrexate (MTX) ........................................................................................................................ 46 
19.1.1.1 
MTX Treatment Instruction in Case of Elevation in Liver Enzymes ......................................... 46 
19.1.2 
Folic Acid .......................................................................................................................................... 47 
19.1.3 
Oral Corticosteroids ......................................................................................................................... 47 
19.1.4 
Nonsteroidal anti-inflammatory Drugs (NSAID) .............................................................................. 47 
19.1.5 
Non-NSAID Analgesics ..................................................................................................................... 47 
19.2 
Prohibited Medicines............................................................................................................................... 47 
19.3 
Rescue Treatment.................................................................................................................................... 48 
19.4 
Treatment Compliance ............................................................................................................................ 48 
20 
Schedule of Visits ......................................................................................................................................... 48 


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20.1 
Visits ........................................................................................................................................................ 50 
20.1.1 
Visit 1, Screening (up to 14 days prior to the Baseline Visit) ........................................................... 50 
20.1.2 
Visit 2, the Baseline Visit (Day 0) ..................................................................................................... 51 
20.1.3 
Visit 3, 1. Week treatment Visit ....................................................................................................... 51 
20.1.4 
Visit 4, 2. Week treatment Visit ....................................................................................................... 52 
20.1.5 
Visit 5, 3. Week treatment Visit ....................................................................................................... 52 
20.1.6 
Visit 6, 4. Week treatment Visit ....................................................................................................... 53 
20.1.7 
Visit 7, One-week post-treatment ................................................................................................... 53 
20.1.8 
Final safety Follow-up Call and EOS ................................................................................................. 54 
21 
Assessments, procedures, and Examinations.............................................................................................. 54 
21.1 
Safety Assessments ................................................................................................................................. 54 
21.1.1 
Medical History ................................................................................................................................ 54 
21.1.2 
Prior and Concomitant Medication ................................................................................................. 55 
21.1.3 
Pregnancy Test ................................................................................................................................ 55 
21.1.4 
Physical Examination ....................................................................................................................... 55 
21.1.5 
Height and Weight ........................................................................................................................... 55 
21.1.6 
Vital Signs ......................................................................................................................................... 55 
21.1.6.1 
Blood pressure, Heart, and Respiratory Rate .......................................................................... 56 
21.1.7 
Lead Electrocardiographic Evaluation ............................................................................................. 56 
21.1.8 
X-ray ................................................................................................................................................. 56 
21.1.9 
Laboratory Assessments .................................................................................................................. 57 
21.1.9.1 
Hematology ............................................................................................................................. 57 
21.1.9.2 
MC1R genotype analysis .......................................................................................................... 57 
21.1.9.3 
Biochemistry ............................................................................................................................ 57 
21.1.9.4 
Thyroid function ...................................................................................................................... 58 
21.1.9.5 
Urinalysis.................................................................................................................................. 58 
21.1.9.6 
Serology ................................................................................................................................... 58 
21.1.9.7 
Safety (AE and SAE) ................................................................................................................. 58 
21.2 
Safety Assessments (Sub-study, only Part 2) ........................................................................................... 58 
21.3 
Efficacy Assessments ............................................................................................................................... 58 
21.3.1 
Swollen Joint Count (SJC) and Tender Joint Count (TJC) ................................................................. 58 
21.3.2 
Clinical Disease Activity Index (CDAI) .............................................................................................. 59 
21.3.3 
Disease Activity Score 28 (DAS28) ................................................................................................... 59 


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21.3.4 
Physician’s Global Assessment of Disease Activity VAS (“Investigator Global VAS”) ...................... 60 
21.3.5 
Patient’s Global Assessment of Disease Activity VAS (“Patient Global VAS”) ................................. 60 
21.3.6 
Patient’s Assessment of Pain VAS (“Patient Pain VAS”) .................................................................. 60 
21.3.7 
Quality of Life and Physical Function ............................................................................................... 60 
21.3.7.1 
Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) ........................... 60 
21.3.7.2 
Health Assessment Questionnaire – Disability Index (HAQ-DI) ............................................... 60 
21.3.8 
American College of Rheumatology Response Rates ...................................................................... 60 
21.4 
Pharmacokinetic Assessments ................................................................................................................ 60 
21.4.1 
PK Sample Collection ....................................................................................................................... 61 
21.5 
Cytokine Samples .................................................................................................................................... 61 
21.6 
Biobanking ............................................................................................................................................... 61 
21.7 
Total Volume of Blood ............................................................................................................................. 61 
22 
Safety ........................................................................................................................................................... 62 
22.1 
Definitions ............................................................................................................................................... 62 
22.2 
Severity Classification .............................................................................................................................. 63 
22.3 
Relationship to Study Drug ...................................................................................................................... 64 
22.4 
Reporting Procedures of Adverse Events ................................................................................................ 64 
22.5 
Reporting Procedures for Serious Adverse Events .................................................................................. 65 
22.6 
Reporting of SAE and SUSAR to the Competent Authorities ................................................................... 65 
22.7 
Expedited Reporting ................................................................................................................................ 65 
22.8 
Contraception and Pregnancy ................................................................................................................. 66 
22.8.1 
Additional Reporting Requirements for Pregnancies ...................................................................... 66 
23 
Statistical Considerations and Methods ...................................................................................................... 66 
23.1 
General Considerations ........................................................................................................................... 67 
23.2 
Determination of Sample Size ................................................................................................................. 67 
23.2.1 
Main study ....................................................................................................................................... 67 
23.2.2 
Sub-study ......................................................................................................................................... 67 
23.3 
Study Participant Characteristics ............................................................................................................. 67 
23.4 
Safety Analysis ......................................................................................................................................... 68 
23.5 
Efficacy Analysis ....................................................................................................................................... 68 
23.5.1 
Analysis of Primary Efficacy Endpoints ............................................................................................ 68 
23.5.2 
Analysis of Secondary Efficacy Endpoints ........................................................................................ 68 
23.5.3 
Analysis of Tertiary Efficacy Endpoints ............................................................................................ 68 


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23.5.4 
Analysis of other Endpoints (if applicable) ...................................................................................... 69 
23.6 
Pharmacokinetic Analyses ....................................................................................................................... 69 
23.7 
Interim Analyses ...................................................................................................................................... 69 
24 
Data Management and Quality Assurance .................................................................................................. 69 
24.1 
Subject Records and Source Data ............................................................................................................ 69 
24.1.1 
Record Retention ............................................................................................................................. 69 
24.1.2 
Source Documents ........................................................................................................................... 70 
24.1.3 
Electronic Case Report Form ........................................................................................................... 70 
24.1.3.1 
Case Report Form Completion ................................................................................................ 70 
24.1.3.2 
Missing Data ............................................................................................................................ 71 
24.2 
Storage and Archiving .............................................................................................................................. 71 
24.3 
Monitoring and Quality Control/Assurance ............................................................................................ 71 
24.4 
End of Trial ............................................................................................................................................... 72 
24.5 
Audit and Inspections .............................................................................................................................. 72 
24.6 
Data processing and quality Control ....................................................................................................... 72 
25 
Data Confidentiality ..................................................................................................................................... 73 
25.1 
Documentation of Subject’s Participation............................................................................................... 73 
25.2 
Data Protection........................................................................................................................................ 73 
25.2.1 
Processing of personal Data ............................................................................................................ 73 
26 
Regulatory Requirements ............................................................................................................................ 74 
26.1 
Institutional Review Board/Independent Ethics Committee .................................................................. 74 
26.1.1 
Updated Documents ........................................................................................................................ 74 
26.2 
Ethical Conduct of the Study ................................................................................................................... 74 
26.3 
Informed Consent .................................................................................................................................... 75 
26.4 
Subject Confidentiality ............................................................................................................................ 76 
26.5 
Investigator Signatory Obligations .......................................................................................................... 76 
27 
Administrative and legal obligations ........................................................................................................... 76 
27.1 
Compensation to Investigator ................................................................................................................. 76 
27.2 
Publication Policy ..................................................................................................................................... 77 
27.3 
Insurance Information ............................................................................................................................. 77 
27.4 
Compensation to Subjects ....................................................................................................................... 77 
28 
References ................................................................................................................................................... 78 
29 
Appendices .................................................................................................................................................. 81 


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29.1 
Appendix A: Informed Consent Procedure .............................................................................................. 81 
29.2 
Revision History ....................................................................................................................................... 82 
29.2.1 
Protocol Version 8.0 to Protocol Version 9.0 .................................................................................. 82 
Protocol Version 7.0 to Protocol Version 8.0 .................................................................................................. 83 
29.2.2 
Protocol Version 6.0 to Protocol Version 7.0 .................................................................................. 83 
29.2.3 
Protocol Version 5.0 to Protocol Version 6.0 .................................................................................. 85 
29.2.4 
Protocol Version 4.0 to Protocol Version 5.0 .................................................................................. 87 
29.2.5 
Protocol Version 3.0 to Protocol Version 4.0 .................................................................................. 87 
29.2.6 
Protocol Version 2.0 to Protocol Version 3.0 .................................................................................. 87 
 
 
 


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7 PROTOCOL SYNOPSIS 
Protocol title 
A double-blind, multi-center, two-part, 
randomized, placebo-controlled study of the 
safety, tolerability, and efficacy of 4 weeks of 
treatment with AP1189 in early rheumatoid 
arthritis (RA) patients with active joint disease 
Protocol no 
SynAct-CS002 
Clinical phase 
IIa 
Estimated study duration 
Study duration: 18 months 
Study participation for each subject is estimated 
to 10 weeks  
Study design 
 
A multicenter, two-part, randomized, double-
blind, placebo-controlled, 4-week study with 
repeated doses of AP1189. The study population 
will consist of newly diagnosed subjects with 
severe active RA (CDAI (Clinical disease activity 
score) > 22) who are to start up-titration with 
methotrexate (MTX). 
Part 1: The subjects will be randomized into:   
• 
Group A: AP1189 dose 50 mg (min. 8 
subjects) or 
• 
Group B: placebo (min. 4 subjects) 
Steering Committee (SC) meeting 
• 
Group C: AP1189 dose 100 mg (min. 8 
subjects) or  
• 
Group D: placebo (min. 4 subjects) 
INTERIM ANALYSIS 
Part 2: All subjects will be randomized into either 
design 1, 2 or 3 based on data from the interim 
analysis.  
• 
Design 1: AP1189 dose 50 mg (44 subjects) 
or placebo (22subjects) plus MTX (10-25 mg) 
weekly 
• 
Design 2: AP1189 dose 100 mg (44 subjects) 
or placebo (22 subjects) plus MTX (10-25 mg) 
weekly 
• 
Design 3: Continue with the same doses as in 
Part 1, in a 1:1:1 ratio (AP1189 50 mg (22 
subjects), AP1189 100 mg (22 subjects) or 


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placebo (22 subjects)) plus MTX (10-25 mg) 
weekly 
Study sites 
The study is to be conducted at sites in Europe 
and Moldova 
Treatment duration 
Multiple dose administration consisting of once-
daily dosing from Day 1 to Day 28, preceded by a 
screening period of up to 2 weeks before the 
first dosing. A 4 weeks safety follow-up period 
will follow the last dose administration  
Study population 
Subjects with severe active RA, defined as CDAI > 
22, who are about to begin up-titration with 
MTX 
Study objectives 
 
 
Primary safety objective: 
• 
To compare the safety of AP1189 against 
placebo by evaluating adverse events 
(AEs), serious adverse events (SAEs), and 
laboratory abnormalities 
Primary efficacy objective: 
• 
Effect of AP1189 vs. placebo in subjects 
with severe active RA (CDAI > 22), 
undergoing up-titration with MTX, by 
showing a change in CDAI from severe 
(CDAI > 22) to moderate (CDAI ≤ 22) 
after 4 weeks treatment compared to 
baseline  
Secondary efficacy objectives: 
To compare the effects of AP1189 against 
placebo by assessing: 
• 
Proportion of subjects achieving a 
reduction of more than 10 (ten) swollen 
and/or tender joints at week 4 
compared to baseline 
• 
Proportion of subjects achieving a 
change in CDAI score at week 4 
compared to baseline 
o Proportion of subjects with a 5-
point decrease 
o Proportion of subjects with a 10-
point decrease 
o Proportion of subjects with a 15-
point decrease 
• 
Proportion of subjects achieving a 
change in value to ≤ 3.2 as measured by 


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DAS28 (disease activity score 28) at 
week 4 compared to baseline 
• 
Change in subject-reported quality of life 
(using Health Assessment Questionnaire 
– Disability Index (HAQ-DI)) at week 4 
compared to baseline 
• 
Change in subject-reported fatigue 
(using Functional Assessment of Chronic 
Illness Therapy [FACIT]-Fatigue) at week 
4 compared to baseline 
• 
Proportion of subjects achieving ACR 
(American College of Rheumatology) 
response assessed by ACR 20, ACR 50, 
and ACR70 
Tertiary objectives: 
Effect of AP1189 compared to placebo at week 4 
compared to baseline on inflammatory and 
collagen destructive biomarkers. The biomarkers 
include: 
• 
CXCL13 (chemokine ligand 13) 
• 
IL-1β (interleukin 1 beta) 
• 
IL-6 (interleukin 6) 
• 
IL-10 (interleukin 10) 
• 
TNF-α (tumor necrosis factor alpha) 
 
Arthroscopy Sub-Study (only Part 2 at selected 
sites): 
• 
Effect of AP1189 compared to placebo 
on joint structures and inflammation as 
assessed by synovial biopsy at baseline 
and after 4 weeks treatment 
Investigation product 
AP1189 powder in bottle 
Reference product 
Placebo powder in bottle 
Main criteria for inclusion  
1. Written informed consent has been 
obtained prior to initiating any study specific 
procedures  
2. Male and female subjects, 18 to 85 years of 
age 
3. Confirmed diagnosis of RA according to the 
2010 ACR/EULAR RA classification criteria  
4. Arthritis with joint swelling and tenderness 
of a minimum of three joints out of 68 joints 
tested 
5. Candidate for MTX treatment 
6. Is about to begin treatment with MTX 


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7. Tested positive for anti-Cyclic Citrullinated 
Peptide (anti-CCP) or rheumatoid factor (RF) 
8. Severe active RA (CDAI > 22) at screening 
and baseline 
9. Negative QuantiFERON-in-Tube test (QFG-IT) 
(Mantoux test can be used if QFG-IT is not 
possible) 
10. Subjects should be able to complete (read 
and write) the Patient-Reported Outcome 
questionnaires (PRO questionnaires) 
11. Females of child-bearing potential may only 
participate if using reliable means of 
contraception (for detailed information see 
section 17.8) or are post-menopausal 
(menstrual periods stopped at least 12 
months ahead of the enrolment in the trial) 
Surgically sterilized women at least 6 months 
prior to screening 
12. Females of childbearing potential must have 
a negative pregnancy test at screening and 
baseline 
Exclusion criteria 
1. Participation in any other study involving 
investigational drug(s) within 4 weeks prior 
to study entry 
2. Major surgery (including joint operation) 
within 8 weeks prior to screening or planned 
surgery within 1 month following 
randomization 
3. Rheumatic autoimmune disease other than 
RA, including systemic lupus erythematosus 
(SLE), mixed connective tissue disease 
(MCTD), scleroderma, polymyositis, or 
significant systemic involvement secondary 
to RA (e.g., vasculitis, pulmonary fibrosis or 
Felty’s syndrome). Sjögren’s syndrome with 
RA is allowable 
4. Functional class IV as defined by the ACR 
Criteria for Classification of Functional Status 
in RA or wheelchair/bedbound 
5. Prior history of or current inflammatory joint 
disease other than RA (e.g., gout, reactive 
arthritis, psoriatic arthritis, seronegative 
spondyloarthropathy, Lyme disease) 
6. Subjects with fibromyalgia 
7. Initiation or change in dose for NSAIDs 
(including low-dose aspirin and COX-2 


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inhibitors) within 2 weeks prior to dosing 
with IMP 
8. Corticosteroids are prohibited within 2 
weeks prior to screening (and during the 
entire treatment period and until the final 
visit (Visit 7) 
9. Evidence of serious uncontrolled 
concomitant cardiovascular, nervous system, 
pulmonary (including obstructive pulmonary 
disease), renal, hepatic, endocrine (including 
uncontrolled diabetes mellitus), or 
gastrointestinal disease 
10. Have prior renal transplant, current renal 
dialysis, or severe renal insufficiency 
(determined by a derived glomerular 
filtration rate (GFR) using Cockcroft Gault 
formula of ≤30 ml/min/1,73m² calculated by 
the local lab) 
11. Uncontrolled disease states, such as asthma, 
psoriasis, or inflammatory bowel disease 
where flares are commonly treated with oral 
or parenteral corticosteroids 
12. Evidence of active malignant disease (except 
basal cell carcinoma of the skin that has 
been excised and cured) 
13. Pregnant women or nursing (breastfeeding) 
mothers 
14. History of alcohol, drug, or chemical abuse 
within the 6 months prior to screening 
15. Neuropathies or other painful conditions 
that might interfere with pain evaluation 
16. Body weight of >150 kg  
EXCLUSION CRITERIA 17-20 ONLY APPLY 
FOR SUBJECTS IN NORWAY: 
17. Evidence of moderate and/or severe organ 
dysfunction  
18. Abnormal chest x-ray (as per the discretion 
of the investigator) 
19. Evidence of positive hepatitis serology 
20. Evidence of peptic ulcer disease 
Sample size considerations 
The sample size is calculated to provide an 
acceptable precision of a 95% confidence 
interval for the primary endpoint, the mean 
change in CDAI from baseline.  
 


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8 INTRODUCTION AND RATIONALE 
8.1 
Introduction 
Inflammatory processes play a pivotal role in health and disease, not only in classical inflammatory diseases as 
arthritis and inflammatory bowel disease (IBD) but also in major lifestyle associated diseases as diabetes and 
atherosclerosis.   
Inflammatory processes consist of an acute phase induced by an injury where inflammation is initiated and 
dominated by proinflammatory reactions. The inflammation will subsequently either be resolved, and the 
system will go back to normal physiological status or alternatively develop further and enter into a more chronic 
phase. The chronic phase is dominated by irreversible and deleterious effects on tissues and organs and thus 
impact the overall body hemostasis.  
Until recently pro-resolving processes, i.e., processes that facilitate the restoring of a normal physiological 
steady state, have been considered passive. Most treatment concepts have been focusing on pro-inflammatory 
pathways and leucocyte recruitment, and thereby on the possibility to reduce the severity of the acute phase of 
the inflammation. The only major treatment concept available to reduce the severity in established 
inflammatory processes is the use of corticosteroids, which, unfortunately, do have several unwanted adverse 
effects when administrated in a daily dose regimen. 
8.2 
Resolution of Inflammation 
Today pro-resolving processes are considered active processes and the scientific field of resolution of 
inflammation (RoI) is one of the most promising fields of today´s inflammatory research. A key point within RoI 
is the identification of specialized pro-resolving mediators (SPM) signaling through specific receptors present in 
immune competent cells, including the white blood cells. 
A key feature of SPM is that they, besides the classic anti-inflammatory effects such as inhibition of pro-
inflammatory cytokine secretion and inhibition of neutrophils recruitment and infiltration, have specific effects 
on processes that stimulate RoI. Therefore, the most fundamental effect of SPM that discriminate them from 
classic anti-inflammatory mediators is SPM´s ability to stimulate non-phlogistic activation of macrophages, 
which means that SPM is able to stimulate macrophages to clear the inflammatory process from apoptotic 
neutrophils and microbial particles by efferocytosis. The result is that SPM can facilitate RoI and thereby speed 
up the processes that bring the system back to a normal physiological steady state and reduce the risk of 
developing chronic and thus treatment-resistant conditions1. 
An example of an endogen system playing a significant role in RoI is the melanocortin (MC) system, where the 
peptide α-melanocyte stimulating hormone (αMSH) is secreted from white cells and other immune competent 
cells and binds to MC receptors (MCRs) and thereby facilitates RoI. Consequently, the effects are mediated in a 
paracrine and autocrine fashion (i.e., signaling local within a tissue/organ by stimulation of adjacent cells or 
even the cells that secrete the SPM). 
The understanding of this system including the understanding of how to target the systems by use of an agonist 
to the MCRs makes the MC system a very attractive target for pharmaceutical development. 


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8.3 
The Melanocortin System 
The immune modulation effects of the MCs have been known for more than two decades. With the 
identification of specific receptors and the development of new analogues with improved properties over those 
of the natural agonist αMSH. Some development projects have been set up that aimed to use the potential of 
these peptides as anti-inflammatory and/or organ protective agents. Natural peptides, especially 
adrenocorticotrophic hormone (ACTH) and αMSH, as well as synthetic analogues as the AP1189 peptide, are 
anti-inflammatory and have organ protective effects in several in vivo models2. In addition, it has been shown 
that that MCs induce pro-resolving effects as phagocytosis and efferocytosis3, which gives new aspect for MC-
based therapy. 
8.4 
Melanocortin Receptors  
MC binds to MCRs. Five subtypes of MCRs have been described, all are G-coupled receptors, where the ability to 
stimulate cyclic adenosine monophosphate (cAMP) in the different subtypes of MCRs have been used to 
characterize the agonist's potency and specificity. They are described in the next sections (from Catania et al.4). 
A central role in the anti-inflammatory effects of MCR stimulation has been explained by the ability to inhibit 
activation of the transcriptions factor nuclear factor-kappa B (NFκB) and thereby the ability to inhibit synthesis 
and secretion of pro-inflammatory mediators. 
In addition to this classical cAMP-mediated pathway, MCR stimulation also has the potential to stimulate other 
pathways associated with extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation, and intracellular 
calcium (Ca2+) mobilization5. In a broader aspect, this raises the possibility that MCRs shows functional 
selectivity, alternatively called biased agonism, i.e., that the MCRs exists in different active conformations, each 
one creating a distinct signal yielding to multiple functional outcomes. If this is the case, then it could potentially 
be possible to identify compounds that would be able to induce the classical cAMP pathway and not ERK1/2 
phosphorylation, and intracellular Ca2+ mobilization and other compounds stimulating ERK1/2 phosphorylation, 
and intracellular Ca2+ mobilization, but not cAMP generation.  
8.4.1 
MC1 Receptor (MC1R) 
MC1R was the first member of the MCR gene family to be cloned. The cloned complementary deoxyribonucleic 
acid (cDNA) encoded a 317-amino acid protein with the transmembrane topography characteristic of receptors 
that couple to heterotrimeric G proteins. αMSH/MC1R interactions contribute to regulation of skin physiology 
and melanogenesis6. Binding of αMSH to its MC1R in melanocytes starts a signal cascade that activates adenylyl 
cyclase, increases intracellular cAMP, and induces activity of tyrosinase, the rate-limiting enzyme in the 
eumelanin synthetic pathway7, 8. MC1R messenger ribonucleic acid (mRNA) in the skin is up-regulated by its own 
melanocortin ligands and by endothelin-19. Furthermore, MC1R expression appears to be regulated by the 
microphthalmia-associated transcription factor (MITF). This transcription factor belongs to the family of bHLH-LZ 
(basic helix-loop-helix leucine zipper) type transcription factors and promotes transcription of genes for 
melanogenesis-related enzymes such as tyrosinase. It is clear that MC1R functions extend well beyond 
regulation of melanogenesis. MC1R expression occurs in macrophage/monocytic cells, lymphocytes with 
antigen-presenting and cytotoxic functions, neutrophils, endothelial cells, astrocytes, and fibroblasts. Peripheral 
blood-derived dendritic cells were likewise found to express. Transactivation of MC1R in inflammatory cells 
causes marked reduction of activation and translocation to the nucleus of the transcription factor NFκB 10. 
Consequently, there are marked anti-inflammatory effects exerted through inhibition of NFκB -mediated 


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transcription. Although receptor density in inflammatory cells is less than that in melanocytes, it appears that 
receptor affinity is much greater.  
8.4.2 
MC2 Receptor (MC2R) 
MC2R, also known as ACTH receptor, is selectively activated by adrenocorticotropic hormone. The ACTH 
receptor/MC2R gene was originally isolated by homology screening of human cDNA and genomic DNA libraries. 
The ACTH receptor gene encodes a 297-amino acid G protein-coupled receptor and shows the characteristic 
seven transmembrane spanning domains that form the ligand binding site. The physiological influences of ACTH 
on production and release of steroids by the adrenal cortex, their circadian variation, and stress-related 
fluctuations are mediated by MC2R11, 12. Binding of ACTH to its receptor stimulates adenylyl cyclase and induces 
increases in cell cAMP; this leads to activation of protein kinase A, which promotes expression of steroidogenic 
enzymes. In situ hybridization studies revealed dense expression of MC2R in the zona glomerulosa and zona 
fasciculata of the adrenal cortex13, the sites of mineralocorticoid and glucocorticoid production. The zona 
reticularis showed less mRNA labeling. MC2R expression in adrenal cells is upregulated by its ligand ACTH. In 
addition to the adrenal glands, the MC2R mRNA has been found in murine adipocytes, where it is believed to 
mediate stress-induced lipolysis in response to ACTH14. However, ACTH does not appear to regulate adipocyte 
function in humans and other primates, as human adipocytes lack expression of MC2R15.  
8.4.3 
MC3 Receptor (MC3R) 
MC3R gene encodes a G protein-linked receptor, coupled to both cAMP - and inositol 
phospholipid - Ca2+ - mediated signaling systems. The MC3R is the only MCR activated by MSH with potency 
similar to that of other. MC3R expression occurs in brain, placenta, and gut but not in melanoma cells or in the 
adrenal gland16. MC3R expression also occurs in the heart, in human monocytes, and in mouse peritoneal 
macrophages. A map of MC3R expression in the brain obtained by in situ hybridization showed abundant 
presence in the hypothalamus and limbic system, but signals for this receptor were also present in the septum, 
thalamus, hippocampus, and midbrain17. MC3R appears to participate in modulation of autonomic functions, 
feeding, and inflammation18. Hypotension and bradycardia elicited by the release of αMSH from the arcuate 
neurons appear to be mediated by MC3R and MC4R located in the medullary dorsal-vagal complex19. 
Participation of MC3R in energy homeostasis was disclosed in MC3R-deficient mice, which showed increased fat 
mass, reduced lean mass, and higher ratio of weight gain to food intake20. Recent data suggest that MC3R 
activation mediates protective influences of MC’s in myocardial ischemia/ reperfusion-induced arrhythmias in 
rats21. Furthermore, activation of MC3R has clear anti-inflammatory influences22.  
8.4.4 
MC4 Receptor (MC4R) 
MC4R was the second neural MCR to be cloned. Its affinity for the melanocortins has certain similarities with 
that of MC1R. The order of potency for activation of MC4R is αMSH = ACTH > βMSH >> γMSH. MC4R is a 332-
amino acid protein encoded by a single exon of 999 nucleotides. The rat homologous gene is 93% identical to 
the human gene23, which suggests that the gene is highly conserved in mammals. By the use Northern blot 
analysis and in situ hybridization techniques, MC4R was found primarily in the brain. The distribution of this 
receptor in the central nervous system is much broader than that of MC3R and includes the cortex, the 
thalamus, the hypothalamus, the brainstem, and the spinal cord24. Conversely, the MC4R was not detected in 
peripheral cells in an extensive study including 20 different tissues. Distribution of MC4R is consistent with its 
involvement in autonomic and neuroendocrine functions. Evidence that this receptor subtype regulates food 
intake and energy expenditure is based on gene-targeting in mice, which results in maturity-onset obesity, with 


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hyperphagia, hyperinsulinemia, and hyperglycinemia. Homozygous MC4R-deficient mice do not respond to the 
anorectic effects of αMSH. It appears, therefore, that αMSH inhibits food intake through activation of MC4R25. 
Mice with MC4R deficiency have enhanced caloric efficiency, like that observed in the agouti obesity syndrome 
and in the MC3R-null mice. Mice lacking both MC3R and MC4R are significantly heavier than those deficient in 
MC4R only, suggesting that the two receptors serve nonredundant functions in the regulation of energy 
homeostasis. Research also indicates that MC4R modulates erectile function and sexual behavior, possibly 
through neuronal circuitry in spinal cord erectile centers and somatosensory afferent nerve terminals of the 
penis26.  
8.4.5 
MC5 Receptor (MC5R) 
MC5R is similar to the MC1R and MC4R in its capacity to recognize αMSH and ACTH but not -MSH (αMSH ≥ 
ACTH >> -MSH). MC5R contributes to regulation of exocrine gland function and to certain immune responses. 
The MC5R was the last of the MCR gene family to be cloned. The human gene encodes for a protein of 325 
amino acids. MC5R is ubiquitously expressed in peripheral tissues. It occurs in the adrenal glands, fat cells, 
kidney, liver, lung, lymph nodes, bone marrow, thymus, mammary glands, testis, ovary, pituitary testis, uterus, 
esophagus, stomach, duodenum, skin, lung, skeletal muscle, and exocrine glands. Presence of MC5R in B- and T-
lymphocytes suggests a function in immune regulation. Indeed, data suggest that αMSH participates in B-
lymphocyte function via the activation of the Jak/STAT pathway, the intracellular phosphorylation pathway used 
by cytokines and growth factors, through specific binding to the MC5R. Furthermore, αMSH can induce CD25+ 
CD4+ regulatory T cells through the MC5R expressed on primed T cells27. Targeted disruption of the MC5R gene 
produced mice with a severe defect in water repulsion and thermoregulation caused by decreased production 
of sebaceous lipids28. High expression of MC5R occurs in multiple exocrine tissues, and the receptor is required 
for production of porphyrins by the Harderian gland and for protein and tear secretion by the lacrimal gland. 
These data suggest a coordinated system for regulation of exocrine gland function by melanocortin peptides; 
also, that the MC5R is the mediator of the sebotrophic activity of αMSH described in early studies29.  
8.4.6 
Anti-inflammatory Effects of Melanocortins 
The anti-inflammatory effects of MCs are exerted through inhibition of inflammatory mediators and by 
inhibition of inflammatory cell migration. MCs exert these effects in a variety of cells including monocytes, 
macrophages, subtypes of T-cells, endothelial cells, and epithelial cells. It is thought that the main pathway for 
the anti-inflammatory effect is through MC1R and MC3R stimulation.  
Most cell types responsive to the anti-inflammatory effect of MCs express the MC1R, i.e., monocytes, 
macrophages, neutrophils, mast cells, fibroblasts, dendritic cells, astrocytes, and microglia. Both human and 
murine macrophages among other cell types express the MC3R, and an increasing number of reports have 
identified MC3R mediated anti-inflammatory effects in vitro and in vivo in models of both acute and more 
sustained/chronic inflammation. Of specific interest are recent findings that anti-inflammatory effects on αMSH 
and other non-specific MCR agonists are absent in disease models in MC3R -/- mice, suggesting a profound role 
of MC3R in the anti-inflammatory effects of MCs. Furthermore, selective MC1R agonists have been shown to 
lack organ protective effects in models of ischemia-reperfusion including models of myocardial infarction. On 
the other hand, it has recently been shown that long term treatment of the selective MC1R agonists MS05 has 
beneficial effects in a model of nephrotic syndrome30. Consequently, anti-inflammatory intervention reaching 
the MC system should most likely be targeting both the MC1R and MC3R.  


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9 NON-CLINICAL STUDIES 
9.1 
Summary of pre-clinical Studies 
The non-clinical development program on AP1189, including toxicology and safety pharmacology studies, was 
conducted in accordance with the International Conference on Harmonization (ICH) Guideline entitled ‘Non-
Clinical Safety Studies for the Conduct of Human Clinical Trials for Pharmaceuticals’53. 
All relevant information on the methodologies and the study results are detailed in the Investigator Brochure. 
 
10 CLINICAL STUDIES 
10.1 Phase I Study Results 
In the phase I study, the first dose of AP1189 in healthy volunteers was administered in single ascending dosing 
using a suspension for oral administration (SynActCS001 Part I), in a bioequivalence study using oral suspension 
as well as tablets (SynActCS001 Part II) and in 14 days repeated dosing. Fourteen days repeated dosing was 
initiated using a tablet formulation (SynActCS001 Part III) and was completed (SynActCS001 Part IV) using the 
same suspension used in Part I.  
A total of 111 subjects were randomized: 104 young healthy male volunteers and eight (8) post-menopausal 
women. In Part I, 56 subjects received a single oral dose on one occasion (42 received AP1189 and 14 subjects 
received placebo).  In Part II, eight (8) subjects received one single AP1189 oral dose in three occasions 
separated by one-week wash-out. In Part III, eleven (11) subjects received a single oral dose daily for 14 days (8 
subjects received AP1189 and three (3) placebo) and finally in Part IV; thirty-six (36) subjects were treated with 
AP1189/ placebo once daily for 14 days (27 subjects received AP1189, and nine (9) received placebo). 
10.1.1 
Summary of Results from Phase I; Part I, II and III 
As planned per protocol, the study Part I and II were completed. Study Part I was a randomized, double-blind, 
placebo-controlled, single ascending dose study with AP1189 or placebo administered as an oral suspension. 
Seven male groups with healthy volunteers (48 males), and 1 female group with 8 healthy female post-
menopausal volunteers (defined by at least a two-year amenorrhea period and an FSH level >30 I.U/L.) received 
a single ascending dose with AP1189/ placebo administered as an oral suspension of IMP dissolved in SyrSpend 
ALKA in fasting conditions. The two first male groups were composed of 3 subjects receiving active and one subject 
placebo; the other groups consisted of 6 subjects receiving active IMP and two subjects receiving placebo. Forty-
eight (48) healthy male volunteers aged 19 to 39 years and eight (8) healthy postmenopausal female volunteers, 
aged 47 to 60 years were included.  
The male subjects were treated with oral suspensions with doses in the range of 15-800 mg active IMP (15 mg, 50 
mg, 100 mg, 200 mg, 400 mg, 600 mg, or 800 mg) or placebo. The females were treated with 400 mg active IMP 
or placebo suspensions.  
Pharmacokinetic (PK) results showed that in male subjects on the dose range 50 - 800 mg, AP1189 was rapidly 
absorbed with a median tmax (time at which the Cmax is observed) between 1 and 4 hours. The inter-individual 
variability was low to moderate for Cmax (maximum plasma concentration) and AUCs (area under the curve) (< 
36%). Mean t1/2 was near to 20 h (CV% < 20%). 


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Mean Vd/F was between 556 and 784 L with a CV% below 35% and mean CL/F was between 20.26 and 31.26 L/h 
with a CV% below 50%. 
In female subjects, after administration of 400 mg of AP1189, Cmax and AUCs were slightly increased compared to 
male subjects. The apparent clearance was lower in the female population (17.26 L/h) and the apparent volume 
of distribution was similar. However, statistically, no conclusion could be made on the gender effect. 
Twenty (20) subjects reported a total of 38 Treatment-Emergent Adverse Events (TEAEs). All TEAEs were of mild 
(27) or moderate (11) severity. No severe AEs nor serious AEs were reported during the study.  Twenty-two (22) 
of the 38 TEAEs were considered related to the study treatment: 21 of these events were after administration of 
200 to 800 mg AP1189, and one event was after the administration of placebo.  
The most frequent related TEAEs were gastrointestinal disorders (19 events reported by fourteen (14) subjects): 
nausea (7 events), abdominal pain (5 events), vomiting (3 events), diarrhea (2 events), abdominal distension (1 
event) and dyspepsia (1 event). The frequency of these related TEAEs increased with the dose. Nevertheless, the 
amount of vehicle in the suspension increased with the dose leading to a consistency and taste increase of the 
study medicine. This change of consistency and taste of the suspension could be involved in this effect. Amongst 
the TEAEs considered as not related, headache was reported by seven (7) subjects. Other TEAEs were sporadic.  
Some mean changes and individual abnormalities were observed on laboratory parameters, vital signs, and ECG 
parameters. Most of these changes and abnormalities were limited and considered as not clinically significant.   
A total of four (4) male subjects treated with active IMP had isolated increases in aminotransferases (no 
concomitant changes in alkalic phosphatases or bilirubin were reported). The increases, which reached up to 1.6 
above the normal upper value of ALT were observed in one (1) subject treated with 400 mg, two (2) subjects 
treated with 600 mg and one (1) subject treated with 800 mg. No increases in aminotransferases above the 
normal upper range were seen in placebo-treated subjects. 
No treatment-related changes in vital signs were observed.  
No AP1189 associated increases in QTcF (the corrected QT interval by Fredericia) nor changes in any other 
cardiac parameters were identified during continuous 24-hours 1000 HZ Holter ECG recording evaluation. 
Based on the safety evaluation, it can be concluded that the maximum tolerated dose (MTD) was not reached. 
At the maximum administrated dose (MAD) the exposure obtained was more than 10x above what is expected 
to be the exposure level for obtaining therapeutic efficacy. Therefore, it was decided not to continue to dose 
escalation above 800 mg. 
Study Part II was a comparative bioavailability study of an AP1189 tablet vs. the oral suspension with additional 
assessment of food effect following administration of the tablet, according to a three-way cross-over design. A 
200 mg AP1189 dose administered once as an oral suspension, and on two separate occasions as two 100 mg 
AP1189 tablets; once during fasting conditions and once after a high-fat breakfast were tested. The results 
following dosing with the suspension confirmed the findings from study part 1. Data from the administration of 
the tablet showed lower exposure with higher variability compared to data from the suspension.  
Based on results from the Study Part I and II, it was decided in Part III to investigate, daily doses of AP1189 
tablets of 100 mg (Group 1), 200 mg (Group 2) and 400 mg (Group 3) respectively. Part III was designed as a 


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randomized, double-blind, placebo-controlled, multiple ascending dose study with AP1189 administered as 
tablets.  
The pharmacokinetic (PK) results obtained in Group 1 of the Study Part III, after a 14-day repeated dose, showed 
a high and unpredicted degree of bioavailability both within and between subjects. Exposure judged on Cmax 
was seen in the span from below the limit of quantification (BLQ) up to levels expected to be more than three 
times the exposure expected to induce therapeutic effects. Consequently, it was decided by the sponsor to 
interrupt the study with the tablet formulation. 
Due to the good safety and PK results obtained with the oral suspension in the Study Part I, the sponsor decided 
to amend the study by adding a Part IV to the study that was identical to Study Part III but conducted with the 
oral suspension in fasting conditions, allowing to evaluate properly study objectives.         
10.1.2 
Summary of Result from Part IV  
Study Part IV was a randomized, double-blind, placebo-controlled, repeat dose study with AP1189 or placebo 
administered as an oral suspension given once daily for 14 days. Three cohorts of 12 subjects (9 on active; 3 on 
placebo) each were dosed with the same formulation as used in part 1 of the study. The dose levels tested were 
50mg, 100mg or 200 mg with matching placebo. 
10.1.3 
PK, Part IV Cohort 1 
The dose was 50 mg once daily.  
The detailed PK report supports this data. Cmax was observed between 1- and 2.5-hours post-dose regardless of 
the day of dosing. Steady state was achieved on Day 7 with Cmax around 180 ng/mL, which is expected to be the 
exposure level needed to induce efficacy. 
10.1.4 
PK, Part IV Cohort 2 
The dose was 100 mg once daily. 
The PK analysis showed a steep increase in the plasma concentration, as expected, and reached Cmax around 400 
ng/ml at steady state, i.e., a peak increase by approximately 2-fold, when compared to findings in cohort 1. 
10.1.5 
PK, Part IV Cohort 3 
The dose was 200 mg once daily. 
As for the two other cohorts, Cmax was reached within 1-2 hours post dosing. Cmax levels reached up to 900 ng/ml 
(group average) with the highest measured level of 1.300 ng/ml. As the expected peak exposure needed to 
induce therapeutic efficacy is expected to be around 170-180 ng/ml, the exposure at the 200 mg dose levels, 
based on Cmax is up 5x and for the individual with the highest exposure more than 7x expected therapeutic 
range.  
Based on the PK profile obtained in part 4 of the study, the effective dose using the AP1189 in SyrSpend ALKA 
would be expected to be around 50 mg.  


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10.1.6 
Safety Conclusion from Part 4 
Fourteen (14) subjects reported a total of 35 Treatment-Emergent Adverse Events (TEAEs). All TEAEs were of 
mild (27) or moderate (8) severity. No severe AEs nor serious AEs were reported during the study.  Four (4) of 
the 35 TEAEs were considered possibly related to the study treatment. These 4 events were all related to 
gastrointestinal disorders were seen after administration of the investigational drug (two (2) in the same subject 
at the 50 mg dose level (one episode of diarrhea and one episode of abdominal cramp, two (2) in the same 
subject at the 200 mg dose level (one episode of nausea and one episode of vomiting). Amongst the TEAEs 
considered as not related, headache was reported by nine (9) subjects, seven (7) treated with the investigational 
drug and two (2) treated with placebo. Other TEAEs were sporadic.  
Some mean changes and individual abnormalities were observed on laboratory parameters, vital signs, and ECG 
parameters. Most of these changes and abnormalities were limited and considered as not clinically significant. 
The QTcF evaluation from continuous 1000 Hz Holter ECG recording performed on day 14 and compared t Day-1 
(baseline) is still ongoing based on exposure/response statistical analysis as recommended by Agencies in FIH. 
No individual QTcF clinically significant values were observed at any time of this study part in repeated standard 
12 lead safety ECG. 
A total of five (5) subjects all included in Cohort 3 (200 mg), three (3) treated with active and two (2) treated 
with placebo had isolated increases in aminotransferases (no concomitant changes in alkalic phosphatases or 
bilirubin were reported). The increases were most pronounced in the subjects treated with active where the 
increase reached up to 3.6x and 2.9x above the normal upper value (ALT). All values returned to normal 
following completion of the study.  
Based on the safety evaluation, it can be concluded that MTD was not reached. At the maximum administrated 
dose (MAD) the exposure obtained 5x above what is expected to be the exposure level for obtaining therapeutic 
efficacy. Therefore, it was decided not to continue to dose escalation above 200 mg daily. 
 


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Consequently, AP1189 present a good safety profile allowing its administration to patients at 50 mg or 100 mg 
doses for four weeks. 
Additional information regarding AP1189, including its physicochemical properties and the results of in vitro and 
in vivo non-clinical studies of its pharmacology, pharmacokinetics, and toxicology, is presented in the IB.  
 
11 INDICATION 
11.1 Rheumatoid Arthritis 
Rheumatoid arthritis (RA) is a progressive, systemic autoimmune disease characterized by inflammation of the 
synovium leading to irreversible destruction and disability of the joints and adverse psychological effects. RA 
patients have fatigue, anemia, and osteopenia. Rheumatoid arthritis primarily affects women with twice the 
rate compared with men and the prevalence of RA is approximately 0.5-1 % of the population of developed 
regions with a 4-fold higher frequency in women than in men31. There is considerable evidence for both genetic 
and environmental contributions and a peak incidence of onset between 40 and 60 years of age32.  
Conventional RA therapy consists of treatment with NSAIDs, corticosteroids, and disease-modifying anti-
rheumatic drugs (DMARD). MTX represents one of the most widely used DMARD for RA, yet less than half of the 
patients with RA show substantial and sustained clinical improvement in disease signs and symptoms33.  
Interleukin-6 (IL-6) is a proinflammatory, multifunctional cytokine produced by a variety of cell types. IL-6 is 
involved in such diverse processes as T-cell activation, B-cell differentiation, induction of acute phase proteins, 
stimulation of hematopoietic precursor cell growth and differentiation, promotion of osteoclast differentiation 
from precursor cells, proliferation of hepatic dermal and neural cells, bone metabolism, and lipid metabolism34, 
35, 36, 37, 38. IL-6 has been implicated in the pathogenesis of a variety of diseases including autoimmune diseases, 
osteoporosis, neoplasia, and aging34, 35. IL-6 exerts its effects through a ligand-specific receptor (IL-6R) present 
both in soluble and membrane-expressed forms. 
Elevated IL-6 levels have been reported in the serum and synovial fluid of RA patients, indicative of production 
of IL-6 by the synovium39, 40. IL-6 levels correlate with disease activity in RA39, and clinical efficacy is accompanied 
by a reduction in serum IL-6 levels41. 
Despite the considerable list of approved treatments for RA, there are significant numbers of patients who do 
not achieve remission or indeed an adequate reduction in disease activity. 
11.2 AP1189, an anti-inflammatory lead Compound 
AP1189 is an oral available immune modulating compound with both anti-inflammatory and pro-resolving 
effects targeting the MC-system. Receptor pharmacology has defined AP1189 as a biased agonist on the MC1R 
and MC3R mediating its pharmacological effects through activation of the ERK1/2 pathway and by Ca2+ 
mobilization. Of specific interest is that AP1189 do not stimulate the cAMP pathway in relevant test systems and 
therefore through non-cAMP mediated pathways have the ability to induce anti-inflammatory and pro-resolving 
effects without inducing the unwanted side effect of pigmentation through cAMP stimulation in melanocytes. 


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Non-clinical data, generated on AP1189, indicates that this drug candidate can be further developed into a 
pharmaceutical product with unique properties in inflammatory diseases. Currently, there are no anti-
inflammatory drugs on the market with a mechanism of action like that of AP1189.  
AP1189 is, in contrast to peptide analogs of αMSH, oral available with a PK profile that gives the possibility to 
apply a once-daily dosing regimen in clinical development. 
11.3 Rationale for the Study 
The melanocortin as a target for immune modulation therapy is well described. The potential for classical 
agonist inducing anti-inflammatory and/or organ protective effects has been described in numerous 
publications over the last two decades and development programs aiming to bring compounds to market has 
been ongoing for the last decade. Among these projects is the AP124/ABT-719 program with a peptide agonist 
to the melanocortin peptides that have been dosed to more than 300 cardiac surgery patients at risk for 
developing post-operative loss of kidney function.  
In the US, the Acthar gel has now reached an annual sale of above 1.4 billion $. The active ingredient in the 
compound is ACTH. ACTH mode of action is two-fold, it stimulates glucocorticoid release from the adrenal 
glands, and it has direct anti-inflammatory effects on inflamed tissue/organs. The effects on the adrenal glands 
are mediated through the ACTH specific MC2R, whereas the direct anti-inflammatory effects are mediated 
through stimulation of MC1R and MC3R. Importantly there is increasing evidence that the MC2R mediated 
effects merely are unwanted side-effects (as skin pigmentation) of the ACTH derived therapy, which in any case 
limits the use of Acthar gel to the difficult to treat cases where standard treatment has shown to be insufficient. 
Acthar gel is used for nephrotic syndrome, multiple sclerosis, and rheumatoid diseases, where the effects of the 
compound are significant, even though the compound is limited to treat difficult cases.  Consequently, 
compounds directly targeting the MC1R and MC3R without unwanted effects mediated through MC2R 
stimulation would be an advantageous approach.  
Classical MCR agonists, as the endogen αMSH or the AP214/ABT-719 mentioned above, activate the MCRs 
through classical Gs-mediated pathways thereby inducing intracellular cAMP accumulation. Recent publications 
have shown that the MCRs can be activated not only to induce cAMP but also to induce ERK phosphorylation 
and intracellular Ca2+ mobilization. This quality allows for the identification of compounds that work as a biased 
agonist on the MCRs, i.e., compounds that do not stimulate cAMP but stimulate ERK phosphorylation and/or 
intracellular Ca2+ mobilization.  
AP1189 is an example of a compound working as a biased agonist on the MC1R and MC3R. The compound has 
the immune modulating effects comparable to the classical MCR agonist, but since it does not stimulate cAMP, 
the ability to stimulate melanocytes and thereby skin pigmentation is absent. The latter is potentially a major 
advantage compared to the classical MCR agonist (and ACTH) where the most undesirable side-effect is the 
induction of pigmentation following repeated dosing. 
AP1189 has shown efficacy in animal models of arthritis and IBD and its ability to treat membranous nephritis is 
currently being investigated. 
Therefore, it is hypothesized that AP1189 may be beneficial as a treatment for RA.  


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11.3.1 
Dose Selection 
In this study, the doses of 50 mg and 100 mg AP1189 are selected based on safety, tolerability, and 
pharmacokinetic results from the PH16028/SynAct-CS001 trial.  
Based on in vitro studies in disease models (see section 11.1.3.1.1 in the IB), it is hypothesized that the ideal 
plasma profile of the compound should induce a peak exposure of AP1189 around 170 ng/ml. As the compound 
is an agonist, where continued receptor activation could result in the development of tolerance, it is further 
hypothesized that the trough concentration of the compound, should be kept well below what is needed to 
induce maximal efficacy. The peak respectively trough concentrations identified in the repeated dose part of the 
Phase 1 study with AP1189 (PH16028/SynAct-CS001 trial) were during steady conditions as follows:  
   
C Max (mean +/- SD, N=9) 
C Trough (Mean +/- SD, N=9) 
50 mg once daily 
180 ± 38 ng/ml 
46 ± 14 ng/ml 
100 mg once daily 
427 ± 76 ng/ml 
100 ± 25 ng/ml 
200 mg once daily  
893 ± 198 ng/ml 
186 ± 45 ng/ml 
Based on the above assumption, the plasma profile following 50 or 100 mg once daily dosing fulfills the 
assumptions about both C max and C trough with 100 mg inducing a somewhat supratherapeutic exposure. 200 
mg, on the other hand, induce plasma levels with plasma concentrations, that based on the above assumption 
increased the likely hood to induce tolerance. 
Consequently, the dose levels to be used in the current study will be 50 and 100 mg. 
11.3.2 
Benefits and Risks of Participation 
The potential benefits of participation, for all subjects in this study, is close monitoring of their medical condition 
and safety. Those randomized to an active treatment may have a benefit of less pain in affected joints. Subjects 
randomized to placebo are not expected to obtain any additional benefit, beyond close monitoring of their 
medical condition and safety. 
Based on available non-clinical data, AP1189 appears to be well tolerated at dose levels that induce exposure 
well above the expected therapeutic level expected to be reached with CMax values around 175 ng/ml.  
The toxicology studies showed clinical signs from the gastrointestinal system (reduced appetite, vomiting, and 
loose stools), the central nervous system (subdued behavior). The clinical signs were most pronounced 
following iv dosing and thereby expected to be associated with high peak concentrations that hardly will be 
possible to reach following oral dosing. Further, AP1189 at high dose levels induced increased liver weight in 
rats and minipigs increased kidney weight in minipigs and increased the weight of the ovaries in female rats. 
Also, hypertrophy/hyperplasia of the thyroid glands was found to be most prominent in the rats. Follow-up 
studies in minipigs have identified that the treatment-induced increases liver weight was fully reversible 
following recovery associated with a fully reversible induction of phase I and phase II enzymes. Consequently, 
the liver findings are to be considered related to increased workload due to fully reversible phase 1 and phase 2 
enzyme induction. Likewise, the follicular thyroid hyperplasia in rats most likely is associated with increased 
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In Phase 1 clinical trials laboratory parameters of the thyroid gland, such as thyroid-stimulating hormone, as well 
as liver enzymes, has been evaluated to monitor any effect in humans. No treatment-related effects were 
identified on thyroid hormones. Regarding liver enzymes, temporal increases up to 1.5x the upper normal value 
was identified following single dosing at supratherapeutic doses (600 and 800 mg) in a few individuals. Likewise, 
increases in ALAT was identified following repeat dosing at the 200 ng/ml dose level where 3 out of 9 subjects 
showed increases above the normal upper level, where one measurement at one occasion reached 3x above the 
normal upper level. However, 2 out of 3 placebo-treated individuals in the same cohort of subjects did also show 
increases above the normal upper level. All increased in liver enzymes were without concomitant changes in 
alkalic phosphatases, and bilirubin, and all values returned to normal at the end of the study. Nevertheless, liver 
values should be carefully monitored in upcoming clinical trials, and any clinically significant increases in liver 
enzymes should be carefully assessed and assessed relative to the subjects’ pretreatment liver function and co-
medication.      
Studies on the compound’s ability to induce metabolic pathways in primary human hepatocytes have identified 
AP1189 as a weak inducer of CYP1A2 (also weak compared to omeprazole). Co-medication with compounds 
metabolized through the CYP1A2 pathway should therefore until further be avoided.   
The cardiovascular study in minipigs showed an increase in relative heart rate at the highest dose tested 
(80 mg/kg). Consequently, even if this study did not reveal any treatment-related effects on blood pressure and 
ECG parameters, particular attention has been applied to the heart in Phase 1 clinical study. Dedicated tendency 
analysis on continued ECG assessments was conducted after both single and multiple dosing in Phase 1. The 
analyses that included testing of changes in ECG following dosing with a positive control knowing to induce QT 
prolongation showed no treatment effects of AP1189 on ECG or heart rate. Consequently, AP1189 has shown 
excellent cardiovascular safety. 
Based on AUCs, the increase seems to be supra-proportional with an increase of 2.36 for AUC0-t and 2.17 for 
AUC0-∞ when dose increased by 2. However, in the light of the small sample size (N = 3 or N = 6) this result should 
be interpreted with caution. 
Around 10% of AP1189 dose was excreted unchanged in the urine in 24 h on the dose range 50 - 800 mg. Mean 
CLr ranged from 2.96 to 4.68 L/h. Consequently, until specific PK evaluation in patients with severe impaired 
kidney function has been conducted, subjects with stage 5 Chronic Kidney Disease or higher (i.e., eGFR < 30 
ml/min) should be excluded in clinical studies. 
Up to now, AP1189 has shown an excellent safety profile at all doses tested under the different conditions applied 
either in single or repeated administration for 14 days. As the maximum tolerated dose was not reached in Phase 
1 and as the exposure following repeat dosing of AP1189 given as oral suspension showed that the exposure at 
the highest dose tested reached up to 5x the expected therapeutic levels, it is considered appropriate and safe to 
continue dosing in clinical phase 2 at the 50 and 100 mg dose levels. 
The effect of food intake on the absorption of AP1189 in the current suspension formulation has not been 
systematically evaluated. However, it has been shown that the plasma profile of the compound, whether the first 
meal was served 1 hour or 4 hours post-dosing in the feasting state, is very similar. Further, it has been shown 
that intake of a glass of apple juice immediately after dosing does not reduce the absorption. Therefore, it is up 
to the subject whether they would like a glass of juice immediately after dosing.   


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Consequently, AP1189 present an excellent safety profile allowing its administration to patients at 50 mg or 100 
mg doses for 4 weeks.  
This study will provide additional safety and efficacy information on the benefit-risk profile of AP1189. 
 
12 OBJECTIVES 
12.1 Primary safety Objective 
• 
To compare the safety of AP1189 against placebo by evaluating AEs, SAEs, and laboratory abnormalities. 
12.2 Primary efficacy Objective 
• 
Effect of AP1189 vs. placebo in subjects with severe active RA (CDAI > 22), undergoing up-titration with 
MTX, by showing a change in CDAI from severe (CDAI > 22) to moderate (CDAI ≤ 22) after 4 weeks 
treatment compared to baseline. 
12.3 Secondary efficacy Objectives 
To compare the effects of AP1189 against placebo by assessing: 
• 
Proportion of subjects achieving a reduction of more than 10 (ten) swollen and/or tender joints at week 
4 compared to baseline 
• 
Proportion of subjects achieving a change in CDAI score at week 4 compared to baseline 
o Proportion of subjects with a 5-point decrease 
o Proportion of subjects with a 10-point decrease 
o Proportion of subjects with a 15-point decrease 
• 
Proportion of subjects achieving a change in value to ≤ 3.2 as measured by DAS28 at week 4 compared 
to baseline 
• 
Change in subject-reported HAQ-DI at week 4 compared to baseline 
• 
Change in subject-reported fatigue using FACIT-Fatigue at week 4 compared to baseline 
• 
Proportion of subjects achieving American College of Rheumatology (ACR) response assessed by ACR20, 
ACR50, and ACR70 
12.4 Tertiary Efficacy Objectives 
Effect of AP1189 compared to placebo at week 4 compared to baseline on inflammatory and collagen 
destructive biomarkers. The biomarkers include: 
• 
CXCL13 
• 
IL-1β 
• 
IL-6 
• 
IL-10 and TNF-α  


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12.4.1 
Arthroscopy sub-Study 
Effect of AP1189 compared to placebo on joint structures and inflammation as assessed by synovial biopsy at 
baseline and after 4 weeks treatment (only Part 2 at selected sites). 
 
13 SAFETY ENDPOINTS 
13.1 Primary Safety Endpoint 
The safety of AP1189 against placebo by evaluating adverse events (AEs), serious adverse events (SAEs), and 
laboratory abnormalities. 
14 EFFICACY ENDPOINTS 
14.1 Primary Efficacy Endpoint 
The change in CDAI after 4 weeks of treatment compared to baseline will be evaluated by assessing the 
following, by treatment group:  
• 
Mean change in CDAI from baseline to week 4 
• Proportion of subjects with a change in CDAI score from severe (CDAI > 22) to moderate (CDAI ≤ 22) at 
week 4 compared to baseline. 
14.2 Secondary Efficacy Endpoints 
The effects of AP1189 against placebo will be evaluated by assessing the following by treatment group: 
• 
Proportion of subjects achieving a reduction of more than 10 (ten) swollen and/or tender joints (SJC and 
TJC, summarized) at week 4 compared to baseline 
• 
Proportion of subjects achieving a change in CDAI score at week 4 compared to baseline 
o Proportion of subjects with a 5-point decrease 
o Proportion of subjects with a 10-point decrease 
o Proportion of subjects with a 15-point decrease 
• 
Proportion of subjects achieving a change in DAS28 from DAS28 >3.2 to DAS28 ≤ 3.2 at week 4 compared 
to baseline 
• 
Change of HAQ-DI at week 4 compared to baseline  
• 
Change of FACIT-Fatigue at week 4 compared to baseline 
• 
Proportion of subjects achieving ACR response assessed by ACR 20, ACR 50, and AC70 
14.3 Tertiary Efficacy Endpoints 
The effect of AP1189 compared to placebo at week 4 compared to baseline will be further evaluated by assessing 
the following by treatment group: 
• 
CXCL13, IL-1β, IL-6, IL-10, and TNF-α  
• 
Synovial biopsy at baseline and after 4 weeks treatment (only Part 2 at selected sites). 
 


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15 EXPERIMENTAL PLAN 
15.1 Study Design  
This study is a multicenter, two-part, randomized, double-blind, placebo-controlled, 4-week study with repeated 
doses of AP1189. The study population will consist of newly diagnosed subjects with severe active RA (CDAI > 
22) who are to start up-titration with MTX. A minimum of 90 subjects are expected to complete the study, plus 
45 subjects from Bulgaria and/or Moldova for a sub-study (see Section 15.2). Up to 120 subjects are planned to 
be enrolled for the main study to account for discontinuation rate, and up to 60 subjects for the sub-study. The 
rationale for the number of subjects required is outlined in the section on sample size determination. The below 
Figure 1 shows the general study design. 
Figure 1.: General study design (Part 1 and 2) 
Screening Period        
4-Weeks Treatment period 
                         2-Weeks Follow-up  
 
 
Screening  
Baseline 
1. 
Treatment 
Visit 
2. 
Treatment 
visit 
3.  
Treatment 
Visit 
4.  
Treatment 
Visit 
One-week 
Post-treatment 
Visit 
Safety 
Follow-up 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Phone call 
Days -14 to -1 
Day 0 
Day 7 ± 1        Day 14 ± 1      Day 21 ± 1     Day 28 ± 1              Day 35 ± 1         Day 56 ± 2         
15.2 Sub-study of subjects from Bulgaria/Moldova 
As Bulgaria and Moldova did not participate in Part 1 of the study, a sub-study has been added to investigate the 
effect in these two countries separately. In addition to analyzing the main study and the sub-study separately, 
all data will be pooled to investigate the overall effect in all participating countries. 
15.3 Part 1 (main study only) 
Following a successful screening evaluation, subjects who fulfill the enrollment criteria will be randomized in a 
2:1 ratio in group A and B. One group will receive active treatment, and the other group will receive a placebo. 
Before randomization into group C/D (the same 2:1 ratio between active and placebo), the SC will look at 
blinded safety data from group A/B.  
• 
Group A (min. 8 subjects): AP1189 dose 50 mg, once daily for 4 weeks (28 days) plus MTX (10-25 mg) 
weekly  
• 
Group B (min. 4 subjects): placebo for 4 weeks (28 days) plus MTX (10-25 mg) weekly 
SC Meeting 
• 
Group C (min. 8 subjects): AP1189 dose 100 mg, once daily for 4 weeks (28 days) plus MTX (10-25 mg) 
weekly  
• 
Group D (min. 4 subjects): placebo for 4 weeks (28 days) plus MTX (10-25 mg) weekly  
AP1189 or placebo 


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15.3.1 
Number of Subjects in Part 1 
A minimum of 24 subjects is expected to complete Part 1 of the study. About 32 subjects are planned to be 
enrolled in accounting for discontinuation rate.  
The rationale for the number of subjects required is outlined in the section on sample size determination. 
15.4 Part 2 
All subjects will be randomized into one design only, either design 1, 2, or 3 based on data from the interim 
analysis: 
• 
Design 1: AP1189 dose 50 mg (min. 44 subjects) or placebo (min. 22 subjects), once daily for 4 weeks (28 
days) plus MTX (10-25 mg) weekly  
• 
Design 2: AP1189 dose 100 mg (min. 44 subjects) or placebo (min. 22 subjects), once daily for 4 weeks (28 
days) plus MTX (10-25 mg) weekly 
• 
Design 3: Continue with the same doses as in Part 1, in a 1:1:1 ratio (AP1189 50 mg (min. 22 subjects), 
AP1189 100 mg (min. 22 subjects) or placebo (min. 22 subjects)) plus MTX (10-25 mg) weekly 
Following a successful screening evaluation, subjects who fulfill the enrollment criteria will be randomized 
accordingly.  
15.4.1 
Number of Subjects in Part 2 
A minimum of 66 subjects in the main study is expected to complete Part 2 of the study, and 45 subjects in the 
sub-study. About 88 subjects are planned to be enrolled in the main study in accounting for discontinuation 
rate, and about 60 subjects in the sub-study.  
The rationale for the number of subjects required is outlined in the section on sample size determination. 
15.5 Estimated Study Duration  
Total study duration is 18 months, and the study duration for each subject is approximately and up to 10 weeks.  
15.6 Number of Investigational Sites 
The study is to be conducted at sites in Europe and Moldova. 
15.7 Visits during the Study  
Subjects will have the following study visits: A Screening Visit (up to 2 weeks prior to baseline), a Baseline Visit 
(Day 0 visit), four visits during the treatment period (week 1, 2, 3 and 4) and the Follow Up Visit seven days after 
administration of the last study drug. Investigator or study nurse will make an End of Study (EOS) follow-up call 
to the subject four weeks after the subject took the last IMP to follow-up on outstanding safety issues (AE/ SAE). 
The study procedures for each visit are outlined in section 20. 
15.8 Steering Committee (SC) 
The SC is appointed by the sponsor and comprises of the coordinating investigators in Denmark, Sweden and 
Norway and a sponsor medical responsible person. 
All decisions made by the SC will be documented and signed by its members as per the SC Charter (a specific 
charter will be developed to define roles and responsibilities). 


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The SC will review blinded laboratory data from the first min. 12 subjects randomized into group A or B before 
the next min. 12 subjects in Part I, group C/D can be included and randomized.  
The SC will, based on the recommendations from the data monitoring committee (DMC), decide the design for 
Part 2. The SC will meet ad hoc. 
15.9 Data Monitoring Committee (DMC) 
The DMC is established by the sponsor and consists of a group of three study independent members: two 
independent external experts (a rheumatologist and a professor and specialist in hepatology and clinical 
pharmacology at Bispebjerg hospital), and an independent external statistician. A specific DMC charter will be 
developed to define roles and responsibilities. 
The DMC will review the unblinded data from the interim analysis of the first min. 24 subjects from Part 1. The 
DMC will recommend a study design for Part 2 to the SC based on these data. All recommendations will be 
documented and signed by the DMC members, and they will provide a summary of the safety and tolerability 
data obtained in Part 1 and their design recommendation for Part 2. 
The independent external statistician will analyze data for the interim analysis, following the procedure 
described in the statistical analysis plan and the protocol. The DMC will hereafter meet ad hoc as appropriate. 
15.10 Criteria for Choice of Design for Part 2 
The criteria for the choice of design 1, 2, or 3 for Part 2 are:  
Design 1: AP1189 dose 50 mg (min. 44 subjects) or placebo (min. 22 subjects) plus MTX (10-25 mg) will be 
applied if: 
• 
The efficacy, evaluated on the number of subjects showing reduced clinical score as defined in the 
protocol, is higher in the 50 mg group than in the 100 mg group. 
 
• 
The safety profile of group A and B (50 mg AP1189 or placebo) is superior to the safety profile of group 
C and D (100 mg AP1189 or placebo). 
The safety evaluation will focus on the number and the severity of the reported AEs and SAEs, on any 
laboratory findings with particular emphasis on liver and thyroid gland parameters, as well as vital 
signs. 
Design 2: AP1189 dose 100 mg (min. 44 subjects) or placebo (min. 22 subjects) plus MTX (10-25 mg) will be 
applied if: 
• 
The efficacy, evaluated on the number of subjects showing reduced clinical score as defined in the 
protocol, is higher in the 100 mg group than in the 50 mg group. 
  
• 
The safety profile of group C and D (100 mg AP1189 or placebo) is superior or comparable to the safety 
profile of group A and B (50 mg AP1189 or placebo). 
The safety evaluation will focus on the number and the severity of the reported AEs and SAEs, on any 
laboratory findings with particular emphasis on liver and thyroid gland parameters, as well as vital 
signs. 


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Design 3: Continue with the same doses as in Part 1, in a 1:1:1 ratio (AP1189 50 mg (min. 22 subjects), AP1189 
100 mg (min. 22 subjects) or placebo (min. 22 subjects)) plus MTX (10-25 mg) will be applied if: 
• 
The evaluation shows comparable safety profiles and comparable efficacy, evaluated on the number of 
subjects showing reduced clinical score as defined in the protocol, in the 50 and 100 mg groups. 
 
• 
The safety evaluation will focus on the number and the severity of the reported AE and SAE, on any 
laboratory findings with particular emphasis on liver and thyroid gland parameters, as well as vital 
signs. 
15.11 Stopping Rules 
In case of occurrence of a serious medical event (e.g., stroke, convulsion, etc.) or any SAE considered as related 
to the study drug, the DMC could decide to put the study on hold to unblind the study. After that, depending on 
the results of the unblinding, the study could either be stopped or continued. 
 
16 STUDY POPULATION 
The study population will consist of subjects with severe active RA, defined as CDAI > 22, who are about to begin 
up-titration with MTX.   
16.1 Subject Selection Criteria  
The study can fulfill its objectives only if appropriate subjects are enrolled. The following eligibility criteria are 
designed to select subjects for whom protocol treatment is considered appropriate. All relevant medical and 
non-medical conditions should be taken into consideration when deciding whether this protocol is suitable for a 
subject. 
16.2 Inclusion Criteria 
Subject eligibility should be reviewed and documented by an appropriately qualified member of the 
investigator’s study team before subjects are included in the study. The following are requirements for entry 
into the study. 
1. Written informed consent has been obtained prior to initiating any study specific procedures  
2. Male and female subjects, 18 to 85 years of age 
3. Confirmed diagnosis of RA according to the 2010 ACR/EULAR RA classification criteria  
4. Arthritis with joint swelling and tenderness of a minimum of three joints out of 68 joints tested 
5. Candidate for MTX treatment 
6. Is about to begin treatment with MTX 
7. Tested positive for anti-CCP or RF 
8. Severe active RA (CDAI > 22) at screening and baseline 
9. Negative QFG-IT (Mantoux test can be used if QFG-IT is not possible) 
10. Subjects should be able to complete (read and write) the PRO questionnaires 
11. Females of child-bearing potential may only participate if using reliable means of contraception (for 
detailed information see section 17.8) or are post-menopausal (menstrual periods stopped at least 12 


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months ahead of the enrolment in the trial). Surgically sterilized women at least 6 months prior to 
screening 
12. Females of childbearing potential must have a negative pregnancy test at screening and baseline. 
16.3 Exclusion Criteria 
Subjects meeting any of the following criteria are not eligible for participation in the study: 
1. Participation in any other study involving investigational drug(s) within 4 weeks prior to study entry 
2. Major surgery (including joint operation) within 8 weeks prior to screening or planned surgery within 1 
month following randomization 
3. Rheumatic autoimmune disease other than RA, including SLE, MCTD, scleroderma, polymyositis, or 
significant systemic involvement secondary to RA (e.g., vasculitis, pulmonary fibrosis or Felty’s 
syndrome). Sjögren syndrome with RA is allowable 
4. Functional class IV as defined by the ACR Criteria for Classification of Functional Status in RA or 
wheelchair/bedbound 
5. Prior history of or current inflammatory joint disease other than RA (e.g., gout, reactive arthritis, 
psoriatic arthritis, seronegative spondyloarthropathy, Lyme disease) 
6. Subjects with fibromyalgia 
7. Initiation or change in dose for NSAIDs (including low-dose aspirin and COX-2 inhibitors) within 2 weeks 
prior to dosing with the IMP 
8. Corticosteroids are prohibited within 2 weeks prior to screening (and during the entire treatment period 
and until the final visit (Visit 7) 
9. Evidence of serious uncontrolled concomitant cardiovascular, nervous system, pulmonary (including 
obstructive pulmonary disease), renal, hepatic, endocrine (including uncontrolled diabetes mellitus), or 
gastrointestinal disease 
10. Have prior renal transplant, current renal dialysis, or severe renal insufficiency (determined by a derived 
glomerular filtration rate (GFR) using Cockcroft Gault formula of ≤30 ml/min/1,73m² calculated by the 
local lab) 
11. Uncontrolled disease states, such as asthma, psoriasis, or inflammatory bowel disease where flares are 
commonly treated with oral or parenteral corticosteroids 
12. Evidence of active malignant disease (except basal cell carcinoma of the skin that has been excised and 
cured) 
13. Pregnant women or nursing (breastfeeding) mothers 
14. History of alcohol, drug, or chemical abuse within the 6 months prior to screening 
15. Neuropathies or other painful conditions that might interfere with pain evaluation 
16. Body weight of >150 kg.  
EXCLUSION CRITERIA 17-20 ONLY APPLY FOR SUBJECTS IN NORWAY: 
17. Evidence of moderate and/or severe organ dysfunction  
18. Abnormal chest x-ray (as per the discretion of the investigator) 
19. Evidence of positive hepatitis serology 
20. Evidence of peptic ulcer disease 
 


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16.4 Recruitment of Subjects 
It is intended that potential subjects for this study will be identified amongst patients referred to the clinic for 
further treatment and diagnosing. Potentially suitable subjects will be approached by the investigating team at 
the site to ascertain whether they would be interested in participating in the study. Interested subjects will be 
provided with an information sheet and undergo consenting procedures prior to any other study procedures.  
16.4.1 
Subject Participation Card 
A study participation card will be provided to each subject in the study. The card will indicate that the subject is 
participating in a clinical trial and give the name and contact details of the sponsor and the investigator/study 
site. The subjects will be asked to retain this card while they are participating in the trial and show it to any 
other medical practitioners they consult during this time. They will be advised to contact the investigator/study 
site if there are any questions. 
16.5 Withdrawal 
16.5.1 
Subject may decide to withdraw 
Subjects will be informed that they have the right to withdraw from the study at any time and for any reason 
without prejudice to his or her future medical care by the physician or the institution. 
Subjects who prematurely discontinued from the study will not be replaced. The date for premature 
discontinuation will be recorded in the subject's source documents and electronic Case Report Form (eCRF).  
If a subject is discontinued at any time after entering the study, the investigator should make a reasonable effort 
to ascertain the reason(s) while fully respecting the subject’s rights, as a subject is not obliged to give a reason(s) 
for withdrawing. The investigator or site personnel should make every effort to contact the subject to assess his 
or her status and complete the termination page on the eCRF. In the case of subject discontinuation, the 
procedures described for the End of Study will be applied, where possible.   
16.5.2 
Discontinuation of Individual Subjects 
The investigator may also withdraw a subject from the treatment or the study for any of the following reasons:  
• 
If a subject who does not meet enrolment criteria is inadvertently enrolled 
• 
Enrolment in any other clinical trial with a study drug 
• 
In case of severe worsening of symptoms, the investigator will be able to provide joint injections with 
corticosteroid as rescue medication. The use of local joint injections will be at the discretion of the 
investigator. The IMP/placebo treatment will continue as planned 
• 
If the subject, for any reason, requires treatment with another therapeutic agent (rescue medication not 
included) that has been demonstrated to be effective for treatment of the study indication, 
discontinuation from the study occurs prior to the introduction of the new agent  
• 
For medical or safety reasons 
• If a female becomes pregnant 
In case of early subject discontinuation and the reason for discontinuation (if it is known) will be registered in 
the eCRF and source documentation. 


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The sponsor can also decide to end the study for safety, regulatory, or other reasons consistent with applicable 
laws, regulations, and GCP. If the sponsor decides to stop the study, the subject should be informed of the 
reason hereof. 
 
17 TREATMENT PLAN AND PROCEDURES 
17.1 Subject Identification  
Each subject who signs the informed consent will be assigned a unique subject number (01-1001 site 1, 02-1001 
etc.), which will be used as the subject’s identification in the eCRF and on all source documentation throughout 
the study.  The screened subjects will be consecutively numbered, and the first available number, as listed in the 
eCRF, will be used. In the case of re-screening, a new screening number will be allocated. Subjects who are 
assigned a subject number but fails the randomization will be registered as a screen failure on the screening list 
and in the eCRF. 
17.2 Randomization and Treatment Assignment 
Following a successful screening evaluation, eligible subjects will be randomized into the study.  
Each subject will be assigned a unique randomization number in ascending order, based on a list provided by HB 
Medical, and assigned a protocol specified drug treatment. Randomization numbers should be assigned 
according to the list and should not be omitted or reused. 
An external statistician will prepare the randomization list and emergency code envelopes. The randomization 
list will be kept strictly confidential, filed securely by HB Medical (or designee), and accessible only to authorized 
persons per HB Medical’s Standard Operating Procedures (SOPs) until the time of unblinding. A copy of the list is 
sent to PharmaLex Denmark, who is handling the pharmacovigilance.  
The study treatment will be unknown to the Clinical Research Organization (CRO) and sponsor personnel 
associated with the study, all subjects, the investigator, and all site personnel except for the unblinded 
pharmacist(s) and personnel at HB Medical and the unblinded statistician responsible for preparing the 
randomization list.  
 
18 INVESTIGATIONAL PRODUCT(S) 
The individual study drug information is presented in the below tables. 
Table 1, Test Treatment  
Name 
AP1189 
Dosage strength 
50 mg, 100 mg  
Formulation 
Powder  
Route of 
Oral 
Supplier 
SynAct Pharma  
Table 2, Reference Treatment 


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Name 
Placebo 
Dosage strength 
0 mg 
Formulation 
Powder 
Route of 
Oral 
Supplier 
SynAct Pharma 
A description of the pharmaceutical properties and composition of the formulation of AP1189 is provided in the 
IB. 
18.1 Description of AP1189 Investigational Product 
18.1.1 
Nomenclature 
IUPAC: E-N-[trans-3-{1-(2-nitrophenyl)-1H-pyrrole-2-yl}-allylideneamino] guanidinium acetate 
Proprietary: AP1189 
18.1.2 
Drug Substance 
The substance is an acetic acid salt that appears as an odorless, yellow solid.  
➢ Structural formula 
 
➢ Molecular formula: C16H18N6O4 
18.1.3 
Basic physical and chemical Characteristics 
The molecular weight is 358.35 for the salt and 298.30 for the free base. 
18.2 Packaging and Labeling 
The sponsor (or designee) will provide HB Medical with study drug. IMP/placebo will be delivered the sites in 
bottles with screw caps and labeled following all applicable regulatory requirements and Good Manufacturing 
Practice Guidelines.  
The label on the box containing the bottles with IMP will include the following information:  
• 
Study number 
• 
AP1189/ placebo powder in bottle  
• 
Batch number 
• 
Randomization number 
• 
Expiry date 
• 
Storage conditions 
• 
Name and phone number of the responsible investigator 


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• 
Sponsor name and address 
• 
For clinical trial use only 
• 
Keep out of reach of children        
The label on the bottles containing AP1189/placebo, which is to be dispensed to subjects, will include the 
following information:  
• 
Study number 
• 
AP1189/ placebo powder in bottle  
• 
Randomization number 
• 
Batch number 
• 
Storage conditions 
• 
Name and phone number of the responsible investigator 
• 
Sponsor name and address 
• 
For clinical trial use only 
• 
Keep out of reach of children        
Labels on the box and the bottles will be in the local language.  
18.3 Drug Supplies 
After receipt of all required documentation, including written approval from the IEC/IRB and CA, HB Medical will 
supply sufficient study drug/ placebo for the clinical sites to conduct the study, as appropriate.  
18.3.1 
Drug Accountability 
The investigator at each site must maintain adequate records documenting the receipt, use, loss, or other 
disposition of drug supplies.  
The site pharmacist/study nurse (as appropriate per country) will verify that study drug supplies are received 
intact and in the correct quantities which will be documented by signing and dating the Proof of Receipt. The 
site pharmacist/study nurse will also sign and date a Proof of Receipt for the corresponding code envelopes. An 
accurate (running) inventory of study drug will be kept by the site and will include the batch number, date of 
receipt, subject number, date, and initials of the person who dispense the drug, and finally the date and amount 
of study drug each subject return to the site. A sample of the Drug Accountability Form, following instructions 
provided by the monitor, will also be provided to the site pharmacist/study nurse. Accountability of the study 
drug will be performed and verified by the monitor throughout the study duration.  
All unused IMP/placebo must be registered, accounted for, and returned to HB Medical or destroyed per 
instructions from SynAct Pharma and according to local regulations. The investigator, subinvestigator(s), and/or 
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18.3.2 
Storage and Handling 
The IMP/placebo will be stored in a secure limited access area in accordance with required storage conditions. 
The study pharmacist/investigator at each site will be responsible for the correct storage and handling of the 
study products.  
Both AP1189 and placebo should be stored at room temperature between +15°C and 25°C. All study drug must 
be protected from light and moisture. They should not be refrigerated or frozen.  
18.4 Administration and handling of Study Drug 
The study drug will be dispensed four times during a subject’s participation in Part 1 and Part 2 respectively; at 
the Baseline Visit, visit 2, visit 3 and at visit 4. The study drug will be in a box with 8 bottles (study drug for one 
week’s use) containing powder of either AP1189/placebo, a funnel, and a measuring cup.  
The subject adds 50 ml of tap water to the powder in the bottle, shakes well for about 1 minute allowing all 
powder to dissolve and then immediately drink the solution. The subject must rinse the bottle two times with 50 
ml water to ensure ingesting all the medicine in the bottle. Between each rinse, the content of the bottle is 
drunk. Each subject will use one bottle daily during the treatment period.  
The subjects will be instructed to take the suspension once daily in the morning about an hour before breakfast 
during the treatment period. It is up to the subject whether they would like to drink a glass of apple juice 
immediately after dosing. On the visit days, the medication should first be taken after blood sampling has been 
done.     
At the Baseline Visit, the subject will receive a diary to make daily records of what time the treatment is taken.  
The investigator or her/his designee is responsible for explaining the correct use of the study drug and the diary 
to each subject, and the subjects will receive a written instruction too.  
Subjects will be instructed to return empty bottles, unopened bottles, and the diary at each visit. 
The effect of food intake on the absorption of AP1189 in the current suspension formulation has not been 
systematically evaluated. However, it has been shown that the plasma profile of the compound, whether the 
first meal was served 1 hour or 4 hours post-dosing in the fasting state, is very similar. Further, it has been 
shown that intake of a glass of apple juice immediately after dosing does not reduce the absorption.  
18.5 Blinding 
18.5.1 
Blinding of Investigational Product 
This study is conducted under double-blind conditions primarily to minimize bias in the reporting, collection, and 
initial assessment of data.  
The investigator, study personnel, as well as sponsor personnel involved in the conduct of the study, will be 
blinded to the study medication. Except in the case of emergency, the study randomization codes will not be 
available to the above personnel until after the completion of the study and final data review.  
Emergency code envelopes, which each investigational site will receive every time they receive a new batch of 
IMP, will be kept in a secure environment at the individual study site. A code, which reveals the treatment 


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allocated for a specific subject, may in case of emergency be opened during the study if the choice of treatment 
depends upon it.  
18.5.2 
Breaking the Blind 
The study blind can be broken if, in the opinion of the investigator, it is in the subject's best interest to know the 
study drug assignment. SynAct Pharma must be notified before breaking the blind unless identification of the 
study drug is required for emergency therapeutic measures. If an emergency therapeutic measure is necessary 
which warranted breaking of the blind, SynAct Pharma must be notified within 24 hours of the blind being 
broken. The date and reason for blind breaking must be recorded in source documentation.  
 
19 PRIOR AND CONCOMITANT MEDICATION 
Prior medications and therapies are taken within 4 weeks prior to the Screening Visit. Concomitant medications 
are those medications, other than study drug, taken after the Screening Visit. Both prior medications, as well as 
concomitant medications, will be recorded in the eCRF by generic name. 
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, and/or herbal 
supplements) that the subject is receiving up to 4 weeks prior to screening or receives at any time during the 
study will to be recorded along with the reason for use, date(s) of administration including start and end dates, 
and dosage information including dose, route, and frequency.   
19.1 Permitted Medicines 
Permitted medications are any medications required per the medical history and not explicitly 
prohibited by the protocol during the trial. These standard of care medications are part of the subject’s previous 
treatment and will therefore not be provided by the sponsor. Any such medications prescribed or used should 
be recorded in the eCRF. 
19.1.1 
Methotrexate (MTX) 
All subjects should follow the local guideline for each hospital and/or country for starting treatment with MTX 
and continue MTX treatment throughout their participation in the study. MTX is not provided by the sponsor, as 
it is not background treatment but part of the patients' regular treatment. 
19.1.1.1 MTX Treatment Instruction in Case of Elevation in Liver Enzymes  
It is recommended with more frequent blood test in case of elevation of liver enzymes.  
Transaminase Increase:  
Laboratory Value  
Action 
ALT and/or AST increases 
up to > 1 to ≤ 3 x Upper 
Limit of Normal (ULN)  
And bilirubin is within the 
normal range 
IMP and MTX remains unchanged.  
It is recommended with more frequent blood test in case of elevation of liver 
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Laboratory Value  
Action 
ALT and/or AST increases 
> 3 to ≤ 5 x ULN  
And bilirubin is within the 
normal range 
Pause IMP dosing until ALT and/or AST < 3 x ULN and follow recommendations 
above for > 1 to < 3 x ULN  
Upon normalization of ALT and/or AST, IMP resumes  
For persistent increases > 3 x ULN, discontinue IMP 
ALT and/or AST > 5 x ULN  
MTX and IMP discontinue  
Bilirubin > normal range 
MTX and IMP treatment discontinue 
19.1.2 
Folic Acid  
It is possible that AEs commonly associated with MTX treatment will occur. To minimize MTX toxicity, all 
subjects treated with MTX should be on folic acid or equivalent at a dose of at least 5 mg/week according to 
local guidelines and at the discretion of the investigator. Folic acid can either be given as a single dose weekly or 
be divided into daily doses to achieve at least 5 mg folic acid per week. It is the investigator’s decision as to 
which dosing regimen is used. 
19.1.3 
Oral Corticosteroids 
Oral corticosteroids are prohibited within 2 weeks prior to screening and during the entire treatment period and 
until the final visit (Visit 7). Refer to section 19.2 for treatment of asthma patients.  
19.1.4 Nonsteroidal anti-inflammatory Drugs (NSAID) 
Subjects may be treated with NSAIDs throughout the study. The choice and dose of NSAID used are at the 
discretion of the investigator, and the dose must be stable throughout the study. Adjustments to the dose or a 
change in NSAID may only be performed for safety reasons, and this change must be documented in the eCRF.  
19.1.5 
Non-NSAID Analgesics 
Analgesics may be used for pain as required. However, subjects should not take analgesics within 12 hours prior 
to a visit where clinical efficacy assessments are performed and recorded. Adjustments to the analgesic regimen 
may only be made for safety reasons, but any change must be documented in the eCRF. 
19.2 Prohibited Medicines 
The following medications and therapies are not permitted during the trial and would require 
discontinuation of trial treatment: 
• 
Oral, intramuscular, intravenous or intra-articular corticosteroids (permitted after week 5). (Asthma 
patients on stable prophylactic treatment are allowed to use an inhalation spray containing 
adrenocortical hormone. Furthermore, Beta-2 stimulating inhalants with short-term effects (SABA) are 
allowed for an asthma attack to an otherwise well-controlled asthma patient in the opinion of the 
investigator) 
• 
Biologic therapies for RA  
• 
Intravenous immunoglobulin therapy and/or plasmapheresis 
• 
New therapies for RA should not be initiated during the trial. Initiation of any new immunosuppressant 
or immunomodulatory therapy would be considered a treatment failure and should result in withdrawal 
of the subject from the IMP. 


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As a signal for CYP1A2 induction has been observed at 10 µM in a study with human hepatocyte the following 
CYP1A2 substrates are also prohibited: 
• 
Alosetron 
• 
Clozapine 
• 
Flutamide 
• 
Frovatriptan 
• 
Melatonin 
• 
Mexiletine 
• 
mirtazapine 
• 
Olanzapine 
• 
Ramelteon 
• 
Rasagiline 
• 
Ropinirole 
• 
Tacrine 
• 
Theophylline 
• 
Tizanidine 
• 
Triamterene 
• 
zolmitriptan 
 
19.3 Rescue Treatment 
In case of severe worsening of symptoms, the investigator will be able to provide joint injections with 
corticosteroid as rescue medication. The use of local joint injections will be at the discretion of the investigator. 
The IMP/placebo treatment will continue as planned. 
19.4 Treatment Compliance 
Subject’s compliance with study medication will be assessed at each visit. Every attempt will be made to select 
subjects who can understand and comply with instructions. Noncompliant subjects may be discontinued from 
the study at the discretion of the investigator. The sites will maintain drug accountability records and record the 
time and day of drug administration. 
 
20 SCHEDULE OF VISITS 
The schedule of visits and main procedures at each visit are summarized in the study flowchart below and are 
identical for Part 1 and Part 2. 
Table 3: Study Flow Chart  


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Visit 
1 
2 
3 
4 
5 
6 
7 
8 
Screening Baseline 
 
 
 
 
 
EOS 
Safety follow-
up call2  
Week 
-2  
0 
1 
2 
3 
4 
5 
8 
Visit Window 
-14 to -1d 
Day 0 
±1d 
±1d 
±1d 
±1d 
±1d 
±3d 
Informed consent 
X 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
Medical and surgical history 
X 
 
 
 
 
 
 
 
Inclusion/Exclusion criteria 
X 
X 
 
 
 
 
 
  
Pregnancy test (serum β-HCG) 
X 
 
 
 
 
 
 
  
Pregnancy test (dipstick) 
 
X 
X 
X 
X 
X 
X 
 
TB test1  
X 
 
 
 
 
 
 
 
Physical examination 
X 
 
 
 
 
 
X 
 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
 
Height and weight3 
X 
X 
X 
X 
X 
X 
X 
 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
 
Concomitant therapy 
X 
X 
X 
X 
X 
X 
X 
 
Electrocardiogram (ECG) 
X 
X 
X 
X 
X 
X 
X 
 
X-ray of chest, hands, and feet 
X 
 
 
 
 
 
 
 
SJC and TJC 
X 
X 
 
X 
 
X 
X 
 
CDAI 
X 
X 
 
X 
 
X 
X 
 
Investigator Global VAS5  
X 
X 
 
X 
 
X 
X 
 
Patient Global VAS  
X 
X 
 
X 
 
X 
X 
 
Patient Pain VAS  
X 
X 
 
X 
 
X 
X 
 
FACIT-Fatigue 
 
X 
 
X 
 
X 
X 
 
DAS28 
 
X 
 
X 
 
X 
X 
 
HAQ-DI (Health Assessment 
Questionnaire-Disability Index) 
 
X 
 
X 
 
X 
X 
 
SAEs/AEs 
 
X 
X 
X 
X 
X 
X 
X 
Blood samples (biochemistry and TSH, 
T3, and T4) 
X 
X 
X 
X 
X 
X 
X 
 
Blood samples (hematology) 
X 
X 
 
X 
 
X 
X 
 
Blood sample (MC1R genotype 
analysis)7 
 
X 
 
 
 
 
 
 
HBsAg, HBV antibody & HCV 
antibody4 
X 
 
 
 
 
 
 
 
PK (exposure) 
 
 
X 
X 
X 
X 
 
 
C-Reactive Protein (CRP) 
X 
X 
 
X 
 
X 
X 
 
RF or anti-CCP 
X 
 
 
 
 
 
 
 
Cytokines6 
 
X 
 
X 
 
X 
 
 
Urinalysis 
X 
 
 
 
 
 
X 
 
Dispensing of IMP 
 
X 
X 
X 
X 
 
 
 
Accountability of returned IMP 
 
 
X 
X 
X 
X 
 
 
1: QFG-IT (Mantoux test can be used if QFG-IT is not possible) 


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2: WD: Withdrawal. In case of prematurely subject withdrawal, the final visit should occur 7 days after the last IMP. Four weeks after the last IMP the subject will have a final 
safety follow-up call (EOS). 
3: Height only at screening 
4: Hepatitis B surface antigen (HBsAg), Hepatitis B virus (HBV), Hepatitis C virus (HCV) 
5: Visual Analog Scale (VAS) 
6: CXCL13, IL-1β, IL-6, IL-10, and TNF-α 
7: At baseline or any other visit after randomization 
20.1 Visits 
20.1.1 
Visit 1, Screening (up to 14 days prior to the Baseline Visit) 
The purpose of the screening visit is to inform the subject about the trial and to verify that the potentially 
eligible subject fulfills the inclusion criteria for the trial and do not meet any exclusion criteria. The screening 
visit should be performed within 14 days prior to the Baseline Visit. The informed consent must be signed prior 
to any screening assessments.  
The following assessments will be performed: 
• 
Informed consent 
• 
Demographics 
• 
Medical and surgical history 
• 
Inclusion/exclusion criteria 
• 
TB test (QFG-IT (Mantoux test can be used if QFG-IT is not possible)) 
• 
Physical examination 
• 
Vital signs (supine blood pressure (BP) and heart rate) 
• 
Body measurements (height and weight)  
• 
Concomitant medication 
• 
Concomitant therapy 
• 
12-lead ECG 
• 
X-ray of chest, hands, and feet 
• 
Blood samples (haematology, biochemistry and TSH, T3, and T4) 
• 
Pregnancy test (serum) 
• 
HBsAg, HBV antibody & HCV antibody 
• 
Urinalysis (dipstick) 
• 
RF or Anti-CCP 
• 
CRP 
• 
SJC and TJC 
• 
CDAI 
• 
Investigator Global VAS  
• 
Patient Global VAS  


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• 
Patient Pain VAS  
20.1.2 Visit 2, the Baseline Visit (Day 0) 
The subject will come back to the hospital for the Baseline Visit. Inclusion and exclusion criteria will be 
confirmed. If the subject is still eligible for participation, the subject will be randomized. The following 
assessments will be performed: 
• 
Check of inclusion/exclusion criteria 
• 
Vital signs (supine BP and heart rate) 
• 
Changes in concomitant medication 
• 
Changes in concomitant therapy 
• 
12-lead ECG 
• 
Blood samples (hematology, MC1R genotype analysis*, biochemistry and TSH, T3, and T4) 
• 
CRP 
• 
Cytokines 
• 
Pregnancy dipstick test 
• 
Body measurements (weight) 
• 
Adverse event recording  
• 
SJC and TJC 
• 
CDAI 
• 
Investigator Global VAS  
• 
Patient Global VAS  
• 
Patient Pain VAS  
• 
FACIT-Fatigue 
• 
DAS28 
• 
HAQ-DI 
• 
Randomization 
• 
Dispensing of IMP 
* At baseline or any other visit after randomization 
20.1.3 
Visit 3, 1. Week treatment Visit  
The 1. Week Treatment Visit, 7 days (±1 day) after the Baseline Visit. The following assessments will be 
performed: 
• 
PK blood sample 
• 
Blood samples (biochemistry and TSH, T3, and T4) 
• 
Changes in concomitant medication 
• 
Changes in concomitant therapy 


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• 
12-lead ECG 
• 
Pregnancy dipstick test 
• 
Body measurements (weight) 
• 
Adverse event recording  
• 
Accountability of returned IMP and dispensing of new IMP 
20.1.4 
Visit 4, 2. Week treatment Visit  
The 2. Week Treatment Visit, 14 days (±1 day) after the Baseline Visit. The following assessments will be 
performed: 
• 
PK blood sample 
• 
Vital signs (supine BP and heart rate) 
• 
Changes in concomitant medication 
• 
Changes in concomitant therapy 
• 
12-lead ECG 
• 
Blood samples (hematology, biochemistry and TSH, T3, and T4) 
• 
Cytokines 
• 
CRP 
• 
Pregnancy dipstick test 
• 
Body measurements (weight) 
• 
Adverse event recording  
• 
SJC and TJC 
• 
CDAI 
• 
Investigator Global VAS  
• 
Patient Global VAS  
• 
Patient Pain VAS  
• 
FACIT-Fatigue 
• 
DAS28 
• 
Accountability of returned IMP and dispensing of new IMP 
20.1.5 
Visit 5, 3. Week treatment Visit  
The 3. Week Treatment Visit, 21 days (±1 day) after the Baseline Visit. The following assessments will be 
performed: 
• 
PK blood sample 
• 
Blood samples (biochemistry and TSH, T3, and T4) 
• 
Changes in concomitant medication 
• 
Changes in concomitant therapy 


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• 
12-lead ECG 
• 
Pregnancy dipstick test 
• 
Body measurements (weight) 
• 
Adverse event recording  
• 
Accountability of returned IMP and dispensing of new IMP  
20.1.6 
Visit 6, 4. Week treatment Visit  
The 4. Week Treatment Visit 28 days (±1 day) after the Baseline Visit. The following assessments will be 
performed: 
• 
PK blood sample 
• 
Vital signs (supine BP and heart rate) 
• 
Changes in concomitant medication 
• 
Changes in concomitant therapy 
• 
12-lead ECG 
• 
Blood samples (hematology, biochemistry and TSH, T3, and T4) 
• 
CRP 
• 
Cytokines 
• 
Pregnancy dipstick test 
• 
Body measurements (weight) 
• 
Adverse event recording  
• 
SJC and TJC 
• 
CDAI 
• 
Investigator Global VAS  
• 
Patient Global VAS  
• 
Patient Pain VAS  
• 
FACIT-Fatigue 
• 
DAS28 
• 
HAQ-DI 
• 
Accountability of returned IMP  
20.1.7 
Visit 7, One-week post-treatment  
The subject will return to the hospital for a final visit, 7 (±2 days) days after the last IMP has been taken. The 
following assessments will be performed: 
• 
Pregnancy dipstick test  
• 
Urinalysis (dipstick) 
• 
Blood samples (hematology, biochemistry and TSH, T3, and T4) 


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• 
Vital signs (supine BP and heart rate) 
• 
CRP 
• 
Physical examination 
• 
Body measurements (weight) 
• 
Adverse event recording  
• 
Changes in concomitant medication 
• 
Changes in concomitant therapy 
• 
12-lead ECG 
• 
SJC and TJC 
• 
CDAI 
• 
Investigator Global VAS  
• 
Patient Global VAS  
• 
Patient Pain VAS  
• 
FACIT-Fatigue 
• 
DAS28 
• 
HAQ-DI 
20.1.8 
Final safety Follow-up Call and EOS 
Investigator or study nurse will call the subject 4 weeks after the subject took the last IMP to follow-up on 
outstanding safety issues (AE/SAE).  
 
21 ASSESSMENTS, PROCEDURES, AND EXAMINATIONS 
Subjects must provide written informed consent before any study-related procedures are performed. 
Subject-related events and activities including specific instructions, procedures, concomitant medications, 
dispensing of study drug, and descriptions of AEs should be recorded in the appropriate source documents and 
the eCRF. 
The schedule of assessments is provided in a study flow chart (Table 3) and is listed in Section 205. Unless 
otherwise specified, the investigator or accredited study personnel will perform all assessments. 
Extra visits, examinations, tests, and interventions can be performed at any time if clinically indicated, as judged 
by the investigator. 
21.1 Safety Assessments 
21.1.1 
Medical History 
A complete medical (and surgical) history of each subject will be collected and documented during screening to 
determine the subject’s eligibility for the trial. The medical history will include, but may not be limited to, prior 
and current concomitant disease and treatments, including all previous and current therapies for RA. 


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Relevant medical history will be recorded in the eCRF and includes diagnosis and assessments of any current 
medical condition and concurrent health conditions. 
21.1.2 
Prior and Concomitant Medication 
Prior medications/therapies will be reported if taken up to 4 weeks prior to the Screening Visit. Concomitant 
medications/therapies, herbal medication, and over-the-counter medication will be reported at every visit 
throughout the trial. 
21.1.3 
Pregnancy Test 
For all females of childbearing potential, a serum pregnancy test will be performed at screening and at all the 
following visits the pregnancy test will be a urine dipstick test. In the event of pregnancy, the subject is not 
allowed to receive further study treatment and must be withdrawn from the study. The pregnancy must be 
reported to the sponsor on a Pregnancy form and followed until the end of pregnancy.  
21.1.4 
Physical Examination 
A full physical examination (including examination of general appearance, skin, neck (including thyroid), eyes, 
ears, nose, throat, heart, lungs, abdomen, lymph nodes, musculoskeletal, cardiovascular, nervous systems, and 
joints) will be carried out by a physician at screening and at the final visit (Visit 7) or early withdrawal.  Any 
clinically significant abnormalities at screening will be noted on the medical history pages of the eCRF. During 
the study, if in the opinion of the investigator there are any clinically significant changes in the physical 
examination findings (abnormalities), they will be recorded as AEs.  
21.1.5 
Height and Weight 
Subject height will be measured at the Screening Visit, while weight will be assessed at all visits except at the 
visit 8 (EOS/Safety follow-up call).  
21.1.6 
Vital Signs 
Vital signs will be collected for evaluation by the investigator. Reference values for the vital signs are presented 
in the table below. If any value is outside the reference range, the measurement will be repeated at the 
investigator’s discretion, and the final measurement will be reported in the eCRF. 
Table 4, Reference values for vital signs 
Vital Sign Parameter 
Range 
Systolic blood pressure 
90–140 mm Hg 
Diastolic blood pressure 
60–90 mm Hg 
Heart rate (resting) 
50–100 beats per minute (bpm) 
Respiratory rate 
12–20 breaths per minute 
  
All vital sign values will be evaluated for clinically notable results as defined in Table 5, Any subject with a 
clinically notable vital sign abnormality will be immediately evaluated by qualified personnel to ensure that any 
required acute medical intervention or other appropriate supportive medical care is provided. All vital sign 
abnormalities, including clinically notable vital sign abnormalities, will be evaluated using appropriate medical 


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judgment to determine whether they represent AEs. Vital sign abnormalities that require medical intervention 
(beyond confirmatory vital sign collection) are to be regarded as AEs. Vital signs will be assessed at all visits. 
Table 5, Criteria used to identify clinically notable vital sign abnormalities 
Vital Sign Parameter 
Value 
Systolic blood pressure 
≥ 160 mm Hg or < 90 mm Hg 
Diastolic blood pressure 
≥ 105 mm Hg or ≤ 50 mm Hg 
Heart rate 
≥ 120 bpm or < 40 bpm 
Respiratory rate 
< 12 breaths per minute or > 20 breaths per minute 
 
21.1.6.1 Blood pressure, Heart, and Respiratory Rate 
Blood pressure and pulse rate will be measured on the non-dominant arm after 5 minutes of supine rest.  Blood 
pressure will be recorded in mmHg, heart rate will be measured in bpm and respiratory rate in breaths per 
minutes.  
21.1.7 
Lead Electrocardiographic Evaluation 
A twelve (12) lead ECGs will be obtained on all subjects at every visit throughout the trial. The ECG should be 
performed after the subject has rested quietly for at least 10 minutes.  
The following ECG parameters will be obtained from the digital 12-lead ECG recordings: rhythm, heart rate (as 
measured by RR interval), PR interval, QRS duration, and QT interval. The corrected QT interval (QTcF) will be 
calculated using Fridericia’s formula (QTc=QT/∛RR)43 or by using CliniCalc: 
(https://www.clinigate.com/clinicalc/corrected-qt-interval-qtc.php)  
The investigator must evaluate all ECGs as normal/abnormal and if abnormal as clinically significant or not 
clinically significant. The printout of the ECG should be signed and dated. The overall evaluation 
(normal/abnormal) will be recorded on the eCRF, and if abnormal, the specific abnormality will be recorded too. 
Each print-out must include the following information: trial number, subject’s screening number, date of birth, 
and date and time of recording. All reference to the subject’s name and/or social security number must be 
erased from the print-out so that only the subject's screening number is used as identification. 
21.1.8 
X-ray 
A chest x-ray (only at the Screening Visit) will be used to reveal active current or history of tuberculosis and 
atypical mycobacterial disease, clinically significant abnormalities on chest x-ray as determined by the 
investigator.  
X-ray of hands and feet (only at the Screening Visit): radiographic changes typical of RA on posteroanterior hand 
and wrist x-rays.  
If the subject has a chest x-ray and/or x-ray of hands and feet that are no older than 6 months the x-rays can be 
used for the evaluation. 


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The average radiation dose for adults is 60 microsievert (µSv) per x-ray image, which is a very shallow dose. In 
comparison, the average background radiation (i.e., the average radiation that an individual is exposed to per 
year from natural background radiation sources) is 1000 µSv. The radiation dose that a subject is exposed to is 
thus evaluated to be safe. Furthermore, the additional information, which such images can provide about 
radiographic changes typical for rheumatoid arthritis, is anticipated as valuable knowledge for the project.  
21.1.9 
Laboratory Assessments 
The study sites will use local laboratories to perform standard hematology, biochemistry, and urine analyzes. 
Laboratory results will be evaluated by the investigator for inclusion and exclusion criteria. Also, the investigator 
will assess whether any values reflect AEs and if so, report them as described in section 18. 
The latest updated reference ranges from the local laboratory will be used to identify subjects with clinically 
notable laboratory values. 
21.1.9.1 Hematology 
Hemoglobin, white blood cell (WBC) count (total and differential: leukocytes, neutrophils, eosinophils, 
basophils, lymphocytes, monocytes), red blood cells (RBC), thrombocytes and hemoglobin A1c (HbA1C). The 
hematology blood samples will be taken at screening, baseline, after 2 weeks and 4 weeks treatment and Visit 7. 
21.1.9.2 MC1R genotype analysis 
The human melanocortin receptor type 1 (MC1R) is a highly polymorphic gene. It is known that some receptor 
variants are associated with loss of function when characterized by the receptor’s ability to induce cAMP 
accumulation. There is evidence that the loss of function is restricted to the cAMP pathway, i.e., the ability to 
stimulate the ERK phosphorylation pathway, the pathway stimulated by AP1189, for most receptor variants are 
preserved.  
At baseline or any other visit after randomization, a blood sample will be taken once to identify the MC1R 
variant in randomized patients. 
The blood sample is stored at -80 ° in a research biobank until shipment and subsequent analysis at Statens 
Serum Institut (SSI). The genotype sequencing method is used in the blood sample analysis, meaning that only 
the gene variations that have to do with the melanocortin receptor are examined. 
The company Genetelligence is responsible for the interpretation of the genetic tests, and the results are only 
used in the above study. 
All blood samples will be destroyed after analysis, and no samples will be saved for future research. 
21.1.9.3 Biochemistry  
Sodium, potassium, chloride, calcium, glucose, creatinine, urea, albumin, unconjugated and total bilirubin, 
aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP), gamma-glutamyl 
transferase (GGT) and INR. The biochemistry blood samples will be taken at all visits. A serum β-HCG pregnancy 
test will be taken at screening (dipstick pregnancy test at all other visits).  


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21.1.9.4 Thyroid function 
Thyroxine (T4) total or free, triiodothyronine (T3) total or free, and the thyroid-stimulating hormone (TSH). 
Blood samples for measuring the thyroid function will be taken at all visits. 
21.1.9.5 Urinalysis 
A dipstick urine test for blood, protein, and glucose will be performed at the site at the Screening Visit and Visit 
7. If any of the results are abnormal and clinically significant, a urine sample will, at the discretion of the 
investigator, be sent for urine culture at the local laboratory. 
21.1.9.6 Serology 
RF or anti-CCP, HBsAg, HBV antibody and HCV antibody (only at screening). 
RF is an antibody that is detectable in the blood of approximately 80% of adults with RA.  
CRP is an acute phase reactant, a protein made by the liver and released into the blood within a few hours after 
tissue injury, the start of an infection, or other cause of inflammation. The CRP will most often be increased by 
inflammation. One of the aims of treatment is to reduce the CRP to normal levels. CRP will be measured at 
screening, baseline, after 2 weeks and 4 weeks treatment and at Visit 7. 
21.1.9.7 Safety (AE and SAE) 
Safety measures (AEs, SAEs, including laboratory abnormalities) will be registered during the whole study 
duration. 
21.2 Safety Assessments (Sub-study, only Part 2) 
The arthroscopy sub-study in Part 2 (only at selected sites), will assess the effect of 4 weeks treatment with 
AP1189/placebo compared to baseline by examining synovial fluid: (evaluating the change in the percentage of 
polymorphs, monocytes, and lymphocytes in synovial fluid). 
In RA the immunohistological features of synovial inflammation change as the clinical manifestations change in 
response to conventional disease-modifying antirheumatic drugs, pulse methylprednisolone, or intra-articular 
glucocorticoids45, 45, 46, 47, 48, 49, 50, 51. These observations from many clinicopathological research protocols have 
provided compelling evidence to support the inclusion of synovial biopsy and tissue analysis in studies of the 
cause, pathogenesis, prognosis, and effects of treatment52.   
21.3 Efficacy Assessments 
The following tests and procedures have been selected to evaluate the efficacy of AP1189 and to 
describe the clinical improvement in subjects with RA. The tests and procedures will be performed according to 
the Study Flow Chart in section 18, Table 3. 
21.3.1 
Swollen Joint Count (SJC) and Tender Joint Count (TJC) 
An assessment of 66 joints for swelling and 68 joints for tenderness will be made at screening, baseline, after 2 
weeks and 4 weeks treatment and Visit 7. Joints will be assessed and classified as swollen/not swollen and 
tender/not tender by pressure and joint manipulation on physical examination. The subject will be asked for 
pain sensations on these manipulations and watched for spontaneous pain reactions. Any positive response to 
pressure, movement, or both will then be categorized as tender-versus-nontender. Swelling is defined as 


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palpable fluctuating synovitis of the joint. Swelling secondary to osteoarthrosis will be assessed as not swollen 
unless there is unmistakable fluctuation.  
Joint assessments of one particular subject should be performed by the same assessor (if at all possible) 
throughout the trial to minimize inter-observer variation. 
21.3.2 
Clinical Disease Activity Index (CDAI) 
The CDAI is a useful clinical composite score for following patients with RA. 
Descriptive changes in CDAI where CDAI = SJC (28) + TJC (28) + PGA + IGA  
• 
SJC (28): Swollen 28-Joint Count (shoulders, elbows, wrists, MCPs, PIPs including thumb IP, knees)  
• 
TJC (28): Tender 28-Joint Count (shoulders, elbows, wrists, MCPs, PIPs including thumb IP, knees) 
• 
PGA: Patient Global Disease Activity (patient’s self-assessment of overall RA disease activity on a scale 0-
100 where 100 is maximal activity)  
• 
IGA: Physician’s Global Disease Activity (evaluator’s assessment of the subject’s overall RA disease activity 
on a scale 0-100 where 100 is maximal activity) 
The CDAI will be scored at screening, baseline, after 2 weeks and 4 weeks treatment and at Visit 7. 
21.3.3 
Disease Activity Score 28 (DAS28) 
The DAS28 is a combined index for measuring disease activity in RA. The index includes swollen and tender joint 
counts, CRP, and general health status. In this trial CRP will be used to calculate the DAS28 score. The index is 
calculated using the following formula: 
DAS28-CRP(4) = 0.56*sqrt(TJC28) + 0.28*sqrt(SJC28) + 0.36*ln(CRP+1) + 0.014*GH + 0.96 
 
Where, TJC = tender joint count on 28 joints, SJC = swollen joint count on 28 joints, ln = natural log, CRP = C-
reactive Protein, and GH = general health, i.e., patient’s global assessment of disease activity (100-mm VAS).  
The DAS28 provides an absolute indication of RA disease activity on a scale of 0.49 to 9.07  
• 
A DAS28 value >5.1 corresponds to a high disease activity  
• 
A DAS28 value between 3.2 and 5.1 corresponds to a moderate disease activity  
• 
A DAS28 value between 2.6 and 3.2 corresponds to a low disease activity 
• 
A DAS28 value < 2.6 corresponds to remission 
Compared to an initial value the disease activity of the subject can be classified as follows: 
 
Current DAS28 
DAS28 decrease from initial value 
> 1.2 
> 0.6 but ≤ 1.2 
≤ 0.6 
 
≤ 3.2  
Inactive  
Good improvement  
Moderate 
improvement  
No improvement  
>3.2 but ≤ 5.1  
Moderate  
Moderate 
improvement  
Moderate 
improvement  
No improvement  
> 5.1  
Very active  
Moderate 
improvement  
No improvement  
No improvement  
 


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The DAS28 will be scored at baseline, after 2 weeks and 4 weeks treatment and at Visit 7. 
21.3.4 
Physician’s Global Assessment of Disease Activity VAS (“Investigator Global VAS”) 
The physician’s assessment of the subject’s current disease activity on a 100 mm horizontal VAS. The extreme 
left end of the line should be described as “no disease activity” (symptom-free and no arthritis symptoms) and 
the extreme right end as “maximum disease activity.” The efficacy assessor should complete this. Investigator 
Global VAS will be measured at screening, baseline, after 2 weeks and 4 weeks treatment and at Visit 7. 
21.3.5 
Patient’s Global Assessment of Disease Activity VAS (“Patient Global VAS”) 
The subject’s overall assessment of their current disease activity on a 100 mm horizontal VAS. The extreme left 
end of the line should be described as “no disease activity” symptom-free and no arthritis symptoms) and the 
extreme right end as “maximum disease activity” (maximum arthritis disease activity). Patient Global VAS will be 
measures at screening, baseline, after 2 weeks and 4 weeks treatment and at Visit 7. 
21.3.6 
Patient’s Assessment of Pain VAS (“Patient Pain VAS”) 
The subject’s assessment of his/her current level of pain on a 100 mm horizontal VAS. The extreme left end of 
the line should be described as “no pain” and the extreme right end as “unbearable pain.” Patient Pain VAS will 
be measured at screening, baseline, after 2 weeks and 4 weeks treatment and at Visit 7. 
21.3.7 
Quality of Life and Physical Function 
21.3.7.1 Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) 
The FACIT-Fatigue assessment is a 13-item questionnaire with subjects scoring each item on a 5-point scale. The 
assessment was originally developed for chronic illnesses and is now validated for patients with RA. FACIT-
Fatigue will be scored at baseline, after 2 weeks and 4 weeks treatment and at Visit 7.  
21.3.7.2 Health Assessment Questionnaire – Disability Index (HAQ-DI) 
HAQ-DI is a validated tool to evaluate physical function. It consists of 20 questions referring to 8 component 
sets: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities. HAQ-DI will be scored at 
baseline, after 2 weeks and 4 weeks treatment and at Visit 7. 
21.3.8 
American College of Rheumatology Response Rates 
The ACR (American College of Rheumatology) Criteria is a standard criterion to measure the effectiveness of 
various arthritis medications or treatments in clinical trials for RA.  
The ACR response rates ACR20, ACR50, and ACR70 are defined as ≥20%, ≥50% and ≥70% improvement, 
respectively, in swollen and tender joint counts (SJC/TJC) and 3 of the following 5 assessments: Patient’s Global 
Assessment of Disease Activity (see above), Physician’s Global Assessment of Disease Activity (see above), 
Patient’s Assessment of Pain (see above), Health Assessment Questionnaire (HAQ-DI, see above), and C-Reactive 
Protein (CRP). 
21.4 Pharmacokinetic Assessments  
The collection, processing, packing and shipping of PK, and cytokine samples are described in a separate Lab 
Manual for the study.   


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21.4.1 
PK Sample Collection  
Plasma PK samples for exposure-response analysis will be taken after 1, 2, 3- and 4-weeks treatment.  
21.5 Cytokine Samples 
Plasma samples for CXCL13, IL-1β, IL-6, IL-10, and TNF-α analysis will be taken at baseline, after 2 weeks and 4 
weeks treatment. 
21.6 Biobanking 
The following samples are kept at frozen storage in a biobank or similar, as applicable per country, during the 
study: 
• 
Cytokines (CXCL13, IL-1β, IL-6, IL-10, and TNF-α), plasma 
• 
PK, plasma 
Analysis of all cytokines and PK will be performed at a central laboratory (Eurofins ADME BIOANALYSIS, 75A 
Avenue de Pascalet, 30310 Vergèze, France). The samples will be sent and analyzed on a regular basis.  
All samples will be destroyed immediately after analysis. No samples are kept for future research.  
Instructions for collection, processing, handling, and shipment of the frozen samples will be outlined in a 
laboratory manual.  
The total volume of blood for biobanking is approximately 46 mL. 
As France is part of the EU, the Data Protection Regulation and the Data Protection Act will be respected.  
21.7 Total Volume of Blood 
The total volume of blood to be collected from any subject during the trial will be up to 180 mL across 7 visits 
and will not exceed 36 mL at any one visit (see Table 6).  
Table 6: Volume of Blood during the Trial 


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(mL blood) 
Lab. 
Tests1 
PK  
(plasma) 
Cytokine 
samples 
(plasma) 
CXCL13 
samples 
(plasma) 
Maximum per Visit 
Visit 1, Screening 
Visit 
36 
0 
0 
0 
36 
Visit 2, Baseline 
Visit 
17 
0 
5 
5 
27 
Visit 3, 1. week 
treatment 
15 
4 
0 
0 
19 
Visit 4, 2. week 
treatment 
17 
4 
5 
5 
31 
Visit 5, 3. week 
treatment 
15 
4 
0 
0 
19 
Visit 6, 4. week 
treatment 
17 
4 
5 
5 
31 
Visit 7, final visit 
17 
0 
0 
0 
17 
Total during study 
134 
16 
15 
15 
180 
1: Laboratory tests include a 15 mL blood sample for the analysis of hematology, biochemistry parameters, TSH, T4, T3, and serum β-HCG (pregnancy test 
at screening), as applicable, according to the study flowchart. 
 
22 SAFETY  
Adverse events will be monitored from the time that the subject gives informed consent and throughout the 
study, and will be elicited by direct, non-leading questioning or by spontaneous reports. Further details for AE 
reporting can be found in section 18.4. 
Conditions that started before signing the informed consent and for which no symptoms or treatment are 
present until the first administration of study drug (e.g., seasonal allergy without acute complaints), are 
recorded as medical/surgical history. 
22.1 Definitions 
Adverse Events (AE): According to the International Conference of Harmonization (ICH), an AE is 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.  
An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal or investigational product, whether or 
not considered related to the medicinal or investigational product. Pre-existing conditions which worsen during 
a study are to be reported as AEs. 
Adverse Reaction (AR): All untoward and unintended responses to an investigational medicinal product related 
to any dose administered.  
Serious Adverse Events (SAE): An SAE is any AE occurring at any dose that in the view of either the investigator 
or sponsor, results in any of the following outcomes:  


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• 
Results in death, or 
• 
Is life threatening, that is any event that places the patient at immediate risk of death from the event as 
it occurred. It does not include an event that, had it occurred in a more severe form, might have caused 
death, or 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization, or 
• 
Results in persistent or significant disability/incapacity, or 
• Is a congenital anomaly/birth defect 
Important medical events that may not result in death, be life-threatening, or require hospitalization may be 
considered a serious adverse event when, based upon appropriate medical judgment, they may jeopardize the 
subject and may require medical or surgical intervention to prevent one of the outcomes listed in this definition. 
• 
Hospitalization is defined as any in-patient admission (more than 24 hours). 
• 
Prolongation of hospitalization is defined as any extension of an in-patient hospitalization beyond the stay 
anticipated/required in relation to the original reason for the initial admission, as determined by the 
investigator or treating physician. Prolongation in the absence of a precipitating, treatment-emergent, 
clinical AE (i.e., not associated with the development of a new AE or worsening of a pre-existing condition) 
may meet criteria for "seriousness" but is not an adverse experience and thus is not subject to immediate 
reporting.  
• 
Preplanned or elective treatments/surgical procedures should be noted in the subject’s screening 
documentation. Hospitalization for a preplanned or elective treatment/surgical procedure should not be 
reported as an SAE unless there are complications or sequelae which meet the criteria for seriousness 
described above. 
Planned hospitalizations that occur exclusively for study procedures must not be documented as SAEs. 
Serious Adverse Reaction (SAR): Any serious adverse experience considered by the investigator to be related to 
the investigational product is a SAR. 
Suspected Unexpected Serious Adverse Reactions (SUSARs): SUSARs are serious reactions that are not listed in 
the IB and that the investigator identifies as related to the investigational product or procedure.   
22.2 Severity Classification 
The severity of an event is evaluated in order to subcategorize events. Severity is not seriousness.  A very severe 
event can be non-serious, and a serious event can be of mild severity. All AEs (including SAEs) are to be recorded 
on the AE page of the subject’s eCRF. Each event will be graded for severity using Common Terminology Criteria 
for Adverse Events (CTCAE), v4.03 grading scale: June 14, 2010.  
The following grading will apply: 
• 
Mild (Grade 1) - Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated.  
• 
Moderate (Grade 2) - Moderate; minimal, local, or non-invasive intervention indicated; limiting age-
appropriate instrumental Activity of Daily Living (ADL). 


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• 
Severe (Grade 3) - Severe or medically significant but not immediately life-threatening; hospitalization 
or prolongation of hospitalization indicated; disabling; limiting self-care ADL. 
• 
Life-threatening (Grade 4) - Life-threatening consequences; urgent intervention indicated. 
• 
Death (Grade 5) related to AE. 
22.3 Relationship to Study Drug 
A determination will be made of the relationship (if any) between an adverse event and the study drug. A causal 
relationship is present if a determination is made that there is a reasonable possibility that the adverse event 
may have been caused by the study drug. 
The investigator should determine the relationship of an AE to the study drug after thorough consideration of all 
facts that are available and will be assessed using the following definitions: 
• 
Definitely not related: Temporal relationship to study drug administration is missing or implausible, or 
there is an evident other cause 
• 
Probably not related: Temporal relationship to study drug administration makes a causal relationship 
improbable; and other drugs, chemicals, or underlying disease provide plausible explanations 
• 
Possibly related: The AE occurred in a reasonable time after study drug administration but could be 
related to an underlying disease, environmental or toxic factors, or other drug or therapy 
• 
Probably related: Reasonable time sequence to the administration of study drug and unlikely to be 
attributed to concurrent disease or the drugs or chemicals, and which follows a clinically reasonable 
response on withdrawal (dechallenge). Rechallenge information is not required 
• 
Definitely related: Plausible time relationship to study drug administration and event cannot be explained 
by concurrent disease or other drugs or chemicals. The response to withdrawal of the drug (dechallenge) 
should be clinically plausible. The event must be definitive pharmacologically or phenomenologically, 
using a satisfactory rechallenge procedure if necessary 
22.4 Reporting Procedures of Adverse Events 
The responsible for ensuring that all AEs (as defined in Section 18.1) observed by the staff at the clinic or 
reported by subjects are collected and recorded in the subject’s medical notes and the eCRF. The condition of 
each subject will be monitored throughout the study. 
All AEs will be reported starting from the time informed consent for study participation is provided and until the 
final visit (End of Study/Early Termination visit) has occurred. All AEs that are ongoing at the subject’s last visit 
must be followed until resolution or for 4 weeks after the study drug administration, whichever comes first.    
A cluster of signs and symptoms that results from a single cause should be reported as a single AE (e.g., fever, 
elevated WBC, cough, abnormal check x-ray, etc. can all be reported as Pneumonia). The investigator must 
assign the following adverse event attributes: adverse event diagnosis or syndrome(s) (if known, signs or 
symptoms if not known); dates of onset and resolution; severity; assessment of relatedness to investigational 
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22.5 Reporting Procedures for Serious Adverse Events 
All SAE reporting start at the time the subject has been administered the first dose of study drug and until end 
of study visit. Ongoing SAEs must be followed until the event resolves, or the event sequelae stabilize, or it is 
unlikely that any additional information can be obtained. 
In the event of an SAE, the investigator must: 
• 
Complete the provided SAE report Form with the following information, as a minimum: 
o valid EudraCT number, 
o sponsor study number, 
o one identifiable coded subject, 
o one identifiable reporter, 
o one SUSAR, 
o one suspect IMP (including active substance name- code), 
o A causality assessment. 
 
• 
All SAEs are to be reported to the sponsor (or designee) within 24 hours of awareness of the event. Send 
it to: 
o PharmaLex contact information: pv-nordic@pharmalex.com  
• 
Obtain and maintain in the subject’s medical record all pertinent medical records, information, and 
medical judgments from colleagues, who assisted in the treatment and follow-up of the subject. 
• 
Provide PharmaLex with additional information that may become available using the SAE reporting 
form. All documents submitted to PharmaLex that contains information regarding the SAE must be 
redacted (blacked out) for protected confidential health information, including subject initials. The 
assigned subject screening number should instead be recorded on each of the documents. 
22.6 Reporting of SAE and SUSAR to the Competent Authorities 
In the event of a fatal and life-threatening SUSAR, the sponsor should report at least a minimum of information 
to the CA, IECs/IRBs no later than 7 days after being made aware of the event. SUSARs which are not fatal and 
not life-threatening are to be reported within 15 days of awareness. When/if follow up information becomes 
available, this should be submitted to the authorities within 15 days of receipt. 
PharmaLex should compile and submit listings of all SARs in a Development Safety Update Report (DSUR) to the 
CA, IECs/IRBs once a year, as applicable. 
22.7 Expedited Reporting 
The sponsor will ensure that processes are in place for submission of reports of Suspected Unexpected Serious 
Adverse Reactions (SUSARs) occurring during the study to the CA, IECs/IRBs and other investigators concerned 
by study drug. Reporting will be done in accordance with the applicable regulatory requirements. 


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22.8 Contraception and Pregnancy 
The effects of AP1189 on a fetus during pregnancy are unknown. Therefore, women who are of childbearing 
potential should use one of the below contraceptive methods which, when used consistently and correctly are 
considered as highly effective birth control methods. Contraception must be used during the study and two 
weeks after the last IMP has been taken (equal to 5 times T1/2). 
Highly effective birth control methods to be used during the study: 
Oral contraceptives, implant, transdermal patch contraceptives, injection contraceptives, intravaginal 
contraceptive ring, and intrauterine device (IUD) or depot injection. 
Sterile or non-fertile subjects are exempt from the requirement for contraception. To be considered sterile or 
non-fertile, one should generally be surgically sterilized (vasectomy / bilateral tubectomy, hysterectomy and 
bilateral ovariectomy) or be postmenopausal, defined as missed menstruation for at least 12 months prior to 
enrollment in the study. 
In addition, true abstinence (total abstinence from heterosexual intercourse) when this is in line with the 
preferred and usual lifestyle of the subject. 
 
At all visits, subjects should be reminded of the importance of maintaining contraception and avoiding 
pregnancy during the study. 
Subjects with a positive pregnancy result prior to baseline (Day 0) will not be eligible to participate in the study. 
If a female subject becomes pregnant during the treatment period of the study, she must stop taking the study 
medication and immediately inform the investigator. The investigator should report all pregnancies within 24 
hours to PharmaLex on an SAE report Form provided. The investigator should counsel the subject and discuss 
the risks of continuing with the pregnancy and the possible effects on the fetus. Monitoring of the subject 
should continue until the conclusion of the pregnancy. Information regarding a pregnancy occurrence in a study 
subject and the outcome of the pregnancy will be collected. 
Male subjects: Either the partner uses one of the above safe methods or the subject and his partner use double 
barrier meaning condom in combination with a diaphragm. Male subjects must inform their partner(s) of the 
risks of becoming pregnant and for reporting any pregnancy to the study doctor. 
22.8.1 
Additional Reporting Requirements for Pregnancies 
If a female subject of childbearing potential becomes pregnant during the study, the coordinating investigator will 
immediately notify the sponsor, within 24 hours of being made aware of the event. Complete the provided 
Pregnancy Report Form and send it to: 
• 
PharmaLex (or designee) contact information: pv-nordic@pharmalex.com 
The investigator should follow any subject who becomes pregnant, while participating in a clinical study, 
throughout the pregnancy. The investigator should document the outcome of the pregnancy and provide a copy 
of the documentation to the PharmaLex.  
 
23 STATISTICAL CONSIDERATIONS AND METHODS 


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23.1 General Considerations 
Before breaking the treatment codes, all decisions on the evaluability of the data from each individual subject 
will be made and documented, and each subject will be assigned to the appropriate analysis data set. The 
following analysis sets will be used for the statistical analysis: 
Safety:  
All subjects who received the study medication at least once, analyzed by received  
  
treatment 
PK: 
All the subjects who completed the study and did not have any protocol deviation or events  
  
implying a bias for the PK evaluation 
Efficacy: 
All randomized subjects who received the study medication at least once, analyzed by  
  
randomized treatment (intention to treat). A second analysis of the primary efficacy  
  
endpoint, for robustness, will be performed for all randomized subjects who complete the  
  
study without any major protocol violations (per protocol) 
A Statistical Analysis Plan (SAP) describing the planned statistical analyses in detail, including interim analyses, 
will be prepared by CroxxMed, and validated by the sponsor prior to any unblinding of data. 
23.2 Determination of Sample Size 
Calculations of sample size are based on a 95% confidence interval for the mean change in CDAI from baseline.  
23.2.1 
Main study 
For a sample size of 25 subjects, and a standard deviation for the mean change of 3 points, a 95% confidence 
interval will be around 2.8 points wide with 80% probability. This interval width provides a good precision of the 
estimate of the primary efficacy endpoint. For a sample size of 30 subjects, the interval will be around 2.5 points 
wide, which provides even better precision. If the sample size is larger, or if the standard deviation is smaller, 
the interval will be shorter (i.e., the precision will be higher). A larger standard deviation than 3 points is 
unlikely. SAS proc power is used for the calculations. 
The study is designed to provide a minimum of 30 subjects in each of the treatment groups that proceed to Part 
2, and a total of 90 patients.  
23.2.2 
Sub-study 
For the countries in the sub-study, a smaller effect size is expected compared to the main study. Thus, a smaller 
variation (standard deviation) is expected for the mean change in CDAI from baseline. For a sample size of 15 
subjects and a standard deviation for the mean change of 2.5 points, a 95% confidence interval will be around 
3.2 points wide with 80% probability. This interval width provides an acceptable  precision of the estimate of the 
primary efficacy endpoint. 
The sub-study is designed to provide a minimum of 15 subjects in each of the treatment groups (Part 2 only). 
23.3 Study Participant Characteristics 
The following demographic parameters will be analyzed by descriptive statistics: 
• 
Demographic characteristics (including age, weight, and height) 


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• 
Medical history 
23.4 Safety Analysis 
The primary safety endpoint is the safety of AP1189 against placebo by evaluating adverse events (AEs), serious 
adverse events (SAEs), and laboratory abnormalities. All safety parameters (ECG, vital signs, AEs/SAEs, 
laboratory abnormalities, etc.) will be summarized by treatment and time point. 
23.5 Efficacy Analysis  
All efficacy endpoints will be evaluated by treatment group using descriptive statistics. Confidence intervals will 
be presented where appropriate. 
23.5.1 
Analysis of Primary Efficacy Endpoints 
The change in CDAI after 4 weeks of treatment compared to baseline will be evaluated by assessing the 
following descriptive statistics by treatment group:  
• Mean change in CDAI from baseline to week 4 (with confidence interval for the mean change) 
• Proportion of subjects with a change in CDAI score from severe (CDAI > 22) to moderate (CDAI ≤ 22) at 
week 4 compared to baseline (with Clopper-Pearson confidence interval for the proportion) 
23.5.2 
Analysis of Secondary Efficacy Endpoints 
The effects of AP1189 against placebo will be evaluated by descriptive statistics, assessing the following by 
treatment group: 
• 
Proportion of subjects achieving a reduction of more than 10 (ten) swollen and/or tender joints (SJC and 
TJC, summarized) at week 4 compared to baseline 
• 
Proportion of subjects achieving a change in CDAI score after 4 weeks of treatment compared to 
baseline 
o Proportion of subjects with a 5-point decrease 
o Proportion of subjects with a 10-point decrease 
o Proportion of subjects with a 15-point decrease 
• 
Proportion of subjects achieving a change in DAS28 from DAS28 > 3.2 to DAS28 ≤ 3.2 at week 4 compared 
to baseline 
• 
Change of HAQ-DI at week 4 compared to baseline 
• 
Change of FACIT-Fatigue at week 4 compared to baseline 
• 
Proportion of subjects achieving ACR response assessed by ACR 20, ACR 50, and AC70 
23.5.3 
Analysis of Tertiary Efficacy Endpoints 
The effect of AP1189 compared to placebo will be further evaluated by descriptive statistics, assessing the 
following by treatment group: 
• 
CXCL13, IL-1β, IL-6, IL-10, and TNF-α at week 4 compared to baseline 
• 
Synovial biopsy at baseline and after 4 weeks treatment (only Part 2 at selected sites) 


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23.5.4 
Analysis of other Endpoints (if applicable) 
The following efficacy parameters will be summarized by treatment and time point, using descriptive statistics: 
• 
Investigator Global VAS  
• 
Patient Pain VAS  
• 
CRP  
23.6 Pharmacokinetic Analyses 
Descriptive statistics will be used for an exploratory description of exposure in relation to effect. Plasma 
concentrations will be used to measure exposure.  
23.7 Interim Analyses 
An independent external statistician will conduct the interim analysis.  
All safety parameters (ECG, vital signs, AEs/SAEs, laboratory abnormalities, etc.) and efficacy data for the 
primary efficacy endpoint will be summarized by treatment and time point for the subjects included in Part 1 of 
the study. The choice of design for Part 2 will be based on the results from the interim analysis.  
The independent external statistician will ensure that the interim analyses are a completely confidential process, 
investigators and other study personnel will be kept blind and will only be informed about the decision of design 
choice for Part 2 of the study. 
 
24 DATA MANAGEMENT AND QUALITY ASSURANCE 
24.1 Subject Records and Source Data 
24.1.1 
Record Retention 
To enable evaluations and/or audits from regulatory authorities or sponsor, the investigator agrees to keep 
records. The records must include the identity of all participating subjects (sufficient information to link records, 
e.g., eCRFs and hospital records), all original signed informed consent documents, safety reporting forms, source 
documents, and detailed records of treatment disposition, and adequate documentation of relevant 
correspondence (e.g., letters, meeting minutes, telephone calls reports). The investigator should retain the 
records according to ICH, local regulations, or as specified in the Clinical Study Agreement (CSA). 
If the investigator becomes unable for any reason to continue to retain study records for the required period 
(e.g., retirement, relocation), the sponsor should be prospectively notified. The study records must be 
transferred to a designee acceptable to the sponsor, such as another investigator, another institution, or an 
independent third party arranged by the sponsor. Investigator records must be kept for a minimum of 25 years 
after completion or discontinuation of the study or for longer if required by applicable local regulations. 
The investigator must obtain sponsor's written permission before disposing of any records, even if retention 
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24.1.2 
Source Documents 
It is essential that the patient record contains all important details about the subject's participation in the study. 
The investigator or designated person will agree, as a minimum requirement, to record the following 
information in the patient record:  
The following information should be entered in the subject’s source documents: 
• 
Study number, brief description, or title of the study 
• 
The date that the subject gave written consent 
• 
The date of all subject visits 
• 
Medical history, including a detailed history of the study disease 
• 
Documentation of all procedures conducted during the trial 
• 
All concurrent medications (list all prescription, non-prescription, and herbal medicine being taken at the 
time of enrolment). At each subsequent visit, changes to the list of medications and concurrent 
procedures should be recorded 
• 
Occurrence and status of any adverse events 
• 
All SAEs 
• 
The date the subject exited the study, and a notation as to whether the subject completed the study or 
the reason for discontinuation. 
In most cases, the source documents are the hospital's or the physician's patient record. In these cases, data 
collected in the eCRFs must match the data in those charts.  
In some cases, the eCRF, or part of the eCRF, may also serve as source documents. In these cases, it will be 
described in a source data location form and available at the investigator’s site as well as in the Trial Master File 
(TMF) and clearly identify those data that will be recorded in the eCRF, and for which the eCRF will stand as the 
source document. 
24.1.3 
Electronic Case Report Form  
In this study, the term eCRF is used as an abbreviation for an electronic data report form. The eCRF includes 
recordings of all study data from each subject. Computerized data cleaning checks will be used in addition to 
manual review to check for discrepancies and to ensure consistency and completeness of the data. Queries will 
be issued within the system to solve discrepancies. An electronic audit trail will be used to track all data changes 
in the database.  
24.1.3.1 Case Report Form Completion 
An eCRF is required and should be completed for each included subject. The completed original eCRF are the 
sole property of SynAct Pharma and should not be made available in any form to third parties, except for 
authorized representatives of SynAct Pharma or appropriate regulatory authorities, without written permission 
from SynAct Pharma.  
The investigator has ultimate responsibility for the collection and reporting of all clinical, safety and laboratory 
data entered on the eCRF and any other data collection forms (source documents) and ensuring that they are 


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accurate, authentic/original, attributable, complete, consistent, legible, timely, enduring and available when 
required. The eCRF must be signed by the investigator or by an authorized staff member to attest that the data 
contained on the eCRF is true. Any corrections to entries made in the eCRF, source documents must be dated, 
initialed, and explained (if necessary) and should not obscure the original entry. For eCRFs, this is handled within 
the data entry system. 
24.1.3.2 Missing Data 
If any information is not available, and the investigator considers that it will never be available (e.g., the weight 
on a particular visit was not recorded), the investigator will document the missing value in the eCRF and, if 
appropriate, explain, in a comment in the eCRF, why the investigation was missed out (e.g., the subject was not 
well enough to undergo the procedure). Details on the statistical analysis of missing data will be described in the 
Statistical Analysis Plan (SAP). 
24.2 Storage and Archiving 
If the investigator leaves the employment at the hospital, he/she will inform the sponsor and nominate a 
contact person who will have access to the study documents. The investigator should take measures to prevent 
accidental or premature destruction of these documents. 
Essential documents shall be archived in such a way that ensures that they are readily available upon 
authorities’ request.  
The Investigator Site File (ISF) must not be destroyed without the sponsor’s approval. 
24.3 Monitoring and Quality Control/Assurance 
This study will be monitored at all stages by the clinical research personnel designated by the sponsor; 
CroxxMed ApS. Monitoring will include personal visits and telephone communication to ensure that the 
investigation is conducted according to the protocol and complies with GCP guidelines and applicable regulatory 
requirements. The on-site review of eCRFs will include a review of forms for completeness, clarity, and 
consistency with source documents available for each subject. 
Source data as defined by ICH GCP are all original documents, records, and data such as patient records, hospital 
records, laboratory notes, subject diaries, or imaging data.  
To this end, the investigator agrees to allow regular visits (frequency depending on recruitment) by the study 
monitors and to ensure they have a suitable area in which to work (e.g., a desk) and adequate access to study 
personnel and documents. 
On-site monitoring will include source document verification (SDV). SDV is the procedure whereby the data 
contained in the eCRFs are compared with the primary source data (e.g., patient notes, original recordings from 
automated instruments, X-ray films, ECG tracings, and laboratory results) contained in the patient records held 
at the investigational site and thereby verified as accurate. 
The investigator must be aware that:  
• 
SDV is a part of the routine monitoring process. It will be carried out by designated study personnel and 
will be done in such a way as to preserve subject confidentiality, considering all ethical and legislative 


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requirements. SDV will be carried out by direct comparison of entries made in the eCRF with appropriate 
source data. Direct access to source data requires that the subject gives written, documented consent to 
this 
• 
Where source data are in the form of a computer print-out (e.g., medical records, ECG tracings) they will 
be made available by the investigator to the monitor. Each will be signed and dated by the investigator or 
a designated person, confirming that the print-out is a true and faithful record of the data for that subject. 
These printouts will be filed on-site 
• 
100% SDV will be performed in this study. A source data location form will be agreed with the investigator 
listing all documents considered to be source data along with the location 
For all subjects, subject’s identity (date of birth, sex, initials, and subject screening number), the record of entry 
into the study and signature of informed consent must be verified from source documents as a minimum.  
It is essential that the subject’s participation in the study is recorded in the patient record.  
All trial-specific monitoring procedures, monitoring visits, frequency and extent of source data verification will 
be predefined in a trial specific monitoring plan. 
24.4 End of Trial 
The end of the trial is defined as the last visit for the last subject (LVLS). 
24.5 Audit and Inspections 
The study may be audited or inspected by the sponsor (or a designated CRO), CA or IEC/IRB. If such an audit or 
inspection occurs, the investigator must agree to allow access to the study site, required subject records and 
study documents. If notified of audits/inspections by bodies other than the sponsor, the investigator is to inform 
the sponsor of any such inspection immediately. By signing this protocol, the investigator grants permission to 
personnel from the sponsor, its representatives, and CA or IEC/IRB for on-site monitoring of all appropriate 
study documentation, as well as on-site review of the procedures employed in the eCRF generation, where 
clinically appropriate. The investigator will be informed about the outcome of the audit. 
Quality control procedures regarding statistical analysis will be documented in the SAP: All equipment used in 
the study must be calibrated according to local standards and calibration certificates available for review.  
24.6 Data processing and quality Control 
The designated CRO will be responsible for data processing and quality control. Data management will be 
carried out as described in the CRO’s standard operating procedures, which includes the generation and 
resolution of manual electronic data queries.  
All planned data management procedures will be documented in a study-specific Data Management Plan (DMP) 
prior to the start of the trial. All planned validation checks will be documented and described in a study-specific 
Data Validation Plan. 
The electronic database is located at the Electronic Data Capture (EDC) system vendor. A validated electronic 
audit trail will track data entry and correction. All systems are validated and compliant to the Food and Drug 
Administration’s ordinance 21 CFR part 11. 


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Adverse events, baseline findings, medical/surgical history will be coded using MedDRA terminology (version 
18.0 or later). Medications will be encrypted using the ATC codes (Anatomical Therapeutic Chemical (ATC) 
Classification System). The processes used for coding will be specified in the DMP. 
 
25 DATA CONFIDENTIALITY 
25.1 Documentation of Subject’s Participation 
The investigator must record subject identification data for all subjects who provide informed consent on a 
screening log, regardless of whether they receive any study medication.  
A subject identification list, allocating subject’s clear names to the study identification, must be kept in the ISF 
and must allow for the definite identification of any subject that is enrolled and takes part in the study. Study 
monitors are permitted to review the list but must not make and keep copies.  
The subject’s consent, study participation, the study visits, relevant medical data, concomitant treatment, and 
the occurrence of adverse events must be documented in the subject’s patient record. 
25.2 Data Protection 
All parties will ensure the protection of personal subject data and will not include subject names or other 
identifiable data in any reports, publications, or other disclosures, except where required by law.  
When study data is compiled for transfer to sponsor and other authorized parties, subject names, addresses, 
and other identifiable data will be replaced by a numerical code (the subject identification number) consisting of 
a numbering system provided by CroxxMed in order to de-identify study subjects.  
The study sites will maintain a confidential list of subjects who participated in the study linking their numerical 
code to the subject’s actual identity. In the case of data transfer, the sponsor will maintain high standards of 
confidentiality and protection of personal subject data consistent with applicable privacy laws.   
To protect the subject 's identity, the unique subject identification number will be assigned to each study 
subject. This unique identification number will be assigned from a list provided by CroxxMed when the subject is 
first entered and will be used in lieu of the subject's name when the investigator reports AEs and/or other trial- 
related data. Thus, this number will appear on all study-related records for a particular subject. Personal 
information will be treated as confidential but may be reviewed by the sponsor, coordinating investigator, the 
clinical and medical monitors, the IEC/IRB and CA. The data protection principles of GCP, Directive 95/46/EC and 
local data protection regulations will be observed.   
25.2.1 
Processing of personal Data 
The storage of personally identifiable data, including blood tests, is subject to compliance with the General Data 
Protection Regulation (GDPR) and the Danish Data Protection Act. 
All information collected about the participant during the trial will be treated confidentially. Information about 
the name and social security number will not leave the hospital. Participants are asked to sign a Power of 
Attorney, which allows employees designated by SynAct Pharma as well as the health authorities access to their 
journal information for up to 15 years after the end of the trial. 


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Before a subject has given consent for participation, only the journal information required for the recruitment, 
such as diagnosis and medical history, is disclosed. 
After consent has been given, information about the participant's health condition, demography, medical 
history, concomitant medication, and laboratory results will be obtained directly from the patient journal. 
 
26 REGULATORY REQUIREMENTS 
The planning and conduct of this clinical study are subject to national laws. Only when all the requirements and 
approvals have been obtained from CA and IEC/IRB will the study begin.  
26.1 Institutional Review Board/Independent Ethics Committee 
The IEC/IRB reviews the ethical, scientific, and medical appropriateness of a study. 
Before study initiation, the investigator must have a written and dated approval/favorable opinion from the 
IRB/IEC for the protocol, consent form, subject recruitment materials/process (e.g., advertisements), and other 
written information to be provided to subjects and any updates. This approval must be obtained prior to the 
authorization of drug shipments to the study sites and before any study-related procedures can take place. All 
correspondence with the IRB/IEC should be retained in the ISF. 
Any serious adverse events (SAEs) that meet the reporting criteria, as dictated by local regulations, will be 
reported to both the responsible Ethics Committees and CA, as required by local laws. 
26.1.1 
Updated Documents 
The investigator must submit and, where necessary, obtain approval from the CA and IRB/IEC for all subsequent 
protocol amendments and changes to the informed consent document. Also, the investigator should promptly 
report to the CA and/or IEC/IRB following local procedures: 
• 
Major protocol deviation potentially affecting subject safety and integrity to eliminate immediate hazards 
to the trial subjects 
• 
Changes increasing the risk to subjects and/or affecting the conduct of the trial significantly 
• 
Any adverse drug reactions that are both serious and unexpected 
• 
New information that may affect the safety of the subjects or the conduct of the trial adversely 
The only circumstance in which an amendment may be initiated prior to CA and IRB/IEC approval is where the 
change is necessary to eliminate apparent immediate hazards to the subjects. In that event, the investigator must 
notify the CA and IRB/IEC and sponsor in writing immediately after the implementation. 
26.2 Ethical Conduct of the Study 
This study will be conducted in compliance with the protocol, GCP, as defined by the International Conference 
on Harmonization (ICH) and in accordance with the ethical principles underlying European Union Directive 
2001/20/EC and applicable national or regional regulations/guidelines.  
The study will be conducted in compliance with the protocol. The protocol, any amendments and the subject 
informed consent will receive IRB/IEC approval/favorable opinion prior to initiation of the study. 


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All subjects will have their medical condition, safety and laboratory data closely monitored throughout the 
study.  
All potential serious breaches must be reported to sponsor immediately. A serious breach is a breach of the 
conditions and principles of GCP in connection with the study or the protocol, which is likely to affect, to a 
significant degree, the safety or physical or mental integrity of the subjects of the study or the scientific value of 
the study. 
Study personnel involved in conducting this study will be qualified by education, training, and experience to 
perform their respective task(s). This study will not use the services of study personnel where sanctions have 
been invoked or where there has been scientific misconduct or fraud (e.g., loss of medical licensure or 
debarment). 
The general conclusions from the first in man Phase 1 study were: 
• 
AP1189 administered by oral route as a suspension was well tolerated up to 800 mg in single dose and 
up to 200 mg daily for 14 days in repeated dose 
• 
The most frequent TEAE observed were mild to moderate intensity GI disorders mainly in the single 
dose part while increasing the dose, which could be explained by the amount of vehicle in the 
suspension increasing with the dose leading to a consistency and taste increase of the drug. These 
effects did not lead to any treatment discontinuation for any subject and the GI tolerability was quite 
good when dosing for 14 days 
• 
Cardiovascular safety of AP1189 under the study conditions was excellent 
• 
A total of five (5) subjects all included in cohort 3 (200 mg AP1189/placebo) had isolated increases in 
aminotransferases (no concomitant changes in alkalic phosphatases or bilirubin were reported). Three 
of the five subjects were treated with active drug and two subjects were treated with placebo. All 
elevated liver enzymes had returned to normal values at the EOS visit. 
Consequently, AP1189 present a good safety profile allowing its administration to patients at 50 mg or 100 mg 
doses for 4 weeks.  
26.3 Informed Consent 
Investigators must ensure that subjects are clearly and fully informed about the purpose, potential risks, and 
other critical issues regarding clinical studies in which they volunteer to participate. Freely given written 
informed consent must be obtained from every subject, prior to clinical study participation, including informed 
consent for any screening procedure conducted to establish subject eligibility for the study. 
The investigator is also responsible for asking the subject if he/she agrees to have his/her primary care physician 
informed of the subject’s participation in the current clinical study. If the subject agrees to such notification, the 
investigator shall notify the subject’s primary care physician of the subject’s participation in the study. 
The acquisition of informed consent and the subject’s agreement or refusal of notification of his/her primary 
care physician should be documented in the subject’s medical records, and the informed consent form should 
be signed and personally dated by the subject and by the person who conducted the informed consent 
discussion. The person conducting the informed consent discussion will always be a licensed physician but not 


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necessarily the principal investigator. The original signed informed consent form should be retained following 
institutional policy, and a copy of the signed consent form should be provided to the subject.  
The detailed process of obtaining informed consent is outlined in Appendix A.  
26.4 Subject Confidentiality  
The investigator must ensure that the subject´s confidentiality and integrity are maintained. In the eCRFs or 
other documents transferred to the sponsor, the subject identification number should identify subjects only. 
Documents that are not transferred to sponsor, should be kept in strict confidence by the investigator.  
In compliance with GCP, it is required that the investigator and the institution permit authorized representatives 
of the sponsor, the CA, and the IRB/IEC direct access to review the subject’s original records for verification of 
study-related procedures and data. Direct access includes examining, analyzing, verifying, and reproducing any 
records and reports that are important to the evaluation of the study. The investigator is obligated to inform 
and obtain the consent of the subject to permit named representatives to have access to his/her study-related 
records without violating the confidentiality of the subject.  
26.5 Investigator Signatory Obligations 
The coordinating investigators should sign the clinical study protocol and report, indicating agreement with the 
analyses, results, and conclusions of the report. 
 
27 ADMINISTRATIVE AND LEGAL OBLIGATIONS 
27.1 Compensation to Investigator 
The trial is initiated and financially supported by SynAct Pharma. The details of compensation are specified in 
separate contracts between the sponsor and the investigational sites. The below table gives a more detailed 
overview of the different payments: 
Figure 2: Investigator Payments 
Visit 
Week 
Total payment including  
 
Euro 
Screening 
V1 
 
Baseline 
V2 
 
Treatment Week 1 
V3 
 
Treatment Week 2 
V4 
 
Treatment Week 3 
V5 
 
Treatment Week 4 
V6 
 
Final visit/WD 
V7 
 
Follow-up Call 
V8 
 
Total 
  
 
The total amount is intended to cover the costs incurred by the hospital in connection with the completion of 
the trial. The amount will be paid into the hospital's account. The department's staff and doctors have no 
financial relationship with SynAct Pharma. 


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27.2 Publication Policy 
SynAct Pharma retains exclusive ownership of all data, results, reports, findings, discoveries, and any other 
information collected during this trial. Therefore, SynAct Pharma reserves the right to use the data from the 
present trial, in order to submit them to the regulatory authorities of any country. 
By signing the Investigator Agreement, the investigator agrees that the results of this trial may be used for 
submission to national and/or international regulatory authorities. The regulatory bodies will be notified of the 
investigator's name, address, qualifications, and extent of involvement. 
SynAct Pharma supports the exercise of academic freedom and has no objection to publication by the principal 
investigator of the results of the study based on information collected or generated by the principal investigator, 
whether or not the results are favorable to the SynAct Pharma product. However, to ensure against inadvertent 
disclosure of confidential information or unprotected inventions, the investigator will provide SynAct Pharma an 
opportunity to review any proposed publication or other types of disclosure of the results of the study 
(collectively "Publication") before it is submitted or otherwise disclosed.  
The investigator will provide any publication to SynAct Pharma at least 30 days before they are submitted for 
publication or otherwise disclosed. If any patent action is required to protect intellectual property rights, the 
investigator agrees to delay the disclosure for a period not to exceed an additional 60 days.  
The investigator will, on request, remove any previously undisclosed confidential information before disclosure, 
except for any study- or SynAct Pharma product-related information necessary to the appropriate scientific 
presentation or understanding of the study results.  
If the study is part of a multicenter study, investigator agrees that the first publication is to be a joint publication 
covering all study sites and that any subsequent publications by the principal investigator will reference that first 
publication. However, if a joint manuscript has not been submitted for publication within 12 months of 
completion or termination of the study at all participating sites, the investigator is free to publish separately, 
subject to the other requirements of this section.  
SynAct Pharma fulfills its commitment to publicly disclose clinical trial results through posting the results of 
studies on www.clinicaltrials.gov (ClinicalTrials.gov), the European Clinical Trials Database (EudraCT), and other 
public registries in accordance with applicable local laws/regulations.   
In all cases, SynAct Pharma will report the study results in an objective, accurate, balanced, and complete manner 
regardless of the outcome of the study or the country in which the study was conducted.   
27.3 Insurance Information 
In accordance with the laws and regulations of the country in which the study is performed, the sponsor will 
ensure its liability towards patients sustaining bodily injury as a direct result of participation in the study.  All 
relevant documentation regarding such insurance will be filed in the TMF and/or ISF, as appropriate. 
27.4 Compensation to Subjects 
Subjects will not receive any compensation for participating in this study, but they may be reimbursed for the costs 
related to transportation covered by showing train tickets or similar.  
 
 


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28 REFERENCES 
1. 
Perretti et al. Trends Pharmacol Sci. 36:737-55, 2015 
2. 
Brzoska et al. Endocr Rev. 29:581-602, 2008 
3. 
Montero-Melendez et al. Am J Pathol. 179:259-69, 2011 
4. 
Catania et al., 2004 
5. 
Garcıa-Borron et al. Pigment Cell Res 18: 393–410, 2005 
6. 
Slominski et al., 2000 
7. 
Hunt et al., 1994 
8. 
Abdel-Malek et al., 1995 
9. 
Abdel- Malek, 2001 
10. 
Manna and Aggarwal, 1998 
11. 
Buckley and Ramachandran, 1981 
12. 
Mountjoy et al., 1992 
13. 
Xia and Wikberg, 1996 
14. 
Boston, 1999 
15. 
Chhajlani, 1996 
16. 
Gantz et al., 1993 
17. 
Roselli-Rehfuss et al., 1993 
18. 
Getting, 2002 
19. 
Li et al., 1996 
20. 
Chen et al., 2000 
21. 
Guarini et al., 2002 
22. 
Getting and Perretti, 2000 
23. 
Alvaro et al., 1996 
24. 
Mountjoy et al., 1994 
25. 
Marsh et al., 1999 
26. 
Van der Ploeg et al., 2002 
27. 
Taylor and Namba, 2001 
28. 
Chen et al., 1997 
29. 
Thody and Shuster, 1970 
30. 
Lindskog et al., 2010. 
31. 
Silman AJ, Pearson JE, Epidemiology and genetics of rheumatoid arthritis. Arthritis Res. 2002; 4 Suppl 
3:S265-72. Epub 2002 May 9 


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32. 
Gibofsky A. Overview of epidemiology, pathophysiology, and diagnosis of rheumatoid arthritis. Am J 
Manag Care 2012;18:S295-302 
33. 
Blumberg S, Fox D. Rheumatoid Arthritis: Guidelines for Emerging Therapies. Am J Manag Care. 
2001;7(6):617-26. 
34. 
Hirano T. The biology of interleukin-6. Chem immunol. 1992;51:153-180 
35. 
Keller TK, Wanagat J, Erschler WB. Molecular and cellular biology of interleukin-6 and its receptor. 
Frontiers Biosci. 1996;1:340-357 
36. 
Metzger S, Hassin T, Barash V, Pappo O, Chajek-Shaul T. Reduced body fat and increased hepatic 
lipid synthesis in mice bearing interleukin-6-secreting tumor. Am J Physiol Endocrinol Metab. 
2001;281:E597-E965 
37. 
Tamura T, Udagawa N, Takahashi N, Miyaura C, Tanaka S, Yamada Y, et al. Soluble interleukin-6 
receptor triggers osteoclast formation by interleukin-6. Proc Natl Acad Sci USA. 1993;90:11924-
11928 
38. 
Taub R. Hepatoprotection via the IL-6/Stat3 pathway. J Clin Invest 2003;112:978-980 
39. 
Hirano T, Matsuda T, Turner M, Miyasaka N, Buchan G, Tang B, et al. Excessive production of IL-6/B 
cell stimulatory factor-2 in rheumatoid arthritis. Eur J Immunol. 1988; 18:1797-1801 
40. 
Houssiau FA, Devogelaer JP, Van Damme J, de Deuxchaisnes CN, Van Snick J. IL-6 in synovial fluid 
and serum of patients with rheumatoid arthritis and other inflammatory arthritides. Arthritis 
Rheum. 1988;31:784-788 
41. 
Madhok R, et al. The effect of second line drugs on serum interleukin 6 levels in rheumatoid 
arthritis. Arthritis Rheum. 1990;33:S154. Abstract 
42. 
Salaffi F1, Cimmino MA, Leardini G, Gasparini S, Grassi W. Disease activity assessment of 
rheumatoid arthritis in daily practice: validity, internal consistency, reliability and congruency of the 
Disease Activity Score including 28 joints (DAS28) compared with the Clinical Disease Activity Index 
(CDAI). 2009 Jul-Aug; 27(4):552-9 
 
43. 
https://doi.org/10.1161/JAHA.116.003264. Journal of the American Heart Association. 
2016;5:e003264. Originally published June 17, 2016 
 
44. 
Rooney M, Whelan A, Feighery C, Bresnihan B Changes in lymphocyte infiltration of the synovial 
membrane and the clinical course of rheumatoid arthritis. Arthritis Rheum. 1989;32:361-369 
 
45. 
Walters MT, Smith JL, Moore K, Evans PR, Cawley MID An investigation of the action of disease 
modifying anti-rheumatic drugs on the rheumatoid synovial membrane: reduction in T lymphocyte 
subpopulations and HLA-DP and DQ antigen expression after gold or penicillamine therapy. Ann 
Rheum Dis 1987;30:1–10 
 
46. 
Firestein GS, Paine MM, Littman BH Gene expression (collagenase, tissue inhibitor of 
metalloproteinases, complement and HLA-DR) in rheumatoid arthritis synovium. Quantitative 
analysis and effect of intra-articular corticosteroids. Arthritis Rheum 1991;34:1094–1105 
 


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47. 
Firestein GS, Paine MM, Boyle DL Mechanism of methotrexate action in rheumatoid arthritis. 
Selective decrease in synovial collagenase gene expression. Arthritis Rheum 1994;37:193–200 
 
48. 
Yanni G, Farahat MNMR, Poston RN, Panayi GS Intramuscular gold decreases cytokine expression 
and macrophage numbers in the rheumatoid synovial membrane. Ann Rheum Dis 1994;53:315–322 
 
49. 
Youssef PP, Cormack J, Evill CA, Peter DT, Roberts-Thompson PJ, Ahern MJ, et al. Neutrophil 
trafficking into inflamed joints in patients with rheumatoid arthritis and the effect of 
methylprednisolone. Arthritis Rheum 1996;39:236–242 
 
50. 
Youssef PP, Haynes DR, Triantafillou S, Parker A, Gamble JR, Roberts-Thomson PJ, et al. Effects of 
pulse methylprednisolone on inflammatory mediators in peripheral blood, synovial fluid, and 
synovial membrane in rheumatoid arthritis. Arthritis Rheum 1997;40:1400–1408 
 
51. 
Dolhain RJEM, Tak PP, Dijkmans BAC, de Kuiper P, Breedveld FC, Miltenburg AMM Methotrexate 
treatment reduced inflammatory cell numbers, expression of monokines and of adhesion molecules 
in synovial tissue of patients with rheumatoid arthritis. Br J Rheumatol 1998;37:502–508 
 
52. 
Bresnihan B, Tak PP Synovial tissue analysis in rheumatoid arthritis. Ballieres Clin Rheumatol 
1999;13:645–659 
 
53. 
Non-Clinical Safety Studies for the Conduct of Human Clinical Trials for Pharmaceuticals (M3, rev 1). 
International Conference on Harmonization. Current Step 4 version, dated 9 November 2000. 
 
 


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29 APPENDICES 
29.1 Appendix A: Informed Consent Procedure 
This appendix lists the procedure for the verbal information meeting and obtaining of consent from the 
subjects.  
A possible subject, who has been diagnosed with RA in the clinic, will be contacted by the investigator and 
approached for the study. If the subject is expressing interest in the study, the information sheet will be handed 
out, and the subject will be invited to a verbal information meeting.  
The information must be given by the investigator or her designee (physician), who has the scientific knowledge 
to the disease area and a thorough knowledge of the protocol.  
The possible subject will be informed that the meeting is an inquiry for participation in a scientific trial and that 
the person has the right to bring a companion to the information meeting. 
The possible subject’s right to remain “not known on health condition” will be taken into consideration.  
The verbal information will be given based on the written information document, which will be provided during 
the information meeting. 
The information will be given in plain language, without any technical or value-laden phrases.  
The information will be given in such a manner, that it is adapted to the person. 
The information will take place without any disturbance or interruptions.  
The possible subject will have the possibility to asked questions. 
The person, giving the verbal information, is responsible for ensuring, that the possible subject has understood 
all information provided, before entering into the study.  
Consent to participate in the study is given based on the written and verbal information and should, therefore, 
in the case no time for consideration is required, be given in relation to the information meeting. If time for 
consideration is desired, a new appointment should be made.   
The responsible investigator signs the consent form in continuation of the information meeting. 
If new information concerning the effect, risks, side effects, complication or inconveniences in the study is 
revealed during the study, or if the study design is considerably changed, the subject will be informed hereof. In 
such cases, the subject must re-consent to continue in the study.  
If the study is prematurely discontinued, the subject must be informed hereof.  
The subject will be asked if he/she agrees to have his/her primary care physician informed of his/her 
participation in the clinical study. If the subject agrees to such notification, the investigator shall inform the 
subject’s primary care physician of the subject’s participation in the clinical study.  


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29.2 Revision History 
29.2.1 Protocol Version 8.0 to Protocol Version 9.0 
Version Date 
Version 8.0, 04SEP2020 
Version 9.0, 14JAN2021 
Page 
Section 
WAS 
IS 
18, 37 
Synopsis, 15.6 
The study is to be conducted at sites in 
Europe 
The study is to be conducted at sites in 
Europe and Moldova 
36 
15.1 Study Design 
A minimum of 90 subjects are expected to 
complete the study. Up to 120 subjects 
are planned to be enrolled to account for 
discontinuation rate. The rationale for the 
number of subjects required is outlined in 
the section on sample size determination. 
The below Figure 1 shows the general 
study design. 
A minimum of 90 subjects are expected to 
complete the study, plus 45 subjects from 
Bulgaria and/or Moldova for a sub-study 
(see Section 15.2). Up to 120 subjects are 
planned to be enrolled for the main study 
to account for discontinuation rate, and 
up to 60 subjects for the sub-study. The 
rationale for the number of subjects 
required is outlined in the section on 
sample size determination. The below 
Figure 1 shows the general study design. 
36 
15.2 Sub-study of 
subjects from 
Bulgaria/ Moldova 
 
As Bulgaria and Moldova did not 
participate in Part 1 of the study, a sub-
study has been added to investigate the 
effect in these two countries separately. 
In addition to analyzing the main study 
and the sub-study separately, all data will 
be pooled to investigate the overall effect 
in all participating countries. 
 
36 
15.3 Part 1 
15.2 Part 1 
15.3 Part 1 (main study only) 
37 
15.4.1 Number of 
Subjects in Part 2 
A minimum of 66 subjects is expected to 
complete Part 2 of the study. About 88 
subjects are planned to be enrolled in 
accounting for discontinuation rate.  
The rationale for the number of subjects 
required is outlined in the section on 
sample size determination. 
 
A minimum of 66 subjects in the main 
study is expected to complete Part 2 of 
the study, and 45 subjects in the sub-
study. About 88 subjects are planned to 
be enrolled in the main study in 
accounting for discontinuation rate, and 
about 60 subjects in the sub-study.  
The rationale for the number of subjects 
required is outlined in the section on 
sample size determination. 
 
67 
23.2 Determination 
of Sample Size 
 
23.2.1 Main Study 
67 
23.2 Determination 
of Sample Size 
 
23.2.2 Sub-study  
For the countries in the sub-study, a 
smaller effect size is expected compared 
to the main study. Thus, a smaller 
variation (standard deviation) is expected 
for the mean change in CDAI from 
baseline. For a sample size of 15 subjects 
and a standard deviation for the mean 
change of 2.5 points, a 95% confidence 
interval will be around 3.2 points wide 
with 80% probability. This interval width 
provides an acceptable precision of the 
estimate of the primary efficacy 
endpoint. 


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The sub-study is designed to provide a 
minimum of 15 subjects in each of the 
treatment groups (Part 2 only). 
 
 
Protocol Version 7.0 to Protocol Version 8.0 
Version Date 
Version 7.0, 23APR2020 
Version 8.0, 04SEP2020 
8 
5. Glossary of 
Abbreviations 
 
- 
Statens Serums Institut (SSI) 
48 Study Flow 
Chart 
Table 3 
- 
Blood sample (MC1R genotype analysis)  
 
49 
20.1.2 Visit 2, the 
Baseline Visit 
Blood samples (hematology, biochemistry 
and TSH, T3, and T4) 
Blood samples (hematology, MC1R 
genotype analysis, biochemistry and TSH, 
T3, and T4) 
56 
21.1.9.2 MC1R 
genotype analysis 
- 
The human melanocortin receptor type 1 
(MC1R) is a highly polymorphic gene. It is 
known that some receptor variants are 
associated with loss of function when 
characterized by the receptor’s ability to 
induce cAMP accumulation. There is 
evidence that the loss of function is 
restricted to the cAMP pathway, i.e., the 
ability to stimulate the ERK 
phosphorylation pathway, the pathway 
stimulated by AP1189, for most receptor 
variants are preserved.  
At baseline or any other visit after 
randomization, a blood sample will be 
taken once to identify the MC1R variant 
in randomized patients. 
The blood sample is stored at -80 ° in a 
research biobank until shipment and 
subsequent analysis at Statens Serum 
Institut (SSI). The genotype sequencing 
method is used in the blood sample 
analysis, meaning that only the gene 
variations that have to do with the 
melanocortin receptor are examined. 
The company Genetelligence is 
responsible for the interpretation of the 
genetic tests, and the results are only 
used in the above study. 
All blood samples will be destroyed after 
analysis, and no samples will be saved for 
future research. 
56 
21.1.9.3 Thyroid 
function 
Thyroxine (T4) free, Triiodothyronine (T3) 
total or free, and the thyroid-stimulating 
hormone (TSH).  
Thyroxine (T4) total or free, 
Triiodothyronine (T3) total or free, and the 
thyroid-stimulating hormone (TSH).  
29.2.2 Protocol Version 6.0 to Protocol Version 7.0 
Version Date 
Version 6.0, 22JAN2020 
Version 7.0, 23APR2020 
Page 
Section 
WAS 
IS 


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16 Synopsis, 35 
Study design, 15.2 
Part 1, and 15.3 
Part 2 
• 
Group A: AP1189 dose 50 mg (12 
subjects) or  
• 
Group B: placebo (6 subjects) 
Steering Committee (SC) meeting 
• 
Group C: AP1189 dose 100 mg (12 
subjects) or  
• 
Group D: placebo (6 subjects) 
INTERIM ANALYSIS 
Part 2: All subjects will be randomized into 
either design 1, 2 or 3 based on data from 
the interim analysis. 
• 
Design 1: AP1189 dose 50 mg (36 
subjects) or placebo (18 subjects) 
plus MTX (10-25 mg) weekly 
• 
Design 2: AP1189 dose 100 mg (36 
subjects) or placebo (18 subjects) 
plus MTX (10-25 mg) weekly 
• 
Design 3: Continue with the same 
doses as in Part 1, in a 1:1:1 ratio 
(AP1189 50 mg (18 subjects), AP1189 
100 mg (18 subjects) or placebo (18 
subjects)) plus MTX (10-25 mg) 
weekly 
• 
Group A: AP1189 dose 50 mg (min.8 
subjects) or  
• 
Group B: placebo (min. 4 subjects) 
Steering Committee (SC) meeting 
• 
Group C: AP1189 dose 100 mg (min. 
8 subjects) or  
• 
Group D: placebo (min. 4 subjects) 
INTERIM ANALYSIS 
Part 2: All subjects will be randomized into 
either design 1, 2 or 3 based on data from 
the interim analysis. 
• 
Design 1: AP1189 dose 50 mg (44 
subjects) or placebo (22 subjects) 
plus MTX (10-25 mg) weekly 
• 
Design 2: AP1189 dose 100 mg (44 
subjects) or placebo (22 subjects) 
plus MTX (10-25 mg) weekly 
Design 3: Continue with the same doses as 
in Part 1, in a 1:1:1 ratio (AP1189 50 mg 
(22 subjects), AP1189 100 mg (22 subjects) 
or placebo (22 subjects)) plus MTX (10-25 
mg) weekly 
20 Synopsis 
Sample size 
considerations 
The sample size is calculated to provide an 
acceptable precision of a 90% confidence 
interval for the primary endpoint, the 
mean change in CDAI from baseline 
The sample size is calculated to provide an 
acceptable precision of a 95% confidence 
interval for the primary endpoint, the 
mean change in CDAI from baseline 
27 
10.1.2 Summary of 
Result from Part IV 
(unblinded, non-
validated data as 
the full report of 
data is still 
pending) 
10.1.2 Summary of Result from Part IV 
(unblinded, non-validated data as the full 
report of data is still pending) 
10.1.2 Summary of Result from Part IV  
28 
10.1.6 Safety 
Conclusion from 
Part 4, (unblinded, 
non-validated data 
as the full report of 
data is still 
pending) 
 
10.1.6 Safety Conclusion from Part 4, 
(unblinded, non-validated data as the full 
report of data is still pending) 
 
10.1.6 Safety Conclusion from Part 4 
 
 
34 
15.1 Study Design 
A minimum of 90 subjects are expected to 
complete the study. Up to 120 subjects 
are planned to be enrolled to account for 
up to 25 % discontinuation rate. 
A minimum of 90 subjects are expected to 
complete the study. Up to 120 subjects 
are planned to be enrolled to account for 
discontinuation rate. 
35 
15.2.1 Number of 
Subjects in Part 1 
A minimum of 36 subjects is expected to 
complete Part 1 of the study. About 48 
subjects are planned to be enrolled in 
accounting for approximately 25 % 
discontinuation rate.  
A minimum of 24 subjects is expected to 
complete Part 1 of the study. About 32 
subjects are planned to be enrolled in 
accounting for discontinuation rate. 
36 
15.3.1 Number of 
Subjects in Part 2 
A minimum of 54 subjects is expected to 
complete Part 2 of the study. About 72 
subjects are planned to be enrolled in 
accounting for approximately 25 % 
discontinuation rate.  
A minimum of 66 subjects is expected to 
complete Part 2 of the study. About 88 
subjects are planned to be enrolled in 
accounting for discontinuation rate.  
36 
15.7 Steering 
Committee (SC) 
The SC will review blinded laboratory data 
from the first 18 subjects randomized into 
group A or B before the next 18 subjects in 
The SC will review blinded laboratory data 
from the first min. 12 subjects randomized 
into group A or B before the next min. 12 


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Part I, group C/D can be included and 
randomized.  
subjects in Part I, group C/D can be 
included and randomized.  
36 
15.8 Data 
Monitoring 
Committee (DMC) 
The DMC will review the unblinded data 
from the interim analysis of the first 36 
subjects from Part 1. 
The DMC will review the unblinded data 
from the interim analysis of the first min. 
24 subjects from Part 1. 
37 
15.9 Criteria for 
Choice of Design 
for Part 2 
Design 1: AP1189 dose 50 mg (36 
subjects) or placebo (18 subjects) plus 
MTX (10-25 mg) will be applied if: 
Design 2: AP1189 dose 100 mg (36 
subjects) or placebo (18 subjects) plus 
MTX (10-25 mg) will be applied if: 
Design 3: Continue with the same doses as 
in Part 1, in a 1:1:1 ratio (AP1189 50 mg 
(18 subjects), AP1189 100 mg (18 subjects) 
or placebo (18 subjects)) plus MTX (10-25 
mg) will be applied if: 
Design 1: AP1189 dose 50 mg (min. 44 
subjects) or placebo (min. 22 subjects) 
plus MTX (10-25 mg) will be applied if: 
Design 2: AP1189 dose 100 mg (min. 44 
subjects) or placebo (min. 22 subjects) 
plus MTX (10-25 mg) will be applied if: 
Design 3: Continue with the same doses as 
in Part 1, in a 1:1:1 ratio (AP1189 50 mg 
(min. 22 subjects), AP1189 100 mg (min. 
22 subjects) or placebo (min. 22 subjects)) 
plus MTX (10-25 mg) will be applied if: 
65 
23.2 Determination 
of Sample Size 
Calculations of sample size are based on a 
90% confidence interval for the mean 
change in CDAI from baseline. For a 
sample size of 12 subjects, and a standard 
deviation for the mean change of 3 points, 
a 90% confidence interval will be around 
3.4 points wide with 80% probability. This 
interval width provides an acceptable 
precision of the estimate of the primary 
efficacy endpoint. For a sample size of 18 
subjects, the interval will be around 2.8 
points wide, which provides good 
precision. If the sample size is larger, or if 
the standard deviation is smaller, the 
interval will be shorter (i.e., the precision 
will be higher). A larger standard deviation 
than 3 points is unlikely. SAS proc power is 
used for the calculations. 
The study is designed to provide a 
minimum of 12 subjects in each treatment 
group, and a total of 90 patients. 
Calculations of sample size are based on a 
95% confidence interval for the mean 
change in CDAI from baseline. For a 
sample size of 25 subjects, and a standard 
deviation for the mean change of 3 points, 
a 95% confidence interval will be around 
2.8 points wide with 80% probability. This 
interval width provides a good precision of 
the estimate of the primary efficacy 
endpoint. For a sample size of 30 subjects, 
the interval will be around 2.5 points 
wide, which provides even better 
precision. If the sample size is larger, or if 
the standard deviation is smaller, the 
interval will be shorter (i.e., the precision 
will be higher). A larger standard deviation 
than 3 points is unlikely. SAS proc power is 
used for the calculations. 
The study is designed to provide a 
minimum of 30 subjects in each of the 
treatment groups that proceed to Part 2, 
and a total of 90 subjects. 
29.2.3 Protocol Version 5.0 to Protocol Version 6.0 
Version Date 
Version 5.0, 16DEC2019 
Version 6.0, 22JAN2020 
Page 
Section 
WAS 
IS 
18 Synopsis, 38 
(16.2) 
Main criteria for 
inclusion (11) 
11. NSAIDs (up to the maximum 
recommended dose) are permitted if the 
dose has been stable for at least 6 weeks 
prior to baseline 
 
 
19 Synopsis, 39 
(16.3) 
Main criteria for 
exclusion  
 
EXCLUSION CRITERIA 17-20 ONLY APPLY 
FOR SUBJECTS IN NORWAY: 
17. Evidence of moderate and/or severe 
organ dysfunction  
18. Abnormal chest x-ray (as per the 
discretion of the investigator) 
19. Evidence of positive hepatitis 
serology 
20. Evidence of peptic ulcer disease 


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17 Synopsis, 36 
Synopsis and 
section 15.5 
The study is to be conducted at 6 sites 
distributed between Denmark, Sweden 
and Norway 
The study is to be conducted at sites in 
Europe 
56 and Table 3, 
page 48 
21.1.9.3 
Thyroxine (T4) free, triiodothyronine (T3) 
total, and the thyroid-stimulating 
hormone (TSH). Blood samples for 
measuring the thyroid function will be 
taken at all visits 
Thyroxine (T4) free, triiodothyronine (T3) 
total or free, and the thyroid-stimulating 
hormone (TSH). Blood samples for 
measuring the thyroid function will be 
taken at all visits 
36 
15.7 
The SC is appointed by the sponsor and 
comprises of the coordinating 
investigators and a sponsor medical 
responsible person. 
All decisions made by the SC will be 
documented and signed by its members as 
per the SC Charter (a specific charter will 
be developed to define roles and 
responsibilities). 
The SC will review blinded laboratory data 
from the first 18 subjects randomized into 
group A or B before the next 18 subjects in 
Part I, group C/D can be included and 
randomized.   
The SC will, based on the 
recommendations from the data 
monitoring committee (DMC), decide the 
design for Part 2. The SC will meet ad hoc. 
 
The SC is appointed by the sponsor and 
comprises of the coordinating 
investigators in Denmark, Sweden and 
Norway and a sponsor medical 
responsible person. 
All decisions made by the SC will be 
documented and signed by its members as 
per the SC Charter (a specific charter will 
be developed to define roles and 
responsibilities). 
The SC will review blinded laboratory data 
from the first 18 subjects randomized into 
group A or B before the next 18 subjects in 
Part I, group C/D can be included and 
randomized.   
The SC will, based on the 
recommendations from the data 
monitoring committee (DMC), decide the 
design for Part 2. The SC will meet ad hoc. 
34, 66 
14.2, 23.5.2 
The effects of AP1189 against placebo will 
be evaluated by assessing the following by 
treatment group: 
• 
Proportion of subjects achieving 
a reduced number of swollen 
and tender joints (SJC and TJC, 
respectively) at week 4 
compared to baseline 
• 
Proportion of subjects achieving 
a change in CDAI score at week 4 
compared to baseline 
o 
Proportion of subjects 
with a 5-point 
decrease 
o 
Proportion of subjects 
with a 10-point 
decrease 
o 
Proportion of subjects 
with a 15-point 
decrease 
• 
Proportion of subjects achieving 
a change in DAS28 at week 4 
compared to baseline 
• 
Change of HAQ-DI at week 4 
compared to baseline  
• 
Change of FACIT-Fatigue at week 
4 compared to baseline 
• 
Proportion of subjects achieving 
ACR response assessed by ACR 
20, ACR 50, and AC70 
 
The effects of AP1189 against placebo will 
be evaluated by assessing the following by 
treatment group: 
• 
Proportion of subjects achieving 
a reduction of more than 10 
(ten) swollen and/or tender 
joints (SJC and TJC summarized) 
at week 4 compared to baseline 
• 
Proportion of subjects achieving 
a change in CDAI score at week 4 
compared to baseline 
o 
Proportion of subjects 
with a 5-point 
decrease 
o 
Proportion of subjects 
with a 10-point 
decrease 
o 
Proportion of subjects 
with a 15-point 
decrease 
• 
Proportion of subjects achieving 
a change in DAS28 from 
DAS28>3.2 to DAS28 ≤ 3.2 at 
week 4 compared to baseline 
• 
Change of HAQ-DI at week 4 
compared to baseline  
• 
Change of FACIT-Fatigue at week 
4 compared to baseline 
• 
Proportion of subjects achieving 
ACR response assessed by ACR 
20, ACR 50, and AC70 
 
 


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29.2.4 Protocol Version 4.0 to Protocol Version 5.0 
Version Date 
Version 4.0, 31OCT2019 
Version 5.0, 16DEC2019 
Page 
Section 
WAS 
IS 
17 Synopsis, 33 
Study Objectives  
• Proportion of subjects achieving a 
reduction of more than ten swollen 
joints at week 4 compared to baseline 
• Proportion of subjects achieving a 
reduction of more than 10 tender joints 
at week 4 compared to baseline 
• Proportion of subjects achieving a 
reduction of more than 10 (ten) 
swollen and/or tender joints at week 4 
compared to baseline 
18 Synopsis, 38 
(16.2) 
Main criteria for 
inclusion (4) 
Polyarthritis with joint swelling and 
tenderness of a minimum of three joints 
out of 68 joints tested 
Arthritis with joint swelling and 
tenderness of a minimum of three joints 
out of 68 joints tested 
36 
15.8 
The DMC is established by the sponsor 
and consists of a group of three study 
independent members: two independent 
external experts (a Scientific & Medical 
Director (chief physician) and a professor 
and specialist in hepatology and clinical 
pharmacology at Bispebjerg hospital), and 
an independent external statistician. 
The DMC is established by the sponsor 
and consists of a group of three study 
independent members: two independent 
external experts (a rheumatologist and a 
professor and specialist in hepatology and 
clinical pharmacology at Bispebjerg 
hospital), and an independent external 
statistician. 
34, 66 (23.5.1) 
14.1 and 23.5.1 
The change in CDAI score from severe 
(CDAI > 22) to moderate (CDAI ≤ 22) after 
4 weeks of treatment compared to 
baseline, by treatment group. 
 
The change in CDAI after 4 weeks of 
treatment compared to baseline will be 
evaluated by assessing the following, by 
treatment group:  
• Mean change in CDAI from baseline to 
week 4 
• Proportion of subjects with a change 
in CDAI score from severe (CDAI > 22) 
to moderate (CDAI ≤ 22) at week 4 
compared to baseline 
45  
19.1.1.1 
In case of an increase in ALT equal to 3x 
the upper normal level, MTX treatment 
must be stopped for one week. The 
IMP/placebo treatment continues 
unchanged. After one week, treatment 
with MTX resumes if the liver enzymes are 
normalized. 
If ALT increases again, the MTX tablet 
treatment is changed to MTX injection.  
For a more detailed instruction see 
Appendix B. 
It is recommended with more frequent 
blood test in case of elevation of liver 
enzymes. 
 
 
Transaminase Increase:  
A table is added with the information 
from section 29.2 (minor changes added), 
and Section 29.2 is deleted 
 
52 
20.1.7 
 
Urinalysis (dipstick) 
29.2.5 Protocol Version 3.0 to Protocol Version 4.0 
Version Date 
Version 3.0, 23AUG2019 
Version 4.0, 31OCT2019 
Page 
Section 
WAS 
IS 
17, 36 
7, 15.5 
The study is to be conducted at 6 sites 
distributed between Denmark, Sweden 
and the UK 
The study is to be conducted at 6 sites 
distributed between Denmark, Sweden 
and Norway 
 
 
 
 
 
 
 
 
29.2.6 Protocol Version 2.0 to Protocol Version 3.0 
Version Date 
Version 2.0, 20MAY2019 
Version 3.0, 23AUG2019 
Page 
Section 
WAS 
IS 


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6 
5 
CL/F          Apparent total clearance 
Cmax        Maximum plasma concentration 
CL/F          Apparent total clearance 
CLr            Renal clearance 
Cmax        Maximum plasma concentration 
15 
7 
INTERIM ANALYSIS 
Part 2: All subjects will be randomized into 
either design 1, 2 or 3 based on data from 
the interim analysis.  
Design 1: AP1189 dose 50 mg (36 subjects) 
or placebo (18 subjects)  
Design 2: AP1189 dose 100 mg (36 
subjects) or placebo (18 subjects) 
Design 3: Continue with the same doses as 
in Part 1, in a 1:1:1 ratio (AP1189 50 mg 
(18 subjects), AP1189 100 mg (18 subjects) 
or placebo (18 subjects)) 
INTERIM ANALYSIS 
Part 2: All subjects will be randomized into 
either design 1, 2 or 3 based on data from 
the interim analysis.  
Design 1: AP1189 dose 50 mg (36 subjects) 
or placebo (18 subjects) plus MTX (10-25 
mg) weekly 
Design 2: AP1189 dose 100 mg (36 
subjects) or placebo (18 subjects)  
plus MTX (10-25 mg) weekly 
Design 3: Continue with the same doses as 
in Part 1, in a 1:1:1 ratio (AP1189 50 mg 
(18 subjects), AP1189 100 mg (18 subjects) 
or placebo (18 subjects))  
plus MTX (10-25 mg) weekly 
16 
32 
7 
12.3 
Secondary efficacy objectives: (bullet 
point 3) 
• 
Proportion of subjects achieving 
a change in CDAI score 
• 
Proportion of subjects achieving 
a change in value to ≤ 3.2 as 
measured by DAS28 (disease 
activity score 28) at week 4 
compared to baseline 
 
Secondary efficacy objectives: (bullet 
point 3) 
• 
Proportion of subjects achieving 
a change in CDAI score at week 
4 compared to baseline 
o 
Proportion of subjects 
with a 5-point 
decrease 
o 
Proportion of subjects 
with a 10-point 
decrease 
o 
Proportion of subjects 
with a 15-point 
decrease 
• 
Proportion of subjects achieving 
a change in value to ≤ 3.2 as 
measured by DAS28 (disease 
activity score 28) at week 4 
compared to baseline 
 
17 
32 
 
 
 
 
 
 
 
 
 
32 
7 
12.4 
 
 
 
 
 
 
 
 
 
12.4 
Tertiary objectives: 
Effects of AP1189 compared to placebo at 
week 4 compared to baseline on 
inflammatory and collagen destructive 
biomarkers. The biomarkers include, but 
are not limited to: 
CXCL13 
IL-1β 
IL-6 
IL-10 and TNF-α 
 
A complete list of the biomarkers to be 
evaluated in the study is available in the 
study-specific Laboratory Manual. 
Tertiary objectives: 
Effects of AP1189 compared to placebo at 
week 4 compared to baseline on 
inflammatory and collagen destructive 
biomarkers. The biomarkers include: 
CXCL13 
IL-1β 
IL-6 
IL-10 and TNF-α 
 
19 
37 
7 
16.3 
(15.3 Exclusion Criteria) 
9. 
Evidence of serious uncontrolled 
concomitant cardiovascular, nervous 
system, pulmonary (including 
obstructive pulmonary disease), 
renal, hepatic, endocrine (including 
uncontrolled diabetes mellitus), or 
gastrointestinal disease 
(16.3 Exclusion Criteria) 
9. Evidence of serious uncontrolled 
concomitant cardiovascular, nervous 
system, pulmonary (including obstructive 
pulmonary disease), renal, hepatic, 
endocrine (including uncontrolled 
diabetes mellitus), or gastrointestinal 
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10. Uncontrolled disease states, such as 
asthma, psoriasis, or inflammatory 
bowel disease where flares are 
commonly treated with oral or 
parenteral corticosteroids 
11. Evidence of active malignant disease 
(except basal cell carcinoma of the 
skin that has been excised and cured) 
12.  Pregnant women or nursing  
(breastfeeding) mothers 
13. History of alcohol, drug, or chemical 
abuse within the 6 months prior to 
screening 
14. Neuropathies or other painful 
conditions that might interfere with 
pain evaluation 
15. Body weight of >150 kg 
10. Have prior renal transplant, current 
renal dialysis or severe renal insufficiency 
(determined by a derived glomerular 
filtration rate (GFR) using Cockcroft Gault 
formula of ≤ 30 ml/min/1,73m2 
calculated by the local lab 
11. Uncontrolled disease states, such as 
asthma, psoriasis, or inflammatory bowel 
disease where flares are commonly 
treated with oral or parenteral 
corticosteroids 
12. Evidence of active malignant disease 
(except basal cell carcinoma of the skin 
that has been excised and cured) 
 13. Pregnant women or nursing  
(breastfeeding) mothers 
14. History of alcohol, drug, or chemical 
abuse within the 6 months prior to 
screening 
15. Neuropathies or other painful 
conditions that might interfere with pain 
evaluation 
16. Body weight of >150 kg 
 
24 
10.1 
In the phase I study, the first dose of 
AP1189 in healthy volunteers was 
administered in single ascending dosing 
using a suspension for oral administration 
(AP1189SynActCS001 Part I), in a 
bioequivalence study using oral 
suspension as well as tablets ( 
AP1189SynActCS001 Part II) and in 14 
days repeated dosing. Fourteen days 
repeated dosing was initiated using a 
tablet formulation (AP1189SynActCS001 
Part III) and was completed 
(AP1189SynActCS001 Part IV) using the 
same suspension used in Part I.  
In the phase I study, the first dose of 
AP1189 in healthy volunteers was 
administered in single ascending dosing 
using a suspension for oral administration 
(SynActCS001 Part I), in a bioequivalence 
study using oral suspension as well as 
tablets (SynActCS001 Part II) and in 14 
days repeated dosing. Fourteen days 
repeated dosing was initiated using a 
tablet formulation (SynActCS001 Part III) 
and was completed (SynActCS001 Part IV) 
using the same suspension used in Part I. 
30 
11.3.2 
11.3.2 Benefits and Risks of Participation 
General conclusion from the first in man 
Phase 1 study: 
• 
AP1189 administered by oral 
route as a suspension was well 
tolerated up to 800 mg in single 
dose and up to 200 mg daily for 
14 days in repeated dose 
• 
The most frequent TEAE 
observed were mild to moderate 
intensity GI disorders mainly in 
the single dose part while 
increasing the dose, which could 
be explained by the amount of 
vehicle in the suspension 
increasing with the dose leading 
to a consistency and taste 
increase of the drug. These 
effects did not lead to any 
treatment discontinuation for 
any subject and the GI 
11.3.2 Benefits and Risks of Participation 
The potential benefits of participation, for 
all subjects in this study, is close 
monitoring of their medical condition and 
safety. Those randomized to an active 
treatment may have a benefit of less pain 
in affected joints. Subjects randomized to 
placebo are not expected to obtain any 
additional benefit, beyond close 
monitoring of their medical condition and 
safety. 
Based on available non-clinical data, 
AP1189 appears to be well tolerated at 
dose levels that induce exposure well 
above the expected therapeutic level 
expected to be reached with CMax values 
around 175 ng/ml.  
The toxicology studies showed clinical 
signs from the gastrointestinal system 
(reduced appetite, vomiting, and loose 
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tolerability was quite good when 
dosing for 14 days 
• 
Cardiovascular safety of AP1189 
under the study conditions was 
excellent 
• 
A total of five (5) subjects all 
included in cohort 3 (200 mg 
AP1189/placebo) had isolated 
increases in aminotransferases 
(no concomitant changes in 
alkalic phosphatases or bilirubin 
were reported). Three of the five 
subjects were treated with 
active drug and two subjects 
were treated with placebo. All 
elevated liver enzymes had 
returned to normal values at the 
EOS visit. 
The potential benefit of participation, for 
all subjects in this study, is close 
monitoring of their medical condition and 
safety. Those randomized to an active 
treatment may have a benefit of less pain 
in affected joints. Subjects randomized to 
placebo are not expected to obtain any 
additional benefit, beyond close 
monitoring of their medical condition and 
safety.  
Consequently, AP1189 present a good 
safety profile allowing its administration 
to patients at 50 mg or 100 mg doses for 4 
weeks.  
This study will provide additional efficacy 
and safety information on the benefit-risk 
profile of AP1189 
(subdued behavior). The clinical signs 
were most pronounced 
following iv dosing and thereby expected 
to be associated with high peak 
concentrations that hardly will be 
possible to reach following oral dosing. 
Further, AP1189 at high dose levels 
induced increased liver weight in rats and 
minipigs increased kidney weight in 
minipigs and increased the weight of the 
ovaries in female rats. Also, 
hypertrophy/hyperplasia of the thyroid 
glands was found to be most prominent 
in the rats. Follow-up studies in minipigs 
have identified that the treatment-
induced increases liver weight was fully 
reversible following recovery associated 
with a fully reversible induction of phase I 
and phase II enzymes. Consequently, the 
liver findings are to be considered related 
to increased workload due to fully 
reversible phase 1 and phase 2 enzyme 
induction. Likewise, the follicular thyroid 
hyperplasia in rats most likely is 
associated with increased hepatic 
turnover of thyroid hormones.  
In Phase 1 clinical trials laboratory 
parameters of the thyroid gland, such as 
thyroid-stimulating hormone, as well as 
liver enzymes, has been evaluated to 
monitor any effect in humans. No 
treatment-related effects were identified 
on thyroid hormones. Regarding liver 
enzymes, temporal increases up to 1.5x 
the upper normal value was identified 
following single dosing at 
supratherapeutic doses (600 and 800 mg) 
in a few individuals. Likewise, increases in 
ALAT was identified following repeat 
dosing at the 200 ng/ml dose level where 
3 out of 9 subjects showed increases 
above the normal upper level, where one 
measurement at one occasion reached 3x 
above the normal upper level. However, 
2 out of 3 placebo-treated individuals in 
the same cohort of subjects did also show 
increases above the normal upper level. 
All increased in liver enzymes were 
without concomitant changes in alkalic 
phosphatases, and bilirubin, and all 
values returned to normal at the end of 
the study. Nevertheless, liver values 
should be carefully monitored in 
upcoming clinical trials, and any clinically 
significant increases in liver enzymes 
should be carefully assessed and assessed 
relative to the subjects’ pretreatment 
liver function and co-medication.      
Studies on the compound’s ability to 
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human hepatocytes have identified 
AP1189 as a weak inducer of CYP1A2 
(also weak compared to omeprazole). Co-
medication with compounds metabolized 
through the CYP1A2 pathway should 
therefore until further be avoided.   
The cardiovascular study in minipigs 
showed an increase in relative heart rate 
at the highest dose tested (80 mg/kg). 
Consequently, even if this study did not 
reveal any treatment-related effects on 
blood pressure and ECG parameters, 
particular attention has been applied to 
the heart in Phase 1 clinical study. 
Dedicated tendency analysis on 
continued ECG assessments was 
conducted after both single and multiple 
dosing in Phase 1. The analyses that 
included testing of changes in ECG 
following dosing with a positive control 
knowing to induce QT prolongation 
showed no treatment effects of AP1189 
on ECG or heart rate. Consequently, 
AP1189 has shown excellent 
cardiovascular safety. 
Based on AUCs, the increase seems to be 
supra-proportional with an increase of 
2.36 for AUC0-t and 2.17 for AUC0-∞ 
when dose increased by 2. However, in 
the light of the small sample size (N = 3 or 
N = 6) this result should be interpreted 
with caution. 
Around 10% of AP1189 dose was 
excreted unchanged in the urine in 24 h 
on the dose range 50 - 800 mg. Mean CLr 
ranged from 2.96 to 4.68 L/h. 
Consequently, until specific PK evaluation 
in patients with severe impaired kidney 
function has been conducted, subjects 
with stage 5 Chronic Kidney Disease or 
higher (i.e., eGFR < 30 ml/min) should be 
excluded in clinical studies. 
Up to now, AP1189 has shown an 
excellent safety profile at all doses tested 
under the different conditions applied 
either in single or repeated 
administration for 14 days. As the 
maximum tolerated dose was not 
reached in Phase 1 and as the exposure 
following repeat dosing of AP1189 given 
as oral suspension showed that the 
exposure at the highest dose tested 
reached up to 5x the expected 
therapeutic levels, it is considered 
appropriate and safe to continue dosing 
in clinical phase 2 at the 50 and 100 mg 
dose levels. 
The effect of food intake on the 
absorption of AP1189 in the current 


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suspension formulation has not been 
systematically evaluated. However, it has 
been shown that the plasma profile of 
the compound, whether the first meal 
was served 1 hour or 4 hours post-dosing 
in the feasting state, is very similar. 
Further, it has been shown that intake of 
a glass of apple juice immediately after 
dosing does not reduce the absorption. 
Therefore, it is up to the subject whether 
they would like a glass of juice 
immediately after dosing.   
Consequently, AP1189 present an 
excellent safety profile allowing its 
administration to patients at 50 mg or 100 
mg doses for 4 weeks.  
This study will provide additional safety 
and efficacy information on the benefit-
risk profile of AP1189. 
 
32 
13  
13 EFFICACY ENDPOINTS 
13 SAFETY ENDPOINTS 
32 
13.1 
13.1 Primary Efficacy Endpoints 
The change in CDAI score from severe 
(CDAI > 22) to moderate (CDAI ≤ 22) after 
4 weeks of treatment compared to 
baseline, by treatment group 
13.1 Primary Safety Endpoint  
The safety of AP1189 against placebo by 
evaluating adverse events (AEs), serious 
adverse events (SAEs), and laboratory 
abnormalities. 
33 
14 and 14.1 
13  EFFICACY ENDPOINTS 
13.1 Primary Efficacy Endpoints 
The change in CDAI score from severe 
(CDAI > 22) to moderate (CDAI ≤ 22) after 
4 weeks of treatment compared to 
baseline, by treatment group. 
14 EFFICACY ENDPOINTS 
14.1  Primary Efficacy Endpoints 
The change in CDAI score from severe 
(CDAI > 22) to moderate (CDAI ≤ 22) after 
4 weeks of treatment compared to 
baseline, by treatment group. 
33 
14.2 
13.2 Secondary Efficacy Endpoints 
The effects of AP1189 against placebo will 
be evaluated by assessing the following by 
treatment group: 
• 
Proportion of subjects achieving 
a reduced number of swollen 
and tender joints (SJC and TJC, 
respectively) at week 4 
compared to baseline 
• 
Proportion of subjects achieving 
a change in CDAI  
• 
Proportion of subjects achieving 
a change in DAS28 at week 4 
compared to baseline 
• 
Change of HAQ-DI at week 4 
compared to baseline  
• 
Change of FACIT-Fatigue at week 
4 compared to baseline 
Proportion of subjects achieving ACR 
response assessed by ACR 20, ACR 50, and 
AC70 
14.2 Secondary Efficacy Endpoints 
The effects of AP1189 against placebo will 
be evaluated by assessing the following by 
treatment group: 
• 
Proportion of subjects achieving 
a reduced number of swollen 
and tender joints (SJC and TJC, 
respectively) at week 4 
compared to baseline 
• 
Proportion of subjects achieving 
a change in CDAI score at week 
4 compared to baseline 
o 
Proportion of subjects 
with a 5-point 
decrease 
o 
Proportion of subjects 
with a 10-point 
decrease 
o 
Proportion of subjects 
with a 15-point 
decrease 
• 
Proportion of subjects achieving 
a change in DAS28 at week 4 
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• 
Change of HAQ-DI at week 4 
compared to baseline  
• 
Change of FACIT-Fatigue at week 
4 compared to baseline 
Proportion of subjects achieving ACR 
response assessed by ACR 20, ACR 50, and 
AC70 
34 
15.3 
14.3 All subjects will be randomized into 
one design only, either design 1, 2, or 3 
based on data from the interim analysis:  
• 
Design 1: AP1189 dose 50 mg 
(36 subjects) or placebo (18 
subjects), once daily for 4 weeks 
(28 days) plus MTX (10-25 mg) 
weekly  
• 
Design 2: AP1189 dose 100 mg 
(36 subjects) or placebo (18 
subjects), once daily for 4 weeks 
(28 days) plus MTX (10-25 mg) 
weekly  
• 
Design 3: Continue with the 
same doses as in Part 1, in a 
1:1:1 ratio (AP1189 50 mg (18 
subjects), AP1189 100 mg (18 
subjects) or placebo (18 
subjects))  
Following a successful screening 
evaluation, subjects who fulfill the 
enrollment criteria will be randomized 
accordingly. 
15.3 All subjects will be randomized into 
one design only, either design 1, 2, or 3 
based on data from the interim analysis:  
• 
Design 1: AP1189 dose 50 mg 
(36 subjects) or placebo (18 
subjects), once daily for 4 weeks 
(28 days) plus MTX (10-25 mg) 
weekly  
• 
Design 2: AP1189 dose 100 mg 
(36 subjects) or placebo (18 
subjects), once daily for 4 weeks 
(28 days) plus MTX (10-25 mg) 
weekly  
• 
Design 3: Continue with the 
same doses as in Part 1, in a 
1:1:1 ratio (AP1189 50 mg (18 
subjects), AP1189 100 mg (18 
subjects) or placebo (18 
subjects)) plus MTX (10-25 mg) 
weekly 
Following a successful screening 
evaluation, subjects who fulfill the 
enrollment criteria will be randomized 
accordingly. 
35 
15.8 
14.8 Data Monitoring Committee (DMC) 
The DMC is established by the sponsor 
and consists of a group of three study 
independent members: two independent 
external experts (a Scientific & Medical 
Director (chief physician) and a specialist 
in internal medicine and former professor 
of pharmacotherapy), and an independent 
external statistician. A specific DMC 
charter will be developed to define roles 
and responsibilities. 
The DMC will review the unblinded data 
from the interim analysis of the first 36 
subjects from Part 1. The DMC will 
recommend a study design for Part 2 to 
the SC based on these data. All 
recommendations will be documented 
and signed by the DMC members, and 
they will provide a summary of the safety 
and tolerability data obtained in Part 1 
and their design recommendation for Part 
2. 
The independent external statistician will 
analyze data for the interim analysis, 
following the procedure described in the 
statistical analysis plan and the protocol.  
The DMC will hereafter meet ad hoc as 
appropriate. 
15.8 Data Monitoring Committee (DMC) 
The DMC is established by the sponsor 
and consists of a group of three study 
independent members: two independent 
external experts (a Scientific & Medical 
Director (chief physician) and a professor 
and specialist in hepatology and clinical 
pharmacology at Bispebjerg hospital, and 
an independent external statistician. A 
specific DMC charter will be developed to 
define roles and responsibilities. 
The DMC will review the unblinded data 
from the interim analysis of the first 36 
subjects from Part 1. The DMC will 
recommend a study design for Part 2 to 
the SC based on these data. All 
recommendations will be documented 
and signed by the DMC members, and 
they will provide a summary of the safety 
and tolerability data obtained in Part 1 
and their design recommendation for Part 
2. 
The independent external statistician will 
analyze data for the interim analysis, 
following the procedure described in the 
statistical analysis plan and the protocol.  
The DMC will hereafter meet ad hoc as 
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35 
15.9 
14.9 Criteria for Choice of design for Part 2 
Design 1: AP1189 dose 50 mg (36 
subjects) or placebo (18 subjects) will be 
applied if:  
Design 2: AP1189 dose 100 mg (36 
subjects) or placebo (18 subjects) will be 
applied if: 
Design 3: Continue with the same doses as 
in Part 1, in a 1:1:1 ratio (AP1189 50 mg 
(18 subjects), AP1189 100 mg (18 subjects) 
or placebo (18 subjects)) will be applied if: 
15.9 Criteria for Choice of design for Part 2 
Design 1: AP1189 dose 50 mg (36 
subjects) or placebo (18 subjects) plus 
MTX (10-25 mg) will be applied if:  
Design 2: AP1189 dose 100 mg (36 
subjects) or placebo (18 subjects) plus 
MTX (10-25 mg) will be applied if: 
Design 3: Continue with the same doses as 
in Part 1, in a 1:1:1 ratio (AP1189 50 mg 
(18 subjects), AP1189 100 mg (18 subjects) 
or placebo (18 subjects)) plus MTX (10-25 
mg) will be applied if: 
36 
15.10 
14.10 Stopping Rules 
In case of occurrence of a serious medical 
event (e.g., stroke, convulsion, etc.) or any 
SAE considered as related to the study 
drug, the DMC could decide to ask for 
unblinding to put the study on hold. After 
that, depending on the results of the 
unblinding, the study could either be 
stopped or continued. 
15.10 Stopping Rules  
In case of occurrence of a serious medical 
event (e.g., stroke, convulsion, etc.) or any 
SAE considered as related to the study 
drug, the DMC could decide to put the 
study on hold to unblind the study. After 
that, depending on the results of the 
unblinding, the study could either be 
stopped or continued. 
38 
16.5.2 
15.5.2 Discontinuation of Individual 
Subjects 
The investigator may also withdraw a 
subject from the treatment or the study 
for any of the following reasons:  
• 
If a subject who does not meet 
enrolment criteria is 
inadvertently enrolled 
• 
Enrolment in any other clinical 
trial with a study drug 
• 
If the subject, for any reason, 
requires treatment with another 
therapeutic agent that has been 
demonstrated to be effective for 
treatment of the study 
indication, discontinuation from 
the study occurs prior to the 
introduction of the new agent 
• 
The investigator stops the 
subject’s participation in the 
study for medical or safety 
reasons 
• 
If a female becomes pregnant 
In case of early subject discontinuation 
and the reason for discontinuation (if it is 
known) will be registered in the eCRF and 
source documentation. 
The sponsor can also decide to end the 
study for safety, regulatory, or other 
reasons consistent with applicable laws, 
regulations, and GCP. If the sponsor 
decides to stop the study, the subject 
should be informed of the reason hereof. 
16.5.2 Discontinuation of Individual 
Subjects 
The investigator may also withdraw a 
subject from the treatment or the study 
for any of the following reasons:  
• 
If a subject who does not meet 
enrolment criteria is 
inadvertently enrolled 
• 
Enrolment in any other clinical 
trial with a study drug 
• 
In case of severe worsening of 
symptoms, the investigator will 
be able to provide joint 
injections with corticosteroid as 
rescue medication. The use of 
local joint injection will be at 
the discretion of the 
investigator. The IMP/placebo 
treatment will continue as 
planned 
• 
If the subject, for any reason, 
requires treatment with another 
therapeutic agent (rescue 
medication not included) that 
has been demonstrated to be 
effective for treatment of the 
study indication, discontinuation 
from the study occurs prior to 
the introduction of the new 
agent 
• 
For medical or safety reasons 
• 
If a female becomes pregnant 
In case of early subject discontinuation 
and the reason for discontinuation (if it is 
known) will be registered in the eCRF and 
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The sponsor can also decide to end the 
study for safety, regulatory, or other 
reasons consistent with applicable laws, 
regulations, and GCP. If the sponsor 
decides to stop the study, the subject 
should be informed of the reason hereof. 
39 
17.1 
16.1 Subject Identification 
Each subject who signs the informed 
consent will be assigned a unique subject 
number (01-101 site 1, 02-101 site 2, etc.), 
which will be used as the subject’s 
identification in the eCRF and on all source 
documentation throughout the study.  The 
screened subjects will be consecutively 
numbered, and the first number at the 
screening list will be used to the first 
subject screened. In the case of re-
screening, a new screening number will be 
allocated. Subjects who are assigned a 
subject number but fails the 
randomization will be registered as a 
screen failure on the screening list. 
17.1 Subject Identification  
Each subject who signs the informed 
consent will be assigned a unique subject 
number (01-1001 site 1, 02-1001 etc.), 
which will be used as the subject’s 
identification in the eCRF and on all source 
documentation throughout the study.  The 
screened subjects will be consecutively 
numbered, and the first available number 
as listed in the CRF, will be used. In the 
case of re-screening, a new screening 
number will be allocated. Subjects who 
are assigned a subject number but fails 
the randomization will be registered as a 
screen failure on the screening list and in 
the CRF. 
39 
17.2 
16.2 Randomization and Treatment 
Assignment 
Following a successful screening 
evaluation, eligible subjects will be 
randomized into the study.  
Each subject will be assigned a unique 
randomization number in ascending order, 
based on a list provided by HB Medical, 
and assigned a protocol specified drug 
treatment. Randomization numbers 
should be assigned according to the list 
and should not be omitted or reused. 
The randomization list is based on block 
randomization.  
An external statistician will prepare the 
randomization list and emergency code 
envelopes. The randomization list will be 
kept strictly confidential, filed securely by 
HB Medical (or designee), and accessible 
only to authorized persons per HB 
Medical’s Standard Operating Procedures 
(SOPs) until the time of unblinding. A copy 
of the list is sent to PharmaLex Denmark, 
who is handling the pharmacovigilance.  
When a site has an eligible subject, they 
will send a Study Order Form to HB 
Medical. HB Medical will then prepare a 
batch of three treatments (for practical 
purposes) and send it by courier to the 
site together with the corresponding 
emergency code envelopes for the batch.  
The study treatment will be unknown to 
the Clinical Research Organization (CRO) 
and sponsor personnel associated with the 
study, all subjects, the investigator, and all 
site personnel except for the unblinded 
pharmacist(s) at HB Medical and the 
17.2 Randomization and Treatment 
Assignment 
Following a successful screening 
evaluation, eligible subjects will be 
randomized into the study.  
Each subject will be assigned a unique 
randomization number in ascending order, 
based on a list provided by HB Medical, 
and assigned a protocol specified drug 
treatment. Randomization numbers 
should be assigned according to the list 
and should not be omitted or reused. 
An external statistician will prepare the 
randomization list and emergency code 
envelopes. The randomization list will be 
kept strictly confidential, filed securely by 
HB Medical (or designee), and accessible 
only to authorized persons per HB 
Medical’s Standard Operating Procedures 
(SOPs) until the time of unblinding. A copy 
of the list is sent to PharmaLex Denmark, 
who is handling the pharmacovigilance.  
The study treatment will be unknown to 
the Clinical Research Organization (CRO) 
and sponsor personnel associated with the 
study, all subjects, the investigator, and all 
site personnel except for the unblinded 
pharmacist(s) and personnel at HB 
Medical and the unblinded statistician 
responsible for preparing the 
randomization list.  
 


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unblinded statistician responsible for 
preparing the randomization list.  
41 
18.3.1 
17.3.1 Drug Accountability 
The investigator at each site must 
maintain adequate records documenting 
the receipt, use, loss, or other disposition 
of drug supplies.  
The site pharmacist/study nurse (as 
appropriate per country) will verify that 
study drug supplies are received intact 
and in the correct quantities which will be 
documented by signing and dating the 
Proof of Receipt. An accurate (running) 
inventory of study drug will be kept by the 
site and will include the batch number, 
date of receipt, subject number, date, and 
initials of the person who dispense the 
drug, and finally the date and amount of 
study drug each subject return to the site. 
A sample of the Drug Accountability Form, 
following instructions provided by the 
monitor, will also be provided to the site 
pharmacist/study nurse. Accountability of 
the study drug will be performed and 
verified by the monitor throughout the 
study duration.  
All unused IMP/placebo must be 
registered, accounted for, and returned to 
SynAct Pharma or destroyed per 
instructions from SynAct Pharma and 
according to local regulations. The 
investigator, subinvestigator(s), and/or 
site pharmacist/study nurse agree not to 
supply study medication to any persons 
not enrolled in the study. 
18.3.1 Drug Accountability 
The investigator at each site must 
maintain adequate records documenting 
the receipt, use, loss, or other disposition 
of drug supplies.  
The site pharmacist/study nurse (as 
appropriate per country) will verify that 
study drug supplies are received intact 
and in the correct quantities which will be 
documented by signing and dating the 
Proof of Receipt. The site 
pharmacist/study nurse will also sign and 
date a Proof of Receipt for the 
corresponding code envelopes.  An 
accurate (running) inventory of study drug 
will be kept by the site and will include the 
batch number, date of receipt, subject 
number, date, and initials of the person 
who dispense the drug, and finally the 
date and amount of study drug each 
subject return to the site. A sample of the 
Drug Accountability Form, following 
instructions provided by the monitor, will 
also be provided to the site 
pharmacist/study nurse. Accountability of 
the study drug will be performed and 
verified by the monitor throughout the 
study duration.  
All unused IMP/placebo must be 
registered, accounted for, and returned to 
HB Medical or destroyed per instructions 
from SynAct Pharma and according to 
local regulations. The investigator, 
subinvestigator(s), and/or site 
pharmacist/study nurse agree not to 
supply study medication to any persons 
not enrolled in the study. 
42 
18.4 
17.4 Administration and Handling of Study 
Drug 
The study drug will be dispensed four 
times during Part 1 and Part 2 
respectively; at the Baseline Visit, visit 2, 
visit 3 and at visit 4. The study drug will be 
in a box with 8 bottles (study drug for one 
week’s use) containing powder of either 
AP1189/placebo, a funnel, and a 
measuring cup.  
The subject adds 50 ml of tap water to the 
powder in the bottle, shakes well for 
about 1 minute so that all the powder is 
dissolved and then immediately drink the 
solution. To ensure that the subject gets 
all the medicine in the bottle, the subject 
must rinse with 50 ml of water a few 
times. Between each rinse, the content of 
the bottle is drunk. Each subject will use 
one bottle daily during the treatment 
period.   
18.4 Administration and Handling of Study 
Drug 
The study drug will be dispensed four 
times during a subject’s participation in 
Part 1 and Part 2 respectively; at the 
Baseline Visit, visit 2, visit 3 and at visit 4. 
The study drug will be in a box with 8 
bottles (study drug for one week’s use) 
containing powder of either 
AP1189/placebo, a funnel, and a 
measuring cup.  
The subject adds 50 ml of tap water to the 
powder in the bottle, shakes well for 
about 1 minute allowing all powder to 
dissolve and then immediately drink the 
solution. The subject must rinse the 
bottle two times with 50 ml water to 
ensure ingesting all the medicine in the 
bottle. Between each rinse, the content of 
the bottle is drunk. Each subject will use 


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The subjects will be instructed to take the 
suspension once daily in the morning 
during the treatment period, except on 
visit days, where no medication should be 
taken before after blood sampling has 
been done.     
At the Baseline Visit, the subject will 
receive a diary to make daily records of 
what time the treatment is taken.  
The investigator or her/his designee is 
responsible for explaining the correct use 
of the study drug and the diary to each 
subject, and the subjects will receive a 
written instruction too.  
Subjects will be instructed to return empty 
bottles, unopened bottles and the diary at 
each visit. 
one bottle daily during the treatment 
period.   
The subjects will be instructed to take the 
suspension once daily in the morning 
about an hour before breakfast during 
the treatment period. It is up to the 
subject whether they would like to drink 
a glass of apple juice immediately after 
dosing. On the visit days, the medication 
should first be taken after blood sampling 
has been done.     
At the Baseline Visit, the subject will 
receive a diary to make daily records of 
what time the treatment is taken.  
The investigator or her/his designee is 
responsible for explaining the correct use 
of the study drug and the diary to each 
subject, and the subjects will receive a 
written instruction too.  
Subjects will be instructed to return empty 
bottles, unopened bottles and the diary at 
each visit. 
The effect of food intake on the 
absorption of AP1189 in the current 
suspension formulation has not been 
systematically evaluated. However, it has 
been shown that the plasma profile of the 
compound, whether the first meal was 
served 1 hour or 4 hours post-dosing in the 
fasting state, is very similar. Further, it has 
been shown that intake of a glass of apple 
juice immediately after dosing does not 
reduce the absorption. 
43 
19.1.1 
18.1.1 Methotrexate (MTX) 
All subjects should follow the local 
guideline for starting treatment with MTX 
and continue MTX treatment throughout 
their participation in the study. MTX is not 
provided by the sponsor, as it is part of the 
patients' regular treatment. 
19.1.1 Methotrexate (MTX) 
All subjects should follow the local 
guideline for each hospital and/or 
country for starting treatment with MTX 
and continue MTX treatment throughout 
their participation in the study. MTX is not 
provided by the sponsor, as it is not 
background treatment but part of the 
patients' regular treatment. 
44 
19.1.3 
18.1.3 Oral Corticosteroids 
Oral corticosteroids are prohibited within 
2 weeks prior to screening and during the 
entire treatment period and until the final 
visit (Visit 7).  
19.1.3 Oral Corticosteroids 
Oral corticosteroids are prohibited within 
2 weeks prior to screening and during the 
entire treatment period and until the final 
visit (Visit 7). Refer to section 19.2 for 
treatment of asthma patients. 
44 
19.2 
18.2 Prohibited Medicines 
The following medications and therapies 
are not permitted during the trial and 
would require 
discontinuation of trial treatment: 
• 
Oral, intramuscular, intravenous 
or intra-articular corticosteroids 
(permitted after week 5) 
• 
Biologic therapies for RA  
19.2 Prohibited Medicines 
The following medications and therapies 
are not permitted during the trial and 
would require 
discontinuation of trial treatment: 
• 
Oral, intramuscular, intravenous 
or intra-articular corticosteroids 
(permitted after week 5). 
(Asthma patients on stable 
prophylactic treatment are 
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• 
Intravenous immunoglobulin 
therapy and/or plasmapheresis 
New therapies for RA should not be 
initiated during the trial. Initiation of any 
new immunosuppressant or 
immunomodulatory therapy would be 
considered a treatment failure and should 
result in withdrawal of the subject from 
the IMP 
spray containing adrenocortical 
hormone. Furthermore, Beta-2 
stimulating inhalants with 
short-term effects (SABA) are 
allowed for an asthma attack to 
an otherwise well-controlled 
asthma patient in the opinion of 
the investigator)  
• 
Biologic therapies for RA  
• 
Intravenous immunoglobulin 
therapy and/or plasmapheresis 
• 
New therapies for RA should not 
be initiated during the trial. 
Initiation of any new 
immunosuppressant or 
immunomodulatory therapy 
would be considered a 
treatment failure and should 
result in withdrawal of the 
subject from the IMP. 
As a signal for CYP1A2 induction has been 
observed at 10 μM in a study with human 
hepatocyte the following CYP1A2 
substrates are also prohibited:  
Alosetron  
Clozapine  
Flutamide  
Frovatriptan  
Melatonin  
Mexiletine  
Mirtazapine  
Olanzapine  
Ramelteon  
Rasagiline  
Ropinirole  
Tacrine  
Theophylline 
Tizanidine 
Triamterene 
Zolmitriptan 
45 
19.4 
18.3 Treatment Compliance 
19.4 Treatment Compliance 
45 
19.3 
 
19.3 Rescue Treatment 
In case of severe worsening of symptoms, 
the investigator will be able to provide 
joint injections with corticosteroid as 
rescue medication. The use of local joint 
injections will be at the discretion of the 
investigator. The IMP/placebo treatment 
will continue as planned. 
51 
21.1.2 
20.1.2 Prior and Concomitant Medication 
Prior medications/therapies will be 
reported if taken up to 4 weeks prior to 
the Screening Visit. Concomitant 
medications/ therapies, will be reported at 
every visit throughout the trial. 
21.1.2 Subject Identification  
Prior medications/therapies will be 
reported if taken up to 4 weeks prior to 
the Screening Visit. Concomitant 
medications/ therapies, herbal 
medication, and over-the-counter 
medication will be reported at every visit 
throughout the trial. 
52 
21.1.5 
20.1.5 Height and Weight 
21.1.5 Height and Weight 


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Subject height will be measured at the 
Screening Visit, while weight will be 
assessed at all visits except at the visit 7 
Early Withdrawal Visit. 
Subject height will be measured at the 
Screening Visit, while weight will be 
assessed at all visits except at the visit 8 
(EOS/Safety follow-up call). 
53 
21.1.8 
20.1.8 X-ray 
A chest x-ray (only at the Screening Visit) 
will be used to reveal active current or 
history of tuberculosis and atypical 
mycobacterial disease, clinically significant 
abnormalities on chest x-ray as 
determined by the investigator. If the 
subject has a chest x-ray that is no older 
than 6 month the x-ray can be used for 
the evaluation.  
X-ray of hands and feet (only at the 
Screening Visit): radiographic changes 
typical of RA on posteroanterior hand and 
wrist x-rays. 
21.1.8 X-ray 
A chest x-ray (only at the Screening Visit) 
will be used to reveal active current or 
history of tuberculosis and atypical 
mycobacterial disease, clinically significant 
abnormalities on chest x-ray as 
determined by the investigator.  
X-ray of hands and feet (only at the 
Screening Visit): radiographic changes 
typical of RA on posteroanterior hand and 
wrist x-rays. 
54 
21.1.9.2 
20.1.9.2 Biochemistry 
Sodium, potassium, chloride, calcium, 
glucose, creatinine, urea, albumin, 
unconjugated and total bilirubin, 
aspartate transaminase (AST), alanine 
transaminase (ALT), alkaline phosphatase 
(ALP), gamma-glutamyl transferase (GGT) 
and CRP. The biochemistry blood samples 
will be taken at all visits. A serum β-HCG 
pregnancy test will be taken at screening 
(dipstick pregnancy test at all other visits). 
21.1.9.2 Biochemistry  
Sodium, potassium, chloride, calcium, 
glucose, creatinine, urea, albumin, 
unconjugated and total bilirubin, 
aspartate transaminase (AST), alanine 
transaminase (ALT), alkaline phosphatase 
(ALP), gamma-glutamyl transferase (GGT) 
and INR. The biochemistry blood samples 
will be taken at all visits. A serum β-HCG 
pregnancy test will be taken at screening 
(dipstick pregnancy test at all other visits). 
54 
21.1.9.4 
20.1.9.4 Urinalysis 
A dipstick urine test for blood, protein, 
and glucose will be performed at the site 
at the Screening Visit and Visit 7. If any of 
the results are abnormal, a urine sample 
will, be sent to microscopic examination at 
the local laboratory. 
21.1.9.4 Urinalysis  
A dipstick urine test for blood, protein, 
and glucose will be performed at the site 
at the Screening Visit and Visit 7. If any of 
the results are abnormal and clinically 
significant, a urine sample will, at the 
discretion of the investigator, be sent for 
urine culture at the local laboratory. 
64 
23.4 
 
23.4 Safety Analysis 
The primary safety endpoint is the safety 
of AP1189 against placebo by evaluating 
adverse events (AEs), serious adverse 
events (SAEs), and laboratory 
abnormalities. All safety parameters 
(ECG, vital signs, AEs/SAEs, laboratory 
abnormalities, etc.) will be summarized 
by treatment and time point. 
64 
23.5 
22.4 Efficacy Analysis 
All efficacy endpoints will be evaluated by 
treatment group using descriptive 
statistics. Confidence intervals will be 
presented where appropriate. 
23.5 Efficacy Analysis 
All efficacy endpoints will be evaluated by 
treatment group using descriptive 
statistics. Confidence intervals will be 
presented where appropriate. 
65 
23.5.1 
22.4.1 Analysis of Primary Endpoints 
The change in CDAI after 4 weeks of 
treatment compared to baseline will be 
evaluated by descriptive statistics, by 
treatment group. 
23.5.1 Analysis of Primary Efficacy 
Endpoints 
The change in CDAI score from severe 
(CDAI > 22) to moderate (CDAI ≤ 22) after 
4 weeks of treatment compared to 
baseline, by treatment group. 
64 
23.5.2 
22.4.2 Analysis of Secondary Endpoints 
The effects of AP1189 against placebo will 
be evaluated by descriptive statistics, 
23.5.2 Analysis of Secondary Efficacy 
Endpoints 


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assessing the following by treatment 
group: 
• 
Proportion of subjects achieving 
a reduced number of swollen and 
tender joints (SJC and TJC, 
respectively) 
at 
week 
4 
compared to baseline 
• 
Proportion of subjects with a 
change in CDAI score from 
severe (CDAI > 22) to moderate 
(CDAI ≤ 22) after 4 weeks of 
treatment compared to baseline  
• 
Proportion of subjects achieving 
a change in DAS28 at week 4 
compared to baseline 
• 
Change of HAQ-DI at week 4 
compared to baseline 
• 
Change of FACIT-Fatigue at week 
4 compared to baseline 
• 
Proportion of subjects achieving 
ACR response assessed by ACR 
20, ACR 50, and AC70  
 
The effects of AP1189 against placebo will 
be evaluated by descriptive statistics, 
assessing the following by treatment 
group:  
• 
Proportion of subjects achieving 
a reduced number of swollen 
and tender joints (SJC and TJC, 
respectively) at week 4 
compared to baseline  
• 
Proportion of subjects achieving 
a change in CDAI score after 4 
weeks of treatment compared 
to baseline  
o 
Proportion of subjects 
with a 5-point 
decrease  
o 
Proportion of subjects 
with a 10-point 
decrease  
o 
Proportion of subjects 
with a 15-point 
decrease  
• 
Proportion of subjects achieving 
a change in DAS28 at week 4 
compared to baseline  
• 
Change of HAQ-DI at week 4 
compared to baseline  
• 
Change of FACIT-Fatigue at week 
4 compared to baseline  
• 
Proportion of subjects achieving 
ACR response assessed by ACR 
20, ACR 50, and AC70  
65 
23.5.3 
22.4.3 Analysis of Tertiary Endpoints 
23.5.3 Analysis of Tertiary Efficacy 
Endpoints 
64 
(22.6) is now part 
of 23.4 
22.6 Safety Evaluation 
All safety parameters (ECG, vital signs, 
AEs/SAEs, laboratory abnormalities, etc.) 
will be summarized by treatment and time 
point. 
The old text in 22.6 Safety Evaluation is 
now part of 23.4 Safety Analysis 
65 
23.7 
22.7 Interim Analysis 
An independent external statistician will 
conduct the interim analysis.  
All safety parameters (ECG, vital signs, 
AEs/SAEs, laboratory abnormalities, etc.) 
and efficacy data for the primary study 
endpoint will be summarized by treatment 
and time point for the subjects included in 
Part 1 of the study. The choice of design 
for Part 2 will be based on the results from 
the interim analysis.  
The independent external statistician will 
ensure that the interim analyses are a 
completely confidential process, 
investigators and other study personnel 
will be kept blind and will only be 
informed about the decision of design 
choice for Part 2 of the study. 
23.7 Interim Analysis 
An independent external statistician will 
conduct the interim analysis.  
All safety parameters (ECG, vital signs, 
AEs/SAEs, laboratory abnormalities, etc.) 
and efficacy data for the primary efficacy 
endpoint will be summarized by treatment 
and time point for the subjects included in 
Part 1 of the study. The choice of design 
for Part 2 will be based on the results from 
the interim analysis.  
The independent external statistician will 
ensure that the interim analyses are a 
completely confidential process, 
investigators and other study personnel 
will be kept blind and will only be 
informed about the decision of design 
choice for Part 2 of the study. 
65 
24.1.1 
23.1.1 Record Retention 
If the investigator becomes unable for any 
reason to continue to retain study records 
24.1.1 Record Retention 
If the investigator becomes unable for any 
reason to continue to retain study records 


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for the required period (e.g., retirement, 
relocation), the sponsor should be 
prospectively notified. The study records 
must be transferred to a designee 
acceptable to the sponsor, such as 
another investigator, another institution, 
or an independent third party arranged by 
the sponsor. Investigator records must be 
kept for a minimum of 15 years after 
completion or discontinuation of the study 
or for longer if required by applicable local 
regulations. 
for the required period (e.g., retirement, 
relocation), the sponsor should be 
prospectively notified. The study records 
must be transferred to a designee 
acceptable to the sponsor, such as 
another investigator, another institution, 
or an independent third party arranged by 
the sponsor. Investigator records must be 
kept for a minimum of 25 years after 
completion or discontinuation of the study 
or for longer if required by applicable local 
regulations. 
68 
24.4 
23.4 Audit and Inspections 
24.4 End of Trial 
The end of the trial is defined as the last 
visit for the last subject (LVLS). 
68 
24.5 
23.4 Audit and Inspections 
24.5 Audit and Inspections 
71 
26.3 
25.3 Informed Consent 
The acquisition of informed consent and 
the subject’s agreement or refusal of 
notification of his/her primary care 
physician should be documented in the 
subject’s medical records, and the 
informed consent form should be signed 
and personally dated by the subject and 
by the person who conducted the 
informed consent discussion (not 
necessarily an investigator). The original 
signed informed consent form should be 
retained following institutional policy, and 
a copy of the signed consent form should 
be provided to the subject.  
 
26.3 Informed Consent 
The acquisition of informed consent and 
the subject’s agreement or refusal of 
notification of his/her primary care 
physician should be documented in the 
subject’s medical records, and the 
informed consent form should be signed 
and personally dated by the subject and 
by the person who conducted the 
informed consent discussion. The person 
conducting the informed consent 
discussion will always be a licensed 
physician but not necessarily the principal 
investigator. The original signed informed 
consent form should be retained following 
institutional policy, and a copy of the 
signed consent form should be provided 
to the subject.  
79 
29.2 
28.2 MTX Treatment Instruction in Case of 
Elevation in Liver Enzymes 
Transaminase Increase: ALT increase up to 
3 times the upper limit is acceptable. With 
an increase below the three (3) times 
upper limit, it is recommended to draw 
the blood samples the day before the next 
MTX treatment. In the case of increases 
above three (3) times upper limit, pause or 
dose reduction in MTX is recommended 
with more frequent blood test. 
29.2 MTX Treatment Instruction in Case of 
Elevation in Liver Enzymes 
Transaminase Increase:  
• ALT increases up to <3 X ULN (bilirubin 
is within the normal range) is acceptable. 
IMP and MTX remains unchanged. It is 
recommended to draw the blood samples 
the day before the next MTX treatment.  
• In the case of ALT increases >3 - ≤5 X 
ULN and bilirubin is within the normal 
range, pause IMP. Upon normalization of 
ALT, IMP resumes  
• In case of ALT increases >5 X ULN, MTX 
and IMP discontinue  
• Upon normalization of ALT (and 
bilirubin), MTX and IMP resume  
• At bilirubin > normal range, MTX and 
IMP treatment discontinue  
• IMP resumes if/when ALT is <3 X ULN 
and bilirubin was not elevated  
• ALT and bilirubin should be followed 
until normalized  
It is recommended with more frequent 
blood test in case of elevation of liver 
enzymes. 


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SAP_001.pdf: 
CroxxMed/  
 
Confidential 
 
 
Study SynAct-CS002 – Statistical Analysis Plan 
Page 1 of 55 
 
Version 2.0 22NOV2021 
 
 
STATISTICAL ANALYSIS PLAN 
 
A double-blind, multi-center, two-part, randomized, placebo-
controlled study of the safety, tolerability, and efficacy of 4 weeks 
of treatment with AP1189 in early rheumatoid arthritis (RA) 
patients with active joint disease 
 
 
Protocol Code: 
SynAct-CS002 
Study sponsor: 
SynAct Pharma ApS 
Clinical Study Phase: 
IIa 
Biostatistician: 
Inger Persson 
SAP issue date: 
22 NOV 2021 
SAP version: 
2.0 
This SAP is the property of SynAct Pharma ApS and is a confidential document. It is not to be 
copied or distributed to other parties without prior written authorisation from SynAct 
Pharma ApS. 


CroxxMed/  
 
Confidential 
 
 
Study SynAct-CS002 – Statistical Analysis Plan 
Page 2 of 55 
 
Version 2.0 22NOV2021 
 
Table of Contents 
 
1 
Introduction ......................................................................................................................... 4 
1.1 
Background .......................................................................................................................... 4 
1.2 
Confidentiality Statement .................................................................................................... 4 
1.3 
Compliance with Good Clinical Practice .............................................................................. 4 
1.4 
Work Policy (Standard Operating Procedures) .................................................................... 4 
1.5 
Software and File Storage .................................................................................................... 4 
1.6 
Clean File .............................................................................................................................. 4 
1.7 
Backup and Recovery Procedures ....................................................................................... 4 
1.8 
Archiving .............................................................................................................................. 5 
2 
Study Objective(s) and Design ............................................................................................... 5 
2.1 
Objective(s) and Variables ................................................................................................... 5 
2.1.1Primary Safety Objective ............................................................................................. 5 
2.1.2Primary Safety Variables .............................................................................................. 5 
2.1.3Primary Efficacy Objective ........................................................................................... 5 
2.1.4Primary Efficacy Variables ........................................................................................... 5 
2.1.5Secondary Efficacy Objectives ..................................................................................... 5 
2.1.6Secondary Efficacy Variables ....................................................................................... 6 
2.1.7Tertiary Efficacy Objectives ......................................................................................... 6 
2.1.8Arthroscopy sub-Study ................................................................................................ 6 
2.1.9Exploratory Objective .................................................................................................. 6 
2.2 
Study Type and Design ......................................................................................................... 6 
3 
Statistical Analysis Considerations ........................................................................................ 6 
3.1 
Types of Analysis .................................................................................................................. 6 
3.2 
Analysis Data Sets ................................................................................................................ 7 
3.3 
Measurement Times, Missing Data, and Outliers ............................................................... 7 
3.4 
Prognostic Variables ............................................................................................................ 8 
3.5 
Subgroup Analyses ............................................................................................................... 8 
3.6 
Data Transformation and Derived Variables ....................................................................... 8 
3.7 
Interim Analysis ................................................................................................................. 12 
3.8 
Handling Study Centre Effects ........................................................................................... 13 
3.9 
Multiplicity Issues .............................................................................................................. 14 
3.10 
Handling Withdrawals and Protocol Deviations ................................................................ 14 
3.11 
Concomitant Medication ................................................................................................... 14 
3.12 
Documentation and Other Considerations........................................................................ 14 
4 
Evaluation of Enrolment, Disposition, Exclusions, Evaluable Subjects ................................... 14 
5 
Evaluation of Demographics and Other Baseline Characteristics .......................................... 16 
5.1 
Demographic variables ...................................................................................................... 16 
6 
Efficacy Analysis ................................................................................................................. 17 
6.1 
Description of Efficacy Variables ....................................................................................... 17 


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6.1.1Description of primary efficacy variables .................................................................. 17 
6.1.2Description of secondary efficacy variables .............................................................. 18 
6.1.3Description of tertiary efficacy variables ................................................................... 22 
6.1.4Description of other efficacy variables ...................................................................... 23 
6.2 
Exploratory Analysis........................................................................................................... 24 
7 
Safety and Tolerability Analyses ......................................................................................... 24 
7.1 
Medical history variables ................................................................................................... 25 
7.2 
Prior and concomitant medication variables..................................................................... 25 
7.3 
Pregnancy test ................................................................................................................... 26 
7.4 
Physical Examination ......................................................................................................... 26 
7.5 
Height and Weight ............................................................................................................. 27 
7.6 
Vital Signs ........................................................................................................................... 27 
7.7 
Lead ECGs........................................................................................................................... 28 
7.8 
X-Rays ................................................................................................................................ 29 
7.9 
Laboratory Assessments .................................................................................................... 29 
7.9.1Haematology.............................................................................................................. 29 
7.9.2Biochemistry .............................................................................................................. 31 
7.9.3Thyroid Function ........................................................................................................ 35 
7.9.4Urinalysis.................................................................................................................... 36 
7.9.5Serology ..................................................................................................................... 37 
7.9.6MC1R Genotype Analysis ........................................................................................... 37 
7.10 
Adverse Events .................................................................................................................. 38 
8 
Quality Control Procedures ................................................................................................. 40 
8.1 
Programming ..................................................................................................................... 40 
8.2 
Derived Data Sets .............................................................................................................. 40 
8.3 
Data Listings ....................................................................................................................... 40 
8.4 
Calculated Data .................................................................................................................. 40 
8.5 
Tables ................................................................................................................................. 40 
8.6 
Consistency of Summary Tables and Data Listings ............................................................ 40 
8.7 
Documentation of Quality Control .................................................................................... 40 
Appendix 1: Statistical Analysis Plan Authentication and Authorisation ....................................... 41 
Appendix 2: Statistical section(s) of the Study Protocol ............................................................... 43 
Appendix 3: Data Monitoring Committee Charter ........................................................................ 43 
Appendix 4: Specifications for Tables, Figures, and Listings .......................................................... 43 
Appendix 5: Revision History ...................................................................................................... 44 
 


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1 
INTRODUCTION 
1.1 
Background 
The methods and presentation of data analyses proposed for this study are described in detail in this 
Statistical Analysis Plan (SAP), in order to avoid post hoc decisions that may affect the interpretation 
of the statistical analysis.  
This SAP is based on the analyses described in the protocol and the data actually obtained in the 
study. Any deviations from the methods in the protocol will be described and explained in section 
3.12. 
The preparation of this SAP was completed prior to unblinding of the study.  
1.2 
Confidentiality Statement 
This SAP is a confidential document that belongs to the sponsor. It is not to be copied or distributed 
to other parties without written approval from the sponsor. 
1.3 
Compliance with Good Clinical Practice 
This SAP is designed to ensure compliance with appropriate ICH guidelines, particularly E9 (Statistical 
Principles for Clinical Trials) and E3 (Structure and Content of Clinical Study Reports). 
1.4 
Work Policy (Standard Operating Procedures) 
The following statistical Standard Operating Procedures (SOP) belonging to CroxxMed ApS will be 
followed during the conduct of the study: 
 
• 
SOP for Statistical Protocol input, Analysis and Study Reporting 
• 
SOP for Statistical Programming 
1.5 
Software and File Storage 
The data will be processed within the SAS/Windows environment. The statistical report will be 
written in Microsoft Office Word 2010. 
Electronic documents will be protected with a study-specific password.  
- Software: SAS, version 9.4.  
- Location: Original database at CroxxMed ApS, the study statistician will obtain copies. The study 
statistician will keep SAS programs during the conduct of the analysis.  
1.6 
Clean File 
A Clean File meeting will be held just before closing the database for the final analysis. At this 
meeting, it will be decided which subjects will be included in the analysis(-es), and the database will 
be declared clean and accurate.  
The randomization code can be broken after Clean File and entered/loaded into the database in 
accordance with the Clean File Protocol. 
1.7 
Backup and Recovery Procedures 
A system backup will be run every night, and the data will be stored in secure settings at a hosted 
server at the Electronic Data Capture vendor’s premises.  


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1.8 
Archiving  
Electronic documents will be stored at CroxxMed during the conduct of the study. The original SAP 
(with signatures) will be filed in the Trial Master File once the study is closed. The Trial Master File 
will be in paper form, and electronic documents will be stored as a backup for a short period of time 
after study closure. 
 
2 
STUDY OBJECTIVE(S) AND DESIGN 
2.1 
Objective(s) and Variables 
2.1.1 
Primary Safety Objective  
• 
To compare the safety of AP1189 against placebo by evaluating AEs, SAEs, and laboratory 
abnormalities.  
2.1.2 
Primary Safety Variables 
AEs, SAEs, and laboratory abnormalities.  
See section 3.6 for details of the calculation of primary safety variables. 
2.1.3 
Primary Efficacy Objective  
• 
Effect of AP1189 vs. placebo in subjects with severe active RA (CDAI > 22), undergoing up-
titration with MTX, by showing a change in CDAI from severe (CDAI > 22) to moderate or 
lower (CDAI ≤ 22) after 4 weeks treatment compared to baseline. 
2.1.4 
Primary Efficacy Variables 
The change in CDAI after 4 weeks of treatment compared to baseline will be evaluated by assessing 
the following, by treatment group:  
• 
Mean change in CDAI from baseline to week 4  
• 
Proportion of subjects with a change in CDAI score from severe (CDAI > 22) to moderate 
(CDAI ≤ 22) at week 4 compared to baseline.  
 
See section 3.6 for details of the calculation of primary efficacy variables. 
2.1.5 
Secondary Efficacy Objectives 
To compare the effects of AP1189 against placebo by assessing:  
• 
Proportion of subjects achieving a reduction of more than 10 (ten) swollen and/or tender 
joints at week 4 compared to baseline  
• 
Proportion of subjects achieving a change in CDAI score at week 4 compared to baseline  
o Proportion of subjects with a 5-point decrease  
o Proportion of subjects with a 10-point decrease  
o Proportion of subjects with a 15-point decrease  
• 
Proportion of subjects achieving a change in value to ≤ 3.2 as measured by DAS28 at week 4 
compared to baseline  


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• 
Change in subject-reported HAQ-DI at week 4 compared to baseline  
• 
Change in subject-reported fatigue using FACIT-Fatigue at week 4 compared to baseline  
• 
Proportion of subjects achieving American College of Rheumatology (ACR) response assessed 
by ACR20, ACR50, and ACR70  
 
2.1.6 
Secondary Efficacy Variables 
The secondary efficacy variables are described in 2.1.5 above, with the following addition: 
• 
The number of swollen and/or tender joints are found by summarizing SJC and TJC.  
See section 3.6 for details of calculation of secondary efficacy variables. 
2.1.7 
Tertiary Efficacy Objectives  
Effect of AP1189 compared to placebo at week 4 compared to baseline on inflammatory and collagen 
destructive biomarkers. The biomarkers include:  
• 
CXCL13  
• 
IL-1β  
• 
IL-6  
• 
IL-10  
• 
TNF-α  
 
2.1.8 
Arthroscopy sub-Study  
Effect of AP1189 compared to placebo on joint structures and inflammation as assessed by synovial 
biopsy at baseline and after 4 weeks treatment (only for Part 2 at selected sites, if applicable). 
2.1.9 
Exploratory Objective  
NA 
2.2 
Study Type and Design 
Study Phase: IIa  
Study Design: Double-blind, multi-center, two-part, randomized, placebo-controlled study with 4 
weeks of treatment with AP1189 in early rheumatoid arthritis (RA) 
Study Flow Chart: Study flow chart is shown in the study protocol, Table 3, section 20 Schedule of 
Visits. 
 
3 
STATISTICAL ANALYSIS CONSIDERATIONS 
3.1 
Types of Analysis 
All safety parameters (ECG, vital signs, AEs/SAEs, laboratory abnormalities, etc.) will be summarized 
by treatment and time point. Continuous variables will be summarized using n, mean, standard 
deviation, median, minimum, and maximum values. For categorical (nominal) variables, the number 


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of patients per category, and percent of the total number of patients will be presented. 
 
Descriptive statistics (continuous and categorical variables summarized as above) will be used for an 
exploratory description of exposure. Plasma concentrations will be used to measure exposure. 
All efficacy endpoints will be evaluated by treatment group using descriptive statistics (continuous 
and categorical variables summarized as above). Confidence intervals will be presented where 
appropriate. 
3.2 
Analysis Data Sets 
 
The sets of subjects to be analyzed are defined as follows: 
• The safety analysis set consists of all subjects who received the study medication at least once, 
analyzed by received treatment. 
• The pharmacokinetic (PK) analysis set consists of all subjects who completed the study and did 
not have any protocol deviation or events implying a bias for the PK evaluation. 
• The efficacy analysis set consists of all randomized subjects who received the study medication at 
least once, analyzed by randomized treatment (intention to treat). A second analysis of the 
primary efficacy endpoint, for robustness, will be performed for all randomized subjects who 
complete the study without any major protocol violations (per protocol). 
All safety and tolerability analyses will be conducted on the safety data set, all PK analyses will be 
conducted on the pharmacokinetic data set, and all efficacy analyses will be conducted on the 
efficacy data set.  
3.3 
Measurement Times, Missing Data, and Outliers 
 
Measurement Times 
The first date registered (screening visit) is to be used to define Baseline visit (Week 0 visit, within 14 
days from screening). Week 1 visit is defined to be 7 days (±1 day) after Baseline, Week 2 visit 14 
days (±1 day) after Baseline, Week 3 visit 21 days (±1 day) after Baseline, Week 4 visit 28 days (±1 
day) after Baseline, final visit 7 (±2) days after the last investigational medicinal product has been 
taken, and visit 8 (end of study follow-up call) 4 weeks (±3 days) after the last investigational 
medicinal product has been taken, as described in protocol section 20.1. Any dates outside these visit 
windows are noted by the Data Manager during data validation as protocol deviations. 
Missing Data 
Subjects with missing data will be included where possible, e.g. in the description of the patient 
population. Wherever the analysis requires data on a variable, subjects with missing data on that 
variable will be excluded from the analysis (e.g. when calculating changes from baseline). Missing 
items will not be imputed in any way, however plasma concentration values below the level of 
quantification will be set to LoQ/2 for the pharmacokinetic analysis.  
Outliers 
No procedure for dealing with outliers was foreseen in the trial protocol and therefore one analysis 
with the actual values and at least one other analysis eliminating or reducing the outlier effect will be 
performed and differences between their results will be discussed.  


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3.4 
Prognostic Variables 
NA 
3.5 
Subgroup Analyses 
A sub-study taking place in Bulgaria and Moldova was added to the clinical study protocol. The sub-
study was added to investigate if the effect of AP1189 in newly diagnosed subjects with severe RA 
who are to start up-titration with methotrexate is comparable in these two countries compared to 
the main study. In addition to analyzing the main study and the sub-study separately, all data will be 
pooled to investigate the overall effect in all participating countries.  
3.6 
Data Transformation and Derived Variables 
 
Demographic analysis 
Age at inclusion (years) will be calculated from date of birth and screening date. 
Efficacy analysis 
The HAQ-DI scale will be scored in accordance with Bruce and Fries, The Health Assessment 
Questionnaire (HAQ), Clinical and Experimental Rheumatology, 2005. Maska et al. summarize the 
scoring procedure as below (see https://onlinelibrary.wiley.com/doi/full/10.1002/acr.20620): 
“1) identify the highest subcategory score from each of the 8 categories. Adjust for use of aids/help 
by increasing the category score from 0 or 1 to a 2 if use of aids/help for that category (utilize table 
of companion aids/help for HAQ categories). If the category score is already a 2 or 3, no adjustment 
is made; 2) sum the category scores; and 3) divide the final sum by the number of categories 
answered to obtain the final HAQ score rounded to the nearest value evenly divisible by 0.125. 
Requires a minimum of 6 categories answered; if less, do not score.” 
The FACIT-Fatigue total subscale will be scored in accordance with  
http://www.ser.es/wp-content/uploads/2015/03/FACIT-F_INDICE.pdf.  
 
Change from baseline to week 4 (value at week 4 minus value at baseline) will be calculated for the 
following variables: 
• 
CDAI 
• 
DAS28 
• 
HAQ-DI total score 
• 
FACIT-Fatigue total subscale score 
• 
number of swollen and/or tender joints (summarizing SJC and TJC) 
• 
CXCL13 
• 
IL-1β 
• 
IL-6  
• 
IL-10  
• 
IL-6/IL-10 ratio 
• 
TNF-α 
 


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In addition, percent change from baseline to week 4 (change from baseline as defined above divided 
by the baseline value) will be calculated for the following variables: 
• 
CXCL13 
• 
IL-1β 
• 
IL-6  
• 
IL-10  
• 
IL-6/IL-10 ratio 
• 
TNF-α 
  
Indicators noting the following will be constructed, based on the above defined change in CDAI score 
from baseline to week 4: 
• 
a 5-point decrease 
• 
a 10-point decrease 
• 
a 15-point decrease 
• 
a 20-point decrease 
• 
a 30-point decrease 
 
Indicators noting a change in CDAI score will be constructed as follows: 
• 
from severe (CDAI > 22) to moderate or lower (CDAI ≤ 22) at week 4 compared to baseline 
• 
from severe (CDAI > 22) to low or remission (CDAI ≤ 10) at week 4 compared to baseline 
• 
from severe (CDAI > 22) to remission (CDAI ≤ 2.8) at week 4 compared to baseline 
Indicators noting a change in DAS28 will be constructed as follows: 
• 
from > 3.2 to ≤ 3.2 at week 4 compared to baseline 
• 
An indicator noting a change in DAS28 from high (DAS28 > 5.1) to moderate or lower (DAS28 
≤ 5.1) at week 4 compared to baseline 
 
For the calculation of ACR response rates, indicators noting the following will be constructed: 
• 
≥20% improvement (reduction) in swollen and tender joint counts (SJC and TJC summarized) 
at week 4 compared to baseline 
• 
≥50% improvement (reduction) in swollen and tender joint counts (SJC and TJC summarized) 
at week 4 compared to baseline 
• 
≥70% improvement (reduction) in swollen and tender joint counts (SJC and TJC summarized) 
at week 4 compared to baseline 
• 
≥20% improvement (reduction) in Patient’s Global Assessment of Disease Activity (dataset 
VAS) at week 4 compared to baseline 
• 
≥50% improvement (reduction) in Patient’s Global Assessment of Disease Activity at week 4 
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• 
≥70% improvement (reduction) in Patient’s Global Assessment of Disease Activity at week 4 
compared to baseline 
• 
≥20% improvement (reduction) in Physician’s Global Assessment of Disease Activity (dataset 
VAS) at week 4 compared to baseline 
• 
≥50% improvement (reduction) in Physician’s Global Assessment of Disease Activity at week 
4 compared to baseline 
• 
≥70% improvement (reduction) in Physician’s Global Assessment of Disease Activity at week 
4 compared to baseline 
• 
≥20% improvement (reduction) in Patient’s Assessment of Pain at week 4 compared to 
baseline 
• 
≥50% improvement (reduction) in Patient’s Assessment of Pain at week 4 compared to 
baseline 
• 
≥70% improvement (reduction) in Patient’s Assessment of Pain at week 4 compared to 
baseline 
• 
≥20% improvement (increase) in Health Assessment Questionnaire (HAQ-DI) total score at 
week 4 compared to baseline 
• 
≥50% improvement (increase) in Health Assessment Questionnaire (HAQ-DI) total score at 
week 4 compared to baseline 
• 
≥70% improvement (increase) in Health Assessment Questionnaire (HAQ-DI) total score at 
week 4 compared to baseline 
• 
≥20% improvement (reduction) in C-Reactive Protein (CRP) at week 4 compared to baseline 
• 
≥50% improvement (reduction) in C-Reactive Protein (CRP) at week 4 compared to baseline 
• 
≥70% improvement (reduction) in C-Reactive Protein (CRP) at week 4 compared to baseline 
 
The ACR response rates ACR20, ACR50, and ACR70 are defined as follows (using the indicators 
above): 
≥20%, ≥50% and ≥70% improvement at week 4 compared to baseline, respectively, in:  
• 
Swollen and tender joint counts (SJC and TJC summarized), and 3 of the following 5 
assessments: 
o Patient’s Global Assessment of Disease Activity 
o Physician’s Global Assessment of Disease Activity 
o Patient’s Assessment of Pain 
o Health Assessment Questionnaire (HAQ-DI) 
o C-Reactive Protein (CRP) 
 
The Patient Global Assessment of Disease Activity RA, the Investigator Global Assessment of Disease 
Activity RA, and the CDAI score will be presented in absolute values and values relative to placebo by 
dividing the mean, median, min, and max values for each active treatment group by the 
corresponding value for the placebo group. 
An indicator noting whether a subject received rescue treatment (joint injections with corticosteroid) 
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through the concomitant medication listings to define which subjects received rescue treatment 
before analyses. 
 
Pharmacokinetic analysis 
Plasma concentration values below the level of quantification will be set to LoQ/2 for the analysis. 
Safety analysis 
The QT interval on the ECGs is corrected from Bazett, Hodges or ECAPS to Fridericia. The laboratory 
values from the different sites may be reported in different units, which will be corrected to: 
Variable 
Unit to be used 
in 
analyses/report 
Conversion formula(s) 
Comments 
Corrected QT Interval (QTc) 
QTc Fridericia 
QTcF = QT/(RR1/3) 1 
The reported QT and RR 
intervals will be used to 
calculate QTcF. 
HbA1c 
mmol/mol 
 
mmol/L used at sites in 
Moldova and Bulgaria 
White blood cell 
10E9/L 
 
g/dl used at some sites 
Neutrophils 
10E9/L 
 
g/dl used at some sites 
Lymphocytes 
10E9/L 
 
g/dl used at some sites 
Monocytes 
10E9/L 
 
g/dl used at some sites 
Eosinophils 
10E9/L 
 
g/dl used at some sites 
Basophils 
10E9/L 
 
g/dl used at some sites 
Hemoglobin 
mmol /L 
 
g/dl used at some sites 
Red blood cells (RBC) 
10E12/L 
 
g/dl used at some sites 
Thrombocytes 
10E9/L 
 
g/dl used at some sites 
Alanine transaminase (ALT) 
U/L 
(µkat/L) *60 = U/L2 
µkat/L used at some sites 
Aspartate transaminase (AST) 
U/L 
(µkat/L) *60 = U/L2 
µkat/L used at some sites 
γ−glutamyltransferase (GGT) 
U/L 
(µkat/L) *60 = U/L2 
µkat/L used at some sites 
Bilirubin (total) 
mol/L 
 
 
Bilirubin (conjugated) 
mol/L 
 
µkat/L used at some sites 
Alkaline phosphatase (ALP) 
U/L 
(µkat/L) *60 = U/L2 
µkat/L used at some sites 
Glucose (non-fasting) 
mmol/L 
 
 
TSH 
10E3/L 
(U/L) /1000 = mIU/L 
mIE/L 
 
Total T3 
nmol/L 
 
 


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Free T3 
pmol/L 
 
Sweden and Denmark 
measure Total T3, while 
Norway measures Free T3. 
Free T4 
pmol/L 
 
Some sites measure Total T4 
Potassium 
mmol/L 
 
 
Sodium 
mmol/L 
 
 
Chloride 
mmol/L 
 
Site 04 measures chloride in 
whole blood, the other sites 
in plasma 
Calcium 
mmol/L 
 
 
Albumin 
g/L 
 
 
Creatinine 
mol/L 
 
 
C-Reactive Protein (CRP) 
mg/L 
 
 
Urea 
mmol/L 
 
 
1 https://www.clinigate.com/clinicalc/corrected-qt-interval-qtc.php 
2 http://unitslab.com/node/55  
Conversion formulas available from relevant medical sources will be used and documented in the 
Statistical Report. 
All the clinical sites are using their local laboratory to measure safety parameters, which means that 
different reference intervals will apply. 
Additional units might be collected and will be converted according to standard practice. 
Lab values reported as a non-numerical value (e.g., ‘<1’) will be converted to an appropriate 
numerical value for numerical analyses (e.g., calculation of mean values). The team will decide the 
numerical value to be used before analyses. Lab values below the level of quantification will be set to 
LoQ/2 for the analyses. 
Urine culture results will be entered as free text. The text entries will be combined into categories for 
summaries, where the categories will be decided by the team before analyses. 
 
3.7 
Interim Analysis 
An interim analysis has been performed, evaluating the first (minimum) 24 subjects from Part 1 of 
the trial in order to assess the safety and efficacy of the investigational product before proceeding to 
Part 2. Version 1 of this analysis plan was used for the interim analysis. 
All safety parameters (ECG, vital signs, AEs/SAEs, laboratory abnormalities, etc.) and efficacy data for 
the primary efficacy endpoint were summarized by treatment and time point for the subjects 
included in Part 1 of the study, i.e., the following tables (see Appendix 4 for details) were presented 
(any MedDRA coding of AEs will not be performed for the interim): 
o Table 11.4.1.3 (CDAI score) 


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o Table 11.4.1.4 (CDAI score, change from baseline to week 4) 
o Table 11.4.1.5 (CDAI score, change from severe (CDAI > 22) to moderate (CDAI ≤ 22) 
at week 4 compared to baseline) 
o Table 12.2.1.1 to Table 12.5.5.1 (all safety tables).  
 
Listings showing the following data were also presented: 
• 
Patient disposition (including end of study information), i.e., the following listings (see 
Appendix 4 for details):  
o Listing 6.4.1 (Visit Registration) 
o Listing 6.4.2 (Informed Consent, Randomization, Subject Summary) 
o Listing 6.4.3 (Alcohol Consumption) 
o Listing 16.2.8.1 TB and Serology Tests) 
o Listing 6.4.10 (Inclusion Exclusion Criteria) 
• 
Demographics and baseline characteristics, i.e. the following listings (see Appendix 4 for 
details): 
o Listing 16.2.4.1 (Demographics) 
o Listing 6.4.5 (Vital Signs) 
o Listing 16.2.4.3 (Age) 
• 
Safety profiles (laboratory values, adverse events, related adverse events, serious adverse 
events (SAE), adverse events leading to withdrawal), i.e., the following listings (see Appendix 
4 for details): 
o Listing 16.2.8.2 (Blood Biochemistry) 
o Listing 16.2.8.3 (Blood Haematology) 
o Listing 16.2.7.1 (Adverse Event Q). 
• 
Efficacy data for the primary study endpoint 
o Listing 16.2.6.3 (CDAI) 
o Listing 16.2.6.7 (Changes from baseline in CDAI) 
 
An independent external statistician conducted the interim analysis. The external statistician is 
included in the Data Monitoring Committee (DMC) established by the sponsor. The DMC reviewed 
the unblinded data from the interim analysis and recommended one of the three study designs for 
Part 2 to the Steering Committee. The criteria for choice of design are described in the Data 
Monitoring Committee Charter (Appendix 3). All recommendations are documented and signed by 
the DMC members, and they provided a summary of the safety and tolerability data obtained in Part 
1 and their design recommendation for Part 2. 
The independent external statistician will ensure that the interim analysis is a completely confidential 
process. Sponsor, investigators, and other study personnel will be kept blind.  The Steering 
Committee's final decision on design choices for Part 2 of the study was communicated to all 
investigators and study personnel as soon as the decision was made. 
At the end of the study, any discrepancies between the final and the interim data, which could 
significantly impact the analysis, should be documented. 
3.8 
Handling Study Centre Effects 
Study centers will be presented separately in summaries of the primary endpoints in the final 
analysis, reported by country and individual sites. In addition to absolute values for each treatment 
group, values relative to the effect in the placebo group will be presented. 


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3.9 
Multiplicity Issues 
No multiplicity issues are present in this study. 
3.10 
Handling Withdrawals and Protocol Deviations 
All protocol deviations that occur during the study will be considered for their severity/impact and 
taken into consideration when subjects are assigned to analysis data sets, see section 3.2. Details of 
subject assignment to the analysis data sets will be listed.  
3.11 
Concomitant Medication 
Any recorded concomitant medications (including prescription, non-prescription, and herbal 
medications) will be listed by subject number, including the generic or trade name, strength, 
frequency of dosing, and the reason for its use.  
3.12 
Documentation and Other Considerations 
Protocol Section 12.2 Primary efficacy Objective states “Effect of AP1189 vs. placebo in subjects with 
severe active RA (CDAI > 22), undergoing up-titration with MTX, by showing a change in CDAI from 
severe (CDAI > 22) to moderate (CDAI ≤ 22) after 4 weeks treatment compared to baseline.” The cut-
off values for the CDAI score correspond to severe (CDAI>22) or moderate or lower (CDAI ≤ 22), 
which is the wording used in this analysis plan. 
Protocol Section 12.3 Secondary efficacy Objectives states that the “Proportion of subjects achieving 
American College of Rheumatology (ACR) response assessed by ACR20, ACR50, and ACR70” will be 
assessed. These responses will be assessed at week 4 compared with baseline (no time point was 
specified in the protocol). 
Protocol Section 12.4 Tertiary Efficacy Objectives states that the “Effect of AP1189 compared to 
placebo at week 4 compared to baseline on inflammatory and collagen destructive biomarkers” will 
be assessed. The comparison to baseline will be made by calculating the change for these biomarkers 
(CXCL13, IL-1β, IL-6, IL-10, and TNF-α) at week 4 compared with baseline (the calculation of a change 
from baseline was not specified in the protocol). In addition, the ratio IL-6/IL-10 will be evaluated in 
the same way. 
Protocol Section 23.6 Pharmacokinetic Analyses states that “Descriptive statistics will be used for an 
exploratory description of exposure in relation to effect.” However, only one sample is taken at each 
visit (for some visits), with variability in the time from last dosing to sampling. Thus, the relationship 
between exposure and effect is not possible to evaluate, and exposure will therefore be described 
without relation to effect.. 
No other changes to analyses specified in the protocol have been identified at the time of writing this 
SAP. 
 
 
4 
EVALUATION OF ENROLMENT, DISPOSITION, EXCLUSIONS, EVALUABLE SUBJECTS 
Variables are listed below (CRF annotation presented in parenthesis), along with a short description 
of how they will be presented.  
For a list of proposed tables, see Appendix 4. 
 


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Variable (CRF annotation) 
How to be presented 
Visit or Follow-up call performed (VRYN) 
# patients by visit (included in patient 
disposition table)  
Date of visit (VRDT) 
Listing only 
Informed consent (INFC) 
 
Listing only 
Date of subject signature (INFCDT) 
 
Listing only 
Date of investigator signature (INFCIDT) 
 
Listing only 
Alcohol consumption (SUNCF, SUAC, SUENDDT) 
Listing only 
QuantiFERON-in-Tube test taken (TBYN) 
Listing only 
QuantiFERON-in-Tube test Date (TBDT) 
Listing only 
QuantiFERON-in-Tube test Result (TBRES) 
Listing only 
All inclusion/exclusion criteria met (IEYN, INCL1, 
INCL1, INCL3), INCL4, INCL5, INCL6, INCL7, 
INCL8, INCL9, INCL10, INCL11, INCL12, INCL13, 
EXCL1, EXCL2, EXCL3, EXCL4, EXCL5, EXCL6, 
EXCL7, EXCL8, EXCL9, EXCL101, EXCL10, EXCL11, 
EXCL12, EXCL13, EXCL14, EXCL15, EXCL17, 
EXCL18, EXCL19, EXCL20) 
# patients not meeting any criteria, by visit 
(performed both at screening and inclusion), 
included in patient disposition table 
Patient eligibility (ELIGYN) 
# patients and % /category  
(2 categories: Yes/No), included in patient 
disposition table 
Randomization date (RNDT) 
Listing only 
Randomization number (RN) 
Listing only 
IMP dispensed, Date, and Kit number 
(IMPDISYN, IMPDISDT, IMPDISNO) 
Listing only 
Patient diary handed out (DIARYHO) 
Listing only 
IMP from the previous week returned, Number 
of bottles used, Number of bottles unused, 
Number of bottles missing (IMPRETYN, 
IMPRETDT, IMPUSE, IMPUNUSE, IMPMISS) 
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IMP diary: Date, time, Medication taken 
(DIA1DT, DIA1TM, DIA1MED, DIA1REAS, 
DIA2DT, DIA2TM, DIA2MED, DIA2REAS, DIA3DT, 
DIA3TM, DIA3MED, DIA3REAS, … , DIA30DT, 
DIA30TM, DIA30MED, DIA30REAS) 
Listing only 
Completed study (DSSTAT) 
# patients and % /category  
(2 categories: Yes/No), included in patient 
disposition table 
Date of completion/Screen failure/Early 
withdrawal (DSDAT) 
Listing only 
Primary reason for not completing (DSDE1COD, 
DSSPEC) 
# patients and % /category  
(6 categories: Screen Failure/Adverse Event/ 
Subject choice/Investigator choice/Non-
compliance with study protocol/Other,  
plus any reason for ‘other’), included in patient 
disposition table 
Due to AE No. (DSAENO) 
Listing only 
 
 
5 
EVALUATION OF DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS 
Demographic/Baseline variable summaries will be provided for all subjects in the safety analysis set, 
by treatment as well as for all subjects in total, by time point for variables measured more than once.  
Variables are listed below (CRF annotation presented in parenthesis), along with a short description 
of how they will be presented.  
For a list of proposed tables, see Appendix 4. 
5.1 
Demographic variables  
 
Variable (CRF annotation) 
How to be presented 
Date of birth (BRTHDT) 
Listing only (and used to define age) 
Age at inclusion (derived, see Section 3.6) 
n, mean, sd, median, min, max,  
# patients and % /age group (4 age groups: <18/ 
18-64/65-84/>85/Total) 
Gender (SEX) 
# patients and % /category  
(3 categories: Female/Male/Unknown) 


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Ethnicity (ETHNIC) 
# patients and % /category  
(2 categories: Hispanic or Latino/Not Hispanic 
or Latino) 
Race (RACE, RACEOTH) 
# patients and % /category  
(6 categories: American Indian or Alaska 
Native/Asian/Black or African American/Native 
Hawaiian or Pacific Islander/White/Other,  
plus any specification of ‘other’) 
Height (HEIGHT) 
n, mean, sd, median, min, max 
Weight (WEIGHT) at screening 
n, mean, sd, median, min, max  
 
 
6 
EFFICACY ANALYSIS 
6.1 
Description of Efficacy Variables 
Efficacy variable summaries will be provided for all subjects in the efficacy analysis set, by treatment 
and by rescue treatment received within the 4-week treatment period as well as for all subjects in 
total, by time point for variables measured more than once.  
Variables are listed below (CRF annotation presented in parenthesis), along with a short description 
of how they will be presented. Numeric codes are defined in the annotated CRF. 
For a list of proposed tables, see Appendix 4. 
6.1.1 
Description of primary efficacy variables 
 
Variable (CRF annotation) 
How to be presented 
Patient Global Assessment of Disease Activity RA, 
cm (PGADA, dataset CDAI) 
n, mean (95% CI), sd, median, min, max, by 
visit 
Patient Global Assessment of Disease Activity RA, 
cm, relative to placebo (derived, see Section 3.6) 
Mean, median, min, max, by visit, country, 
and site 
Investigator Global Assessment of Disease 
Activity RA, cm (IGADA, dataset CDAI) 
n, mean (95% CI), sd, median, min, max, by 
visit 
Investigator Global Assessment of Disease 
Activity RA, cm, relative to placebo (derived, see 
Section 3.6) 
mean, median, min, max, by visit, country, 
and site 
CDAI score calculated (CDAI) 
n, mean (95% CI), sd, median, min, max, by 
visit 


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CDAI score calculated, relative to placebo 
(derived, see Section 3.6) 
Mean, median, min, max, by visit, country, 
and site 
CDAI change from baseline to week 4 (derived, 
see Section 3.6) 
n, mean (95% CI), sd, median, min, max, by 
visit 
Proportion of subjects with a change in CDAI 
score from severe (CDAI > 22) to moderate or 
lower (CDAI ≤ 22) at week 4 compared to 
baseline (derived, see Section 3.6) 
# patients and % /category  
(2 categories: Yes/No) 
 
 
 
6.1.2 
Description of secondary efficacy variables 
 
Variable (CRF annotation) 
How to be presented 
Joint Tenderness and Swelling assessment 
performed (JTSYN) 
# patients and % /category, by visit 
(2 categories: Yes/no) 
Joint Tenderness and Swelling Date (JTSDT) 
Listing only 
Temporomandibular joint tenderness and 
swelling (TJ1L, TJ1R, SJ1L, SJ1R, JOINT1N) 
# patients and % /category, by visit  
(3 categories: present/absent/not done) 
Sternoclavicular joint tenderness and swelling  
(TJ2L, TJ2R, SJ2L, SJ2R, JOINT2N) 
# patients and % /category, by visit  
(3 categories: present/absent/not done) 
Acromioclavicular joint tenderness and swelling 
(TJ3L, TJ3R, SJ3L, SJ3R, JOINT3N) 
# patients and % /category, by visit  
(3 categories: present/absent/not done) 
Shoulder tenderness and swelling  
(TJ4L, TJ4R, SJ4L, SJ4R, JOINT4N) 
# patients and % /category, by visit  
(3 categories: present/absent/not done) 
Elbow tenderness and swelling  
(TJ5L, TJ5R, SJ5L, SJ5R, JOINT5N) 
# patients and % /category, by visit  
(3 categories: present/absent/not done) 
Wrist tenderness and swelling  
(TJ6L, TJ6R, SJ6L, SJ6R, JOINT6N) 
# patients and % /category, by visit  
(3 categories: present/absent/not done) 
Metacarpophalangeal joint I tenderness and 
swelling (TJ7L, TJ7R, SJ7L, SJ7R, JOINT7N) 
# patients and % /category, by visit  
(3 categories: present/absent/not done) 
Metacarpophalangeal joint II tenderness and 
swelling (TJ8L, TJ8R, SJ8L, SJ8R, JOINT8N) 
# patients and % /category, by visit  
(3 categories: present/absent/not done) 


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Metacarpophalangeal joint III tenderness and 
swelling (TJ9L, TJ9R, SJ9L, SJ9R, JOINT9N) 
# patients and % /category, by visit  
(3 categories: present/absent/not done) 
Metacarpophalangeal joint IV tenderness and 
swelling (TJ10L, TJ10R, SJ10L, SJ10R, JOINT10N) 
# patients and % /category, by visit  
(3 categories: present/absent/not done) 
Metacarpophalangeal joint V tenderness and 
swelling (TJ11L, TJ11R, SJ11L, SJ11R, JOINT11N) 
# patients and % /category, by visit  
(3 categories: present/absent/not done) 
Thumb interphalangeal joint tenderness and 
swelling  
(TJ12L, TJ12R, SJ12L, SJ12R, JOINT12N) 
# patients and % /category, by visit  
(3 categories: present/absent/not done) 
Proximal interphalangeal joint II tenderness and 
swelling (TJ13L, TJ13R, SJ13L, SJ13R, JOINT13N) 
# patients and % /category, by visit  
(3 categories: present/absent/not done) 
Proximal interphalangeal joint III tenderness and 
swelling (TJ14L, TJ14R, SJ14L, SJ14R, JOINT14N) 
# patients and % /category, by visit  
(3 categories: present/absent/not done) 
Proximal interphalangeal joint IV tenderness and 
swelling (TJ15L, TJ15R, SJ15L, SJ15R, JOINT15N) 
# patients and % /category, by visit  
(3 categories: present/absent/not done) 
Proximal interphalangeal joint V tenderness and 
swelling (TJ16L, TJ16R, SJ16L, SJ16R, JOINT16N) 
# patients and % /category, by visit  
(3 categories: present/absent/not done) 
Distal interphalangeal joint II tenderness and 
swelling (TJ17L, TJ17R, SJ17L, SJ17R, JOINT17N) 
# patients and % /category, by visit  
(3 categories: present/absent/not done) 
Distal interphalangeal joint III tenderness and 
swelling (TJ18L, TJ18R, SJ18L, SJ18R, JOINT18N) 
# patients and % /category, by visit  
(3 categories: present/absent/not done) 
Distal interphalangeal joint IV tenderness and 
swelling (TJ19L, TJ19R, SJ19L, SJ19R, JOINT19N) 
# patients and % /category, by visit  
(3 categories: present/absent/not done) 
Distal interphalangeal joint V tenderness and 
swelling (TJ20L, TJ20R, SJ20L, SJ20R, JOINT20N) 
# patients and % /category, by visit  
(3 categories: present/absent/not done) 
Knee tenderness and swelling  
(TJ21L, TJ21R, SJ21L, SJ21R, JOINT21N) 
# patients and % /category, by visit  
(3 categories: present/absent/not done) 
Hip tenderness and swelling  
(TJ22L, TJ22R, SJ22L, SJ22R, JOINT22N) 
# patients and % /category, by visit  
(3 categories: present/absent/not done) 
Ankle tenderness and swelling  
(TJ23L, TJ23R, SJ23L, SJ23R, JOINT23N) 
# patients and % /category, by visit  
(3 categories: present/absent/not done) 


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Tarsus tenderness and swelling  
(TJ24L, TJ24R, SJ24L, SJ24R, JOINT24N) 
# patients and % /category, by visit  
(3 categories: present/absent/not done) 
Metatarsophalangeal joint I tenderness and 
swelling (TJ25L, TJ25R, SJ25L, SJ25R, JOINT25N) 
# patients and % /category, by visit  
(3 categories: present/absent/not done) 
Metatarsophalangeal joint II tenderness and 
swelling (TJ26L, TJ26R, SJ26L, SJ26R, JOINT26N) 
# patients and % /category, by visit  
(3 categories: present/absent/not done) 
Metatarsophalangeal joint III tenderness and 
swelling (TJ27L, TJ27R, SJ27L, SJ27R, JOINT27N) 
# patients and % /category, by visit  
(3 categories: present/absent/not done) 
Metatarsophalangeal joint IV tenderness and 
swelling (TJ28L, TJ28R, SJ28L, SJ28R, JOINT28N) 
# patients and % /category, by visit  
(3 categories: present/absent/not done) 
Metatarsophalangeal joint V tenderness and 
swelling (TJ29L, TJ29R, SJ29L, SJ29R, JOINT29N) 
# patients and % /category, by visit  
(3 categories: present/absent/not done) 
Great toe interphalangeal joint tenderness and 
swelling (TJ30L, TJ30R, SJ30L, SJ30R, JOINT30N) 
# patients and % /category, by visit  
(3 categories: present/absent/not done) 
Proximal and distal interphalangeal joints II 
tenderness and swelling  
(TJ31L, TJ31R, SJ31L, SJ31R, JOINT31N) 
# patients and % /category, by visit  
(3 categories: present/absent/not done) 
Proximal and distal interphalangeal joints III 
tenderness and swelling  
(TJ32L, TJ32R, SJ32L, SJ32R, JOINT32N) 
# patients and % /category, by visit  
(3 categories: present/absent/not done) 
Proximal and distal interphalangeal joints IV 
tenderness and swelling  
(TJ33L, TJ33R, SJ33L, SJ33R, JOINT33N) 
# patients and % /category, by visit  
(3 categories: present/absent/not done) 
Proximal and distal interphalangeal joints V 
tenderness and swelling  
(TJ34L, TJ34R, SJ34L, SJ34R, JOINT34N) 
# patients and % /category, by visit  
(3 categories: present/absent/not done) 
TJC sum (TJCSUM, duplicates in datasets JTS and 
CDAI) 
n, mean (95% CI), sd, median, min, max,  
by visit 
Re-entered TJC (28) (TJCENTRY) 
Listing only (used for CDAI calculation) 
SJC sum (SJCSUM, duplicates in datasets JTS and 
CDAI) 
n, mean (95% CI), sd, median, min, max,  
by visit 
Re-entered SJC (28) (SJCENTRY) 
Listing only (used for CDAI calculation) 


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Total number of tender or swollen joints (SJC and 
TJC summarized) 
n, mean (95% CI), sd, median, min, max,  
by visit 
Proportion of subjects achieving a reduction of 
more than 10 (ten) swollen and/or tender joints 
(SJC and TJC, summarized) at week 4 compared 
to baseline (derived, see Section 3.6) 
# patients and % /category (2 categories: 
Achieving/Not achieving reduction) 
Proportion of subjects achieving a 5-point 
decrease in CDAI score after 4 weeks of 
treatment compared to baseline (derived, see 
Section 3.6) 
# patients and % /category (2 categories: 
Achieving/Not achieving decrease) 
Proportion of subjects achieving a 10-point 
decrease in CDAI score after 4 weeks of 
treatment compared to baseline (derived, see 
Section 3.6) 
# patients and % /category (2 categories: 
Achieving/Not achieving decrease) 
Proportion of subjects achieving a 15-point 
decrease in CDAI score after 4 weeks of 
treatment compared to baseline (derived, see 
Section 3.6) 
# patients and % /category (2 categories: 
Achieving/Not achieving decrease) 
DAS28 calculated (DAS28YN) 
# patients and % /category, by visit 
(2 categories: Yes/no) 
DAS28 score (DAS28) 
n, mean (95% CI), sd, median, min, max,  
by visit 
DAS28 change from baseline to week 4 (derived, 
see Section 3.6) 
n, mean (95% CI), sd, median, min, max, by 
visit 
Proportion of subjects achieving a change in 
DAS28 from DAS28 > 3.2 to DAS28 ≤ 3.2 at week 
4 compared to baseline (derived, see Section 3.6) 
# patients and % /category (2 categories: 
Achieving/Not achieving change) 
HAQ-DI questionnaire completed (HAQDIYN) 
# patients and % /category, by visit 
(2 categories: Yes/no) 
HAQ-DI questionnaire Date (HAQDIDT) 
Listing only 
HAQ-DI responses (HAQDI1, HAQDI2, HAQDI3, 
HAQDI4, HAQDI5, HAQDI6, HAQDI7, HAQDI8, 
HAQDI9, HAQAID1, HAQAID2, HAQAID3, 
HAQAID4, HAQAID5, HAQAID6, HAQAID7, 
HAQAID8, HAQAID9, HAQHELP1, HAQHELP2, 
HAQHELP3, HAQHELP4, HAQDI10, HAQDI11, 
# patients and % /category, by visit 
(4 categories for HAQDI items: Without any 
difficulty/With some difficulty/With much 
difficulty/Unable to do; 2 categories for 
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HAQDI12, HAQDI3, HAQDI4, HAQDI5, HAQDI6, 
HAQDI7, HAQDI8, HAQDI9, HAQD20, HAQAID10, 
HAQAID11, HAQAID12, HAQAID13, HAQAID14, 
HAQAID15, HAQAID16, HAQAID17, HAQHELP5, 
HAQHELP6, HAQHELP7, HAQHELP8) 
HAQ-DI pain because of illness past week, mm 
(HAQPAIN) 
n, mean (95% CI), sd, median, min, max,  
by visit 
HAQ-DI total score (derived, see Section 3.6) 
n, mean, sd, median, min, max,  
by visit 
Change of HAQ-DI total score at week 4 
compared to baseline (derived, see Section 3.6) 
N, mean, sd, median, min, max,  
by visit 
FACIT Fatigue Scale completed (FACITYN)  
# patients and % /category, by visit 
(2 categories: Yes/no) 
FACIT Fatigue Item responses (FACIT1, FACIT2, 
FACIT3, FACIT4, FACIT5, FACIT6, FACIT7, FACIT8, 
FACIT9, FACIT10, FACIT11, FACIT12, FACIT13) 
# patients and % /category/item, by visit 
(5 categories per item; Not at all/A little 
bit/Somewhat/Quite a bit/Very much) 
FACIT Fatigue total subscale score (derived, see 
Section 3.6) 
n, mean, sd, median, min, max,  
by visit 
Change of FACIT-Fatigue total subscale score at 
week 4 compared to baseline (derived, see 
Section 3.6) 
n, mean, sd, median, min, max,  
by visit 
Proportion of subjects achieving ACR response 
assessed by ACR 20 (derived, see Section 3.6) 
# patients and % /category (2 categories: 
Achieving/Not achieving ACR 20) 
Proportion of subjects achieving ACR response 
assessed by ACR 50 (derived, see Section 3.6) 
# patients and % /category (2 categories: 
Achieving/Not achieving ACR 50) 
Proportion of subjects achieving ACR response 
assessed by ACR 70 (derived, see Section 3.6) 
# patients and % /category (2 categories: 
Achieving/Not achieving ACR 70) 
 
6.1.3 
Description of tertiary efficacy variables 
 
Variable (CRF annotation) 
How to be presented 
Sample collected for Cytokines (BIOPERF) 
# patients and % /category, by visit 
(2 categories: Yes/no) 
Cytokines sample Date (BIODT) 
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Cytokines sample Time (BIOTM) 
Listing only 
CXCL13 (pg/mL) (cytokines data) 
n, mean, sd, median, min, max, by visit 
IL-1β (pg/mL) (cytokines data) 
n, mean, sd, median, min, max, by visit 
IL-6 (pg/mL) (cytokines data) 
n, mean, sd, median, min, max, by visit 
IL-10 (pg/mL) (cytokines data) 
n, mean, sd, median, min, max, by visit 
IL-6/ IL-10 ratio (derived, see Section 3.6) 
n, mean, sd, median, min, max, by visit 
TNF-α (pg/mL) (cytokines data) 
n, mean, sd, median, min, max, by visit 
Change in CXCL13 at week 4 compared to 
baseline (pg/mL) (derived, see Section 3.6) 
n, mean (95% CI), sd, median, min, max 
Change in IL-1β at week 4 compared to baseline 
(pg/mL) (derived, see Section 3.6) 
n, mean (95% CI), sd, median, min, max 
Change in IL-6 at week 4 compared to baseline 
(pg/mL) (derived, see Section 3.6) 
n, mean (95% CI), sd, median, min, max 
Change in IL-10 at week 4 compared to baseline 
(pg/mL) (derived, see Section 3.6) 
n, mean (95% CI), sd, median, min, max 
Change in IL-6/ IL-10 ratio at week 4 compared to 
baseline (pg/mL) (derived, see Section 3.6) 
n, mean (95% CI), sd, median, min, max 
Change in TNF-α at week 4 compared to baseline 
(pg/mL) (derived, see Section 3.6) 
n, mean (95% CI), sd, median, min, max 
 
6.1.4 
Description of other efficacy variables 
 
Variable (CRF annotation) 
How to be presented 
Subject completed global and pain VAS (PGPVAS) 
# patients and % /category, by visit 
(2 categories: Yes/No) 
Global and Pain VAS Date (PGPDT) 
Listing only 
Patient Assessment of Pain Today, cm (PAP) 
n, mean (95% CI), sd, median, min, max,  
by visit 
Patient Global Assessment of Disease Activity 
Today VAS, cm (PGADA, dataset VAS) 
n, mean (95% CI), sd, median, min, max,  
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Investigator completed Investigator Global VAS 
(IGVAS) 
# patients and % /category, by visit 
(2 categories: Yes/No) 
Investigator Global VAS Date (IGVASDT) 
Listing only 
Investigator Global Assessment of Disease 
Activity Today VAS, cm (IGADA, dataset VAS) 
n, mean (95% CI), sd, median, min, max,  
by visit 
C-Reactive Protein (CRP), mg/L (derived from CRP 
and CRP_U, see Section 7.9.2) 
n, mean, sd, median, min, max, by visit 
C-Reactive Protein (CRP), Out of range and 
Clinically significantly abnormal (CRP_OR, 
CRP_CS) 
# patients and % /category  
(1 category CRP_OR; Yes, 2 categories CRP_CS; 
Yes/No), by visit 
 
 
6.2 
Exploratory Analysis 
 
Variables are listed below (CRF annotation presented in parenthesis), along with a short description 
of how they will be presented.  
For a list of proposed tables, see Appendix 4. 
Variable (CRF annotation) 
How to be presented 
Plasma concentrations of AP1189 (ng/mL) 
Listing only  
 
 
7 
SAFETY AND TOLERABILITY ANALYSES 
All safety parameters (vital signs, ECG, AEs/SAEs, laboratory abnormalities, etc.) will be summarized 
by treatment as well as for all subjects in total, by time point. Individual subject listings will also be 
prepared for all safety variables. Listings will include flagging of clinically notable vital sign 
abnormalities, as defined in protocol Table 5. 
Patients with no post randomization data who cannot be contacted will not be counted in frequency 
tables. If included, such patients would reduce the frequency of Adverse Events.  
Patients will be tabulated according to treatment received. Patients who have not received any trial 
medication (neither active treatment nor placebo) will not be included in frequency tables. 
Variables are listed below (CRF annotation presented in parenthesis), along with a short description 
of how they will be presented.  
For a list of proposed tables, see Appendix 4. 


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7.1 
Medical history variables 
 
Variable (CRF annotation) 
How to be presented 
Any relevant medical and/or surgical history 
(MHYN) 
# patients and % /category  
(2 categories: Yes/no) 
Medical diagnosis/surgical procedure 
(MHTERM, MHONG) 
# patients and % per diagnosis/procedure 
(unknown no. of categories) 
Medical diagnosis/surgical procedure start date 
(MHSTDAT) 
Listings only 
 
7.2 
Prior and concomitant medication variables  
 
Variable (CRF annotation) 
How to be presented 
Any concomitant medications (screening) or 
changes since last visit (CMYN) 
# patients and % /category  
(2 categories: Yes/No), by visit 
Reported generic name of medication (CMTRT) 
Listing only 
Total daily dose (CMDOSE) 
Listing only 
Unit (CMDOSU) 
Listing only 
Route of administration (CMROUTE) 
Listing only 
Frequency (CMDOSFRQ) 
Listing only 
Start date (CMSTDC) 
Listing only 
Stop date (CMENDC) 
Listing only 
Ongoing (CMONG) 
Listing only 
Indication (CMIND) 
Listing only 
AE no, if given to AE (CMAENO) 
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7.3 
Pregnancy test 
 
Pregnancy test taken (PTYN, PTREAS, UPTYN, 
UPTREAS) 
# patients and % /category, by visit  
(2 categories: Yes/no) 
Date of pregnancy test (PTDAT, UPTDAT) 
Listing only 
Result of pregnancy test (PTRES, UPTRES) 
# patients and % /category, by visit  
(2 categories: Negative/Positive) 
 
7.4 
Physical Examination 
 
Physical examination performed (PEYN) 
# patients and % /category, by visit  
(2 categories: Yes/no) 
Date of physical exam (PEDT) 
Listing only 
General appearance, normal/abnormal, 
clinically significant (GENAPP, GENAPP_DES, 
GENAPP_CS) 
# patients and % /category, by visit  
(3 categories for GENAPP: 
Normal/Abnormal/Not Done, plus any 
description if abnormal; 2 categories for 
GENAPP_CS: Yes/no) 
Dermatological, normal/abnormal, clinically 
significant (SKIN, SKIN_DES, SKIN_CS) 
# patients and % /category, by visit  
(3 categories for SKIN: Normal/Abnormal/Not 
Done, plus any description if abnormal; 2 
categories for SKIN_CS: Yes/no) 
Thyroid, normal/abnormal, clinically significant 
(THYR, THYR_DES, THYR_CS) 
# patients and % /category, by visit  
(3 categories for THYR: Normal/Abnormal/Not 
Done, plus any description if abnormal; 2 
categories for THYR_CS: Yes/no) 
Head, neck, throat, normal/abnormal, clinically 
significant (HNT, HNT_DES, HNT_CS) 
# patients and % /category, by visit  
(3 categories for HNT: Normal/Abnormal/Not 
Done, plus any description if abnormal; 2 
categories for HNT_CS: Yes/no) 
Heart / Lungs, normal/abnormal, clinically 
significant (RESP, RESP_DES, RESP_CS) 
# patients and % /category, by visit  
(3 categories for RESP: Normal/Abnormal/Not 
Done, plus any description if abnormal; 2 
categories for RESP_CS: Yes/no) 


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Abdomen, normal/abnormal, clinically 
significant (ABDOM, AB_DES, AB_CS) 
# patients and % /category, by visit  
(3 categories for ABDOM: 
Normal/Abnormal/Not Done, plus any 
description if abnormal; 2 categories for 
ABDOM_CS: Yes/no) 
Lymph nodes, normal/abnormal, clinically 
significant (LYMPH, LYMP_DES, LYMP_CS) 
# patients and % /category, by visit  
(3 categories for LYMPH: Normal/Abnormal/Not 
Done, plus any description if abnormal; 2 
categories for LYMP_CS: Yes/no) 
Musculoskeletal, normal/abnormal, clinically 
significant (MUSKU, MUSKU_DES, MUSCU_CS) 
# patients and % /category, by visit  
(3 categories for MUSKU: 
Normal/Abnormal/Not Done, plus any 
description if abnormal; 2 categories for 
MUSCU_CS: Yes/no) 
Cardiovascular, normal/abnormal, clinically 
significant (HEART, HEART_DES, HEART_CS) 
# patients and % /category, by visit  
(3 categories for HEART: Normal/Abnormal/Not 
Done, plus any description if abnormal; 2 
categories for HEART_CS: Yes/no) 
Neurological, normal/abnormal, clinically 
significant (NEUR, NEUR_DES, NEUR_CS) 
# patients and % /category, by visit  
(3 categories for NEUR: Normal/Abnormal/Not 
Done, plus any description if abnormal; 2 
categories for NEUR_CS: Yes/no) 
Joints, normal/abnormal, clinically significant 
(JOINT, JOIN_DES, JOIN_CS) 
# patients and % /category, by visit  
(3 categories for JOINT: Normal/Abnormal/Not 
Done, plus any description if abnormal; 2 
categories for JOIN_CS: Yes/no) 
 
7.5 
Height and Weight 
 
Height (HEIGHT) 
Listing only 
Weight (WEIGHT) 
Listing only 
Weight, clinically significant (WEIGHT_CS) 
Listing only 
 
7.6 
Vital Signs 
 


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Variable (CRF annotation) 
How to be presented 
Vital signs measured (VSYN) 
# patients and % /category  
(2 categories: Yes/No), by visit 
Date of vital signs (VSDT)  
Listing (and used to define visit) 
Time of vital signs (VSTM)  
Listing only 
Systolic BP, mmHg (SBP) 
n, mean, sd, median, min, max, by visit 
Systolic BP, clinically significant (SBP_CS) 
# patients and % /category  
(2 categories: Yes/No), by visit 
Diastolic BP, mmHg (DBP) 
n, mean, sd, median, min, max, by visit 
Diastolic BP, clinically significant (DBP_CS) 
# patients and % /category  
(2 categories: Yes/No), by visit 
Heart rate, bpm (HR)  
n, mean, sd, median, min, max, by visit 
Heart rate, clinically significant (HR_CS)  
# patients and % /category  
(2 categories: Yes/No), by visit 
Respiratory rate, breaths/min (RR) 
n, mean, sd, median, min, max, by visit 
Respiratory rate, clinically significant (RR_CS) 
# patients and % /category  
(2 categories: Yes/No), by visit 
 
7.7 
Lead ECGs 
 
Variable (CRF annotation) 
How to be presented 
ECG performed (EGPERF) 
# patients and % /category, by visit 
(2 categories: Yes/No) 
ECG Date (EGDT) 
Listing only 
Rhythm, bpm (ECRHYT, ECRHYOT) 
# patients and % /category, by visit  
(7 categories: Sinus normal/Tachycardia/Atrial 
fibrillation/Atrial flutter/Bradycardia/ 
Ventricular fibrillation/Other,  
plus any specification for other) 


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RR Interval, beats/min (EGRR) 
n, mean, sd, median, min, max, by visit 
PR Interval, msecs (EGPR) 
n, mean, sd, median, min, max, by visit 
QRS Duration, msecs (EGQRS) 
n, mean, sd, median, min, max, by visit 
QT Interval, msecs (EGQT) 
n, mean, sd, median, min, max, by visit 
QTcF Interval, msecs (EGQTCF). Derived from 
RR Interval (EGRR) and QT Interval (EGQT) if 
missing, see Section 3.6. 
n, mean, sd, median, min, max, by visit 
Overall interpretation (EGINTPRT) 
# patients and % /category, by visit  
(4 categories: Normal/Abnormal, clinically 
insignificant/ Abnormal, clinically significant/ 
Unable to Evaluate) 
Description of abnormal findings (EGDESC) 
List of descriptions, by visit 
7.8 
X-Rays 
 
Variable (CRF annotation) 
How to be presented 
Chest X-ray taken (XRCYN) 
# patients and % /category  
(2 categories: Yes/No) 
Chest X-ray Date (XRCDT) 
Listing only 
Hands and feet X-ray taken (XRHF) 
# patients and % /category  
(2 categories: Yes/No) 
Hands and feet X-ray Date (XRHFDT) 
Listing only 
7.9 
Laboratory Assessments 
7.9.1 
Haematology 
 
Variable (CRF annotation) 
How to be presented 
Blood sample collected for analysis of 
Haematology (BLHPERF) 
# patients and % /category, by visit 
(2 categories: Yes/No) 
Haematology sample Date (BLHDT) 
Listing only 
Haematology sample Time (BLHTM) 
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HbA1c, collected unit1 (HBA1C, HBA1C_U) 
Listing only (units converted to mmol/L) 
HbA1c, mmol/mol (derived from HBA1C above) 
n, mean, sd, median, min, max, by visit 
HbA1c, Out of range and Clinically significantly 
abnormal (HBA1C_OR, HBA1C_CS) 
# patients and % /category  
(1 category HBA1C_OR; Yes, 2 categories 
HBA1C_CS; Yes/No), by visit 
White blood cell, collected unit (WBCC, WBCC_U) 
Listing only (units converted to 10E9/L) 
White blood cell, 10E9/L (derived from WBCC 
above) 
n, mean, sd, median, min, max, by visit 
White blood cell, Out of range and Clinically 
significantly abnormal (WBCC_OR, WBCC_CS) 
# patients and % /category  
(1 category WBCC_OR; Yes, 2 categories 
WBCC_CS; Yes/No), by visit 
Neutrophils, collected unit (NEUT, NEUT_U) 
Listing only (units converted to 10E9/L) 
Neutrophils, 10E9/L (derived from NEUT above) 
n, mean, sd, median, min, max, by visit 
Neutrophils, Out of range and Clinically 
significantly abnormal (NEUT_OR, NEUT_CS) 
# patients and % /category  
(1 category NEUT_OR; Yes, 2 categories 
NEUT_CS; Yes/No), by visit 
Lymphocytes, collected unit (LYMPO, LYMPO_U) 
Listing only (units converted to 10E9/L) 
Lymphocytes, 10E9/L (derived from LYMPO 
above) 
n, mean, sd, median, min, max, by visit 
Lymphocytes, Out of range and Clinically 
significantly abnormal (LYMPO_OR, LYMPO_CS) 
# patients and % /category  
(1 category LYMPO_OR; Yes, 2 categories 
LYMPO_CS; Yes/No), by visit 
Monocytes, collected unit (MONOC, MONOC_U) 
Listing only (units converted to 10E9/L) 
Monocytes, 10E9/L (derived from MONOC above) n, mean, sd, median, min, max, by visit 
Monocytes, Out of range and Clinically 
significantly abnormal (MONOC_OR, MONOC_CS) 
# patients and % /category  
(1 category MONOC_OR; Yes, 2 categories 
MONOC_CS; Yes/No), by visit 
Eosinophils, collected unit (EOSIN, EOSIN_U) 
Listing only (units converted to 10E9/L) 
Eosinophils, 10E9/L (derived from EOSIN above) 
n, mean, sd, median, min, max, by visit 


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Eosinophils, Out of range and Clinically 
significantly abnormal (EOSIN_OR, EOSIN_CS) 
# patients and % /category  
(1 category EOSIN_OR; Yes, 2 categories 
EOSIN_CS; Yes/No), by visit 
Basophils, collected unit (BASO, BASO_U) 
Listing only (units converted to 10E9/L) 
Basophils, 10E9/L (derived from BASO above) 
n, mean, sd, median, min, max, by visit 
Basophils, Out of range and Clinically significantly 
abnormal (BASO_OR, BASO_CS) 
# patients and % /category  
(1 category BASO_OR; Yes, 2 categories 
BASO_CS; Yes/No), by visit 
Hemoglobin, collected unit (HB, HB_U) 
Listing only (units converted to mmol/L) 
Hemoglobin, mmol /L (derived from HB above) 
n, mean, sd, median, min, max, by visit 
Hemoglobin, Out of range and Clinically 
significantly abnormal (HB_OR, HB_CS) 
# patients and % /category  
(1 category HB_OR; Yes, 2 categories HB_CS; 
Yes/No), by visit 
Red blood cells (RBC), collected unit (RBC, 
RBC_U) 
Listing only (units converted to 10E12/L) 
Red blood cells (RBC), 10E12/L (derived from RBC 
above) 
n, mean, sd, median, min, max, by visit 
Red blood cells (RBC), Out of range and Clinically 
significantly abnormal (RBC_OR, RBC_CS) 
# patients and % /category  
(1 category RBC_OR; Yes, 2 categories 
RBC_CS; Yes/No), by visit 
Thrombocytes, collected unit (THRC, THRC_U) 
Listing only (units converted to 10E9/L) 
Thrombocytes, 10E9/L (derived from THRC 
above) 
n, mean, sd, median, min, max, by visit 
Thrombocytes, Out of range and Clinically 
significantly abnormal (THRC_OR, THRC_CS) 
# patients and % /category  
(1 category THRC_OR; Yes, 2 categories 
THRC_CS; Yes/No), by visit 
1 Different laboratories might use different units. All values collected in different units than the units 
to be used for analysis will be converted, see section 3.6. 
 
7.9.2 
Biochemistry 
 
Variable (CRF annotation) 
How to be presented 


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Blood sample collected for analysis of 
Biochemistry (BLBPERF) 
# patients and % /category, by visit 
(2 categories: Yes/No) 
Biochemistry sample Date (BLBDT) 
Listing only 
Biochemistry sample Time (BLBTM) 
Listing only 
Alanine transaminase (ALT), collected unit1 (ALT, 
ALT_U) 
Listing only (units converted to U/L) 
Alanine transaminase (ALT), U/L (derived from 
ALT above) 
n, mean, sd, median, min, max, by visit 
Alanine transaminase (ALT), Out of range and 
Clinically significantly abnormal (ALT_OR, ALT_CS) 
# patients and % /category  
(1 category ALT_OR; Yes, 2 categories ALT_CS; 
Yes/No), by visit 
Aspartate transaminase (AST), collected unit 
(AST, AST_U) 
Listing only (units converted to U/L) 
Aspartate transaminase (AST), U/L (derived from 
AST above) 
n, mean, sd, median, min, max, by visit 
Aspartate transaminase (AST), Out of range and 
Clinically significantly abnormal (AST_OR, 
AST_CS) 
# patients and % /category  
(1 category AST_OR; Yes, 2 categories AST_CS; 
Yes/No), by visit 
γ−glutamyltransferase (GGT), collected unit (GGT, 
GGT_U) 
Listing only (units converted to U/L) 
γ−glutamyltransferase (GGT), U/L (derived from 
GGT above) 
n, mean, sd, median, min, max, by visit 
γ−glutamyltransferase (GGT), Out of range and 
Clinically significantly abnormal (GGT_OR, 
GGT_CS) 
# patients and % /category  
(1 category GGT_OR; Yes, 2 categories 
GGT_CS; Yes/No), by visit 
Bilirubin (total), collected unit (BILIT, BILIT_U) 
Listing only (units converted to µmol/L) 
Bilirubin (total), µmol/L (derived from BILIT 
above) 
n, mean, sd, median, min, max, by visit 
Bilirubin (total), Out of range and Clinically 
significantly abnormal (BILIT_OR, BILIT_CS) 
# patients and % /category  
(1 category BILIT_OR; Yes, 2 categories 
BILIT_CS; Yes/No), by visit 


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Bilirubin (conjugated), collected unit (BILIC, 
BILIC_U) 
Listing only (units converted to µmol/L) 
Bilirubin (conjugated), µmol/L (converted from 
BILIC above) 
n, mean, sd, median, min, max, by visit 
Bilirubin (conjugated), Out of range and Clinically 
significantly abnormal (BILIC_OR, BILIC_CS) 
# patients and % /category  
(1 category BILIC_OR; Yes, 2 categories 
BILIC_CS; Yes/No), by visit 
Bilirubin (unconjugated), µmol/L, calculated 
(BILICALC)  
n, mean, sd, median, min, max, by visit 
Bilirubin (unconjugated), Out of range and 
Clinically significantly abnormal (BILIUN_OR, 
BILIUN_CS) 
# patients and % /category  
(1 category BILIUN_OR; Yes, 2 categories 
BILIUN_CS; Yes/No), by visit 
Alkaline phosphatase (ALP), collected unit (ALP, 
ALP_U) 
Listing only (units converted to U/L) 
Alkaline phosphatase (ALP), U/L (derived from 
ALP above) 
n, mean, sd, median, min, max, by visit 
Alkaline phosphatase (ALP), Out of range and 
Clinically significantly abnormal (ALP_OR, 
ALP_CS) 
# patients and % /category  
(1 category ALP_OR; Yes, 2 categories ALP_CS; 
Yes/No), by visit 
Glucose (non-fasting), collected unit (GLUC, 
GLUC_U) 
Listing only (units converted to mmol/L) 
Glucose (non-fasting), mmol/L (derived from 
GLUC above) 
n, mean, sd, median, min, max, by visit 
Glucose (non-fasting), Out of range and Clinically 
significantly abnormal (GLUC_OR, GLUC_CS) 
# patients and % /category  
(1 category GLUC_OR; Yes, 2 categories 
GLUC_CS; Yes/No), by visit 
Potassium, collected unit (POT, POT_U) 
Listing only (units converted to mmol/L) 
Potassium, mmol/L (derived from POT above) 
n, mean, sd, median, min, max, by visit 
Potassium, Out of range and Clinically 
significantly abnormal (POT_OR, POT_CS) 
# patients and % /category  
(1 category POT_OR; Yes, 2 categories 
POT_CS; Yes/No), by visit 
Sodium, collected unit (SOD, SOD_U) 
Listing only (units converted to mmol/L) 


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Sodium, mmol/L (derived from SOD above) 
n, mean, sd, median, min, max, by visit 
Sodium, Out of range and Clinically significantly 
abnormal (SOD_OR, SOD_CS) 
# patients and % /category  
(1 category SOD_OR; Yes, 2 categories 
SOD_CS; Yes/No), by visit 
Chloride, collected unit (CHLOR, CHLOR_U) 
Listing only (units converted to mmol/L) 
Chloride, mmol/L (derived from CHLOR above) 
n, mean, sd, median, min, max, by visit 
Chloride, Out of range and Clinically significantly 
abnormal (CHLOR_OR, CHLOR_CS) 
# patients and % /category  
(1 category CHLOR_OR; Yes, 2 categories 
CHLOR_CS; Yes/No), by visit 
Calcium, collected unit (CALC, CALC_U) 
Listing only (units converted to mmol/L) 
Calcium, mmol/L (derived from CALC above) 
n, mean, sd, median, min, max, by visit 
Calcium, Out of range and Clinically significantly 
abnormal (CALC_OR, CALC_CS) 
# patients and % /category  
(1 category CALC_OR; Yes, 2 categories 
CALC_CS; Yes/No), by visit 
Albumin, collected unit (ALB, ALB_U) 
Listing only (units converted to g/L) 
Albumin, g/L (derived from ALB above) 
n, mean, sd, median, min, max, by visit 
Albumin, Out of range and Clinically significantly 
abnormal (ALB_OR, ALB_CS) 
# patients and % /category  
(1 category ALB_OR; Yes, 2 categories ALB_CS; 
Yes/No), by visit 
Creatinine, collected unit (CREA, CREA_U) 
Listing only (units converted to цmol/L) 
Creatinine, цmol/L (derived from CREA above) 
n, mean, sd, median, min, max, by visit 
Creatinine, Out of range and Clinically 
significantly abnormal (CREA_OR, CREA_CS) 
# patients and % /category  
(1 category CREA_OR; Yes, 2 categories 
CREA_CS; Yes/No), by visit 
C-Reactive Protein (CRP), collected unit (CRP, 
CRP_U) 
Listing only (units converted to mg/L) 
C-Reactive Protein (CRP), mg/L (derived from CRP 
above) 
Presented with Secondary Efficacy Variables 
C-Reactive Protein (CRP), Out of range and 
Clinically significantly abnormal (CRP_OR, 
CRP_CS) 
# patients and % /category  
(1 category CRP_OR; Yes, 2 categories CRP_CS; 
Yes/No), by visit 


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Urea, collected unit (UREA, UREA_U) 
Listing only (units converted to mmol/L) 
Urea, mmol/L (derived from UREA above) 
n, mean, sd, median, min, max, by visit 
Urea, Out of range and Clinically significantly 
abnormal (UREA_OR, UREA_CS) 
# patients and % /category  
(1 category UREA_OR; Yes, 2 categories 
UREA_CS; Yes/No), by visit 
INR (INR) 
n, mean, sd, median, min, max, by visit 
INR, Out of range and Clinically significantly 
abnormal (INR_OR, INR_CS) 
# patients and % /category  
(1 category INR_OR; Yes, 2 categories INR_CS; 
Yes/No), by visit 
1 Different laboratories might use different units. All values collected in different units than the units 
to be used for analysis will be converted, see section 3.6. 
 
 
 
7.9.3 
Thyroid Function 
 
Variable (CRF annotation) 
How to be presented 
TSH, collected unit1 (TSH, TSH_U) 
Listing only (units converted to 10E3/L) 
TSH, 10E3/L (derived from TSH above) 
n, mean, sd, median, min, max, by visit 
TSH, Out of range and Clinically significantly 
abnormal (TSH_OR, TSH_CS) 
# patients and % /category  
(1 category TSH_OR; Yes, 2 categories TSH_CS; 
Yes/No), by visit 
Total T3, collected unit (TT3, TT3_U) 
Listing only (units converted to nmol/L) 
Total T3, nmol/L (derived from TT3 above) 
n, mean, sd, median, min, max, by visit 
Total T3, Out of range and Clinically significantly 
abnormal (TT3_OR, TT3_CS) 
# patients and % /category  
(1 category TT3_OR; Yes, 2 categories TT3_CS; 
Yes/No), by visit 
Free T3, collected unit (FT3, FT3_U) 
Listing only (units converted to pmol/L) 
Free T3, pmol/L (derived from FT3 above) 
n, mean, sd, median, min, max, by visit 


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Free T3, Out of range and Clinically significantly 
abnormal (FT3_OR, FT3_CS) 
# patients and % /category  
(1 category FT3_OR; Yes, 2 categories FT3_CS; 
Yes/No), by visit 
Total T4, collected unit (TT4, TT4_U) 
Listing only (units converted to nmol/L) 
Total T4, nmol/L (derived from TT4 above) 
n, mean, sd, median, min, max, by visit 
Total T4, Out of range and Clinically significantly 
abnormal (TT4_OR, TT4_CS) 
# patients and % /category  
(1 category TT4_OR; Yes, 2 categories TT4_CS; 
Yes/No), by visit 
Free T4, collected unit (FT4, FT4_U) 
Listing only (units converted to pmol/L) 
Free T4, pmol/L (derived from FT4 above) 
n, mean, sd, median, min, max, by visit 
Free T4, Out of range and Clinically significantly 
abnormal (FT4_OR, FT4_CS) 
# patients and % /category  
(1 category FT4_OR; Yes, 2 categories FT4_CS; 
Yes/No), by visit 
1 Different laboratories might use different units. All values collected in different units than the units 
to be used for analysis will be converted, see section 3.6. 
7.9.4 
Urinalysis 
 
Variable (CRF annotation) 
How to be presented 
Urine sample collected for analysis (UAPERF) 
# patients and % /category, by visit 
(2 categories: Yes/No) 
Urine sample Date (UADT) 
Listing only 
Urine sample Time (UATM) 
Listing only 
Urinalysis result Blood (UABLOOD) 
# patients and % /category, by visit 
(2 categories: Negative/Positive) 
Urinalysis result Protein (UAPROT) 
# patients and % /category, by visit 
(2 categories: Negative/Positive) 
Urinalysis result Glucose (UAGLUC) 
# patients and % /category, by visit 
(2 categories: Negative/Positive) 
Sample sent for urine culture (UCULTYN) 
# patients and % /category, by visit 
(2 categories: Yes/No) 


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Urine culture result (UCULTRES) 
# patients and % /category, by visit 
(Categories to be based on text entries) 
Urine culture clinically significant (UCULTCS) 
# patients and % /category, by visit 
(2 categories: Yes/No) 
 
7.9.5 
Serology 
 
Variable (CRF annotation) 
How to be presented 
Serology blood sample collected (BLSYN) 
# patients and % /category  
(2 categories: Yes/No) 
Serology blood sample Date (BLSDT) 
Listing only 
Rheumatoid Factor (RF) Test result (RF, RFND) 
# patients and % /category  
(3 categories: Negative/Positive/Not done) 
Anti-CCP Test result (ACCP, ACCPND) 
# patients and % /category  
(3 categories: Negative/Positive/Not done) 
HBsAg Test result (HBSAG) 
# patients and % /category  
(3 categories: Negative/Positive/Not done) 
HBV antibody Test result (HBVANTI) 
# patients and % /category  
(3 categories: Negative/Positive/Not done) 
HCV antibody Test result (HCVANTI) 
# patients and % /category  
(3 categories: Negative/Positive/Not done) 
 
 
7.9.6 
MC1R Genotype Analysis 
 
Variable (CRF annotation) 
How to be presented 
Blood sample Date 
Listing only 
MC1R genotype result 
# patients and % /category  
(2 categories: MC1R Present/Not present) 
 


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7.10 
Adverse Events 
 
Variable (CRF annotation) 
How to be presented 
Any new (or changes to) AE (AEYN) 
# patients and % /category  
(2 categories: Yes/No), by visit 
AE description/Term (AETERM) 
Listing only (used for MedDRA coding) 
AE MedDRA term (coding performed by DM) 
# patients and % /MedDRA term 
(x categories), by visit 
AE start date (AESTDAT) 
Listing only 
AE end date (AEENDAT) 
Listing only 
AE ongoing (AEONG) 
Listing only 
Date site aware of AE (AEAWDT) 
Listing only 
AE severity (AESEV) 
# patients and % /category 
(5 categories: Mild/Moderate/Severe/Life-
threatening/Death), by visit 
Relationship to study treatment (AEREL) 
# patients and % /category 
(5 categories: Definitely not related/Probably 
not related/Possibly related/Probably 
related/Definitely related), by visit 
Action taken with study drug (AEACT) 
# patients and % /category 
(5 categories: Dose not changed/Dose 
interrupted/Drug withdrawn/Not applicable/ 
Unknown), by visit 
AE outcome (AEOUT) 
# patients and % /category 
(6 categories: Fatal, Not recovered/Not 
Resolved, Recovered/Resolved, 
Recovered/Resolved with sequelae, 
Recovering/Resolving 
Unknown), by visit  
Medication given to treat AE (AETREAT) 
# patients and % /category 
(2 categories: Yes/No), by visit  


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Serious Adverse Event (AESER, AESER1, AESER2, 
AESER3, AESER4, AESER5, AESER6) 
# patients and % /category 
(2 categories for AESER: Yes/No, plus number of 
each kind of SAE: Death, Life-threatening, 
Inpatient hospitalisation or prolongation of 
existing hospitalisation, Persistent or significant 
disability/incapacity, Congenital anomaly or 
birth defect, and/or Important medical event), 
by visit  
SAE report Date (SAEREPDT) 
Listing only 
Date of birth (BRTHDT) 
Listing only 
Sex (GENDER) 
Listing only 
Height, cm (HEIGHT, AE dataset) 
Listing only 
Weight, kg (SAEWGHT) 
Listing only 
SAE description (SAEDESC) 
Included in SAE table 
Phase of study at time of event (SAESP) 
# patients and % /category (4 categories: 
Screening/Treatment/Wash-out/Follow-up), 
included in SAE table 
Study Drug Information (SAESD, SAEFREQ, 
SAEFADT, SAELADT) 
Listing only 
SAE abate after stopping study medication 
(SAEDECH) 
Listing only 
SAE reappear after reintroduction of study 
medication (SAERECH) 
Listing only 
Blinding code broken (SAEBBROK, SAEBBDT) 
Listing only 
Concomitant medication (SAECM) 
Listing only 
Relevant medical history (SAEMH) 
Listing only 
Hospitalisation Details (SAEHOSP, SAEADT, 
SAEDDT) 
Listing only 
Death Details (SAEDEDT, SAEPCAUS, SAEAUTO, 
SAEINF) 
Listing only 
 


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The incidence of AEs will be summarized by the reported AE term. A subject will be counted only 
once in the incidence count for a specific AE term, although an AE term might be reported more than 
once for a particular subject.  
 
Separate summaries will be provided for relationship (yes, no) to study drug. An AE will be 
considered related to study drug if the investigator reported the event to be “definitely, probably, 
possibly, or unlikely” related to treatment on the CRF.  
 
 
8 
QUALITY CONTROL PROCEDURES 
The statistical programming and analyses will be performed on a fully quality assured database. 
The accuracy and validity of the output, tables, listings, and appendices will be ensured by 
performing a minimum of the following tasks: 
8.1 
Programming  
✓ Validated generic code (such as pre-written and validated SAS macros) will be used whenever 
possible 
✓ Any programs written for the purpose of data tabulation, data listing, or graphical presentations 
will be checked by comparing the output with the original database 
8.2 
Derived Data Sets 
✓ All data sets derived from the study database will be checked to ensure that they contain the 
intended data 
8.3 
Data Listings 
✓ At least 5% of data in listings will be verified against the database 
✓ It will be assured that all patients in the study appear in data listings by checking that the number 
of patients in different groups add up to the correct total 
✓ All listings will be visually checked for outliers and obvious discrepancies 
✓ Codes used for data listings will be verified 
8.4 
Calculated Data 
✓ Calculated data will be checked for obvious discrepancies 
✓ At least 20% of the data calculated for efficacy parameters (descriptive statistics, p-values, etc.) 
will be recalculated  
8.5 
Tables 
✓ Population sizes and percentages will be checked 
✓ All tables will be visually checked for outliers and obvious discrepancies 
8.6 
Consistency of Summary Tables and Data Listings 
✓ The consistency of summary tables and data listings will be verified  
8.7 
Documentation of Quality Control 
The performed quality control will be documented and signed by the Biostatistician.  


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APPENDIX 1: 
STATISTICAL ANALYSIS PLAN 
AUTHENTICATION AND AUTHORISATION 


Nov 23 2021


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APPENDIX 2: STATISTICAL SECTION(S) OF THE STUDY PROTOCOL 
Separate document. 
 
APPENDIX 3: DATA MONITORING COMMITTEE CHARTER 
Separate document. 
 
APPENDIX 4: SPECIFICATIONS FOR TABLES, FIGURES, AND LISTINGS 
Separate document. 
 
 
 


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APPENDIX 5: REVISION HISTORY 
Version Date 
Version 1.0, 9OCT2020 
Version 2.0, 07OCT2021 
 
Page 
Section 
WAS 
IS 
Reason for change 
5 
2.1.3 Primary 
Efficacy Objective 
Effect of AP1189 vs. placebo in 
subjects with severe active RA 
(CDAI > 22), undergoing up-
titration with MTX, by showing a 
change in CDAI from severe 
(CDAI > 22) to moderate (CDAI 
≤ 22) after 4 weeks treatment 
compared to baseline. 
Effect of AP1189 vs. placebo in subjects with severe 
active RA (CDAI > 22), undergoing up-titration with 
MTX, by showing a change in CDAI from severe 
(CDAI > 22) to moderate or lower (CDAI ≤ 22) after 
4 weeks treatment compared to baseline. 
Clarification. 
6 
2.2 Study Type and 
Design 
Study Flow Chart: Study flow 
chart is shown in the study 
protocol, Table 3. 
Study Flow Chart: Study flow chart is shown in the 
study protocol, Table 3, section 20 Schedule of 
Visits. 
Clearer reference 
7 
3.1 Types of Analysis 
Descriptive statistics (continuous 
and categorical variables 
summarized as above) will be 
used for an exploratory 
description of exposure in 
relation to effect. 
Descriptive statistics (continuous and categorical 
variables summarized as above) will be used for an 
exploratory description of exposure in relation to 
effect. 
 
8  
3.5 Subgroup 
Analyses 
No subgroup analyses are being 
planned for. 
A sub-study taking place in Bulgaria and 
Moldova was added to the clinical study protocol. 
The sub-study was added to investigate if the 
effect of AP1189 in newly diagnosed subjects with 
severe RA who are to start up-titration with 
methotrexate is comparable in these two countries 
compared to the main study. In addition to 
analyzing the main study and the sub-study 
separately, all data will be pooled to investigate 
the overall effect in all participating countries. No 
subgroup analyses are being planned for. 
Addition of sub-study in protocol v.9.0. 
8 
3.6 Data 
Transformation and 
Derived Variables 
Change from baseline to week 4 
(value at week 4 minus value at 
baseline) will be calculated for 
the following variables: 
Change from baseline to week 4 (value at week 4 
minus value at baseline) will be calculated for the 
following variables: 
• CDAI 
Addition of exploratory analysis 


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• CDAI 
• HAQ-DI total score 
• DAS28 
• HAQ-DI total score 
9 
3.6 Data 
Transformation and 
Derived Variables 
Indicators noting the following 
will be constructed, based on the 
above defined change in CDAI 
score from baseline to week 4: 
• a 5-point decrease 
• a 10-point decrease 
• a 15-point decrease 
Indicators noting the following will be constructed, 
based on the above defined change in CDAI score 
from baseline to week 4: 
• a 5-point decrease 
• a 10-point decrease 
• a 15-point decrease 
• a 20-point decrease 
• a 30-point decrease 
Addition of exploratory analyses 
9 
3.6 Data 
Transformation and 
Derived Variables 
An indicator noting a change in 
CDAI score from severe (CDAI > 
22) to moderate (CDAI ≤ 22) at 
week 4 compared to baseline will 
be constructed. 
 
An indicator noting a change in 
DAS28 from > 3.2 to ≤ 3.2 at 
week 4 compared to baseline will 
be constructed. 
An indicator Indicators noting a change in CDAI 
score will be constructed as follows: 
• from severe (CDAI > 22) to moderate or lower 
(CDAI ≤ 22) at week 4 compared to baseline will be 
constructed. 
• from severe (CDAI > 22) to low or remission 
(CDAI ≤ 10) at week 4 compared to baseline 
• from severe (CDAI > 22) to remission (CDAI ≤ 
2.8) at week 4 compared to baseline 
 
An indicator Indicators noting a change in DAS28 
will be constructed as follows: 
• from > 3.2 to ≤ 3.2 at week 4 compared to baseline 
will be constructed. 
• from high (DAS28 > 5.1) to moderate or lower 
(DAS28 ≤ 5.1) at week 4 compared to baseline 
Addition of exploratory analyses 
10 
3.6 Data 
Transformation and 
Derived Variables 
Lab values are reported in 
different units at different sites 
and will be transformed to the 
following units:  
 
Lab values are reported in different units at different 
sites and will be transformed to the following units: 
The QT interval on the ECGs is corrected from 
Bazett, Hodges or ECAPS to Fridericia. The 
laboratory values from the different sites may be 
reported in different units, which will be 
corrected to: 
New information from sites. 
11 
3.6 Data 
Transformation and 
Derived Variables 
 
Addition of Variable: Corrected QT Interval (QTc) 
New information from sites. 


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11 
3.6 Data 
Transformation and 
Derived Variables 
 
Addition of Unit to be used in analyses/report: QTc 
Fridericia 
New information from sites. 
11 
3.6 Data 
Transformation and 
Derived Variables 
 
Addition of Conversion formula(s): 
QTcF = QT/(RR1/3) 1 
New information from sites. 
11 
3.6 Data 
Transformation and 
Derived Variables 
 
Addition of Comments: 
The reported QT and RR intervals will be used to 
calculate QTcF. 
New information from sites. 
11 
3.6 Data 
Transformation and 
Derived Variables 
HbA1c unit 
mmol/mol  mmol/L 
 
Addition of Comment: mmol/L used at sites in 
Moldova and Bulgaria 
New information from sites. 
11 
3.6 Data 
Transformation and 
Derived Variables 
Variables White blood cell, 
Neutrophils, Lymphocytes, 
Monocytes, Eosinophils,  
Basophils, Hemoglobin, 
Red blood cells (RBC), 
Thrombocytes 
Addition of Comment: 
 
g/dl used at some sites 
New information from sites. 
11 
3.6 Data 
Transformation and 
Derived Variables 
Variables  
Alanine transaminase (ALT), 
Aspartate transaminase (AST), 
γ−glutamyltransferase (GGT), 
Alkaline phosphate (ALP) 
Addition of Comment: 
 
µkat/L used at some sites 
New information from sites. 
11 
3.6 Data 
Transformation and 
Derived Variables 
Footnote 1 (several places in the 
table) 
2 1 
New information from sites. 
11 
3.6 Data 
Transformation and 
Derived Variables 
Variable Free T4 
Addition of Comment: 
 
Some site measure Total T4 
 
12 
3.6 Data 
Transformation and 
Derived Variables 
Addition of footnote 
1 https://www.clinigate.com/clinicalc/corrected-qt-
interval-qtc.php 
New information from sites. 
12 
3.6 Data 
Transformation and 
Derived Variables 
1 http://unitslab.com/node/55 
2 http://unitslab.com/node/55 
Addition of footnote above. 


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12 
3.6 Data 
Transformation and 
Derived Variables 
Site 21 measures serum 
biochemistry, while all the other 
sites measure plasma 
biochemistry, which means that 
different reference intervals must 
be used. 
All the clinical sites are using their local 
laboratory to measure safety parameters, which 
means that different reference intervals will 
apply. 
Site 21 measures serum biochemistry, while all the 
other sites measure plasma biochemistry, which 
means that different reference intervals must be used. 
New information from sites. 
12 
3.6 Data 
Transformation and 
Derived Variables 
Lab values reported as a non-
numerical value (e.g., ‘<1’) will 
be transformedconverted to an 
appropriate numerical value for 
numerical analyses (e.g., 
calculation of mean values). The 
team will decide the numerical 
value to be used before analyses.  
Lab values reported as a non-numerical value (e.g., 
‘<1’) will be transformedconverted to an appropriate 
numerical value for numerical analyses (e.g., 
calculation of mean values). The team will decide the 
numerical value to be used before analyses. Lab 
values below the level of quantification will be set 
to LoQ/2 for the analyses. 
Clarification on how to handle this 
special type of lab values. 
12 
3.6 Data 
Transformation and 
Derived Variables 
Change from baseline to week 4 
(value at week 4 minus value at 
baseline) will be calculated for 
the following variables (only Part 
2, selected sites): 
• 
Percentage of 
polymorphs in synovial fluid 
• 
Percentage of 
monocytes in synovial fluid 
• 
Percentage of 
lymphocytes in synovial fluid 
Change from baseline to week 4 (value at week 4 
minus value at baseline) will be calculated for the 
following variables (only Part 2, selected sites): 
• 
Percentage of polymorphs in 
synovial fluid 
• 
Percentage of monocytes in 
synovial fluid 
• 
Percentage of lymphocytes in 
synovial fluid 
The mentioned sub-study will not be 
performed. 
12 
3.7 Interim Analysis 
An interim analysis will be 
performed, evaluating the first 
(minimum) 24 subjects from Part 
1 of the trial in order to assess the 
safety and efficacy of the 
investigational product before 
proceeding to Part 2.  
 
All safety parameters (ECG, vital 
signs, AEs/SAEs, laboratory 
abnormalities, etc.) and efficacy 
An interim analysis will be has been performed, 
evaluating the first (minimum) 24 subjects from Part 
1 of the trial in order to assess the safety and efficacy 
of the investigational product before proceeding to 
Part 2. Version 1 of this analysis plan was used for 
the interim analysis. 
 
All safety parameters (ECG, vital signs, AEs/SAEs, 
laboratory abnormalities, etc.) and efficacy data for 
the primary efficacy endpoint will be were 
summarized by treatment and time point for the 
The interim analysis has already been 
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data for the primary efficacy 
endpoint will be summarized by 
treatment and time point for the 
subjects included in Part 1 of the 
study, i.e., the following tables 
(see Appendix 4 for details) will 
be presented (any MedDRA 
coding of AEs will not be 
performed for the interim): 
subjects included in Part 1 of the study, i.e., the 
following tables (see Appendix 4 for details) will be 
were presented (any MedDRA coding of AEs will 
not be performed for the interim): 
13 
3.7 Interim Analysis 
Listings showing the following 
data will also be presented: 
Listings showing the following data will were also 
be presented: 
The interim analysis has already been 
performed. 
13 
3.7 Interim Analysis 
An independent external 
statistician will conduct the 
interim analysis. The external 
statistician is included in the Data 
Monitoring Committee (DMC) 
established by the sponsor. The 
DMC will review the unblinded 
data from the interim analysis and 
recommend one of the three study 
designs for Part 2 to the Safety 
Committee. The criteria for 
choice of design are described in 
the Data Monitoring Committee 
Charter (Appendix 3). All 
recommendations will be 
documented and signed by the 
DMC members, and they will 
provide a summary of the safety 
and tolerability data obtained in 
Part 1 and their design 
recommendation for Part 2. 
The independent external 
statistician will ensure that the 
interim analysis is a completely 
confidential process. Sponsor, 
investigators, and other study 
An independent external statistician will conducted 
the interim analysis. The external statistician is 
included in the Data Monitoring Committee (DMC) 
established by the sponsor. The DMC will reviewed 
the unblinded data from the interim analysis and 
recommended one of the three study designs for Part 
2 to the Safety Steering Committee. The criteria for 
choice of design are described in the Data 
Monitoring Committee Charter (Appendix 3). All 
recommendations will be are documented and signed 
by the DMC members, and they will provided a 
summary of the safety and tolerability data obtained 
in Part 1 and their design recommendation for Part 2. 
The independent external statistician will ensure that 
the interim analysis is a completely confidential 
process. Sponsor, investigators, and other study 
personnel will be kept blind.  The Steering 
Committee's final decision on design choices for Part 
2 of the study will be was communicated to all 
investigators and study personnel as soon as the 
decision is was made. 
The interim analysis has already been 
performed. 
 
Steering Committee’s name also 
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personnel will be kept blind.  The 
Steering Committee's final 
decision on design choices for 
Part 2 of the study will be 
communicated to all investigators 
and study personnel as soon as 
the decision is made. 
14 
3.12 Documentation 
and Other 
Considerations 
New text added 
Protocol Section 12.2 Primary efficacy Objective 
states “Effect of AP1189 vs. placebo in subjects 
with severe active RA (CDAI > 22), undergoing 
up-titration with MTX, by showing a change in 
CDAI from severe (CDAI > 22) to moderate 
(CDAI ≤ 22) after 4 weeks treatment compared to 
baseline.” The cut-off values for the CDAI score 
correspond to severe (CDAI>22) or moderate or 
lower (CDAI ≤ 22), which is the wording used in 
this analysis plan. 
Clarification. 
14 
3.12 Documentation 
and Other 
Considerations 
However, no samples are 
collected to make a PK 
evaluation, and this will thus not 
be done. 
However, only one sample is taken at each visit 
(for some visits), with variability in the time 
from last dosing to sampling. Thus, the 
relationship between exposure and effect is 
not possible to evaluate, and exposure will 
therefore be described without relation to 
effect. no samples are collected to make a PK 
evaluation, and this will thus not be done. 
New information, PK samples are 
taken once after 1, 2, 3- and 4-weeks of 
treatment. 
18 
6.1.1 Description of 
primary efficacy 
variables 
Proportion of subjects with a 
change in CDAI score from 
severe (CDAI > 22) to moderate 
(CDAI ≤ 22) at week 4 compared 
to baseline (derived, see Section 
3.6) 
Proportion of subjects with a change in CDAI score 
from severe (CDAI > 22) to moderate or lower 
(CDAI ≤ 22) at week 4 compared to baseline 
(derived, see Section 3.6) 
Clarification. 
21 
6.1.2 Description of 
secondary efficacy 
variables 
 
New variables added to the table: 
 
DAS28 change from 
baseline to week 4 
(derived, see Section 3.6) 
n, mean (95% CI), 
sd, median, min, 
max, by visit 
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29 
7.7 Lead ECGs 
QTcF Interval, msecs 
(EGQTCF).  
QTcF Interval, msecs (EGQTCF). Derived from RR 
Interval (EGRR) and QT Interval (EGQT) if 
missing, see Section 3.6. 
New information from sites. 
30 
7.9.1 Haematology 
 
HbA1c, mmol/L (derived from 
HBA1C above) 
HbA1c, mmol/molL (derived from HBA1C above) 
Typo. 
30-36 
7.9.1, 7.9.2, 7.9.3 
units transformed to  
 
(at several places in the text) 
units transformedconverted to 
More accurate language 
36 
7.9.3 Thyroid 
Function 
 
New variables added to the table: 
 
Total T4, collected 
unit (TT4, TT4_U) 
Listing only (units 
converted to nmol/L) 
Total T4, nmol/L 
(derived from TT4 
above) 
n, mean, sd, median, 
min, max, by visit 
Total T4, Out of 
range and Clinically 
significantly 
abnormal (TT4_OR, 
TT4_CS) 
# patients and % 
/category  
(1 category 
TT4_OR; Yes, 2 
categories TT4_CS; 
Yes/No), by visit 
Total T4, collected 
unit (TT4, TT4_U) 
Listing only (units 
converted to nmol/L) 
New variables added to CRF v.7 
38 
7.9.6 MC1R 
Genotype Analysis 
 
New section added, with new table: 
 
Variable (CRF 
annotation) 
How to be presented 
Blood sample Date 
Listing only 
MC1R genotype result 
# patients and % 
/category  
(2 categories: MC1R 
Present/Not present) 
Addition of sample in protocol v.8.0. 
38 
7.10 Adverse Events 
7.9.7 Adverse Events 
7.10 Adverse Events 
Wrong heading numbering. 


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39 
7.11 Safety 
Assessments Sub-
study, only Part 2 (if 
applicable) 
 
7.1 Safety Assessments Sub-
study, only Part 2 (if applicable) 
 
7.11 Safety Assessments Sub-study, only Part 2 (if 
applicable) 
 
Wrong heading numbering. 
40 
1.1 Safety 
Assessments Sub-
study, only Part 2 (if 
applicable)  
 
1.1 Safety Assessments Sub-
study, only Part 2 (if applicable) 
 
Variable (CRF annotation) 
How to be presented 
Synovial biopsy performed
 
# patients and 
% /category  
(2 categories: Yes/No), by visit 
Change in percentage of 
polymorphs in synovial fluid at 
week 4 compared to baseline 
(derived, see Section 3.6) 
n, mean, sd, median, min, max 
Change in percentage of 
monocytes in synovial fluid at 
week 4 compared to baseline 
(derived, see Section 3.6) 
n, mean, sd, median, min, max 
Change in percentage of 
lymphocytes in synovial fluid at 
week 4 compared to baseline 
(derived, see Section 3.6) 
n, mean, sd, median, min, max 
1.1 Safety Assessments Sub-study, only Part 2 (if 
applicable) 
 
Variable (CRF annotation) 
How to be presented 
Synovial biopsy performed 
# patients and % 
/category  
(2 categories: Yes/No), by visit 
Change in percentage of polymorphs in synovial 
fluid at week 4 compared to baseline (derived, see 
Section 3.6) 
n, mean, sd, median, min, max 
Change in percentage of monocytes in synovial fluid 
at week 4 compared to baseline (derived, see Section 
3.6) 
n, mean, sd, median, min, max 
Change in percentage of lymphocytes in synovial 
fluid at week 4 compared to baseline (derived, see 
Section 3.6) 
n, mean, sd, median, min, max 
The mentioned sub-study will not be 
performed. 
43 ff 
Appendix 2, 3, and 4 
 
Moved to separate documents 
The document was growing too large, 
with an increased risk of crashing. 
44-55 
Appendix 5 
 
Revision history added. 
 
Appendix 2 
Whole Appendix 
 
Text from latest available protocol used. 
Protocol updated since previous 
version. 
Appendix 4  
p. 2 
 
 
The font Times New Roman will be used for all 
tables, figures, and listings. 
New specification. 


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Appendix 4  
p. 2 
 
 
Tables and figures for efficacy analyses will be 
repeated with the two AP1189 doses pooled. 
Pooling of doses missed in previous 
version. 
Appendix 4  
p. 18 
Tables for Primary 
Efficacy Analysis 
Tables for Primary Efficacy 
Analysis 
Tables and Figures for Primary Efficacy Analysis 
Figures added. 
Appendix 4  
p. 21-392 
Table 11.4.1.1 to 
Table 11.4.1.59 
 
"Received rescue treatment" 
denotes subjects who received 
rescue treatment during the 4-
week treatment period 
 
(Footnote in several tables) 
"Received rescue treatment" denotes subjects who 
received rescue treatment during the 4-week 
treatment period or follow-up 
Rescue treatment can be given also 
after the study treatment period. 
Appendix 4  
p. 30 
Tables and Figures 
for Primary Efficacy 
Analysis 
 
Addition of Figure1, Figure2, and Figure3 
Graphical representation of CDAI 
score in addition to summary table. 
Appendix 4  
p. 32 
Tables and Figures 
for Primary Efficacy 
Analysis 
Table 11.4.1.5 
CDAI score, 
change from severe (CDAI > 22) 
to moderate (CDAI ≤ 22) at week 
4 compared to baseline 
Table 11.4.1.5 
CDAI score, change from severe 
(CDAI > 22) to moderate or lower (CDAI ≤ 22) at 
week 4 compared to baseline 
Clarification. 
Appendix 4  
p. 32 
Table 11.4.1.5 
Row heading 
Change in CDAI score from 
severe to moderate 
Change in CDAI score from severe to moderate or 
lower 
Clarification. 
Appendix 4  
pp. 84-85 
Tables and Figures 
for Primary Efficacy 
Analysis 
 
Addition of Figure4, Figure5, and Figure6 
Graphical representation of DAS28 
score in addition to summary table. 
Appendix 4  
p. 394 
New section 
 
Tables for Exploratory Efficacy Analysis 
Additional analyses to explore CDAI 
score and DAS28 score changes. 
Appendix 4  
pp. 394-401 
Tables for 
Exploratory Efficacy 
Analysis 
 
Addition of tables: 
Table 11.4.1.60 CDAI score, change from severe 
(CDAI  > 22) to low or remission (CDAI ≤ 10) at 
week 4 compared to baseline 
 
Table 11.4.1.61 CDAI score, change from severe 
(CDAI > 22) to remission (CDAI ≤ 2.8) at week 4 
compared to baseline  
 
Table 11.4.1.62 Proportion of subjects achieving 
a 20- or 30-point decrease in CDAI score after 4 
weeks of treatment compared to baseline 
 
Additional exploratory analyses. 


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Table 11.4.1.63 DAS28 score, change from 
baseline to week 4 
 
Table 11.4.1.64 DAS28 score, change from high 
(DAS28 > 5.1) to moderate or lower (DAS28 ≤ 5.1) 
at week 4 compared to baseline 
 
Table 11.4.1.65 CXCL13, change from baseline 
to week 4 (pg/mL and percent change from 
baseline), by decrease in CDAI score 
 
Table 11.4.1.65 CXCL13, change from baseline 
to week 4 (pg/mL and percent change from 
baseline), by decrease in CDAI score 
 
Table 11.4.1.66 IL-1β, change from baseline to 
week 4 (pg/mL and percent change from 
baseline), by decrease in CDAI score 
 
Table 11.4.1.67 IL-6 change from baseline to 
week 4 (pg/mL and percent change from 
baseline), by decrease in CDAI score 
 
Table 11.4.1.68 IL-10 change from baseline to 
week 4 (pg/mL and percent change from 
baseline), by decrease in CDAI score 
 
Table 11.4.1.69 TNF-α, change from baseline to 
week 4 (pg/mL and percent change from 
baseline), by decrease in CDAI score 
 
Table 11.4.1.70 CDAI score, change from 
baseline to week 4, subgroup of subjects with the 
25% highest CDAI score at baseline 
 
Table 11.4.1.71 CXCL13, change from baseline 
to week 4 (pg/mL and percent change from 


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baseline), subgroup of subjects with the 25% 
highest CDAI score at baseline 
 
Table 11.4.1.72 IL-1β, change from baseline to 
week 4 (pg/mL and percent change from 
baseline), subgroup of subjects with the 25% 
highest CDAI score at baseline 
 
Table 11.4.1.73 IL-6, change from baseline to 
week 4 (pg/mL and percent change from 
baseline), subgroup of subjects with the 25% 
highest CDAI score at baseline 
 
Table 11.4.1.74 IL-10, change from baseline to 
week 4 (pg/mL and percent change from 
baseline), subgroup of subjects with the 25% 
highest CDAI score at baseline 
 
Table 11.4.1.75 TNF-α, change from baseline to 
week 4 (pg/mL and percent change from 
baseline), subgroup of subjects with the 25% 
highest CDAI score at baseline 
 
Table 11.4.1.76 CXCL13, change from baseline 
to week 4 (pg/mL and percent change from 
baseline), by ACR response 
 
Table 11.4.1.77 IL-1β, change from baseline to 
week 4 (pg/mL and percent change from 
baseline), by ACR response 
 
Table 11.4.1.78 IL-6 change from baseline to 
week 4 (pg/mL and percent change from 
baseline), by ACR response 
 
Table 11.4.1.79 IL-10 change from baseline to 
week 4 (pg/mL and percent change from 
baseline), by ACR response 


CroxxMed/  
 
Confidential 
 
 
Study SynAct-CS002 – Statistical Analysis Plan 
Page 55 of 55 
 
Version 2.0 22NOV2021 
 
 
Table 11.4.1.80 TNF-α, change from baseline to 
week 4 (pg/mL and percent change from 
baseline), by ACR response 
 
Appendix 4  
p. 422 
Table 12.4.2.5 
Biochemistry results 
? -glutamyltransferase (GGT), 
U/L 
γ -glutamyltransferase (GGT), U/L 
Typo 
Appendix 4  
p. 501 
Tables for Safety 
Analysis 
Table 12.4.2.7 
hyroid function 
Table 12.4.2.7 
Thyroid function 
Typo. 
Appendix 4  
p. 502 
Table 12.4.2.10 Urine 
sample results 
Column headings: 
 
Urin sample 
 
Clincally significant abnormal 
value 
Urine sample 
 
Clinicially significant abnormal value 
Typos 
Appendix 4  
p. 512 
Tables for Safety 
Analysis 
 
Addition of table:  
Table 12.4.2.15 MC1R Genotype  
Addition of sample in protocol v.8.0. 
Appendix 4  
p. 576 
Tables for Safety 
Analysis 
n = Number of patients in the 
safety analysis set with non-
missing values  
Std = Standard deviation 
RR interval (beats/min) = heart rate 
n = Number of patients in the safety analysis set with 
non-missing values  
Std = Standard deviation 
Addition of footnote for clarity 
Appendix 4  
p. 600 
Tables for 
Pharmacokinetic  
Analysis 
 
Addition of table:  
Table 11.4.4.1 
Drug Exposure (Plasma 
Concentrations) 
PK analyses believed not to be 
performed when SAP v1.0 was written. 
Appendix 4  
p. 601 
Tables for 
Pharmacokinetic  
Analysis 
 
Addition of table:  
Table 11.4.4.2 
Time from last dosing to 
pharmacokinetic sample (hours) 
Timing of PK samples differ between 
individuals. 
Appendix 4  
pp. 602-689 
Listing 6.4.1 to 
Listing 16.2.5.3 
PAGESTATUS 
Column deleted 
Information not relevant as it does not 
contain collected data.