Clinical trial NCT02778399
Conditions: Endometriosis
Keywords: Pelvic Pain Endometriosis Dysmenorrhea Dyspareunia
Sponsor: ObsEva SA
Start date: 2016-07-01; Completion date: 2019-07-01
Enrollment: 328 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective of this study is to assess the efficacy and safety of a range of oral doses of OBE2109 versus placebo, in reducing endometriosis associated pain.

Detailed description:
The study is a prospective, dose-finding, randomized, parallel group, double-blind, placebo-controlled phase 2b study investigating the efficacy and safety of OBE2109 in the treatment of 330 women with moderate-to-severe endometriosis associated pain.

Subject will be randomized to one of 6 treatment groups in a 1:1:1:1:1:1 ratio (1 placebo group, 5 dose groups with different dosage/regimen).

Eligible subjects will be offered the opportunity to continue treatment with OBE2109 in an extension phase. Subjects who do not continue in the extension will enter the treatment-free follow-up phase of the study.

Arms: arm 1: None arm 2: None arm 3: None arm 4: None arm 5: None arm 6: Participants received placebo for the first 12 weeks and were then crossed-over to active treatment with OBE2109 100mg for a further 12 weeks.
Interventions: intervention 1: Placebo intervention 2: OBE2109
Intervention descriptions: intervention 1: Placebo tablets for oral administration once daily intervention 2: OBE2109 tablets for oral administration once daily

Protocol documents:
Prot_SAP_000.pdf: 
15-OBE2109-001 PROTOCOL V1.0 DATED 25 APRIL 2016 
Page 1 of 88 
 
OBSEVA CONFIDENTIAL 
CLINICAL STUDY PROTOCOL 
 
Protocol Number: 
15-OBE2109-001 
EudraCT Number: 
2016-001736-35 
Investigational Medicinal 
Product: 
OBE2109 
Study Title: 
A randomized, double-blind, placebo-controlled, phase 2b 
dose-ranging study to assess the efficacy and safety of 
OBE2109 in subjects with endometriosis associated pain. 
Short Study Title: 
A phase 2b study to assess the efficacy and safety of OBE2109 
in subjects with endometriosis. 
Study Name: 
EDELWEISS 
Version number: 
Version 1.0 
Final Protocol Date: 
April 25, 2016 
Study Sponsor: 
 
ObsEva S.A. 
12, Chemin des Aulx 
1228 Plan-Les-Ouates, Geneva / Switzerland  
Phone +41 22 552 15 50 
Fax +41 22 743 29 21 
 
Clinical Trial Director: 
 
Véronique Lecomte 
ObsEva S.A. 
12, Chemin des Aulx 
1228 Plan-Les-Ouates, Geneva / Switzerland  
Office phone +41 22 552 15 56 
Mobile phone +41 79 845 83 28 
Fax +41 22 743 29 21 
Medical Responsible: 
Elke Bestel 
ObsEva S.A. 
12, Chemin des Aulx 
1228 Plan-Les-Ouates, Geneva / Switzerland  
Office phone +41 22 552 15 68 
Mobile phone +41 78 863 31 30 
Fax +41 22 743 29 21 
CRO Project Manager: 
Vitaliy Solskyy 
Chiltern International Ukraine LLC 
31/33, Smolenska str., block 5 
03057, Kyiv, Ukraine 
Office phone: +38 044 593 65 90 
Mobile: + 38 050 442 55 36 
Fax: +38 044 593 65 91 


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OBSEVA CONFIDENTIAL 
 
 
CONFIDENTIAL AND PROPRIETARY 
This protocol contains confidential and proprietary information about an investigational drug and is 
provided by ObsEva S.A., Plan-les-Ouates, Geneva, Switzerland, for the exclusive use of the 
Investigators of this clinical study and their Health Authorities/IRBs/IECs. This confidential 
information may not be disclosed to any other person without prior written consent of ObsEva S.A. 
Note: Other ObsEva or delegate personnel who may be contacted by study site personnel for this study 
are listed in a separate document, which will be updated on a regular basis when necessary. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 




15-OBE2109-001 PROTOCOL V1.0 DATED 25 APRIL 2016 
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OBSEVA CONFIDENTIAL 
INVESTIGATOR ENDORSEMENT PAGE 
I, the undersigned, am responsible for the conduct of the study at this site and agree to the following: 
• 
I understand and will conduct the study according to the protocol, any approved protocol 
amendments, ICH GCP and all applicable regulatory authority requirements and national laws. 
• 
I will not deviate from the protocol without prior written permission from the sponsor and prior 
review and written approval from the Institutional Review Board or Independent Ethics 
Committee, except where necessary to prevent any immediate danger to the subject. 
• 
I have read and understand fully the Investigator Brochure (IB) for OBE2109, and I am familiar 
with the Investigational Medicinal Product (IMP) and its use according to this protocol. 
• 
I have sufficient time to properly conduct and complete the trial within the agreed trial period, 
and I have available an adequate number of qualified staff and adequate facilities for the 
foreseen duration of the trial to conduct the trial properly and safely. 
• 
I will ensure that any staff at my site(s) who are involved in the study conduct are adequately 
trained regarding the IMP, the protocol and their responsibilities. In the case of delegating any 
of my study responsibilities I will provide the sponsor with a Delegation of Activities certificate. 
• 
I understand that some regulatory authorities require sponsors of clinical studies to obtain and 
supply, when required, details about the Investigators ownership interests in the sponsor or the 
Investigational Medicinal Product and information regarding any financial ties with the sponsor. 
The sponsor will use any such information that is collected solely for the purpose of complying 
with regulatory requirements. I therefore agree to supply the sponsor with any necessary 
information regarding ownership interest and financial ties (including those of my spouse and 
dependent children), and to provide updates as necessary. 
 
 
 
 
 
 
Signature 
 
Date of signature 
 
 
 
 
 
 
 
 
 
 


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OBSEVA CONFIDENTIAL 
TABLE OF CONTENTS 
TABLE OF CONTENTS .................................................................................................... 5 
LIST OF ABBREVIATIONS ........................................................................................... 11 
SYNOPSIS  ...................................................................................................................... 15 
1. 
BACKGROUND INFORMATION ............................................................... 25 
1.1. 
INTRODUCTION TO OBE2109 ........................................................................... 25 
1.2. 
ENDOMETRIOSIS ................................................................................................ 25 
1.3. 
CONVENTIONAL TREATMENT OF ENDOMETRIOSIS ................................ 25 
1.4. 
SUMMARY OF NON-CLINICAL STUDIES....................................................... 26 
1.4.1. 
Non-Clinical Pharmacology ................................................................................... 26 
1.4.2. 
Non-Clinical Pharmacokinetics and Toxicology .................................................... 26 
1.5. 
SUMMARY OF CLINICAL STUDIES ................................................................ 27 
1.5.1. 
PK/PD ..................................................................................................................... 27 
1.5.2. 
Efficacy ................................................................................................................... 28 
1.5.3. 
Safety ...................................................................................................................... 28 
1.6. 
RATIONALE FOR THE CURRENT STUDY ...................................................... 28 
1.7. 
SUMMARY OF OVERALL RISKS AND BENEFITS ........................................ 29 
2. 
OBJECTIVES ............................................................................................... 29 
2.1. 
EFFICACY OBJECTIVES .................................................................................... 29 
2.1.1. 
Primary ................................................................................................................... 29 
2.1.2. 
Secondary ............................................................................................................... 29 
2.2. 
SAFETY OBJECTIVES ......................................................................................... 30 
2.3. 
PHARMACOKINETIC-PHARMACODYNAMIC OBJECTIVES ...................... 30 
3. 
ENDPOINTS ................................................................................................. 30 
3.1. 
EFFICACY ENDPOINTS ...................................................................................... 30 


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OBSEVA CONFIDENTIAL 
3.1.1. 
Primary ................................................................................................................... 30 
3.1.2. 
Secondary ............................................................................................................... 30 
3.2. 
SAFETY ENDPOINTS .......................................................................................... 31 
3.3. 
PHARMACOKINETIC-PHARMACODYNAMIC ENDPOINTS........................ 32 
4. 
STUDY DESIGN ........................................................................................... 32 
5. 
STUDY POPULATION ................................................................................ 34 
5.1. 
SUBJECTS ............................................................................................................. 34 
5.1.1. 
Description of the target population ....................................................................... 34 
5.1.2. 
Number of subjects ................................................................................................. 34 
5.1.3. 
Study region/location .............................................................................................. 34 
5.2. 
ENTRY CRITERIA................................................................................................ 34 
5.2.1. 
Inclusion Criteria .................................................................................................... 34 
5.2.2. 
Exclusion Criteria ................................................................................................... 35 
6. 
STUDY PROCEDURES AND ASSESSMENTS ............................................ 37 
6.1. 
GENERAL INSTRUCTIONS ................................................................................ 37 
6.2. 
OUTLINE OF STUDY PROCEDURES AND ASSESSMENTS ......................... 38 
6.2.1. 
Screening Period – Study Screening visit (11±5 weeks prior to Day 1 visit) ......... 38 
6.2.2. 
Part A treatment period ........................................................................................... 40 
6.2.3. 
Part B treatment period ........................................................................................... 43 
6.2.4. 
Follow-up period without treatment – Study visits Week 28 (Day 197 ± 3 days), 
Week 36 (Day 253 ± 3 days) and Week 48 (Day 309 ± 3 days) ............................ 45 
6.2.5. 
Planned extension of the study ............................................................................... 47 
6.3. 
EFFICACY OBSERVATIONS AND MEASUREMENTS .................................. 47 
6.3.1. 
Pelvic pain .............................................................................................................. 47 
6.3.2. 
Daily activity .......................................................................................................... 47 
6.3.3. 
Uterine bleeding...................................................................................................... 47 
6.3.4. 
Analgesic use .......................................................................................................... 48 


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OBSEVA CONFIDENTIAL 
6.3.5. 
Dyspareunia (pain associated with sexual intercourse) .......................................... 48 
6.3.6. 
Dyschezia (pain associated with defecation) .......................................................... 48 
6.3.7. 
EHP-30, PGIC and question about severity of endometriosis condition ................ 48 
6.3.8. 
Modified Biberoglu and Behrman questionnaire .................................................... 49 
6.4. 
SAFETY OBSERVATIONS AND MEASUREMENTS ....................................... 49 
6.4.1. 
Adverse Events ....................................................................................................... 49 
6.4.2. 
Vital signs ............................................................................................................... 49 
6.4.3. 
Transvaginal ultrasound and endometrial biopsies ................................................. 49 
6.4.4. 
Bone mineral density and DXA .............................................................................. 50 
6.4.5. 
Laboratory parameters ............................................................................................ 50 
6.5. 
OBE2109 AND KP017 PLASMA LEVELS.......................................................... 50 
6.6. 
CONCOMITANT MEDICATIONS AND THERAPIES ...................................... 51 
6.6.1. 
Permitted Medicines ............................................................................................... 51 
6.6.2. 
Prohibited Medicines .............................................................................................. 52 
6.6.3. 
Non-Drug Therapies ............................................................................................... 52 
6.7. 
SUBJECT COMPLETION AND WITHDRAWAL .............................................. 52 
6.7.1. 
Subject Completion ................................................................................................ 52 
6.7.2. 
Subject Withdrawal from Study ............................................................................. 52 
6.7.3. 
Subject Replacement .............................................................................................. 53 
7. 
INVESTIGATIONAL MEDICINAL PRODUCT ......................................... 54 
7.1. 
DESCRIPTION OF INVESTIGATIONAL MEDICINAL PRODUCTS .............. 54 
7.2. 
DOSAGE AND ADMINISTRATION ................................................................... 55 
7.3. 
PACKAGING AND LABELLING ........................................................................ 55 
7.4. 
PREPARATION, HANDLING AND STORAGE ................................................. 57 
7.5. 
IMP ACCOUNTABILITY ..................................................................................... 57 
7.6. 
ASSIGNMENT TO TREATMENT GROUPS ...................................................... 58 
7.7. 
ASSESSMENT OF INVESTIGATIONAL MEDICINAL PRODUCT 
COMPLIANCE ...................................................................................................... 58 


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OBSEVA CONFIDENTIAL 
7.8. 
METHOD OF BLINDING ..................................................................................... 59 
7.9. 
EMERGENCY UNBLINDING ............................................................................. 59 
7.10. 
TREATMENT OF OVERDOSE AND MISUSE .................................................. 59 
7.11. 
OTHER SUPPLIES TO BE USED IN THE STUDY ............................................ 59 
8. 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS ......................... 60 
8.1. 
ADVERSE EVENTS.............................................................................................. 60 
8.1.1. 
Definitions .............................................................................................................. 60 
8.1.2. 
Abnormal laboratory findings and other objective measurements ......................... 62 
8.1.3. 
Baseline Medical Conditions .................................................................................. 62 
8.1.4. 
Exacerbation of endometriosis ............................................................................... 62 
8.1.5. 
Adverse Events of Special Interest ......................................................................... 62 
8.2. 
PROCEDURES FOR ELICITING, RECORDING AND REPORTING ADVERSE 
EVENTS ................................................................................................................. 63 
8.2.1. 
Eliciting Adverse Events ........................................................................................ 63 
8.2.2. 
Recording of Adverse Events in the eCRF ............................................................. 63 
8.2.3. 
Reporting of Adverse Events .................................................................................. 63 
8.3. 
SERIOUS ADVERSE EVENTS ............................................................................ 64 
8.3.1. 
Definitions .............................................................................................................. 64 
8.3.2. 
SAE Urgent Reporting Procedure .......................................................................... 65 
8.4. 
REPORTING TO THE INDEPENDENT ETHICS COMMITTEES/ 
INSTITUTIONAL REVIEW BOARDS AND REGULATORY AUTHORITIES 66 
8.5. 
REPORTING PERIOD .......................................................................................... 66 
8.6. 
PREGNANCY AND IN UTERO DRUG EXPOSURE ......................................... 67 
9. 
DATA ANALYSIS AND STATISTICS ......................................................... 68 
9.1. 
TEST OF HYPOTHESES ...................................................................................... 68 
9.2. 
SAMPLE SIZE ....................................................................................................... 68 
9.3. 
RANDOMIZATION .............................................................................................. 69 
9.4. 
ANALYSIS SETS .................................................................................................. 69 


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OBSEVA CONFIDENTIAL 
9.5. 
DATA ANALYSIS ................................................................................................ 69 
9.5.1. 
Baseline Assessment ............................................................................................... 70 
9.5.2. 
Primary Efficacy Analysis ...................................................................................... 70 
9.5.3. 
Secondary Efficacy Analysis .................................................................................. 70 
9.5.4. 
Safety analysis methodology .................................................................................. 71 
9.5.5. 
Pharmacokinetic analysis methodology.................................................................. 71 
9.5.6. 
Pharmacodynamic analysis methodology ............................................................... 71 
9.5.7. 
Missing Data ........................................................................................................... 71 
9.6. 
STUDY SPECIFIC DATA ANALYSIS ................................................................ 72 
9.6.1. 
Interim Analysis ..................................................................................................... 72 
9.6.2. 
Final Analysis ......................................................................................................... 72 
10. 
STUDY ADMINISTRATION........................................................................ 72 
10.1. 
REGULATORY AND ETHICAL CONSIDERATIONS ...................................... 72 
10.1.1. 
Informed Consent ................................................................................................... 72 
10.1.2. 
Regulatory Authority Approval .............................................................................. 73 
10.1.3. 
Institutional Review Board/ Independent Ethics Committee Requirements .......... 73 
10.1.4. 
End of the study ...................................................................................................... 73 
10.2. 
INVESTIGATOR RESPONSIBILITIES ............................................................... 73 
10.2.1. 
Coordinating Investigator ....................................................................................... 73 
10.3. 
DATA MANAGEMENT ....................................................................................... 73 
10.4. 
STUDY MONITORING ........................................................................................ 73 
10.5. 
REVIEW COMMITTEE(S) ................................................................................... 74 
10.5.1. 
Data Monitoring Committe (DMC) ........................................................................ 74 
10.6. 
SUBJECT CONFIDENTIALITY .......................................................................... 74 
10.7. 
QUALITY ASSURANCE ...................................................................................... 74 
10.8. 
STUDY OR SITE DISCONTINUATION ............................................................. 75 
10.9. 
RETENTION OF ESSENTIAL STUDY DOCUMENTS ..................................... 75 


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OBSEVA CONFIDENTIAL 
11. 
APPENDICES ................................................................................................... 76 
 SCHEDULE OF STUDY ASSESSMENTS ...................................................................... 77 
 MODIFIED BIBEROGLU & BEHRMAN SYMPTOM SEVERITY SCALE* ....................... 78 
 ENDOMETRIOSIS HEALTH PROFILE QUESTIONNAIRE (EHP-30) .............................. 79 
 PATIENT GLOBAL IMPRESSION OF CHANGE ........................................................... 83 
 PIPELLE DE CORNIER® ............................................................................................. 84 
 LABORATORY PARAMETERS ................................................................................... 86 
 REFERENCE LIST ...................................................................................................... 87 
 


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OBSEVA CONFIDENTIAL 
LIST OF ABBREVIATIONS 
ADME 
Absorption, Distribution, Metabolism, Elimination 
AE 
Adverse Event 
Al 
Aluminum 
ALT 
Alanine amino Transferase 
APTT 
Activated Partial Thromboplastin Time 
AMH 
Anti-Müllerian Hormone 
AST 
Aspartate amino Transferase 
AUC 
Area Under the Curve 
AUC (24hr) 
Area Under the plasma concentration time Curve from time 0 to 24hr post-
dose 
AUC0-∞ 
Are Under the Curve from time 0 to infinite time 
AUC0-t 
Are Under the Curve from time 0 to the last measurable time 
AUCτ 
Are Under the Curve to the end of the dosing period 
mB&B 
modified Biberoglu & Behrman 
BMD 
Bone Mineral Density 
BMI 
Body Mass Index 
BP 
Blood Pressure 
bpm 
Beats Per minute 
°C 
Degree Celsius 
CK 
Creatine Kinase 
cm 
Centimeter(s) 
Cmax 
Maximum (peak) concentration of the drug 
COC 
Combined Oral Contraceptives 
CRA 
Clinical Research Associate 
CRO 
Clinical Research Organization 
CV 
Coefficient of Variation 
CYP 
Cytochrome P 
DMC 
Data Monitoring Committee 


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OBSEVA CONFIDENTIAL 
DXA 
Dual-energy X-ray Absorptiometry 
E2 
Estradiol 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
eDiary 
Electronic Diary 
EHP-30 
Endometriosis Health Profile – 30 
EU 
European Union 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FSH 
Follicle-Stimulating Hormone 
g 
Gram(s) 
GCP 
Good Clinical Practice 
γGT 
Gamma-Glutamyl Transferase 
GGT 
Gamma-Glutamyl Transpeptidase 
GLP 
Good Laboratory Practice 
GMP 
Good Manufacturing Practice 
(h)GnRH 
(human) Gonadotropin Releasing Hormone 
hERG 
human Ether-a-go-go-Related Gene 
HDL 
High Density Lipoprotein 
HIV 
Human Immunodeficiency Virus 
hr 
hour 
IB 
Investigator Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IMP 
Investigational Medicinal Product 
INN 
International Nonproprietary Name 
INR 
International Normalized Ratio 
IRB/IEC 
Institutional Review Board / Independent Ethics Committee 


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OBSEVA CONFIDENTIAL 
IUD 
Intra-Uterine Device 
IWRS 
Interactive Web Response System 
kg 
Kilogram(s) 
L 
Liter(s) 
LDH 
Lactate DeHydrogenase 
LDL 
Low Density Lipoprotein 
LEEP 
Loop Electrosurgical Excision Procedure 
LFT 
Liver Function Test 
LH 
Luteinizing Hormone 
LOQ 
Limit Of Quantification 
µmol 
Micromole(s) 
MCH 
Mean Corpuscular Haemoglobin 
MCHC 
Mean Corpuscular Haemoglobin Concentration 
MCV 
Mean Corpuscular Volume 
mg 
Milligram(s) 
min 
Minute(s) 
mL 
Milliliter(s) 
mmHg 
Blood pressure in millimeter of mercury 
MNT 
MicroNucleus Test 
nmol 
Nanomole(s) 
NOAEL 
No Observed Adverse Effect level 
NRS 
Numerical Rating Scale 
NSAID 
NonSteroidal Anti-Inflammatory Drug 
OBE2109 
(2-Hydroxyethyl)trimethylammonium-3-[2-fluoro-5-(2,3-difluoro-6-
methoxybenzyloxy)-4-methoxyphenyl]-2,4-dioxo-1,2,3,4-
tetrahydrothieno[3,4-d]pyrimidine-5-carboxylate 
P4 
Progesterone 
PAP 
Papanikolaou test 
PD 
PharmacoDynamics 


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OBSEVA CONFIDENTIAL 
PGIC 
Patient Global Impression of Change 
P-GP 
Permeability-GlycoProtein 
PK 
PharmacoKinetics 
PPB 
Plasma Protein Binding 
PSF 
Pregnancy Surveillance Form 
PT 
Prothrombin Time 
PVC/Al 
PolyVinyl Chloride/Aluminum 
RBC 
Red Blood Cell 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SERM 
Selective Estrogen Receptor Modulator 
SIN 
Subject Identification Number 
SPRM 
Selective Progesterone Receptor Modulator 
SHBG 
Sex Hormone-Binding Globulin 
SLE 
Systemic Lupus Erythematosus 
SUSAR 
Suspected Unexpected Serious Adverse Reaction  
T1/2 
Elimination half-life 
TEAE(s) 
Treatment Emergent Adverse Event(s) 
TVUS 
TransVaginal UltraSound 
UDS 
Unscheduled DNA Synthesis 
ULN 
Upper Limit of Normal 
US/USA 
United States/United States of America 
VdSS 
Volume of distribution at Steady State 
VRS 
Verbal Rating Scale 
WBC 
White Blood Cell 


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OBSEVA CONFIDENTIAL 
SYNOPSIS 
Study Title: A randomized, double-blind, placebo-controlled, phase 2b dose-ranging study to assess the 
efficacy and safety of OBE2109 in subjects with endometriosis associated pain. 
Code/Name ObsEva Investigational Drug: OBE2109 
Phase of Development: 2 
 
Objectives: 
 
Efficacy objectives  
 
• 
Primary 
To assess the efficacy of a range of oral doses of OBE2109 versus placebo, in reducing pelvic 
pain in subjects with moderate to severe endometriosis pain. 
• 
Secondary 
To assess the efficacy of a range of oral doses of OBE2109 versus placebo in: 
• 
Reducing pelvic pain on days with uterine bleeding and pelvic pain on days with no 
uterine bleeding  
• 
Reducing pain associated with sexual intercourse (dyspareunia) 
• 
Reducing pain associated with defecation (dyschezia) 
• 
Reducing difficulty in performing daily activities 
• 
Reducing subject reported pain symptoms of endometriosis (dysmenorrhea, pelvic pain 
and dyspareunia) and physician assessed objective findings of endometriosis (pelvic 
tenderness and pelvic induration) according to the modified Biberoglu & Behrman 
(mB&B) scale 
• 
Reducing the use of analgesic medication to treat pelvic pain  
• 
Reducing incidence and intensity of uterine bleeding 
• 
Improving quality of life and subject perception of change and severity 
 
Safety objectives  
• 
To assess the safety and tolerability of OBE2109 in subjects with endometriosis. 
 
 
 
 


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OBSEVA CONFIDENTIAL 
Pharmacokinetic (PK)-pharmacodynamic (PD) objectives 
To assess OBE2109 PK and establish the possible relationship between OBE2109 exposure 
and pain, estradiol (E2) level, luteinizing hormone (LH) level and bone mineral density 
(BMD). 
Endpoints: 
Efficacy endpoints  
• 
Primary 
• 
Thirty percent or greater reduction from baseline to week 12 in the mean overall pelvic 
pain score defined as the mean of daily pain scores reported during the preceding 4-
week period, assessed on a 0–3 Verbal Rating Scale (VRS) for pelvic pain. 
• 
Secondary 
• 
Thirty percent or greater reduction from baseline to weeks 4, 8, 16, 20, 24, 28, 32 and 
36 in the mean overall pelvic pain score defined as the mean of daily pain scores 
reported during the preceding 4-week period, assessed on a 0–3 VRS for pelvic pain. 
• 
Thirty percent or greater reduction from baseline to weeks 4, 8, 12, 16, 20, 24, 28, 32 
and 36 in the mean overall pelvic pain score defined as the mean of daily pain scores 
reported during the preceding 4-week period, assessed on a 0–10 Numerical Rating 
Scale (NRS). 
• 
Thirty percent or greater reduction from baseline to weeks 4, 8, 12, 16, 20, 24, 28, 32 
and 36 in the mean pelvic pain score for days with uterine bleeding/spotting and for 
days with no uterine bleeding during the preceding 4-week period, assessed on a 0–10 
NRS and on a 0–3 VRS for pelvic pain. 
• 
The mean pelvic pain score for days with uterine bleeding/spotting, for days with no 
uterine bleeding and all days during the preceding 4-week period, assessed on a 0-10 
NRS and on a 0–3 VRS for pelvic pain at weeks 4, 8, 12, 16, 20, 24, 28, 32 and 36. 
• 
The mean highest pelvic pain score defined as the mean of the 5 highest daily pain 
scores reported during the preceding 4-week period, assessed on a 0–10 NRS at weeks 
4, 8, 12, 16, 20, 24, 28, 32 and 36. 
• 
The incidence of amenorrhea defined as no uterine bleeding or spotting only during 
the preceding 4-week period at weeks 4, 8, 12, 16, 20, 24, 28, 32 and 36. 
• 
The number of days with uterine bleeding (spotting excluded) during the preceding 4-
week period at weeks 4, 8, 12, 16, 20, 24, 28, 32 and 36. 


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OBSEVA CONFIDENTIAL 
• 
The mean of daily dyspareunia scores reported during the preceding 4-week period, 
assessed on a 0-10 NRS and a 0–3 VRS for dyspareunia at weeks 4, 8, 12, 16, 20, 24, 28, 
32 and 36.  
• 
The monthly dyschezia pain score defined as the mean of weekly dyschezia pain scores 
reported during the preceding 4-week period, assessed on a 0–10 NRS at weeks 4, 8, 
12, 16, 20, 24, 28, 32 and 36. 
• 
The use of analgesics for pelvic pain during the preceding 4-week period at weeks 4, 8, 
12, 16, 20, 24, 28, 32 and 36. 
• 
The number of days of analgesic use for pelvic pain during the preceding 4-week period 
at weeks 4, 8, 12, 16, 20, 24, 28, 32 and 36. 
• 
The number of days with pelvic pain during the preceding 4-week period, assessed on 
a 0–3 VRS for pelvic pain at weeks 4, 8, 12, 16, 20, 24, 28, 32 and 36. 
• 
The number of days with moderate to severe pelvic pain during the preceding 4-week 
period, assessed on a 0–3 VRS for pelvic pain at  weeks 4, 8, 12, 16, 20, 24, 28, 32 and 
36. 
• 
The mean of scores for difficulty in performing daily activity reported during the 
preceding 4-week period, assessed on a 0-10 NRS scale at weeks 4, 8, 12, 16, 20, 24, 
28, 32 and 36. 
• 
The severity of subject assessed symptoms (dysmenorrhea, non-menstrual pelvic pain 
and dyspareunia) and physician assessed objective findings (pelvic tenderness and 
pelvic induration) according to the mB&B scale at screening and weeks 12, 24 and 36. 
• 
The Endometriosis Health Profile-30 (EHP-30) score at weeks 12, 24 and 36. 
• 
The Patient Global Impression of Change (PGIC) score at weeks 12, 24 and 36.  
• 
The patient’s impression of severity over the preceding 4-week period at weeks 4, 8, 
12, 16, 20, 24, 28, 32 and 36. 
Safety endpoints 
• 
Change from baseline to weeks 12, 24 and 48 in BMD assessed by dual-energy X-ray 
absorptiometry (DXA) for femoral neck, hip and spine.  
• 
Treatment emergent adverse events (TEAEs) frequency and severity. 
• 
Changes in clinical laboratory assessments (haematology, coagulation parameters, 
biochemistry, hormones, lipids and urinalysis) from baseline to weeks 4, 8, 12, 16, 20, 
24, 28 and 36. 
• 
Any pathological changes from baseline in the endometrium as assessed by histology 
from endometrial biopsies performed at weeks 12 and 24 (and week 36 only if no 


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endometrial biopsy was obtained at week 24 or diagnosis at week 24 was different 
from “benign endometrium”).  
• 
Change from baseline in any other safety parameter including weight, vital signs, 
gynecological assessment, breast assessment and endometrial thickness. 
Pharmacokinetic-pharmacodynamic endpoints 
• 
Plasma levels of OBE2109 and its metabolite KP017 measured pre-dose and 1.5–2 h 
post-dose on Day 1, pre-dose at weeks 4 and 16 visits, and post-dose at weeks 8, 12, 
20 and 24 visits. 
Study Design: The study is a prospective, dose-finding, randomized, parallel group, double-blind, 
placebo-controlled phase 2b study investigating the efficacy and safety of OBE2109 in the treatment of 
women with endometriosis-associated pain. 
The study duration (from the Screening visit to the End-of-Study visit) will be up to 64 weeks per subject. 
The study starts with an 11±5 week screening period evaluating the endometriosis pain over at least 
two full, spontaneous menstrual cycles. During this period, the subject will receive no study drug. 
Eligibility will be confirmed on Day 1 based on data collected during the screening period. On Day 1, 
subject will be randomized to one of 6 treatment groups: placebo, fixed-dose groups at 50, 75, 100 and 
200 mg daily and a titrated-dose group. After randomization, a 24-week active treatment period, 
composed of 2 periods of 12 weeks each (Part A and Part B) and a subsequent 24-week treatment-free 
period will follow.  
In the placebo group, the placebo will be provided for 12 weeks (Part A) after which all placebo subjects 
will be crossed-over on to active treatment (100 mg daily) for a further 12 weeks (Part B).  
In the titrated-dose arm, all subjects will start on 75 mg daily for 12 weeks (Part A) after which the dose 
will be titrated up or down to 100 or 50 mg, or remain at the same dose for the following 12 weeks 
(Part B). Up- or down-titration will depend on the mean of serum E2 assay results collected at weeks 4 
and 8. Serum E2 levels will not be communicated to the investigational and the sponsor study teams to 
maintain the blind. Possible up- or down- titration will occur according to the following algorithm: 
subjects with a mean serum E2 level of <20pg/mL will be down-titrated to 50 mg daily whereas subjects 
with a mean serum E2 level of >50 pg/mL will be up-titrated to 100 mg daily. Subjects with a mean 
serum E2 level from 20 to 50 pg/mL inclusive will remain on 75 mg daily. Mean serum E2 level will be 
defined as the mean of the serum E2 assay results collected at week 4 and week 8. 
After all subjects have completed the first 12-week period, an interim analysis of Part A data to assess 
efficacy and safety parameters will be performed. After all subjects have completed the Part B 
treatment period (week 24), and all data have been entered into the clinical database, cleaned and 
locked, an analysis of Part B data will be performed. The results for the study parts A and B will be 
summarized and described in an integrated Clinical Study Report. 
A 24-week follow-up period without treatment is planned after Part B, or - for subjects willing to 
continue treatment with OBE2109 - an extension study will be proposed. The extension study will 
consist of a further 28 weeks of treatment and a 24-week follow-up period without treatment. 


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An analysis will be performed after week 48 on subjects entering the 24-week follow-up period after 
Part B and reported in an addendum to the integrated Clinical Study Report. 
Treatment will remain blinded up to the end of the study for the Investigator and the subject. 
The extension study will be described in a separate Protocol, and analyzed and reported in a separate 
Clinical Study Report. 
Study Population: Three hundred and thirty (330) women aged 18 to 45 years inclusive with surgically, 
and – if available – histologically confirmed pelvic endometriosis and moderate to severe 
endometriosis-associated pain, will be randomized in approximately 60 sites in the USA and in Europe, 
to one of the six following treatment groups in a 1:1:1:1:1:1 ratio: 
• 
OBE2109 50mg 
• 
OBE2109 75mg 
• 
OBE2109 100mg 
• 
OBE2109 200mg 
• 
OBE2109 75mg titration group 
• 
OBE2109 placebo/100 mg 
Main Eligibility Criteria:  
Inclusion Criteria 
To be eligible for inclusion into this study, the subject must fulfill all of the following criteria: 
1. The subject must provide written informed consent prior to initiation of any study related 
procedures. 
2. The subject must be a female volunteer aged 18 to 45 years inclusive at screening. 
3. The subject must have had surgically, and - if available - histologically confirmed pelvic 
endometriosis (laparoscopy, laparotomy, vaginal fornix or other biopsy) up to 7 years before 
screening. 
4. The subject has moderate to severe endometriosis-associated pain during the screening period 
defined as: 
a. At the screening visit, a score of at least 2 for dysmenorrhea AND at least 2 for non-
menstrual pelvic pain for the previous month assessed with the mB&B scale. 
b. Over two full menstrual cycles (i.e. from day 1 of the first menstruation going over two 
spontaneous menstrual cycles up to the day before the next menstruation i.e. the third 
menstruation) finishing just before the baseline visit: 
i. Mean overall pelvic pain scores of at least 4 on the 0–10 NRS over the 5 days 
with the highest score for each cycle separately, i.e. required for both cycles; 


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ii. At least two days with “moderate” or “severe” pain on the 0–3 VRS for pelvic 
pain over the days with uterine bleeding for each cycle separately, i.e. required 
for both cycles; 
iii. At least two days with “moderate” or “severe” pain on the 0–3 VRS for pelvic 
pain over the days without uterine bleeding for each cycle separately, i.e. 
required for both cycles. 
5. The subject is compliant with e-diary and has completed it on at least 80% of days during the 
two screening menstrual cycles. 
6. The subject has regular menstrual cycles and the total length of the two screening menstrual 
cycles should be between 42 to 76 days. 
7. The subject has a BMI ≥ 18 kg/m2 and ≤ 39 kg/m2 at the screening visit. 
8. If of childbearing potential, the subject agrees to use one of the following birth control methods 
during the entire treatment period of the study: 
a. Sexual abstinence,  
b. Partner with a vasectomy with confirmed azoospermia, 
c. Double non-hormonal barrier contraception such as condom or diaphragm each 
combined with spermicide. 
9. If of non-childbearing potential, the subject must have had tubal ligation sterilization at least 
two months before the screening visit. 
10. The subject must be able to communicate well with the Investigator and research staff and to 
comply with the requirements of the study protocol. 
 
Exclusion Criteria 
To be eligible for inclusion in this study the subject must not meet any of the following criteria: 
1. The subject is pregnant or breast feeding or is planning a pregnancy within the duration of the 
treatment period of the study. 
2. The subject is less than 6 months postpartum or 3 months post-abortion/miscarriage at the 
time of entry into the screening period. 
3. The subject had an interventional surgery for endometriosis performed within a period of 60 
days before screening. 
4. The subject had a hysterectomy or bilateral ovariectomy. 
5. The subject had a tubal sterilization which was performed with ESSURE™. 
6. The subject has an in situ copper intra-uterine device (IUD) or an IUD with progestogen. 
7. The subject had endometrial ablation resulting in amenorrhea. 


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8. The subject has at least one ovarian endometrioma with a diameter of 7 cm or greater. 
9. The subject is likely to require treatment during the study OR received treatment within a 
specified period prior to screening with any of the medications listed below: 
a. Gonadotropin releasing hormone (GnRH) antagonists 
 
3 months 
b. GnRH agonist injections/3-month depot injections 
 
3 months/6 months 
c. Danazol 
 
 
 
 
 
 
3 months 
d. Oral contraceptives and other sex hormones 
 
 
1 month 
e. Depot contraceptives 
 
 
 
 
 
6 months 
f. Selective Progesterone Receptor Modulators (SPRMs), 
 
Selective Estrogen Receptor Modulators (SERMs) 
 
and aromatase inhibitors 
 
 
 
 
3 months 
g. Long acting analgesics (i.e. requiring less than 
 
once daily dosing) 
 
 
 
 
 
1 day 
h. Systemic glucocorticoid treatments 
 
for acute diseases (not depot) 
 
 
 
 
1 month 
10. The subject has a history of or current systemic glucocorticoid therapy for treatment of chronic 
diseases (e.g. Systemic Lupus Erythematosus (SLE), rheumatic arthritis).  
11. The subject did not respond to prior treatment with GnRH agonists or GnRH antagonists for 
endometriosis. 
12. The subject has alanine aminotransferase (ALT), aspartate aminotransferase (AST), or total 
bilirubin levels ≥ 2 times the upper limit of normal OR gamma-glutamyl transpeptidase (GGT) 
level ≥ 3 times the upper limit of normal at screening. 
13. The subject has a known positive HIV or viral Hepatitis serology. 
14. The subject has abnormal uterine bleeding of undiagnosed cause. 
15. The subject had/has clinically significant findings from a Papanikolaou (PAP) smear performed 
within the past 12 months or at the screening visit which will require surgical intervention (e.g. 
Loop electrosurgical excision procedure (LEEP) or cervical conisation). 
16. The subject has chronic pelvic pain that, in the opinion of the Investigator, is not caused by 
endometriosis and requires chronic analgesic or other chronic therapy, or that would interfere 
with the assessment of endometriosis related pain.  
17. The subject has any other clinically significant gynecological condition identified on screening 
transvaginal ultrasound (TVUS) or endometrial biopsy which might interfere with the study 
efficacy and safety objectives. However, uterine fibroids (as long as uterus size ≤ 12 weeks, i.e. 
equivalent gestational weeks) and adenomyosis are allowed. 
18. The subject has a history of, or known osteoporosis or other metabolic bone disease. 


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19. The subject has any known condition, including findings in the medical history or in the 
screening assessments, which in the opinion of the Investigator constitutes a risk or a 
contraindication to the participation of the subject in the trial or that could interfere with the 
trial objectives, conduct or evaluation. 
20. The subject has a mental condition rendering her unable to understand the nature, scope and 
possible consequences of the study, or evidence of an uncooperative attitude. 
21. The subject has current problem with alcohol or drug abuse (including painkiller abuse).  
22. The subject has been administered with any experimental drug in the 12 weeks before dosing. 
Investigational Medicinal Product(s) (IMP): OBE2109 50mg, 75mg and 100mg tablets or placebo 
tablets for oral administration.  
Data Analysis and Statistics: 
Descriptive statistics will be performed on relevant screening and baseline data (i.e. data collected prior 
to the treatment administration) and on demographic characteristics for each treatment group and 
overall.  The other parameters will be individually listed. All measured as well as derived efficacy and 
safety endpoints will be summarized by descriptive statistics for each treatment group and overall, and 
for each time point if applicable. 
Data for the 75mg group and 75mg titrated group will be combined for the analyses of the Part A data. 
All statistical hypothesis tests and confidence intervals will be two sided, using a type I error rate of 
0,05. No adjustment for multiple comparisons will be used for this study. 
o Efficacy analysis methodology 
Mean overall pelvic pain scores will be calculated separately for the VRS and NRS by adding up the daily 
pain scores during each successive 4-week periods and dividing by the actual number of days with non 
missing data  (i.e. nominally 28 days if no missing data). 
Mean pelvic pain scores on uterine bleeding days and non-uterine bleeding days will be calculated by 
adding up the pain scores on the relevant days during each successive 4-week periods (uterine bleeding 
days will be defined as those days on which the subject records any uterine bleeding or spotting in the 
subject eDiary) and dividing by the number of days with non missing data. Both the total number of 
non-missing days in the 4-week period (i.e. nominally 28 days if no missing data) and the number of 
non-missing uterine bleeding days/non-uterine bleeding days will be considered. 
Comparisons between each individual active arm versus the placebo arm will be made for the analysis 
of Part A of the study (except the 75mg group and 75mg titrated group which will be combined). In 
addition, an overall test for dose response will be conducted using all treatment arms. The coefficients 
for this contrast will be defined assuming a linear response on a log (dose+1) scale. Analyses of Part B 
study data will be fully described in the statistical analysis plan. 
The analysis of the primary endpoint will be conducted via a generalized linear model for binary data 
with repeated (correlated) measures, fitted using generalized estimating equations (a marginal model), 


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with the model including terms for treatment group, 4-week period, baseline and the interactions 4-
week period*treatment, 4-week period*baseline. 
In general, between-group comparisons for continuous endpoints will be analyzed via (repeated 
measures) analysis of (co)-variance (repeated measures mixed models) or Wilcoxon Rank Sum tests, 
subject to the underlying distribution of the data. Between-group comparisons for binary endpoints will 
be analyzed via generalized linear models (with repeated measures) and chi-squared tests. Between-
group comparisons for count data (e.g. number of days) will also be analyzed via generalized linear 
models (with repeated measures).  
It is not certain whether the continuous endpoints will be normally or log-normally distributed, and/or 
whether an absolute or proportional change in endpoints will be observed. If deemed necessary, the 
data will be log transformed prior to the analysis. The subsequent results (mean differences and 
corresponding confidence intervals) will be back transformed and hence reported in terms of ratios of 
geometric means. 
o Safety analysis methodology 
Extent of exposure and compliance will be evaluated. 
The safety and tolerability profile will be assessed versus baseline conditions and differences between 
treatment groups and descriptive statistics will be produced, where applicable. 
o Pharmacokinetic analysis methodology 
For descriptive statistics of plasma concentrations mean (arithmetic and geometric), standard 
deviation, median, first and third quartiles, minimum, maximum, coefficient of variation (CV%) and 
number of observations will be provided. Concentrations below the limit of quantification (LOQ) will be 
assigned a value of zero. 
o Pharmacodynamic analysis methodology 
Possible PK-PD relationships will be investigated graphically and through statistical modeling. 
o Missing data handling 
Summary statistics will be based primarily on non-missing values. For hypothesis tests, estimates and 
confidence intervals, missing values for continuous efficacy endpoints analyzed via likelihood methods 
(e.g. repeated measures mixed models) will not be directly imputed as they are handled within the 
analysis itself, under the assumption that the model specification is correct and that the data is missing 
at random. In addition, missing values for endpoints analyzed via generalized estimating equations will 
not be directly imputed as they are handled under the assumption that the model specification is 
correct and the data is missing completely at random. Sensitivity analyses may be conducted to check 
the robustness of the analysis results under alternative assumptions with regards to missing data. 
Further details on the handling of missing values, including the rules applied to incomplete 
questionnaires (including incomplete diary entries) and any planned sensitivity analyses will be defined 
in the Statistical Analysis Plan. 


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o 
Interim analysis 
After all subjects have completed the first 12-week period (Part A), an interim analysis of Part A data to 
assess the efficacy and safety parameters will be performed. The OBE2109 75mg group and OBE2109 
75mg titrated group will be pooled for the analysis of the Part A data. 


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1. 
BACKGROUND INFORMATION 
1.1. 
INTRODUCTION TO OBE2109 
OBE2109 is a new orally active, non-peptide GnRH antagonist. It has been shown to suppress the LH 
and E2 and to significantly reduce endometriosis-associated pain in Japanese women at doses between 
50 and 200 mg daily with a good safety and tolerability profile. It is being developed for the treatment 
of endometriosis-associated pelvic pain. 
1.2. 
ENDOMETRIOSIS 
Endometriosis is one of the most common gynecological diseases (1). It is defined as the presence of 
endometrial-like tissue outside the uterus. The condition is predominantly found in women in their 
reproductive years and disappears spontaneously after menopause. A chronic, inflammatory reaction, 
induced by the ectopic endometrial cells, results in infertility (2) and a variety of pain symptoms 
including dysmenorrhea, dyspareunia, chronic pelvic pain, dysuria and dyschezia (3, 4). Often the pain 
associated with endometriosis is cyclical in nature and reflects the response of the ectopic endometrial-
like tissue to cycling reproductive hormones, particularly estrogens. 
Endometriosis represents a significant economic burden (5). Indeed, the treatment of endometriosis-
associated pain and infertility leads to significant direct costs. In addition, the endometriosis-associated 
signs and symptoms have a significant impact on health related quality of life and often lead to work 
absenteeism and productivity loss (6), especially as the diagnosis of endometriosis is often delayed (7, 
8, 9).    
Guidelines for the management of endometriosis have been published (10,11) and several medical and 
surgical therapies are available. However, an effective and well-tolerated treatment of endometriosis 
remains a largely unmet medical need. 
1.3. 
CONVENTIONAL TREATMENT OF ENDOMETRIOSIS 
The principal objective in treating endometriosis is symptom-relief management. Treatment options for 
women with endometriosis-associated pain are diverse and consist of analgesic therapies, hormonal 
therapies, conservative or minimal invasive surgery, or a combination of these (4). Hormonal therapies 
aim at inhibition of ovulation, prevention of cyclic endometrium growth, and abolition of menstruation 
through achievement of a stable steroid hormone milieu, based on the concept that the response of the 
eutopic and ectopic endometrium is substantially similar (12, 13). 
Combined oral contraceptives (COCs), although not approved for the treatment of endometriosis-
associated pain, are often used as initial therapy. Their administration results in anovulation, reduction 
of menstrual blood flow, decidualization of endometriotic lesions, down regulation of cell proliferation 
and enhanced apoptosis in the endometrium (14). However, over time many women on COCs no longer 
have adequate pain relief and require second-line therapy (15).  
Progestin monotherapy can be efficacious for the reduction in endometriosis-associated pain as it 
induces anovulation and a hypoestrogenic state via suppression of pituitary gonadotropin release. 
Progestins also have direct effects on the endometrium, causing decidualization of eutopic and ectopic 


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endometrium leading to atrophy of the endometriotic implants (16). However, progestin monotherapy 
is often associated with breakthrough bleeding, alterations in mood, weight gain, and breast tenderness 
(17).  
Other therapies with proven efficacy for the treatment of endometriosis-associated pain are often limited 
by undesirable side effects. For example, GnRH agonists lead, through a constant stimulation of the 
GnRH receptor at the pituitary level, to its desensitization and ultimately to suppression of ovulation 
and a marked reduction of serum estrogen levels; thus their use is associated with significant 
hypoestrogenic side-effects. Short-term effects include menopausal symptoms such as hot flashes, 
vaginal dryness, loss of libido and emotional lability, and their long-term use is limited by substantial 
bone mineral density (BMD) reduction (18). 
GnRH antagonists are a promising new potential treatment option that is hypothesized to allow dose-
dependent control of E2 levels reducing endometriosis implants and endometriosis-associated pain 
without hypo-estrogenic side-effect including hot flashes and BMD loss (18). 
1.4. 
SUMMARY OF NON-CLINICAL STUDIES 
1.4.1. 
Non-Clinical Pharmacology 
OBE2109 shows potent affinity for the GnRH receptors in different species particularly the human 
GnRH (hGnRH) receptor and acts as an antagonist in vitro (hGnRH Ki=27.4nM). The affinity of KP017, 
the main metabolite of OBE2109, to hGnRH receptor was shown to be 5 fold lower (Ki=127 nM). 
Specific effects on the endometrium were observed during in vivo studies, with OBE2109 acting through 
suppression of estrogen dependent endometrial proliferation in a rat autograft endometriosis model. It 
is noteworthy that clinical signs such as amenorrhea were also observed in toxicology work in the 
cynomolgus monkey.  
Safety pharmacology studies did not show any adverse effects on the central nervous, respiratory or 
cardiovascular system at exposures significantly exceeding those that would be used in a clinical setting. 
1.4.2. 
Non-Clinical Pharmacokinetics and Toxicology  
 
Pharmacokinetics 
OBE2109 was rapidly and completely absorbed after oral dosing with exposures increasing in a 
generally dose-proportional manner. The volume of distribution and plasma clearance were low. 
OBE2109 is highly bound to plasma proteins (>95%) across a range of species with no concentration 
dependent changes. In human plasma, the major binding protein for OBE2109 was albumin. It does not 
exhibit blood partitioning.  
Tissue distribution of radiolabeled OBE2109 was widespread; there was no indication of unusual 
distribution or accumulation to tissues. Radioactivity was also detected in fetal tissues and milk.  
The major route of biotransformation of OBE2109 was the oxidative O-demethylation to KP017 
(produced via CYP2C9 metabolism) which was observed in hepatocytes of all tested species. The in 
vivo metabolic pathway of OBE2109 in mice, rats and monkeys was comparable to the in vitro data. 


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Excretion of radioactivity from radiolabeled OBE2109 was predominantly via feces in both rats and 
monkeys. 
Pharmacokinetic interaction studies in vitro indicated that drugs possibly co-administered in clinical 
settings (NSAIDs) did not affect the plasma protein binding of OBE2109. An in vitro CYP induction 
study indicated that OBE2109 could induce CYP3A4/5 expression at high concentrations unlikely to be 
reached in the current study. OBE2109 may have direct and time-dependent inhibitory action on 
CYP2C8 activity and could inhibit the OAT3 uptake transporter at clinically relevant concentrations. 
 
Toxicology 
Overall, the toxicological profile of OBE2109 from repeated-dose toxicity studies were dominated by 
the consequences of its pharmacological activity as a GnRH receptor antagonist. During pivotal 
toxicology studies, dose levels of 200 and 10 mg/kg/day OBE2109 were shown to be the NOAEL in the 
main toxicology species rat (26-week daily oral administration) and monkey (39-week daily oral 
administration), respectively, and resulted in therapeutic indices (based on total / unbound exposure) for 
a human dose of 200 mg/day of 6.7 / 4.6 and 0.8 / 3.6, respectively.  
Reproductive toxicity studies, especially fertility studies and embryo-foetal development studies in 
rabbits, were limited in dose by the anti-GnRH effects of OBE2109 preventing conception or leading to 
total litter loss. The effects of OBE2109 on conception were reversible, and rabbit embryo-foetal studies 
showed expected pharmacological activity and no adverse reprotoxic/teratogenic effect. 
OBE2109 was not genotoxic or phototoxic. 
Taken together, the data in this nonclinical package have shown OBE2109 to be an orally available, 
potent, selective GnRH receptor antagonist. Anti-GnRH effects have been demonstrated in a range of 
pharmacology studies, both in vitro and in vivo, and these also dominate the findings in the toxicology 
studies. Toxicology evaluation in mice, rats, dogs and monkeys confirmed exaggerated pharmacological 
activity but no overt toxicity. No genotoxicity or unexpected reproduction toxicology findings in rats 
and rabbits were seen.  
In conclusion, the nonclinical package confirms that OBE2109 supports clinical dosing regimens up to 
200 mg per day. 
1.5. 
SUMMARY OF CLINICAL STUDIES 
The efficacy, safety and PK of OBE2109 were investigated by the originator company (Kissei 
Pharmaceutical Co., LTD. from Japan) in one Phase 1 study (Study KLH1101) in Japanese and 
Caucasian volunteers in single and multiple doses up to 400 mg, and in three Phase 2 studies (Studies 
KLH1201, KLH1202 and KLH1203) in Japanese endometriosis patients at doses up to 200 mg daily for 
12 weeks. 
To date, more than 150 subjects have been exposed to OBE2109 for a duration of up to 3 months. 
1.5.1. 
PK/PD 
OBE2109 was evaluated in a Phase 1 single/repeated-dose study (Study KLH1101) in which Japanese 
and Caucasian pre- and post-menopausal women received single doses of OBE2109 from 12.5 to 400 
mg and repeated doses of 100 to 400 mg once daily for 7 days under fed and fasted conditions. OBE2109 


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was safe and well-tolerated, showed linear pharmacokinetics, a half-life of about 15–20 hours, and little 
difference between pre- and post-menopausal women or between Japanese and Caucasian women. There 
was no apparent effect of food on the extent of absorption and there was a dose-dependent suppression 
of LH, FSH and E2. 
1.5.2. 
Efficacy 
The clinical evidence for the efficacy of OBE2109 is derived from the results of three Phase 2 studies.  
In a Phase 2 clinical study in patients with endometriosis (Study KLH1201), 50 or 200 mg OBE2109 
was orally administered once daily for 8 weeks. OBE2109 improved endometriosis symptoms and 
continuously suppressed E2 in a dose-dependent manner. 
In a Phase 2 clinical study in patients with endometriosis (Study KLH1202), 50, 100, or 200 mg 
OBE2109 or placebo was orally administered once daily after breakfast for 12 weeks. OBE2109 
significantly reduced endometriosis pain symptoms compared with placebo. 
In a Phase 2 clinical study in patients with endometriosis (Study KLH1203), 75 or 150 mg OBE2109 
was orally administered once daily after breakfast for 8 weeks. OBE2109 improved endometriosis 
symptoms and continuously suppressed E2 in a dose-dependent manner. 
1.5.3. 
Safety 
Overall, 42 subjects have been exposed to single doses and 163 subjects to repeated doses of OBE2109.  
Repeated dosing at up to 400 mg OBE2109 was safe and well-tolerated by premenopausal Caucasian 
and Japanese healthy volunteers. In endometriosis patients, doses up to 200 mg daily for up to 12 weeks 
of treatment were well tolerated.  
Most frequent side effects were disturbances of the menstrual cycle (Metrorrhagia) and hypoestrogenic 
AEs (Hot flushes).  
In some subjects, an increase in transaminase values was observed under treatment. However this 
increase was generally reversible under treatment, exceeded 3×ULN in only one single case and was 
never associated with any increase in bilirubin. 
The vast majority of AEs were reported as being of “mild” severity, only few events were reported as 
being of “moderate” severity and only one AE (unrelated to study drug) was reported as of “severe” 
intensity. 
1.6. 
RATIONALE FOR THE CURRENT STUDY 
OBE2109 has been shown to suppress in a dose dependent manner LH and E2 and to significantly 
reduce endometriosis-associated pain in Japanese women at doses between 50 and 200 mg daily, with a 
good safety and tolerability profile. Furthermore, after administration of 50 or 75 mg per day, median 
E2 levels were in the range of 20–50 pg/mL, which is the range expected to provide relief from 
endometriosis symptoms while maintaining BMD (19, 20), suggesting 50 or 75 mg could be an optimal 
dose in Japanese patients. It is anticipated that the US/European population will have a higher average 
weight and therefore a dose range of 50–200 mg is planned for the current study.  


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In addition, a dose titration based on serum E2 levels will be explored in the current study. The rationale 
is to try to maximise the proportion of subjects with mean E2 levels in the range 20–50 pg/ml to see if 
this provides any clinical advantages over a fixed dose regimen. 
The purpose of the current study is therefore to evaluate the safety and efficacy of OBE2109 in non-
Japanese (primarily USA and European) women with surgically confirmed endometriosis and 
associated pelvic pain. It is a Phase 2b double-blind, placebo controlled dose ranging study with the aim 
of establishing doses, regimens and endpoints to be used in pivotal confirmatory Phase 3 studies. 
1.7. 
SUMMARY OF OVERALL RISKS AND BENEFITS 
OBE2109 is a new oral GnRH antagonist which has been shown to significantly reduce endometriosis 
related pain in Japanese patients via dose dependent suppression of LH, FSH and E2. It has a half-life 
consistent with once daily dosing. Efficacy was demonstrated at daily doses of 50–200 mg for 3 months 
and efficacy persisted 1 month after the end of treatment. 
OBE2109 was well-tolerated at these doses. The most commonly reported AEs in the Phase 2 studies 
were metrorrhagia and hot flushes which are related to the biological activity of OBE2109.  
There were no clinically relevant findings in laboratory measurements, vital signs or ECG recordings. 
The administration of OBE2109 results in infrequent, transient, moderate and not dose-related increases 
in transaminase levels which were not associated with any change in bilirubin levels.  
In conclusion, OBE2109 has a favorable benefit/risk ratio and represents a potentially useful therapy for 
treating endometriosis related pain. 
 
2. 
OBJECTIVES 
 
2.1. 
EFFICACY OBJECTIVES 
 
2.1.1. 
Primary 
• To assess the efficacy of a range of oral doses of OBE2109 versus placebo, in reducing 
pelvic pain in subjects with moderate to severe endometriosis pain. 
 
2.1.2. 
Secondary 
To assess the efficacy of a range of oral doses of OBE2109 versus placebo in: 
 
• 
Reducing pelvic pain on days with uterine bleeding and pelvic pain on days with no 
uterine bleeding  
• 
Reducing pain associated with sexual intercourse (dyspareunia)  
• 
Reducing pain associated with defecation (dyschezia) 
• 
Reducing difficulty in performing daily activites  
• 
Reducing subject reported pain symptoms of endometriosis (dysmenorrhea, pelvic pain 
and dyspareunia) and physician assessed objective findings of endometriosis (pelvic 


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OBSEVA CONFIDENTIAL 
tenderness and pelvic induration) according to the modified Biberoglu & Behrman 
(mB&B) scale (22, APPENDIX B) 
• 
Reducing the use of analgesic medication to treat pelvic pain  
• 
Reducing incidence and intensity of uterine bleeding 
• 
Improving quality of life and subject perception of change and severity 
 
2.2. 
SAFETY OBJECTIVES 
• 
To assess the safety and tolerability of OBE2109 in subjects with endometriosis. 
 
2.3. 
PHARMACOKINETIC-PHARMACODYNAMIC OBJECTIVES 
• 
To assess OBE2109 PK and establish the possible relationship between OBE2109 
exposure and pain, E2 level, LH level and bone mineral density (BMD). 
3. 
ENDPOINTS 
3.1. 
EFFICACY ENDPOINTS 
 
3.1.1. 
Primary 
• 
Thirty percent or greater reduction from baseline to week 12 in the mean overall pelvic 
pain score defined as the mean of daily pain scores reported during the preceding 4-
week period assessed on a 0–3 Verbal Rating Scale (VRS) for pelvic pain. 
 
3.1.2. 
Secondary 
• Thirty percent or greater reduction from baseline to weeks 4, 8, 16, 20, 24, 28, 32 and 
36 in the mean overall pelvic pain score defined as the mean of daily pain scores 
reported during the preceding 4-week period, assessed on a 0–3 VRS for pelvic pain. 
• 
Thirty percent or greater reduction from baseline to weeks 4, 8, 12, 16, 20, 24, 28, 32 
and 36 in the mean overall pelvic pain score defined as the mean of daily pain scores 
reported during the preceding 4-week period, assessed on a 0–10 Numerical Rating 
Scale (NRS). 
• 
Thirty percent or greater reduction from baseline to weeks 4, 8, 12, 16, 20, 24, 28, 32 
and 36 in the mean pelvic pain score for days with uterine bleeding/spotting and for 
days with no uterine bleeding during the preceding 4-week period, assessed on a 0–10 
NRS and on a 0–3 VRS for pelvic pain. 
• 
The mean pelvic pain score for days with uterine bleeding/spotting, for days with no 
uterine bleeding and all days during the preceding 4-week period, assessed on a 0–10 
NRS and on a 0–3 VRS for pelvic pain at weeks 4, 8, 12, 16, 20, 24, 28, 32 and 36. 


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• 
 The mean highest pelvic pain score defined as the mean of the 5 highest daily pain 
scores reported during the preceding 4-week period, assessed on a 0–10 NRS at weeks 
4, 8, 12, 16, 20, 24, 28, 32 and 36. 
• 
 The incidence of amenorrhea defined as no uterine bleeding or spotting only during the 
preceding 4-week period at weeks 4, 8, 12, 16, 20, 24, 28, 32 and 36. 
• 
The number of days with uterine bleeding (spotting excluded) during the preceding 4-
week period at weeks 4, 8, 12, 16, 20, 24, 28, 32 and 36. 
• 
 The mean of daily dyspareunia scores reported during the preceding 4-week period, 
assessed on a 0–10 NRS and a 0–3 VRS for dyspareunia at weeks 4, 8, 12, 16, 20, 24, 
28, 32 and 36.  
• 
 The monthly dyschezia pain score defined as the mean of weekly dyschezia pain scores 
reported during the preceding 4-week period, assessed on a 0–10 NRS at weeks 4, 8, 
12, 16, 20, 24, 28, 32 and 36. 
• 
The use of analgesics for pelvic pain during the preceding 4-week period at weeks 4, 8, 
12, 16, 20, 24, 28, 32 and 36. 
• 
The number of days of analgesic use for pelvic pain during the preceding 4-week period 
at weeks 4, 8, 12, 16, 20, 24, 28, 32 and 36. 
• 
 The number of days with pelvic pain during the preceding 4-week period, assessed on 
a 0–3 VRS for pelvic pain at weeks 4, 8, 12, 16, 20, 24, 28, 32 and 36. 
• 
 The number of days with moderate to severe pelvic pain during the preceding 4-week 
period, assessed on a 0–3 VRS for pelvic pain at weeks 4, 8, 12, 16, 20, 24, 28, 32 and 
36. 
• 
 The mean of scores for difficulty in performing daily activity reported during the 
preceding 4-week period, assessed on a 0–10 NRS scale at weeks 4, 8, 12, 16, 20, 24, 
28, 32 and 36 
• 
The severity of subject assessed symptoms (dysmenorrhea, non-menstrual pelvic pain 
and dyspareunia) and physician assessed objective findings (pelvic tenderness and 
pelvic induration) according to the mB&B scale at screening and weeks 12, 24 and 36. 
• 
The Endometriosis Health Profile-30 (EHP-30) score (23, APPENDIX C) at weeks 12, 
24 and 36.  
• 
The Patient Global Impression of Change (PGIC) score (24, 25, APPENDIX D) at 
weeks 12, 24 and 36.  
• 
The patient’s impression of severity over the preceding 4-week period at weeks 4, 8, 
12, 16, 20, 24, 28, 32 and 36. 
 
3.2. 
SAFETY ENDPOINTS 
• 
Change from baseline to weeks 12, 24 and 48 in BMD assessed by dual-energy X-ray 
absorptiometry (DXA) for femoral neck, hip and spine.  
• 
Treatment emergent adverse events (TEAEs) frequency and severity. 


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• 
Changes in clinical laboratory assessments (haematology, coagulation parameters, 
biochemistry, hormones, lipids and urinalysis) from baseline to weeks 4, 8, 12, 16, 20, 
24, 28 and 36. 
• 
Any pathological changes from baseline in the endometrium as assessed by histology 
from endometrial biopsies performed at weeks 12 and 24 (and week 36 only if no 
endometrial biopsy was obtained at week 24 or diagnosis at week 24 was different from 
“benign endometrium”).  
Change from baseline in any other safety parameter including weight, vital signs, 
gynecological assessment, breast assessment and endometrial thickness. 
 
3.3. 
PHARMACOKINETIC-PHARMACODYNAMIC ENDPOINTS 
• 
Plasma levels of OBE2109 and its metabolite KP017 measured pre-dose and 1.5–2hrs 
post-dose on Day 1, pre-dose at weeks 4 and 16 visits, and post-dose at weeks 8, 12, 
20 and 24 visits. 
 
4. 
STUDY DESIGN 
This is a prospective, dose-finding, randomized, parallel group, double-blind, placebo-controlled phase 
2b study investigating the efficacy and safety of OBE2109 in the treatment of women with 
endometriosis-associated pain. 
The study duration (from the Screening visit to the End-of-Study visit) will be up to 64 weeks per 
subject. 
The study starts with an 11±5 week screening period evaluating the endometriosis pain over at least two 
full, spontaneous menstrual cycles. During this period, the subject will receive no study drug. 
Eligibility will be confirmed on Day 1 based on data collected during the screening period. On Day 1, 
subject will be randomized to one of 6 treatment groups: placebo, fixed-dose groups at 50, 75, 100 and 
200 mg daily and a titrated-dose group. After randomization, a 24-week active treatment period, 
composed of 2 periods of 12 weeks each (Part A and Part B), and a subsequent 24-week treatment-free 
period will follow. 
A schematic of the study design is shown in Figure 1. 
 
 


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Figure 1: Study design 
 
 
In the placebo group, the placebo will be provided for 12 weeks (Part A) after which all placebo subjects 
will be crossed-over on to active treatment (100 mg daily) for a further 12 weeks (Part B).  
In the titrated-dose arm, all subjects will start on 75 mg daily for 12 weeks (Part A) after which the dose 
will be titrated up or down to 100 or 50 mg, or remain at the same dose for the following 12 weeks (Part 
B). Up- or down-titration will depend on the mean of serum E2 assay results collected at weeks 4 and 
8. Serum E2 levels will not be communicated to the investigational and the sponsor study teams to 
maintain the blind. Possible up- or down- titration will occur according to the following algorithm: 
subjects with a mean serum E2 level of <20pg/mL will be down-titrated to 50 mg daily whereas subjects 
with a mean serum E2 level of >50 pg/mL will be up-titrated to 100 mg daily. Subjects with a mean 
serum E2 level from 20 to 50 pg/mL inclusive will remain on 75 mg daily. Mean serum E2 level will 
be defined as the mean of the serum E2 assay results collected at week 4 and week 8. 
An Interactive Web Response System (IWRS) will be used to allocate the appropriate treatment.  
After all subjects have completed the first 12-week period, an interim analysis of Part A data to assess 
efficacy and safety parameters will be performed. After all subjects have completed the Part B treatment 
period (week 24), and all data have been entered into the clinical database, cleaned and locked, an 
analysis of Part B data will be performed. The results for the study parts A and B will be summarized 
and described in an integrated Clinical Study Report. 
A 24-week follow-up period without treatment is planned after Part B, or - for subjects willing to 
continue treatment with OBE2109 - an extension study will be proposed. The extension study will 
consist of a further 28 weeks of treatment and a 24-week follow-up period without treatment. 
An analysis will be performed after week 48 on subjects entering the 24-week follow-up period after 
Part B and reported in an addendum to the integrated Clinical Study Report. 
Treatment will remain blinded up to the end of the study for the Investigator and the subject. 
The extension study will be described in a separate Protocol, and analyzed and reported in a separate 
Clinical Study Report. 


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5. 
STUDY POPULATION 
5.1. 
SUBJECTS 
5.1.1. 
Description of the target population 
The target population will be premenopausal women aged 18 to 45 years inclusive at screening, with 
surgically and, if available, histologically confirmed pelvic endometriosis and moderate to severe 
endometriosis-associated pain. 
They must not be planning to become pregnant and must agree to non-hormonal barrier contraception 
from screening to the end of treatment period. 
5.1.2. 
Number of subjects 
Three hundred and thirty (330) randomized subjects are planned in total (approximately 55 subjects per 
group). 
5.1.3. 
Study region/location 
Approximately 60 investigational sites in the US and Europe will conduct the study. Potential back-up 
sites will be identified and qualified and will be activated in case of recruitment issue. Recruitment will 
be competitive beetwen sites. 
5.2. 
ENTRY CRITERIA 
5.2.1. 
Inclusion Criteria 
To be eligible for inclusion into this study, the subject must fulfill all of the following criteria: 
1.  The subject must provide written informed consent prior to initiation of any study related 
procedures. 
2. The subject must be a female volunteer aged 18 to 45 years inclusive at screening. 
3. The subject must have had surgically and - if available - histologically confirmed pelvic 
endometriosis (laparoscopy, laparotomy, vaginal fornix or other biopsy) up to 7 years before 
screening. 
4. The subject has moderate to severe endometriosis-associated pain during the screening period 
defined as: 
a. At the screening visit, a score of at least 2 for dysmenorrhea AND at least 2 for non-
menstrual pelvic pain for the previous month assessed with the mB&B scale. 
b. Over two full menstrual cycles (i.e. from day 1 of the first menstruation going over two 
spontaneous menstrual cycles up to the day before the next menstruation i.e. the third 
menstruation) finishing just before the baseline visit: 


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i. Mean overall pelvic pain scores of at least 4 on the 0–10 NRS over the 5 days 
with the highest score for each cycle separately, i.e. required for both cycles; 
ii. At least two days with “moderate” or “severe” pain on the 0–3 VRS for pelvic 
pain over the days with uterine bleeding for each cycle separately, i.e. required 
for both cycles; 
iii. At least two days with “moderate” or “severe” pain on the 0–3 VRS for pelvic 
pain over the days without uterine bleeding for each cycle separately, i.e. 
required for both cycles. 
5. The subject is compliant with e-diary and has completed it on at least 80% of days during the 
two screening menstrual cycles. 
6. The subject has regular menstrual cycles and the total length of the two screening menstrual 
cycles should be between 42 to 76 days. 
7. The subject has a BMI ≥ 18 kg/m2 and ≤ 39 kg/m2 at the screening visit. 
8. If of childbearing potential, the subject agrees to use one of the following birth control methods 
during the entire treatment period of the study: 
a. Sexual abstinence,  
b. Partner with a vasectomy with confirmed azoospermia, 
c. Double non-hormonal barrier contraception such as condom or diaphragm each 
combined with spermicide. 
9. If of non-childbearing potential, the subject must have had tubal ligation sterilization at least 
two months before the screening visit. 
10. The subject must be able to communicate well with the Investigator and research staff and to 
comply with the requirements of the study protocol. 
5.2.2. 
Exclusion Criteria 
To be eligible for inclusion in this study the subject must not meet any of the following criteria: 
1. The subject is pregnant or breast feeding or is planning a pregnancy within the duration of the 
treatment period of the study. 
2. The subject is less than 6 months postpartum or 3 months post-abortion/miscarriage at the time 
of entry into the screening period. 
3. The subject had an interventional surgery for endometriosis performed within a period of 60 
days before screening. 
4. The subject had a hysterectomy or bilateral ovariectomy.  
5. The subject had a tubal sterilization which was performed with ESSURE™. 
6. The subject has an in situ copper intra-uterine device (IUD) or an IUD with progestogen. 


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7. The subject had endometrial ablation resulting in amenorrhea. 
8. The subject has at least one ovarian endometrioma with a diameter of 7 cm or greater. 
9. The subject is likely to require treatment during the study OR received treatment within a 
specified period prior to screening with any of the medications listed below: 
a. Gonadotropin releasing hormone (GnRH) antagonists 
 
3 months 
b. GnRH agonist injections/ 3-month depot injections 
 
3 months/6 months 
c. Danazol 
 
 
 
 
 
 
3 months 
d. Oral contraceptives and other sex hormones 
 
 
1 month 
e. Depot contraceptives 
 
 
 
 
 
6 months 
f. Selective Progesterone Receptor Modulators (SPRMs),  
 
Selective Estrogen Receptor Modulators (SERMs) 
 
and aromatase inhibitors 
 
 
 
 
3 months 
g. Long acting analgesics (i.e. requiring less than 
once daily dosing) 
 
 
 
 
 
1 day 
h. Systemic glucocorticoid treatments 
 
for acute diseases (not depot) 
 
 
 
 
1 month 
10. The subject has a history of or current systemic glucocorticoid therapy for treatment of chronic 
diseases (e.g. Systemic Lupus Erythematosus (SLE), rheumatic arthritis).  
11. The subject did not respond to prior treatment with GnRH agonists or GnRH antagonists for 
endometriosis. 
12. The subject has alanine aminotransferase (ALT), aspartate aminotransferase (AST), or total 
bilirubin levels ≥ 2 times the upper limit of normal OR gamma-glutamyl transpeptidase (GGT) 
level ≥ 3 times the upper limit of normal at screening. 
13. The subject has a known positive HIV or viral Hepatitis serology. 
14. The subject has abnormal uterine bleeding of undiagnosed cause. 
15. The subject had/has clinically significant findings from a PAP (Papanikolaou) smear performed 
within the past 12 months or at the screening visit which will require surgical intervention (e.g. 
Loop electrosurgical excision procedure (LEEP) or cervical conisation). 
16. The subject has chronic pelvic pain that, in the opinion of the Investigator, is not caused by 
endometriosis and requires chronic analgesic or other chronic therapy, or that would interfere 
with the assessment of endometriosis related pain.  
17. The subject has any other clinically significant gynecological condition identified on screening 
transvaginal ultrasound (TVUS) or endometrial biopsy, which might interfere with the study 
efficacy and safety objectives. However, uterine fibroids (as long as uterus size ≤ 12 weeks, i.e. 
equivalent gestational weeks) and adenomyosis are allowed. 
18. The subject has a history of, or known osteoporosis or other metabolic bone disease. 


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OBSEVA CONFIDENTIAL 
19. The subject has any known condition, including findings in the medical history or in the 
screening assessments, which in the opinion of the Investigator constitutes a risk or a 
contraindication to the participation of the subject in the trial or that could interfere with the 
trial objectives, conduct or evaluation. 
20. The subject has a mental condition rendering her unable to understand the nature, scope and 
possible consequences of the study, or evidence of an uncooperative attitude. 
21. The subject has current problem with alcohol or drug abuse (including painkiller abuse).  
22. The subject has been administered with any experimental drug in the 12 weeks before dosing. 
6. 
STUDY PROCEDURES AND ASSESSMENTS 
6.1. 
GENERAL INSTRUCTIONS 
Before the start of the study, each subject will be provided with a subject information leaflet giving 
details on the Investigational Medicinal Product (IMP), study procedures and potential risks and they 
will also be informed verbally by the Investigator or medical delegate of the overall requirements of the 
study. They will be instructed that they can obtain further information from the Investigator at any time 
and that they are free to withdraw their consent and to discontinue their participation in the project at 
any time without prejudice. 
If the subject is willing to participate in the study, she will be requested to give written informed consent 
prior to conducting any of the study screening procedures after being given sufficient time to consider 
her participation and the opportunity to ask for further details. Two original copies of the consent form 
will be signed and personally dated by both the subject and the Investigator or medical delegate. One 
original signed copy will be kept by the Investigator in the confidential investigator file and the second 
original signed copy will be given to the subject. Although nursing staff may be involved in describing 
the trial to a subject, the Investigator/medical delegate must participate in discussions with the subject 
and personally sign and date the informed consent form (ICF). 
The subject will be asked if she authorizes the Investigator to notify her general practitioner of her 
participation in the trial. 
Upon signature of the ICF, each subject will be assigned a Subject Identification Number (SIN) in the 
electronic Case Report Form (eCRF). Subject Identification Numbers will be made of 5 digits, as 
follows: 
• 
1st digit: country identifier (1 to 4) 
• 
2nd and 3rd digits: site identifier (01 to 99) 
• 
4th and 5th digits: subject number (01 to 99) 
During the whole study, the subject will be identified using the SIN for all documentation and 
discussion. The SIN assigned to a subject in this way must only be used for that subject. 
Should a subject drop out from the study, the SIN will not be re-allocated. 


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An eCRF will be completed for all subjects who signed the ICF. When a subject is subsequently not 
enrolled in the study, the reason for non enrollment will be recorded in the eCRF.  
When a subject has been found to be eligible for the study, the subject will be randomized to one of the 
6 treatment groups in a 1:1:1:1:1:1 ratio (approximately 55 subjects per treatment arm) as shown in 
Figure 1. 
Randomization will be done according to a computer-generated list. Treatment assignments will be 
obtained via the IWRS according to the randomization list. The subject will be allocated a randomization 
number and a treatment kit number via the IWRS. The randomization number allocated to the subject 
will allow any unblinded study personal to identify the treatment group to which the subject is 
randomized. The treatment kit number will correspond to the kit number indicated on the label of the 
study drug. Kit numbers will start from K0001, K0002, K0003 etc. (5-characters). 
At the end of Part A, to maintain the blind and prevent identification of the titrated subjects, all subjects 
will be allocated a new treatment kit number via IWRS for the 12-week Part B treatment period. 
Treatment will remain blinded up to the end of the study for the Investigator and the subject. 
6.2. 
OUTLINE OF STUDY PROCEDURES AND ASSESSMENTS 
All post-baseline visits should take place at the end of the defined period (i.e. week 4 visit should be 
scheduled at the end of week 4, week 8 visit should be scheduled at the end of week 8, etc.). Post-
baseline visits dates are calculated from Day 1 visit date. 
6.2.1. 
Screening Period – Study Screening visit (11±5 weeks prior to Day 1 visit) 
The subject will be informed of the study objectives and overall requirements, and written informed 
consent will be obtained before performing any study-specific procedures that are not standard of care. 
The subject will be considered as included into the study after the ICF is signed and dated by the subject 
and the Investigator or medical delegate.   
The screening period will last up to 11±5 weeks during which the subject will be seen up to three times. 
During this time the following study screening assessments will be completed (see schedule of 
assessments in APPENDIX A): 
- 
Demographic data, height and weight 
- 
Medical history including concomitant diseases, obstetric/gynecological history and history of 
endometriosis including diagnosis and previous treatments 
- 
Assessment of endometriosis pain with the mB&B scale (see APPENDIX B) 
- 
Previous and current treatments recording 
- 
Physical examination 
- 
Vital signs (blood pressure and heart rate) 
- 
Urine pregnancy test  


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- 
TVUS of uterus and ovaries to measure endometrium thickness, to rule out any clinically 
significant gynecological conditions which might interfere with the study efficacy and safety 
objectives and to confirm that the subject has no ovarian endometrioma ≥ 7 cm in diameter 
- 
Gynecological examination, including the mB&B scale (see APPENDIX B) clinical signs 
reporting (pelvic tenderness and pelvic induration) 
- 
Endometrium biopsy (should be performed at least 7 days after the first day of menstruation and 
sent for central assessment). If no tissue is available, the biopsy should be repeated as soon as 
possible in the following days. 
The endometrium biopsy is not required at the screening visit for subjects having performed an 
endometrium biopsy within the past 6 months of the screening visit, which shows no endometrium 
atypical hyperplasia or adenocarcinoma and for which slides are available for current study 
assessment through retrospective central laboratory reading. 
- 
PAP smear 
A screening PAP smear is not required for subjects in whom a PAP smear was performed within 
the 12 months prior to the screening visit and which results indicate no clinically significant 
abnormalities requiring surgical intervention (e.g. LEEP or cervical conisation) and are available 
for source document verification.  
- 
Manual breast examination (by palpation) 
- 
Blood samples for haematology, coagulation parameters, chemistry, lipids and hormone 
assessments 
- 
Urinary protein dipstick. 
- 
Contraception counselling 
The subject will receive double barrier contraception (condoms with spermicide) if necessary. 
In addition, a limited quantity (as per Investigator’s judgement) of ibuprofen and/or 
acetaminophen/paracetamol as standard rescue medication for endometriosis related pain will be given 
to the subject at the screening visit to cover the screening period. 
The subject will be given an eDiary with a user manual to take home and will be trained by the 
Investigator or delegate on how to correctly use and complete it: she will be asked to record her IMP 
intake, pelvic pain, dyspareunia, dyschezia, difficulty in performing daily activities, uterine bleeding, 
impression of severity and use of analgesic drug(s) including dose. These screening assessments should 
cover at least two full menstrual cycles (from day 1 of the first menstruation going over two spontaneous 
menstrual cycles up to the day before the next menstruation i.e. the third menstruation). Subject diary 
completion should be started on the day of screening visit. 
The eDiary should be completed: 
- 
Daily, in the evening at approximately the same time, for IMP intake, pelvic pain, dyspareunia, 
difficulty in performing daily activities, uterine bleeding  and use of analgesic drug(s) including 
dose; 
- 
Weekly, for dyschezia pain; 


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- 
4-weekly, for patient’s impression of severity.  
Any concomitant medications taken after signature of informed consent will be recorded in the eCRF 
(excluding provided analgesics taken for endometriosis related pain which will be recorded daily in the 
eDiary). 
Any AE occurring after signature of informed consent will be recorded in the eCRF. 
The subject will be asked to return to the site between the first and seventh day (inclusive) of her next 
menstrual period (the period after the 2 screening menstrual cycles) for the Day 1 visit. Final assessment 
of her eligibility will be performed including the minimum baseline scores for pelvic pain collected via 
the eDiary. The baseline mean pelvic pain scores will be calculated during the screening period over 
two full, spontaneous menstrual cycles.  
If for logistical reasons beyond her control, the subject is unable to come to the clinic for Day 1 within 
the acceptable time window (1st to 7th day inclusive of the cycle) then the subject will be allowed to start 
Day 1 in the following cycle (again on the 1st to 7th day of the cycle). In this case, the eligibility 
assessments should be assessed based on the first two cycles only. However, the eDiary recording should 
be continued daily during the third cycle. 
6.2.2. 
Part A treatment period 
During the whole study Part A, the subject will be asked to record on her eDiary: 
- 
Daily, at approximately the same time each evening, her IMP intake, pelvic pain, dyspareunia, 
difficulty in performing daily activities, uterine bleeding and use of analgesic drug(s) including 
dose; 
- 
Weekly, her dyschezia pain; 
- 
4-weekly, the patient’s impression of severity.  
 
Baseline visit – Study visit Day 1 
If the subject has successfully completed all screening assessments and is between the first and seventh 
day (inclusive) of starting menstruation, she will go to the investigational site for the following 
evaluations and tests before drug administration: 
- 
Confirm inclusion/exclusion criteria (randomization will not be postponed if the results of the 
endometrium biopsy done during the screening period are not available on Day 1) 
- 
Previous and concomitant treatments recording 
- 
AE recording 
- 
Physical examination 
- 
Vital signs (blood pressure and heart rate) 
- 
Urinary protein dipstick 
- 
eDiary check for good completion 


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- 
EHP-30 questionnaire (see APPENDIX C) completion by the subject  
- 
Urine pregnancy test  
- 
Contraception counselling 
The subject will receive double barrier contraception (condoms with spermicide) if necessary. It will be 
provided upon need at each subsequent visit over the duration of the study. 
In view of the invasive nature of the following assessments it is recommended to perform these upon 
confirmation from the eDiary data that the subject meets the study entry requirement and upon receipt 
of the screening central laboratory results and confirmation that the values meet the study entry 
requirement. The following procedures will be performed and recorded as part of the screening/baseline 
assessments, prior to the first administration of study treatment: 
- 
Fasting blood samples for haematology, coagulation parameters, chemistry, lipids, hormones 
and OBE2109 and KP017 pre-dose plasma levels assessments. 
- 
BMD assessed by DXA for femoral neck, hip and spine. DXA can be performed up to 10 days 
after baseline. 
The DXA scans will be read centrally. 
The subject will then be randomized to one of the six treatment groups and will be provided with the 
study drug and analgesics. The subject will be instructed on how to take the study medication, 
analgesics, and on how to record the administration in the eDiary. The analgesics provided will be used 
only as rescue medication; no prophylactic use of analgesics is allowed during the whole study. The 
subject will be provided as necessary with analgesics at each subsequent visit to cover study period until 
Week 36. 
From Day 1 up to the next scheduled study visit, the subject will be asked to record in the eDiary her 
IMP intake, pelvic pain, dyspareunia, difficulty in performing daily activities, uterine bleeding, 
dyschezia, impression of severity and use of analgesic drug(s) including dose. 
The subject will take her first dose of study medication at the study site. 
After OBE2109/placebo administration, the following procedure will be performed: 
- 
Post-dose PK samples taken about 1.5 to 2.0 h after drug administration. 
Upon completion of the visit, the subject will be provided with emergency contact numbers and will be 
scheduled for her next visits.  
 
Study visits Week 4 (Day 29 ± 3 days) and Week 8 (Day 57 ± 3 days) 
The following tests and evaluations will be performed at week 4 Study Visit and week 8 Study Visit: 
- 
Previous and concomitant treatments recording 
- 
AE recording 
- 
Vital signs (blood pressure and heart rate) 
- 
Urine pregnancy test 


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- 
eDiary check for good completion 
- 
Blood samples for haematology, coagulation parameters, chemistry, lipids, hormones 
- 
Urinary protein dipstick 
- 
Contraception counselling 
The following tests and evaluations will be performed at week 4 Study Visit only: 
- 
Pre-dose PK samples (the approximate time of dose administration on previous day and time of 
taking of the PK sample will be recorded).  
- 
The subject will take her daily dose of study medication at the study site. The time of taking the 
dose will be recorded. 
The following tests and evaluations will be performed at week 8 Study Visit only: 
- 
The subject will take her daily dose at the usual time in the morning at home.  
- 
Post-dose PK samples same day during the site visit (the approximate time of dose 
administration at home and time of taking of the PK sample will be recorded) 
 
Study visit Week 12 (Day 85 ± 3 days) – End-of-Part A visit 
The subject will take her last daily dose of Part A study medication at the usual time in the morning at 
home. The approximate time of dose administration and time of taking of the blood sample will be 
recorded in the eCRF.  
The following tests and evaluations will be performed at week 12 Study Visit: 
- 
Assessment of endometriosis pain with the mB&B scale (see APPENDIX B) 
- 
Previous and concomitant treatments recording 
- 
AE recording 
- 
Physical examination 
- 
Vital signs (blood pressure and heart rate) 
- 
Gynecological examination, including the mB&B scale (see APPENDIX B) clinical signs 
reporting (pelvic tenderness and pelvic induration) 
- 
TVUS of uterus for measuring endometrium thickness and of ovaries for checking their 
normality. 
- 
Urine pregnancy test 
- 
Contraception counselling 
- 
eDiary check for good completion 


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- 
EHP-30 (see APPENDIX C) and PGIC (see APPENDIX D) questionnaires completion by the 
subject   
- 
Post-dose PK samples (the approximate time of dose administration at home and time of taking 
of the PK sample will be recorded) 
- 
Blood samples for haematology, coagulation parameters, chemistry, lipids, hormones 
- 
Urinary protein dipstick 
- 
Endometrium biopsy, unless the endometrium thickness in TVUS is ≤ 5 mm, in which case no 
endometrium biopsy will be necessary, as far as the screening biopsy has provided assessable 
results. Appropriate photo documentation of the endometrium thickness is mandatory and will 
be kept in the source documents. 
- 
BMD assessed by DXA for femoral neck, hip and spine. DXA can be performed ± 10 days from 
study visit. 
The subject will be allocated a new treatment kit number via IWRS for the 12-week Part B treatment 
period. The subject will take her first daily dose of Part B study medication at home in the morning of 
the day following the Week 12 study visit. 
Week 12 study visit constitutes the end of Part A visit. 
6.2.3. 
Part B treatment period 
During the whole study Part B, the subject will be asked to record on her eDiary: 
- 
Daily, at approximately the same time each evening, her IMP intake, pelvic pain, dyspareunia, 
difficulty in performing daily activities, uterine bleeding and use of analgesic drug(s) including 
dose; 
- 
Weekly, her dyschezia pain; 
- 
4-weekly, the patient’s impression of severity.  
 
Study visits Week 16 (Day 113 ± 3 days) and Week 20 (Day 141 ± 3 days) 
The following tests and evaluations will be performed at week 16 Study Visit and week 20 Study Visit: 
- 
Previous and concomitant treatments recording 
- 
AE recording 
- 
Vital signs (blood pressure and heart rate) 
- 
Urine pregnancy test  
- 
Contraception counselling 
- 
eDiary check for good completion 
- 
Blood samples for haematology, coagulation parameters, chemistry, lipids, hormones 


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- 
Urinary protein dipstick 
The following tests and evaluations will be performed at week 16 Study Visit only: 
- 
Pre-dose PK samples (the approximate time of dose administration on the previous day and time 
of taking of the PK sample will be recorded). 
- 
The subject will take her daily dose of study medication at site in the morning. The time of 
taking the dose will be recorded. 
The following tests and evaluations will be performed at week 20 Study Visit only: 
- 
The subject will take her daily dose at the usual time in the morning at home. 
- 
Post-dose PK samples (the approximate time of dose administration at home and time of taking 
of the PK sample will be recorded). 
 
Study visit Week 24 (Day 169 ± 3 days) – End-of-Part B visit 
The subject will take her daily dose at the usual time in the morning at home. 
The following tests and evaluations will be performed at week 24 Study Visit: 
- 
Weight 
- 
Assessment of endometriosis pain with the mB&B scale (see APPENDIX B) 
- 
Previous and concomitant treatments recording 
- 
AE recording 
- 
Physical examination 
- 
Vital signs (blood pressure and heart rate) 
- 
Gynecological examination, including the mB&B scale (see APPENDIX B) clinical signs 
reporting (pelvic tenderness and pelvic induration) 
- 
TVUS of uterus for measuring endometrium thickness and of ovaries for checking their 
normality 
- 
Urine pregnancy test  
- 
Contraception counselling 
- 
eDiary check for good completion 
- 
EHP-30 (see APPENDIX C) and PGIC (see APPENDIX D) questionnaires completion by the 
subject 
- 
Post-dose PK samples (the approximate time of dose administration at home and time of taking 
of the PK sample will be recorded) 
- 
Blood samples for haematology, coagulation parameters, chemistry, lipids, hormones 


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- 
Urinary protein dipstick 
- 
Endometrium biopsy, unless the endometrium thickness in TVUS is ≤ 5 mm, in which case no 
endometrium biopsy will be necessary, as far as the screening biopsy has provided assessable 
results. Appropriate photo documentation of the endometrium thickness is mandatory. 
- 
BMD assessed by DXA for femoral neck, hip and spine. DXA can be performed ± 10 days from 
study visit. 
- 
 The subject will be verbally asked which treatment she believed she received during the blinded 
treatment period. The answer will be recorded in the eCRF.  
Study visit Week 24 constitutes the end of Part B visit. 
The subject will be proposed to continue in an extension study. If the subject accepts, the eCRF exit 
form will be completed and the subject will stop the current study and continue in the extension study 
(see section 6.2.5). 
Otherwise the subject will continue in the treatment-free follow-up period.  
6.2.4. 
Follow-up period without treatment – Study visits Week 28 (Day 197 ± 3 days), Week 
36 (Day 253 ± 3 days) and Week 48 (Day 309 ± 3 days) 
Up to week 36 study visit, the subject will be asked to record on her eDiary: 
- 
Daily, at approximately the same time each evening, her IMP intake, pelvic pain, dyspareunia, 
difficulty in performing daily activities, uterine bleeding and use of analgesic drug(s) including 
dose; 
- 
Weekly, her dyschezia pain; 
- 
4-weekly, the patient’s impression of severity. 
 
Study visit Week 28 (Day 197 ± 3 days)  
The following tests and evaluations will be performed at Week 28 Study Visit: 
- 
Previous and concomitant treatments recording 
- 
AE recording 
- 
Vital signs (blood pressure and heart rate) 
- 
Blood samples for haematology, coagulation parameters, chemistry, lipids, hormones 
- 
Urinary protein dipstick 
- 
eDiary check for good completion  
- 
Urine pregnancy test  
- 
Contraception counselling 


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Study visit Week 36 (Day 253 ± 3 days) 
The following tests and evaluations will be performed at Week 36 Study Visit: 
- 
Weight 
- 
Assessment of endometriosis pain with the mB&B scale (see APPENDIX B) 
- 
Previous and concomitant treatments recording 
- 
AE recording 
- 
Physical examination 
- 
Vital signs (blood pressure and heart rate) 
- 
Gynecological examination, including the mB&B scale (see APPENDIX B) clinical signs 
reporting (pelvic tenderness and pelvic induration) 
- 
Manual breast examination (by palpation) 
- 
TVUS for measuring endometrium thickness and of ovaries for checking their normality 
- 
Urine pregnancy test  
- 
Contraception counselling 
- 
eDiary check for good completion  
- 
EHP-30 (see APPENDIX C) and PGIC (see APPENDIX D) questionnaires completion by the 
subject 
- 
Blood samples for haematology, coagulation parameters, chemistry, lipids, hormones 
- 
Urinary protein dipstick 
- 
Endometrium biopsy: will only be taken if no endometrial biopsy was obtained at week 24 or if 
diagnosis at week 24 was different from “benign endometrium”  
 
Study visit Week 48 (Day 309 ± 3 days) – End of Follow-up visit 
The following evaluation will be performed at Week 48 Study Visit: 
- 
BMD assessed by DXA for femoral neck, hip and spine. DXA can be performed ± 10 days from 
study visit. 
- 
AE recording if related to BMD loss 
- 
Previous and concomitant treatments recording only if treatments with potential impact on 
BMD 
- 
Completion of the eCRF exit form 


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6.2.5. 
Planned extension of the study 
At the end of the treatment period (end of Part B), the subject will be offered the opportunity to continue 
on active treatment for 28 weeks. A separate specific ICF will have to be signed and dated by the subject 
and the Investigator or medical delegate. The design of this extension study will be described in a 
separate protocol.  
6.3. 
EFFICACY OBSERVATIONS AND MEASUREMENTS 
6.3.1. 
Pelvic pain 
Subject’s assessment of pelvic pain will be collected daily via the eDiary using a NRS and a VRS. 
NRS: The subject will be asked to rate her worst endometriosis related pelvic pain in the last 24 hours 
on a 0–10 scale with 0 representing no pelvic pain and 10 representing the worst pelvic pain imaginable. 
VRS: The subject will be asked to choose the category that best describes her endometriosis related 
pelvic pain or discomfort in the last 24 hours: 
0  
No discomfort. 
1  
Mild discomfort but I was easily able to do the things I usually do. 
2  
Moderate discomfort or pain. I had some difficulty doing the things I usually do.  
3  
Severe pain. I had great difficulty doing the things I usually do.  
6.3.2. 
Daily activity 
The subject will be asked in the eDiary if she had any difficulty doing her daily activities in the last 24 
hours on a 0–10 scale with 0 representing no difficulty doing daily activities and 10 representing unable 
to do daily activities. 
6.3.3. 
Uterine bleeding 
The subject will answer in the eDiary a two-item questionnaire assessing the incidence and amount of 
uterine/vaginal bleeding in the last 24 hours. The amount of uterine bleeding will be assessed using the 
following VRS: 
1 - Spotting 
A light amount of bleeding noted, no protection or panty shield only 
2 - Light 
1–2 regular tampons or pads required in 24 hours  
3 - Medium 
3–4 regular tampons or pads required in 24 hours  
4 - Heavy 
More than 4 tampons or pads required in 24 hours 


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Subject will be asked additional questions to identify the first day of her menstrual periods for the 
screening period. 
6.3.4. 
Analgesic use 
The subject eDiary will include daily selection-boxes for ibuprofen (provided by site), 
acetaminophen/paracetamol (provided by site) or other. The subject will be asked to record the number 
of tablets taken and to confirm if the reason for use is her endometriosis related pain.  
If the subject takes another pain medication and/or uses provided analgesics for pain other than her 
endometriosis related pain, she will be asked to record the details in a Pain Medication paper diary and 
bring this to her next site visit so that the details can be recorded in the eCRF. 
6.3.5. 
Dyspareunia (pain associated with sexual intercourse) 
The subject will be asked daily about dyspareunia via the eDiary using a VRS and a NRS: 
VRS: The subject will be asked to rate how her endometriosis related pain interfered with any sexual 
intercourse in the last 24 hours: 
 
Not applicable: I was not sexually active for reasons other than my endometriosis or 
did not have sexual intercourse. 
0  
No discomfort during sexual intercourse. 
1  
I was able to tolerate the discomfort during sexual intercourse. 
2  
Intercourse was interrupted due to pain.  
3  
I avoided sexual intercourse because of pain.  
NRS: If subject reported she had pain during intercourse, the subject will be asked to rate her worst 
endometriosis related pain experienced during or after sexual intercourse in the last 24 hours on a 0–10 
scale with 0 representing no pain and 10 representing the worst pain imaginable. 
6.3.6. 
Dyschezia (pain associated with defecation) 
Dyschezia will be assessed weekly via the eDiary and will be scored by the subject using a 0–10 NRS, 
where 0 represents no pain and 10 represents the worst pain imaginable.  
6.3.7. 
EHP-30, PGIC and question about severity of endometriosis condition 
Subject will complete in addition two questionnaires in the eDiary: EHP-30 and PGIC (see APPENDIX 
C and APPENDIX D). EHP-30 will be completed at baseline and Weeks 12, 24 and 36 visits. PGIC will 
be completed at Weeks 12, 24 and 36 visits. 


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Subject will answer in the eDiary an additional question to describe the severity of her endometriosis 
condition over the preceding 4-week period, with following possible answers: no symptoms, very mild, 
mild, moderate, severe. This question will be asked every 28 days from day 1 up to week 36 included. 
6.3.8. 
Modified Biberoglu and Behrman questionnaire 
Endometriosis pain will be assessed by subject using the mB&B scale (see APPENDIX B) provided as 
paper questionnaire at screening visit and Weeks 12, 24 and 36 visits. This paper questionnaire will be 
kept as source data and corresponding scores recorded in eCRF by the Investigator. 
On the same visits, a gynecological assessment including the assessment of the two clinical signs of the 
B&B - pelvic tenderness and pelvic induration (see APPENDIX B) - will be evaluated. Corresponding 
scores will be recorded in subject source data and in the eCRF by the Investigator. 
6.4. 
SAFETY OBSERVATIONS AND MEASUREMENTS 
6.4.1. 
Adverse Events 
AE data will be collected continuously during the study as described in Section 8. 
AE data will be obtained at scheduled study visits based on physical examination, vital signs and 
biological laboratory assessments (see flowchart in APPENDIX A). In addition, subjects will report 
AEs spontaneously and/or through questioning. 
Complete appropriate data on all AEs experienced for the duration of the reporting period, as defined in 
section 8, will be reported on an ongoing basis in the AE pages of the eCRF. 
A complete physical examination, i.e. weight, examination of organ systems, including thyroid gland, 
lungs, heart, abdomen, liver, kidneys and peripheral pulses (by palpation, auscultation or percussion), 
eyes, ears, nose, throat and skin (by inspection) and neurological reflexes will be performed at 
Screening, on Day 1 and Weeks 12, 24 and 36 visits. In addition, a manual breast examination (by 
palpation) will be performed at Screening and Week 36. Results of the examinations will be recorded 
on source subject data file and in the eCRF. Medical conditions present at screening that do worsen in 
severity and/or frequency during the study will be reported as AEs in the corresponding eCRF page. 
6.4.2. 
Vital signs 
Blood pressure (BP) and heart rate will be measured in sitting position at each monthly visit from the 
screening visit to the Week 36 visit. In case of abnormal vital signs (i.e. BP ≥ 150/100 mmHg or ≤ 90/50 
mmHg and/or heart rate ≥ 100 bpm or ≤ 40 bpm) and if abnormality was not pre-existing, a repeat 
assessment after 5 min should be taken. In case of confirmed abnormality, an AE must systematically 
be reported by the Investigator in the eCRF AE page. The Investigator is to provide a diagnosis rather 
than reporting of individual vital signs parameters whenever possible. 
6.4.3. 
Transvaginal ultrasound and endometrial biopsies 
Endometrial thickness, uterus volume and abnormality (fibroids, adenomyosis, etc…) and left/right 
ovary abnormality status will be assessed by TVUS during screening, at weeks 12, 24 and 36. The print-


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outs of the ultrasound will be interpreted and commented by the gynaecologist and kept as source data. 
Results of the examination will be recorded on source data forms and in the eCRF. 
Endometrial biopsies will be performed for histological assessment during screening, at weeks 12 and 
24. At week 36, endometrial biopsy will only be taken if no endometrial biopsy was obtained at week 
24 or diagnosis at week 24 was different from “benign endometrium” . Endometrial biopsy samples will 
be performed with the Pipelle de Cornier® (APPENDIX E), as it will be described in the manual 
provided by the central laboratory. Endometrial biopsies will be centrally assessed by one single 
independent pathologist blinded to treatment group. 
If at week 12 and week 24, the endometrium thickness in TVUS is ≤ 5 mm, no endometrium biopsy will 
be necessary, as far as the screening biopsy has provided assessable results. In this case the biopsy 
should be taken at week 36. However, if the week 24 biopsy result is available and indicated a benign 
endometrium then another biopsy is not required at week 36. Appropriate photo documentation of the 
endometrium thickness is mandatory and should be kept in the source documents at site. 
6.4.4. 
Bone mineral density and DXA 
Bone mineral density (BMD) of femoral neck, hip and spine will be assessed by DXA at baseline, weeks 
12, 24 and 48. Instructions to measure the BMD and specific subject withdrawal criteria based on BMD 
will be provided in a specific imaging manual, which will be provided to the Investigator. The DXA 
scans will be transferred to a central reading unit who will assess the BMD blinded to treatment group. 
6.4.5. 
Laboratory parameters 
Haematology, coagulation parameters, chemistry, lipids and hormones (serum levels of E2, 
progesterone [P4] and LH) will be assessed from blood samples taken at screening, Day 1 and weeks 4, 
8, 12, 16, 20, 24, 28 and 36. Serum levels of the anti-müllerian hormone (AMH) will be assessed on 
Day 1 and serum levels of the sex hormone-binding globulin (SHBG) will be assessed on Day 1 and 
weeks 12 and 24. Blood samples will be analyzed by the central laboratory. Details of blood sampling 
process, sample handling and shipment are described separately in a laboratory manual provided by the 
central laboratory. Central laboratory reference ranges will be filed in the investigator site file and in the 
trial master file. All laboratory results except E2, AMH, SHBG, P4 and LH levels will be assessed by 
the Investigator/sub-investigator and clinically significant abnormalities compared to screening/baseline 
status will be reported as AEs in the eCRF. E2, AMH, SHBG, P4 and LH levels will not be 
communicated to keep the operational team and the sites blinded to treatment administration. 
The laboratory parameters are listed in APPENDIX F. 
6.5. 
OBE2109 AND KP017 PLASMA LEVELS 
PK blood samples will be collected from each subject for determining OBE2109 and KP017 plasma 
levels. 
On Day 1, blood samples for PK assessment will be taken pre-first dose and 1.5 to 2 h post-first dose.  
On the day of the site visits of weeks 8, 12, 20 and 24, the subject will take her daily dose of IMP at 
home at the usual time in the morning. The blood samples for PK will be taken at the site. The time of 


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OBSEVA CONFIDENTIAL 
dose administration in the morning and time of PK sampling on the same day will be recorded on the 
eCRF.  
On weeks 4 and 16 visits, the subject will be asked to take the dose of IMP at site, after a pre-dose PK 
sampling. The time of dose administration on the previous day and time of taking of the PK sample will 
be recorded on the eCRF.  
Details of blood sampling process, sample handling and shipment are described separately in a 
laboratory manual provided by the central laboratory.  
6.6. 
CONCOMITANT MEDICATIONS AND THERAPIES 
The Investigator will record in the appropriate section of the eCRF all concomitant medications taken 
by the subject during the study, from the date of signature of informed consent and for the duration of 
the reporting period as defined in section 8.5. From week 36 onwards, only concomitant medication 
with potential impact on BMD will be recorded in the eCRF. 
The use of provided analgesics for endometriosis related pain will be recorded solely in the eDiary. 
6.6.1. 
Permitted Medicines 
Analgesics: 
Subjects will be required to restrict if possible the use of analgesic to ibuprofen or 
acetaminophen/paracetamol for the duration of the study, from the screening to the Week 36 visit. 
Standard doses of ibuprofen and acetaminophen/paracetamol will be provided free of charge to the 
subject. The subject eDiary will include selection-boxes for ibuprofen, acetaminophen/paracetamol or 
other, including dosage. The analgesics provided will be used only as rescue medication; no prophylactic 
use of analgesics is allowed during the whole study.  
Contraceptive use: 
For subjects of childbearing potential and requiring contraception, non-hormonal contraception is 
required from beginning of screening period until end of treatment. Two forms of non-hormonal 
contraception will be required e.g. condom with spermicide. Suitable condoms with spermicide will be 
provided free of charge to subjects over the duration of the study. 
After the end of treatment period (end of week 24) until the end of follow-up period, no contraception 
is required. For subjects wanting a contraceptive method, a single form of non-hormonal contraception 
is sufficient.  
Hormonal contraception is prohibited from beginning of screening period until end of week 36. 
OBE2109 could potentially induce CYP3A4 at high concentrations which are not expected with doses 
up to 200 mg daily. However, Investigators should note this potential induction of CYP3A4 in case that 
subjects taking drugs metabolised by CYP3A4 experience attenuation of their effects and should 
consider a dose adjustment of the CYP3A4 substrate or discontinuation of OBE2109 as appropriate. 
Any medications other than those excluded by the protocol (see section 5.2.2 or 6.6.2), which are 
considered necessary for the subject’s welfare and/or which will not interfere with the study medication, 
may be given at the discretion of the Investigator. 


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OBSEVA CONFIDENTIAL 
6.6.2. 
Prohibited Medicines 
Medication listed in exclusion criteria (see Section 5.2.2) will be prohibited up to week 36.  
To consider a subject who is currently taking any prohibited therapies for potential inclusion in this 
study, the Investigator must ensure that the subject has sufficient washout time prior to enrolling the 
subject (see Section 5.2.2). 
Substrates of cytochrome P450 2C8 (CYP2C8) (e.g. montelukast, repaglinide) and of organic anion 
transporter 3 (OAT3) (e.g. benzylpenicillin, sitagliptin, ciprofloxacin, pravastatin, rosuvastatin) are 
prohibited during the treatment period only.  
When a prohibited medication or treatment is necessary for the subject’s well-being, the sponsor must 
be notified and possible alternatives are to be discussed before administration of the prohibited 
medication or treatment whenever possible. 
6.6.3. 
Non-Drug Therapies 
Not applicable. 
6.7. 
SUBJECT COMPLETION AND WITHDRAWAL 
6.7.1. 
Subject Completion 
A subject will be considered as a “completer” when she has completed all study procedures at visit 
Week 24 as described in the protocol. The end of Part B visit on Week 24 constitutes subject completion 
(see APPENDIX A). 
Subjects who did not receive the study drug will be withdrawn from the study and no further study 
procedures will be performed. The eCRF exit form should be completed. 
6.7.2. 
Subject Withdrawal from Study 
Subjects will be informed that they have the right to withdraw from the study at any time, without 
prejudice to their medical care, and that they are not obliged to state the reason(s). Any withdrawal must 
be fully documented in the eCRF exit form and should be followed up by the Investigator.  
The Investigator may withdraw a subject at any time if this is considered to be in the subject’s best 
interest.  
In addition, the sponsor could make a decision to temporarily or permanently discontinue the study for 
safety, ethical, compliance or other reasons. In this case, the subject’s participation may be ended 
prematurely without asking for her consent. 
Subjects discontinuing participation in the study between Day 1 and Week 24 visits should undergo the 
procedures required at Week 24 visit. Subjects discontinuing participation in the study between Week 
24 and Week 36 visits should undergo the procedures required at Week 36 and Week 48 visits. Subjects 
discontinuing participation in the study between Week 36 and Week 48 visits should undergo the 
procedures required at Week 48 visit. 


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Discontinuation criteria 
During the course of the study, the subject may be discontinued for the following reasons: 
- 
Lack of Efficacy: 
Investigator’s judgment only. If subject’s opinion only, check subject’s 
Request. Explain in the comment section of the eCRF Exit Form. 
- 
Adverse Event: 
Includes clinically significant new or worsening existing condition as judged 
by the Investigator. Document in the AE form. 
- 
Subject’s Request: Consent withdrawal, subject moved, schedule conflicts, etc. Specify the 
reason in the comment section of the eCRF Exit Form. 
- 
Protocol Violation: Major protocol violation which may affect the subject’s safety. Specify the 
protocol violation in the comment section of the eCRF Exit Form. 
- 
Lost to Follow-up: 
Document with two phone calls and a certified letter requesting return receipt 
without response. Document in the comment section of the eCRF Exit Form. 
- 
Pregnancy: 
Subjects that have been exposed to study treatment and who become pregnant 
during the treatment period will be immediately withdrawn from treatment. 
Pregnancies that have been exposed to study treatment and occurred up to 
week 36, or started up to 4 weeks after treatment discontinuation in case of 
early withdrawal will be followed up for pregnancy and neonatal outcomes 
at birth. Any pregnancy must be reported with the Pregnancy Surveillance 
Form (see section 8.6). 
- 
Other: 
Specify in the Comments section in the eCRF Exit Form. This reason should 
only be used if the reason for discontinuation is not better accounted for by 
another category. 
Subjects who have an elevation of hepatic enzymes suspicious of drug induced liver toxicity according 
to the Food and Drug Administration (FDA) guidance on drug-induced liver injury (26), i.e. LFT 
increase > 3 x ULN associated with increased bilirubin > 1 x ULN, will be immediately withdrawn from 
treatment and followed up to return to normal of hepatic parameters. 
All subjects withdrawn from treatment will enter – if appropriate – a 24-week follow-up period without 
treatment and continue daily eDiary recording up to Week 36 visit in order to continue to collect efficacy 
data. 
 
Follow-up for discontinued subjects  
Not applicable. 
6.7.3. 
Subject Replacement 
Discontinued subjects who received the study drug will not be replaced. 


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Discontinued subjects who did not receive the study drug may be replaced. 
7. 
INVESTIGATIONAL MEDICINAL PRODUCT  
7.1. 
DESCRIPTION OF INVESTIGATIONAL MEDICINAL PRODUCTS 
The term “Investigational Medicinal Product” (IMP) will refer to either the ObsEva investigational drug 
or the placebo. 
 
Investigational product 
Placebo 
International nonproprietary 
name (INN) 
NA 
NA 
Name of active ingredient 
OBE2109 
NA 
Form 
Film-coated tablet 
Film-coated tablet 
Strength 
50mg, 75mg and 100mg 
placebo  
Dose or concentration of 
active treatment 
50mg, 75mg, 100mg 
and 200mg 
0mg 
Route of administration 
Oral 
Frequency of 
administration 
Once daily for up to 24 weeks  
Manufacturer (Name and 
address) 
Catalent Pharma Solutions 
Steinbeisstrasse 1-2 
D-73614 Schorndorf, 
Germany 
Packaging 
(primary 
and 
secondary) 
PVC/Al blister with 7 tablets 
per blister, blister in two 
different colors (colored Al 
foil) for blinding purpose 
Aluminum pouch 
PVC/Al blister with 7 tablets 
per blister, blister in two 
different colors (colored Al 
foil) for blinding purpose 
Aluminum pouch 
Storage Requirements 
As indicated on the study drug 
kit label 
As indicated on the study drug 
kit label 


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7.2. 
DOSAGE AND ADMINISTRATION 
Investigational Medicinal Products (IMPs) 
OBE2109 and placebo treatments will be supplied as film-coated tablets for oral administration. 
The subjects will be given 3-monthly treatment packs. 
OBE2109 and placebo oral tablet treatments will start on Day 1 between the first and the seventh day 
of menstruation and will be administered once daily, up to about 24 weeks. The subjects will take 2 
tablets in the morning of each day as follows : 
Treatment arm 
Daily dose Part A 
Day 1 to Week 12 
Daily dose Part B 
Week 12 to Week 24 
 
Active tablet 
Placebo tablet 
Active tablet 
Placebo tablet 
50 mg 
1 × 50 mg 
1 × placebo 
1 × 50 mg 
1 × placebo 
75 mg 
1 × 75 mg 
1 × placebo 
1 × 75 mg 
1 × placebo 
100 mg 
1 × 100 mg 
1 × placebo 
1 × 100 mg 
1 × placebo 
200 mg 
2 × 100 mg 
None 
2 × 100 mg 
None 
Titrated arm 
1 × 75 mg 
1 × placebo 
Titrated dose* 
1 × placebo 
Placebo/100 mg 
None 
2 × placebo 
1 × 100 mg 
1 × placebo 
* Dose titrated after 12 weeks based on the mean E2 levels analyzed at weeks 4 and 8 as follows: 
• 
If E2 < 20 pg/mL then reduce the dose to 50 mg daily 
• 
If E2 > 50 pg/mL then increase the dose to 100 mg daily 
• 
If 20 ≤ E2 ≤ 50 pg/mL then dose remains at 75 mg per day 
7.3. 
PACKAGING AND LABELLING 
Study drug will be provided by the sponsor (or delegate) as 3-monthly kits. Each 3-monthly kit will 
contain 13 Aluminum (Al) pouches containing two PVC/Al blisters of two different colors (colored Al 
foil), i.e. sufficient to cover treatment for 13 weeks for each subject. All the 13 pouches and their 
corresponding blisters will be labelled with the same kit number, to be provided to a given subject. 


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Part A – 3-monthly treatment: 13 pouches/3-monthly kit – 26 blisters (13 blisters of each color) – 
7 tablets/blister.
 
 
Part B – 3-monthly treatment: 13 pouches/3-monthly kit – 26 blisters (13 blisters of each color) – 
7 tablets/blister. 
 
On Day 1 and at Week 12 visit, the subject will be given one 3-monthly kit for a total of 13 weeks (i.e. 
including one extra week to cover the allowed time window for visit scheduling). 
Each day, from Day 1 to the last day of Week 24 inclusive, the subject will have to swallow two tablets, 
one from each blister of different color and included in a same pouch. 
In each 3-monthly kit, all 13 pouches will have a label including a tear-off part. The non-tear off part 
will remain affixed to the pouch and one of the 13 tear-off part containing the study number and the kit 
number will be placed into a drug accountability booklet at site.  


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Labels will be printed in the local language of the countries where the study will take place in accordance 
with applicable local regulations, the recommendations of GMP guideline (Annex 13) and FDA 21 CFR 
312.6 part. 
The label on the secondary packaging will indicate at least the following items: 
• Protocol number 
• Kit number 
• Batch number 
• Storage conditions 
• Sponsor name and address 
• Expiry date (for EU only) 
Label examples are filed in the study file at the Investigator’s site and in the trial master file.  
7.4. 
PREPARATION, HANDLING AND STORAGE 
The investigational site will store the IMP according to the specifications of the sponsor. The IMP 
storage conditions will be indicated on each pouch. 
The storage facility at site should be locked and temperature-controlled. 
The storage temperature at the clinical site must be recorded by using a minimum/maximum 
thermometer or electronically 24 hours a day with printouts available on request. 
The IMP may be dispensed only by the pharmacist or by a member of staff specifically authorized by 
the Investigator. 
Any deviations from the recommended storage conditions at the site should be immediately reported to 
the sponsor (or delegate), and the IMP should not be used until authorization has been given by the 
sponsor (or delegate).  
7.5. 
IMP ACCOUNTABILITY 
The Investigator is responsible for ensuring IMP accountability, including reconciliation and 
maintenance of drug records. 
• 
Upon receipt of the IMP, the Investigator (or pharmacist) will check for accurate delivery and 
acknowledge receipt. A copy of acknowledgement of receipt will be retained in the investigator 
file. 
• 
The dispensing of the IMP will be carefully recorded on the appropriate drug accountability 
booklet provided by the sponsor (or delegate) and an accurate accounting will be available for 
verification by the study monitor at each monitoring visit. 
• 
IMP accountability records will include: 
o Confirmation of IMP delivery to the trial site 


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o The inventory at the site of IMP delivered 
o The use of each dose by each subject 
o The return to the sponsor (or delegate) or alternative disposition of unused IMP 
o Dates, quantities, batch numbers and kit numbers assigned to the subject. 
• 
The Investigator should maintain records that adequately document: 
o The subjects were provided with the doses specified by the protocol/amendment(s). 
o All IMP provided were fully reconciled. 
Unused IMP must not be discarded or used for any purpose other than the present study. IMP that has 
been partially dispensed to a subject must not be re-dispensed to a different subject. 
The Study monitor will periodically check the IMP accountability booklet and check all IMP 
dispensations and returns (both unused and used treatments) during the entire study period and prior to 
making arrangements for their return to the sponsor (or delegate) or authorizing their destruction by the 
study site in agreement with the sponsor. 
7.6. 
ASSIGNMENT TO TREATMENT GROUPS 
Prior to the start of the study, a randomization list and a treatment kit list will be generated by a 
designated statistician from the sponsor or delegate to be transmitted to the assigned clinical packaging 
organization for labelling and to a fully integrated IWRS. 
Kit numbers assigned by the IWRS will start from K0001, K0002, K0003 etc. (5-characters) and will 
correspond to the kit number indicated on the label of the study drug. 
Complete blocks of treatment materials will be assigned to the investigational sites. However, the 
shipment of the treatment kits (as individual 3-monthly kits) to each site will be made on an as-needed 
basis depending on the site screening rate.  
Subjects will be randomized to one of six treatment groups in a 1:1:1:1:1:1 ratio, stratified by site. 
7.7. 
ASSESSMENT 
OF 
INVESTIGATIONAL 
MEDICINAL 
PRODUCT 
COMPLIANCE 
Each subject must be instructed to bring with her to each visit both opened and unopened IMP packages, 
in order to allow the assessment of compliance with study treatment.  
The decision to withdraw a non-compliant subject from the study will be discussed between the 
Investigator and the sponsor. A blind review meeting will take place prior to unblinding. Subjects with 
poor compliance and other significant protocol violations may be excluded from the Per Protocol 
Analysis Set. 
During the entire study period, the study monitor will perform drug accountability and the assessment 
of compliance with study treatment by checking both opened and unopened IMP packages, as well as 
empty blisters.  


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7.8. 
METHOD OF BLINDING 
The study design is double blind. The randomization list will be secured in a computer file with restricted 
access to only the designated personnel including those responsible for labelling and handling the study 
medication until the study database is locked and ready to be unblinded. 
Every effort will be done to keep the Investigator, the subject and the sponsor study personnel fully 
blinded. Individual E2, SHBG and LH levels will not be communicated to them.  
7.9. 
EMERGENCY UNBLINDING 
The study blind may be broken for an individual subject only in the case of an emergency when 
knowledge of the IMP is essential for the clinical management of the subject. The Investigator can break 
the blind for a subject by using the IWRS that permits immediate unblinding. In case of doubt as to 
whether emergency unblinding is necessary, the Investigator should contact the sponsor prior to 
breaking the study blind. 
In the case of a code break, the Investigator must inform the sponsor immediately without revealing the 
code to the sponsor study personnel and the complete Study Team. 
If a Serious Adverse Event (SAE) is reported, the ObsEva (or delegate) Representative for 
Pharmacovigilance may unblind the treatment assignment for the affected subject. When applicable, an 
expedited report will be sent to all Investigators in accordance with regulations. 
7.10. 
TREATMENT OF OVERDOSE AND MISUSE  
An overdose is defined as any dose (i.e. quantity of drug given per administration or per day) above the 
maximum dosage defined in the protocol.  
Misuse is the term used if more precise information is not available and additional information is needed 
to determine if there was a “medication error”, “drug abuse” or “overdose”. 
Any details of overdose or misuse must be recorded in the eCRF.  
Any case of overdose or misuse associated with an AE or a SAE must be reported as per the instructions 
detailed in Section 8.2. 
The effects of an overdose of OBE2109 are unknown, but single and repeated doses of up to 400 mg 
were shown to be safe in a Phase 1 single and multiple ascending dose study, and doses up to 200 mg 
daily for 3 months were safe in endometriosis subjects (see Section 1.5). 
7.11. 
OTHER SUPPLIES TO BE USED IN THE STUDY 
A limited quantity (as per Investigator’s judgement) of standard doses of ibuprofen and/or 
acetaminophen/paracetamol will be given to the subject as standard rescue medication for endometriosis 
pain. Ibuprofen and acetaminophen/paracetamol will be sourced by the investigational site and 
reimbursed by the sponsor.  
The subject will have to record the intake of the analgesic rescue medication, including dose, in her 
eDiary. 


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Condoms with spermicide will also be provided by the sponsor free of charge to the subject. 
8. 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
Comprehensive assessments of any apparent toxicity experienced by the subject will be performed 
throughout the course of the study from the time of subject’s signature of informed consent. Study site 
personnel will report any AE, whether observed by the Investigator or reported by the subject (see 
section 8.2.1, Eliciting Adverse Events). 
The safety profile of OBE2109 will be assessed through the recording, reporting and analysis of baseline 
medical conditions, AEs, physical examination findings, vital signs, laboratory tests, BMD assessments. 
The reporting period for AEs is described in section 8.5. 
8.1. 
ADVERSE EVENTS 
8.1.1. 
Definitions 
Adverse Event: 
An adverse event (AE) is defined as any untoward medical occurrence in a clinical trial subject 
administered an investigational medicinal product (IMP) and which does not necessarily have a causal 
relationship with this treatment. It can therefore be any unfavourable sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of an IMP, whether or not 
considered related to the IMP. 
Events occurring prior to first IMP administration in the study are not considered AEs per se, but an 
event that could be due to the disease or specific circumstances in which the subject has been placed 
(i.e. withdrawal of a previous drug to enter the study or “protocol-related”). For monitoring purposes, 
any protocol-related event, as assessed by the Investigator, should be reported on an AE form or an SAE 
form, as appropriate. 
Severity: 
The severity of AEs must be assessed by the Investigator according to the following definitions. The 
term “severity” is used to describe the intensity of a specific event. This has to be distinguished from 
the term “serious”. 
Mild: 
The subject is aware of the event or symptom, but the event or symptom is 
easily tolerated (e.g. no reduction in daily activities is required). 
Moderate: 
The subject experiences sufficient discomfort to interfere with or reduce her 
usual level of activity. 
Severe: 
Significant impairment of functioning: the subject is unable to carry out usual 
activities and/or the subject’s life is at risk from the event.  


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Causality assessment: 
The causality assessment of an AE to the IMP will be rated as follows by the Investigator: 
Not related: 
There is no reasonable possibility of causal relationship between an AE and 
IMP. 
Related: 
There is at least a reasonable possibility of a causal relationship between an 
AE and an IMP. This means that there are facts (evidence) or arguments to 
suggest a causal relationship. 
 
Unexpected Adverse Event: 
Any AE which is not consistent in specificity or severity with the current Investigator’s Brochure, 
including all amendments, is considered unexpected. 
Outcome: 
Outcome describes the status of the AE. The Investigator will provide information regarding the subject 
outcome of each AE, and the options include: 
 
Fatal 
Termination of life as a result of an AE. 
Not recovered/not resolved 
Subject has not recuperated or the AE has not improved. 
Recovering/resolving 
Subject is recuperating or the AE is improving. 
Recovered/resolved 
Subject has recuperated or the AE has resolved. 
Recovered with sequelae/resolved 
with sequelae 
AE has resolved, but the subject has symptoms or pathology. 
Unknown 
Unknown, not observed, not recorded, or refused. 
Action taken regarding study drug: 
The Investigator will provide the action taken regarding study drug in response to each AE, and the 
options include: 
Dose not changed 
No change in the administration of study drug. 
Drug (study drug) interrupted 
Temporary interruption (termination) in the administration of 
study drug. 
Drug (study drug) withdrawn 
Administration of study drug is terminated (no further dosing). 


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Unknown 
Unknown, not observed, not recorded, or refused. 
 
8.1.2. 
Abnormal laboratory findings and other objective measurements 
Abnormal laboratory findings and other objective measurements (e.g. vital signs) must be reported as 
an AE only if assessed by the Investigator as “clinically significant” e.g. meeting at least one of the 
following conditions: 
1. The abnormality suggests a disease and/or organ toxicity AND this abnormality was not present 
at the screening visit or is assessed as having evolved since the screening visit. 
2. The abnormality is a Serious Adverse Event. 
3. The abnormality results in discontinuation of the IMP. 
4. The abnormality requires medical intervention or concomitant therapy. 
The Investigator must initial and date each laboratory report/eCRF page and note directly on the 
report/eCRF page whether or not each out-of-range laboratory result is clinically significant. The 
outcome of this assessment will be reported using an AE or SAE form, as appropriate. 
When reporting an abnormal finding for laboratory parameters or other objective measurements on the 
AE page of the eCRF, a clinical diagnosis should be recorded rather than the abnormal value itself, if 
available (for example, “anaemia” rather than “decreased red blood cell count”). 
For all of these AEs, whether or not related to the treatment, the laboratory test(s) will be followed-up 
as appropriate. 
8.1.3. 
Baseline Medical Conditions 
Medical conditions present at the initial study visit are defined as Baseline Medical Conditions. These 
medical conditions should be adequately documented on the “medical history page of the eCRF”. 
Baseline Medical Conditions that worsen in severity or frequency during the study should be recorded 
and reported as AEs. 
8.1.4. 
Exacerbation of endometriosis 
In this protocol, symptoms and signs of exacerbation or worsening of endometriosis will usually be 
captured in the context of efficacy assessment. Therefore, symptoms, exacerbation or worsening of 
endometriosis will NOT be considered as AEs nor captured on the AE page of the eCRF unless clinically 
significant AND not consistent with the anticipated natural progression of the disease. Lack of efficacy 
of the study drug is NOT considered as an AE. 
8.1.5. 
Adverse Events of Special Interest 
Not Applicable. 


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8.2. 
PROCEDURES FOR ELICITING, RECORDING AND REPORTING ADVERSE 
EVENTS 
8.2.1. 
Eliciting Adverse Events 
Data on AEs will be obtained at scheduled or unscheduled study visits, based on information 
spontaneously provided by the subject and/or through questioning of the subject. 
To elicit AEs, questioning at each study visit should begin with simple non-leading questions. For 
example: 
• 
How have you felt since your last visit? 
• 
Have you had any health problems since you were here last?  
If a subject is seen by a physician not involved with the study in relation to an AE, the Investigator 
should make every effort to contact the treating physician in a timely manner in order to obtain all 
information necessary for the appropriate reporting of the event. 
8.2.2. 
Recording of Adverse Events in the eCRF 
As the quality and precision of acquired AE data are critical, Investigators should use the AE definitions 
provided in the above sections and should follow this guideline when completing the AE pages of the 
eCRF: 
• 
Whenever possible, recognized medical terms should be used to describe AEs rather than 
colloquialisms (for example, ‘influenza’ rather than ‘flu’), and abbreviations should be avoided 
in provided AE term. 
• 
AEs should be described using a specific clinical diagnosis, if this is available, rather than a list 
of component signs or symptoms (for example, ‘congestive heart failure’ rather than ‘dyspnoea, 
rales and cyanosis’).  
• 
However, signs and symptoms that are not linked (as "co-manifestations”) to an identified 
disease or syndrome, or for which an overall diagnosis is not available, should be reported as 
individual AEs in separate eCRF AE page(s).  
• 
Provisional diagnosis (e.g. “suspected Myocardial Infarction”) are acceptable but should be 
followed up to a definite diagnosis, if finally available. 
• 
AEs occurring secondary to other events (e.g. sequelae or complications) should be identified 
by the primary cause. A primary AE, if clearly identifiable, generally represents the most 
accurate clinical term to record in the eCRF. The Investigator should be invited to provide 
his/her opinion of which is the primary AE. 
8.2.3. 
Reporting of Adverse Events 
Complete and accurate data on all AEs experienced for the duration of the reporting period, as defined 
in section 8.5, will be reported on an ongoing basis in the AE pages of the eCRF. 


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It is important that each AE report includes a description of the event, whether it is considered serious 
(and if so the criterion satisfied), its duration (onset and resolution dates), its severity, its relationship to 
the IMP(s), any other potential causality factors, any treatment given or other action taken (including 
dose modification or discontinuation of the IMP) and its outcome. 
8.3. 
SERIOUS ADVERSE EVENTS 
8.3.1. 
Definitions 
A Serious Adverse Event (SAE) is defined as any untoward medical occurrence or effect that at any 
dose: 
• 
results in death, 
i.e. the AE causes or contributes to the death. 
• 
is life-threatening, 
i.e. the AE places the subject at immediate risk of death; it does not refer to AE which 
hypothetically might have caused death if it were more severe. 
• 
requires inpatient hospitalization or prolongation of existing hospitalization, 
i.e. the AE requires at least an overnight admission or prolongs a hospitalization beyond the 
expected length of stay. Hospital admissions for surgery planned before study entry, for social 
reasons, for any elective surgery (i.e. plastic surgery) or for normal disease management 
(including treatment adjustment) are NOT to be considered as SAE according to this criterion.. 
• 
results in persistent or significant disability / incapacity, 
i.e. the AE resulted in a substantial disruption of the subject’s ability to conduct normal 
activities. 
• 
is a congenital anomaly / birth defect, 
i.e. an adverse outcome in a child or fetus of a subject exposed to the IMP before conception  or 
during pregnancy. 
• 
is an important medical event, i.e. is medically significant ; 
Medical and scientific judgment should be exercised in deciding whether an AE is serious in 
other situation. Important medical events that may not be immediately life-threatening or result 
in death or hospitalization but may jeopardise the subject or may require intervention to prevent 
one of the other outcomes listed in the definition above should also be considered serious. 
Examples of such events are intensive treatment in an emergency room, or at home for allergic 
bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization, or 
development of drug dependency or drug abuse. 


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8.3.2. 
SAE Urgent Reporting Procedure 
If a SAE occurs from subject consent up to week 36, with the exception of a SAE related to BMD loss 
which will be reported up to week 48, or, in case of study discontinuation, if the site becomes aware of 
an SAE up to 4 weeks post study treatment discontinuation, regardless of relationship and expectedness, 
the Investigator is to take prompt and appropriate therapeutic action, if necessary, to protect the safety 
of study subjects and report such SAE as following. 
For blinded studies, refer to section 7.9. for instructions related to emergency unblinding. 
The Investigator must notify VOISIN CONSULTING (acting on behalf of ObsEva 
Pharmacovigilance) WITHIN 24 HOURS of awareness of a new SAE or of new information on a 
previously reported SAE (= follow-up). 
To do so, the Investigator must complete a SAE report and any specific eCRF pages if justified by the 
protocol e.g. AE, medical history, concomitant medication eCRF pages and blinded and anonymized 
copies of any other supporting source documents such as lab reports, hospital discharge letter/report, 
etc. ), sign it and send it directly to Voisin Consulting by e-mail using the dedicated e-mail address 
specified below: 
 
Name/Title:  
Voisin Consulting / ObsEva Pharmacovigilance 
 
E-mail:  
obsevasafety@voisinconsulting.com 
VOISIN CONSULTING will notify ObsEva Pharmacovigilance within 1 working day after the receipt 
of the SAE form report or follow-up information, using the same reporting forms. 
The SAE follow-up observation period, for the concerned subjects, will be jointly decided by the 
Investigator or one of the co-investigators (in case of Investigator’s absence) and the sponsor.  
In addition, the Investigator must respond to any request for follow-up information or questions 
regarding the SAE the sponsor may have, within 1 working day for urgent queries or 5 working days 
for normal queries. SAE will be followed until the Investigator and ObsEva agree that the event is 
satisfactorily documented and resolved/stabilized. 
For any new SAE, the following minimum information is required as initial notification: 
• 
Clear identification of the Investigator/Reporter with full contact information or site number, 
• 
Subject identification details (study number, site number, subject’s unique study identification 
number and date of birth), 
• 
IMP(s) administration details (dose and dates), 
• 
Diagnosis of the event (or a brief description of signs/symptoms/clinical course if the diagnosis 
is not available) and the date of onset,  
• 
Seriousness criteria, see 8.3.1, 
• 
Causal relationship (Investigator’s opinion) of the event with the IMP(s) or with the trial 
procedure (e.g. the causality according to the Investigator during screening). 


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8.4. 
REPORTING 
TO 
THE 
INDEPENDENT 
ETHICS 
COMMITTEES/ 
INSTITUTIONAL REVIEW BOARDS AND REGULATORY AUTHORITIES 
The Investigator must comply with any applicable requirements related to the reporting of SAEs 
involving the study subjects to the IEC/IRB that approved the study.  
ObsEva will comply with the applicable regulatory requirements related to the expedited reporting of 
suspected unexpected serious adverse reactions (SUSARs) to the regulatory authorities (e.g. Health 
Authority, Central Ethics Committee, Central IRB). In the US, the sponsor will be responsible, through 
their US Agent, for notifying the FDA of any SUSAR, and the sponsor or designee is responsible for 
notifying the Central IRB; in the European Union (EU), the sponsor or designee is responsible for 
notifying the European Medicines Agency, IEC, and Competent Authorities. In regions/countries other 
than the US/EU, reporting of events to IECs or local authorities will be performed by the 
Investigator/sponsor or designee and in accordance with local procedures/regulations. 
In accordance with ICH GCP guidelines, the sponsor will inform the Investigator of “findings that could 
affect adversely the safety of subjects, impact the conduct of the trial or alter the IEC/IRB’s 
approval/favourable opinion to continue the trial”. In particular and in line with respective regulations, 
the sponsor will inform the Investigator of AEs that are both serious and unexpected (i.e. as per the 
OBE2109 Investigator Brochure) and are considered by the Investigator or the sponsor, to have a 
reasonably possibility of causal relationship between the administered IMP and the AE (i.e. SUSAR). 
The Investigator will keep copies of these safety reports in the investigator’s file. National regulations 
with regards to safety reports notifications to Investigators will be taken into account. 
Unless clearly defined otherwise by national or site-specific regulations, and duly documented, the 
responsible Investigator will promptly notify the concerned IEC/IRB of any safety reports provided by 
the sponsor and provide copies of all related correspondence to the sponsor. Only when specifically 
required by regulations, the sponsor (or delegate) will provide appropriate safety reports directly to the 
concerned IEC/IRB and maintain records of these notifications. 
8.5. 
REPORTING PERIOD 
Adverse Events (AEs) are collected on an ongoing basis from the day of signed informed consent. All 
new AEs and updates on all ongoing AEs or AEs with an unknown outcome, must be recorded up to 
week 36, with the exception of an AE related to BMD loss which will be reported up to week 48. 
Protocol-related events occurring during the screening period (i.e between ICF signature and Day 1 
visit) must be recorded in the eCRFs using the AE form (and SAE form if appropriate) until the date the 
subject is determined to be a screening failure. Beyond that date, only serious or medically relevant 
protocol-related events will be followed-up. 
A last batch of queries will be sent after last study visit if remaining ongoing/unknown outcomes of 
reported AEs are pending. After the last batch of queries with all collected data have been fully 
processed, eCRFs and database will no longer be updated. Only SAEs and medically relevant 
ongoing/unknown outcome AEs will be followed-up until resolution or stabilization, under Voisin 
Consulting responsibility. 


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8.6. 
PREGNANCY AND IN UTERO DRUG EXPOSURE 
Only pregnancies considered related to study treatment by the Investigator (i.e. resulting from a drug 
interaction) are considered as AEs. 
However, all pregnancies that are conceived up to week 36 or up to 4 weeks after the last IMP 
administration for subjects prematurely terminating the study must be recorded using the Pregnancy 
Surveillance Form (PSF) – Part I (History and Start of Pregnancy; PSF-part I), provided by the 
sponsor (or delegate) at the beginning of the study.  
Initial reporting of pregnancies: 
Subjects who become pregnant during the study treatment period will be immediately withdrawn from 
the IMP treatment. 
The Investigator must notify the sponsor in an expedited manner (same as SAE reporting) of any 
pregnancy occurring during the above-mentioned period, by completing the PSF-part I. 
This form should be sent to ObsEva’s Representative for Pharmacovigilance as per the same procedures 
and timelines described for expedited AE reporting in section 8.3.2. This form should be accompanied, 
as needed, by copies of the eCRF Medical History, Previous and Concomitant Therapy and the Exit 
Form. 
Follow-up of pregnancies: 
The Investigator must actively follow-up, document and report to ObsEva’s Representative for 
Pharmacovigilance the progress by tri-monthly updates up to the final outcome of the pregnancy 
using the Pregnancy Surveillance Form – Part II: (Course of Pregnancy; PSF-part II). If the subject 
can no longer be reached (lost to follow-up), documentation of the non-response/contact with two phone 
calls and a letter (certified with return receipt) are required. 
Pregnancy outcomes are not recorded in the eCRF unless considered AEs. 
Pregnancy outcomes must be reported to ObsEva’s Representative for Pharmacovigilance by 
completing the Pregnancy Surveillance Form – Part III: (Course and Outcome of Pregnancy; PSF-
part III). Timelines vary according to the nature of the pregnancy outcome: 
- 
For normal outcomes, ObsEva’s Representative for Pharmacovigilance should be 
 
notified within 45 days of birth/delivery. 
- 
For abnormal outcomes, the fully completed form must be sent to ObsEva’s 
 
Representative for Pharmacovigilance according to the same procedures and timelines 
 
described for expedited AE reporting in section 8.3.2. (within 24 hours of awareness of this 
 
outcome). A SAE Report form must be completed when the subject sustains an event while 
 
PSF-part III must be completed when the child/foetus sustains an event. Abnormal outcomes 
 
are defined as: 
• 
Abnormality of the baby (birth defect): in this case, a SAE form for the child should be 
completed in addition to the PSF-III. 
• 
Abnormality for the pregnancy (spontaneous abortion, stillbirth) or abnormality for the 
birth itself which could fulfil criteria of SAEs (e.g. prolongation of hospitalization due 


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to caesarean section complications): in this case please complete in supplement to the 
PSF-III a SAE form for the mother. 
9. 
DATA ANALYSIS AND STATISTICS 
9.1. 
TEST OF HYPOTHESES 
The primary objective of the study is to assess the efficacy of a range of oral doses of OBE2109 versus 
placebo, in reducing overall pelvic pain in subjects with moderate to severe endometriosis pain. The 
corresponding primary endpoint is a 30% or greater reduction from baseline to week 12 in the mean 
overall pelvic pain score defined as the mean of daily pain scores reported during the preceding 4-week 
period assessed on a 0–3 VRS for pelvic pain. 
The primary objective will be assessed by testing the following hypotheses for each active group 
separately: 
Null hypothesis (H0): There is no difference in the proportion of subjects meeting the primary endpoint 
for the active treatment group compared to placebo. 
H0: p (active) = p (placebo) 
Alternative hypothesis (H1): There is a difference in the proportion of subjects meeting the primary 
endpoint for the active treatment group compared to placebo. 
H1: p (active) ≠ p (placebo) 
Where p is the proportion of subjects with a reduction equal to or above 30% from baseline to week 12 
in the mean overall pelvic pain score reported during the preceding 4-week period. 
Each comparison will be carried out at the two-sided 5% level of statistical significance. No adjustment 
will be made for the multiple active versus placebo group comparisons (four in total: 50mg versus 
placebo, 75mg versus placebo, 100mg versus placebo and 200mg versus placebo) with the 
understanding that this increase the overall type I error rate of the study. 
In addition, an overall test for dose response will be conducted using all treatment arms. The coefficients 
for this contrast will be defined assuming a linear response on a log (dose+1) scale. 
9.2. 
SAMPLE SIZE 
The planned sample size for this study is 55 subjects per treatment arm (330 subjects in total). The 
sample size calculation is based on pairwise comparisons for each active dose versus placebo. A two-
sided type I error of 0.05, not adjusted for multiple comparisons against placebo, will be used for this 
exploratory study. Fifty five (55) subjects per arm will provide a power of 90% assuming a placebo 
response rate of 45.5% and an active treatment response rate of 76.9% (based on data from Kissei’s 
Phase 2 study KLH1202). 


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9.3. 
RANDOMIZATION 
Randomization will be performed via a centralized IWRS. Subjects will be randomized on Day 1 to one 
of six treatment groups in a 1:1:1:1:1:1 ratio for OBE2109 placebo/100mg group, OBE2109 50mg fixed-
dose group, OBE2109 75mg fixed-dose group, OBE2109 100mg fixed-dose group, OBE2109 200mg 
fixed-dose group, OBE2109 75mg titrated-dose group, stratified by site. 
Subjects will be randomized into blocks of a pre-determined length, with complete blocks being 
assigned to the investigational sites. 
9.4. 
ANALYSIS SETS 
The following data sets will be used for the statistical analysis: 
1. Safety Set: All randomized subjects who received at least one dose of double-blind study drug 
irrespective of the treatment received. Subjects will be analyzed according to treatment 
received. 
2. Full Analysis Set (FAS): All randomized subjects who received at least one dose of double-
blind study drug irrespective of the treatment received. Subjects will be analyzed according to 
randomized treatment. 
3. Week 12 Per Protocol (PP) Set: All subjects in the FAS excluding those identified as major 
protocol violators up to Week 12.  
4. Week 24 Per Protocol (PP) Set: All subjects in the FAS excluding those identified as major 
protocol violators up to Week 24. 
5. Pharmacokinetic (PK) Set: all subjects who received active study medication and had no 
major protocol deviations. 
Any pre-planned sub-group analyses will be described in the statistical analysis plan (SAP). 
9.5. 
DATA ANALYSIS 
More details of the proposed statistical analysis will be documented in the SAP, which will be written 
following finalization of the protocol and prior to the interim analysis of the Part A data. 
Analyses of Part B study data will be fully described in the SAP. 
For continuous data and for ordered categorical data, if appropriate, the number of non-missing 
observations, mean, standard deviation, median, first and third quartiles, minimum and maximum will 
be calculated.  
For ordered categorical data and nominal data, absolute counts and relative frequencies (in %) will be 
calculated.  
Data for the 75mg group and 75mg titrated group will be combined for the analyses of the Part A data. 
All statistical hypothesis tests and confidence intervals will be two sided, using a type I error rate of 
0.05. No adjustment for multiple comparisons will be used for this study. 


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Raw data will be listed.  
9.5.1. 
Baseline Assessment 
Descriptive statistics will be performed on relevant screening and baseline data (i.e. data collected prior 
to the treatment administration) and on demographic characteristics for each treatment group and 
overall. There will be no formal comparison of baseline data, that is, no statistical hypothesis testing. 
9.5.2. 
Primary Efficacy Analysis 
Mean overall pelvic pain scores will be calculated separately for the VRS and NRS by adding up the 
daily pain scores during each successive 4-week (28 day) periods and dividing by the actual number of 
days with non missing data (i.e. nominally 28 days if no missing data). The baseline mean overall pelvic 
pain score will be calculated as the mean over the two complete menstrual cycles during screening, 
which may not be exactly 28 days each. 
The percentage of subjects with a 30% or greater reduction from baseline to week 12 (i.e. during the 4 
weeks preceding week 12 time point) in the mean overall pelvic pain score will be summarized by 
descriptive statistics for each treatment group and overall.  
The analysis of the primary endpoint will be conducted via a generalized linear model for binary data 
with repeated (correlated) measures, fitted using generalized estimating equations (a marginal model), 
with the model including terms for treatment group, 4-week period, baseline and the interactions 4-week 
period*treatment, 4-week period*baseline.  
9.5.3. 
Secondary Efficacy Analysis 
Mean overall pelvic pain scores will also be calculated separately for the NRS in the same way as for 
the VRS. 
Mean pelvic pain scores on uterine bleeding days and non-uterine bleeding days will be calculated by 
adding up the pain scores on the relevant days (uterine bleeding days will be defined as those days on 
which the subject records any uterine bleeding or spotting in the subject eDiary) and dividing by the 
number of days with non missing data. Both the total number of non-missing days in the 4-week period 
(i.e. nominally 28 days if no missing data) and the number of non-missing uterine bleeding days/non-
uterine bleeding days will be considered. 
All secondary efficacy endpoints will be summarized by descriptive statistics for each treatment group 
and overall, for each time point, including summaries or change from baseline when applicable. The 
definition of baseline for each endpoint will be defined in the SAP. As with the primary analysis, 
individual active versus placebo arm comparisons will be made. In addition, an overall test for dose 
response will be conducted using all treatment arms. 
In general, between group comparisons for continuous endpoints will be analyzed via (repeated 
measures) analysis of (co)-variance (repeated measures mixed models) or Wilcoxon Rank Sum tests, 
subject to the underlying distribution of the data. Between group comparisons for binary endpoints will 
be analyzed via generalized linear models (with repeated measures) and chi-squared tests. Between-
group comparisons for count data (e.g. number of days) will also be analyzed via generalized linear 
models (with repeated measures).  


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It is not certain whether the continuous endpoints will be normally or log-normally distributed, and/or 
whether an absolute or proportional change in endpoints will be observed. If deemed necessary, the data 
will be log transformed prior to the analysis. The subsequent results (mean differences and 
corresponding confidence intervals) will be back transformed and hence reported in terms of ratios of 
geometric means. 
Potential responder definitions for future studies will be explored. These are likely to incorporate use of 
rescue analgesics and reduction in difficulty of pain with daily activities, in addition to pain. A responder 
threshold that constitutes a meaningful reduction in symptomatology will also be explored, potentially 
by exploring a cumulative distribution and/or via an anchor based method using the PGIC and other 
appropriate endpoints and methods.  
9.5.4. 
Safety analysis methodology 
The safety and tolerability profile will be assessed versus baseline conditions and differences between 
treatment groups and descriptive statistics will be produced, where applicable. No formal hypothesis 
testing of safety data will be undertaken. 
A treatment-emergent analysis will be done for AEs. AEs will be tabulated by MedDRA preferred term 
and system organ class. Tabulations by severity and drug-relatedness will also be made. 
Extent of exposure and compliance will be evaluated. 
The Safety Analysis Set shall be used when summarizing safety data. 
9.5.5. 
Pharmacokinetic analysis methodology 
PK Analysis will be performed by SGS Laboratories. The analyses have to be performed unblinded by 
the analytical laboratory. The analyst may be aware of the subject number, sampling time and dose 
group. For descriptive statistics of plasma concentrations mean (arithmetic and geometric), standard 
deviation, median, 1st and 3rd quartiles, minimum, maximum, coefficient of variation (CV%) and 
number of observations will be provided. Concentrations below the limit of quantification (LOQ) will 
be assigned a value of zero. 
9.5.6. 
Pharmacodynamic analysis methodology 
Possible PK-PD relationships will be investigated graphically and through statistical modeling, whilst 
also exploring possible covariates. 
9.5.7. 
Missing Data 
Summary statistics will be based primarily on non-missing values. For hypothesis tests, estimates and 
confidence intervals, missing values for continuous efficacy endpoints analyzed via likelihood methods 
(e.g. repeated measures mixed models) will not be directly imputed as they are handled within the 
analysis itself, under the assumption that the model specification is correct and that the data is missing 
at random. In addition, missing values for endpoints analyzed via generalized estimating equations will 
not be directly imputed as they are handled under the assumption that the model specification is correct 
and the data is missing completely at random. Sensitivity analyses may be conducted to check the 


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robustness of the analysis results under alternative assumptions with regards to missing data. Further 
details on the handling of missing values, including rules applied to incomplete questionnaires 
(including incomplete diary entries) and any planned sensitivity analyses will be defined in the SAP.  
9.6. 
STUDY SPECIFIC DATA ANALYSIS 
9.6.1. 
Interim Analysis 
An un-blinded interim analysis of Part A data to assess efficacy and safety parameters will be performed 
by an unblinded statistician after all subjects have completed the first 12-week period. The OBE2109 
75mg group and OBE2109 75mg titrated group will be pooled for the analysis of the Part A data. The 
results will be made available to the sponsor for the purpose of planning future studies. 
Every effort will be done to maintain the Investigator, the subject and the study personel fully blinded.  
9.6.2. 
Final Analysis 
After all subjects have completed the Part B treatment period (week 24), a complete analysis of Part A 
and Part B data will be performed. The results for the study parts A and B will be summarized and 
described in an integrated Clinical Study Report. 
A 24-week follow-up period without treatment is planned after Part B. 
An analysis will be performed after week 48 on subjects entering the 24-week follow-up period after 
Part B and reported in an addendum to the integrated Clinical Study Report. 
Treatment will remain blinded up to the end of the study for the Investigator and the subject. 
The extension study will be described in a separate protocol, and analyzed and reported in a separate 
Clinical Study Report 
10. 
STUDY ADMINISTRATION 
10.1. 
REGULATORY AND ETHICAL CONSIDERATIONS 
This study is to be performed in accordance with the protocol, with the ethical principles that have their 
origin in the Declaration of Helsinki (27), the ICH Harmonized Tripartite Guideline for GCP, and all 
applicable local regulatory requirements. 
10.1.1. 
Informed Consent 
Before a subject can participate in the study, she must give written informed consent. The informed 
consent process will be in accordance with ICH GCP, and local regulatory requirements. 


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10.1.2. 
Regulatory Authority Approval 
Before the study is initiated at a site, the sponsor (or its delegate) will obtain approval to conduct the 
study from the appropriate regulatory authority in accordance with any applicable country-specific 
regulatory requirements. 
10.1.3. 
Institutional Review Board/ Independent Ethics Committee Requirements  
Before initiation of the study at a given site, written approval of the protocol, ICF and any information 
presented to potential subjects must be obtained from the appropriate Institutional Review Board or 
Independent Ethics Committee (IRB/IEC). If any amendments to any of these documents occur during 
the study, notification or written approval as appropriate must be obtained prior to their implementation. 
The Investigator is responsible for ensuring that these actions occur.  
Where required by local regulations, the sponsor (or its delegate) is responsible for ensuring IEC/IRB 
approval of the study. 
10.1.4. 
End of the study 
For administrative and safety reporting purposes the end of the study will be defined as the date of the 
final clinical database lock after the last subject has completed Week 48 visit. This provides a single and 
conservative definition across all study sites. 
10.2. 
INVESTIGATOR RESPONSIBILITIES 
The Investigator must be familiar with and conduct the study according to ICH GCP guidelines, the 
FDA Code of Regulation or the EU Clinical Trial Directive and applicable local laws and regulations. 
10.2.1. 
Coordinating Investigator  
Where required by local regulations, national level coordinating Investigators may be appointed. Their 
responsibilities are outlined in a separate agreement with the sponsor. 
10.3. 
DATA MANAGEMENT 
The Investigator or designee will be responsible for recording study data in the eCRF provided by the 
sponsor. It is the Investigator’s responsibility to ensure the accuracy of the data entered in the eCRFs. 
The data will be entered into a validated database. The sponsor or delegate will be responsible for data 
processing, in accordance with the sponsor (or delegate) data management procedures. Database lock 
will occur once quality assurance procedures have been completed. The database will not be locked 
before all data clarifications have been resolved and monitored and the decision on subject evaluation 
has been completed. PDF files of the eCRFs will be sent to the Investigator at the completion of the 
study. 
10.4. 
STUDY MONITORING 
The Investigator must ensure that eCRFs are completed in a timely manner and must allow a sponsor 
representative (e.g. CRA or study monitor) periodical access to subject records and all study-related 


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materials. The frequency of monitoring visits will be determined by factors such as the design of the 
study, the frequency of subject visits and the site enrolment rate. In order to verify that the study is 
conducted in accordance with ICH GCP, regulatory requirements, and the study protocol and that the 
data are authentic, accurate and complete, the study monitor will review eCRFs and other study 
documents and will conduct source data verification. 
Upon study completion, the sponsor representative (e.g. CRA or study monitor) will visit the site to 
conduct a Study termination visit. This will involve collection of any outstanding documentation. 
10.5. 
REVIEW COMMITTEE(S) 
10.5.1. 
Data Monitoring Committe (DMC) 
The DMC is a group of independent experts external to the study that, collectively, has experience in 
the management of subjects with endometriosis, and in the conduct and oversight of randomized clinical 
trials. 
Composition, responsibilities, rules for decision and procedures of the DMC will be described in more 
details in the DMC charter. 
The DMC will be responsible for: 
- 
safeguarding the interests of trial participants, 
- 
assessing the safety of the IMP during the trial (reviewing unblinded safety data and AEs and SAEs, 
on a regular basis, as per charter prepared for the study). 
The DMC will provide advisory support to the Study Director, the trial team and any other sponsor 
representative. The Study Director will be responsible for promptly reviewing the DMC 
recommendations and determine whether expedited reporting of any safety issues, amendments to the 
protocol or changes in study conduct are required. 
10.6. 
SUBJECT CONFIDENTIALITY 
The Investigator and the CRA (or study monitor) representing the sponsor must ensure that the subject’s 
anonymity is maintained. In the eCRFs or other documents submitted to the sponsor, the subject should 
not be identified by her name, but by her assigned SIN. If a subject’s name is included on copies of 
documents to be submitted to the sponsor, the name (except for initials) must be obliterated and the 
assigned SIN added to the documents. 
The Investigator should keep a separate log of SINs, names, addresses, telephone numbers and hospital 
numbers (if applicable). Documents not for submission to the sponsor, such as signed ICFs, should be 
maintained in strict confidentiality by the Investigator. 
10.7. 
QUALITY ASSURANCE 
In compliance with ICH GCP and regulatory requirements, the sponsor, a third party acting on behalf 
of the sponsor, regulatory agencies or IRB/IECs may conduct quality assurance audits at any time during 
or following a study. The Investigator must agree to allow auditors direct access to all study-related 


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documents including source documents, and must agree to allocate his or her time and the time of his or 
her study staff to the auditors in order to discuss findings and issues. 
10.8. 
STUDY OR SITE DISCONTINUATION 
The sponsor may temporarily or permanently discontinue the study for safety, ethical, compliance or 
other reasons. If this is necessary, the sponsor will endeavour to provide advance notification to the site. 
If the site or study is suspended or discontinued, the Investigator will be responsible for promptly 
informing the IEC/IRB.  
Where required by local regulations, the sponsor (or delegate) will be responsible for informing the 
IEC/IRB of study or site discontinuation. In such cases, all study data and unused IMP must be returned 
to the sponsor. 
10.9. 
RETENTION OF ESSENTIAL STUDY DOCUMENTS 
Essential documents as defined by ICH GCP include the signed protocol and any amendment(s), copies 
of the completed eCRFs, signed ICFs from all subjects who consented, hospital records, diary cards and 
other source documents, IEC approvals and all related correspondence including approved documents, 
drug accountability records, study correspondence and a list of the subjects’ names and addresses.  
The Investigator must retain copies of the essential documents for the period specified by ICH GCP and 
by applicable regulatory requirements. 
The Investigator will inform the sponsor of the storage location of the essential documents, and must 
contact the sponsor for approval before disposing of any. The Investigator should take measures to 
prevent accidental or premature destruction of these documents. 
 
 


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11. 
APPENDICES 
 
 SCHEDULE OF STUDY ASSESSMENTS ...................................................................... 77 
 MODIFIED BIBEROGLU & BEHRMAN SYMPTOM SEVERITY SCALE* ....................... 78 
 ENDOMETRIOSIS HEALTH PROFILE QUESTIONNAIRE (EHP-30) .............................. 79 
 PATIENT GLOBAL IMPRESSION OF CHANGE ........................................................... 83 
 PIPELLE DE CORNIER® ............................................................................................. 84 
 LABORATORY PARAMETERS ................................................................................... 86 
 REFERENCE LIST ...................................................................................................... 87 


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SCHEDULE OF STUDY ASSESSMENTS 
Timing1 
Screening 
Part A 
Part B 
Follow-Up 
 11±5 
weeks 
Day 1 
W4 
W8 
W12 
W16 
W20 
W24 
W28 
W36 
W48 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
Demography, height, weight, 
medical history 
X 
 
 
 
 
 
 
X6 
 
X6 
 
Previous/concomitant medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X7 
Inclusion-Exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
 
Physical examination 
X 
X 
 
 
X 
 
 
X 
 
X 
 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Gynecological examination and 
mB&B 
X 
 
 
 
X 
 
 
X 
 
X 
 
Breast manual examination 
X 
 
 
 
 
 
 
 
 
X 
 
Pap test 
X 
 
 
 
 
 
 
 
 
 
 
Endometrium TVUS 
X 
 
 
 
X 
 
 
X 
 
X 
 
Endometrial biopsy 
X 
 
 
 
X2 
 
 
X2 
 
X3  
 
Clinical laboratory & urinary 
protein dipstick 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Blood sample for PK
 
4 
 
X4 
X4 
X 
X 
X4 
X 
X 
 
 
 
OBE2109/Placebo taken daily
 
 
 
 
 
 
 
Subject eDiary completion 
training/check5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
EHP-30 
 
X 
 
 
X 
 
 
X 
 
X 
 
PGIC 
 
 
 
 
X 
 
 
X 
 
X 
 
BMD by DXA 
 
X 
 
 
X 
 
 
X 
 
 
X 
Urine pregnancy test and 
contraceptive counselling 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Question regarding treatment 
received during study 
 
 
 
 
 
 
 
X 
 
 
 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X7 
 
 
 
 
1 All post-baseline visits should take place at the end of the defined period (i.e. week 4 visit should be scheduled at the end of week 4, week 
8 visit should be scheduled at the end of week 8, etc.). Post-baseline visits dates are calculated from Day 1 visit date.    
2  If endometrium thickness in TVUS is ≤ 5 mm, no endometrium biopsy will be necessary, as far as the screening biopsy has provided 
assessable results. 
3 If diagnosis at week 24 was different from “benign endometrium” or if no endometrial biopsy was obtained at week 24, then endometrial 
biopsy must be performed. 
4 PK blood samples should be taken after dosing except on Day 1 when taken before and 1.5 to 2 h after dosing, and at week 4 and 16, when 
taken prior to dosing.  
5 eDiary completion includes daily record of pelvic pain scores, uterine bleeding, dyspareunia symptoms, analgesic use, study treatment, 
difficulty in performing daily activities, weekly record of dyschezia pain score and 4-weekly record of patient’s impression of severity. 
6 Only weight will be recorded.7 Record in eCRF only if related to BMD (any medications with potential impact on BMD or any AEs related 
to BMD loss). 


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MODIFIED BIBEROGLU & BEHRMAN SYMPTOM
 
SEVERITY SCALE* 
 
A. Dysmenorrhea 
None 
0 = No symptoms 
Mild 
1 = Some loss of ability to work or carry out normal activities 
Moderate 2 = Unable to work or carry out normal daily activities for part of 1 or more days 
and/or moderately decreased work efficiency 
Severe  
3 = Unable to work or carry out normal daily activities for 1 or more full days and/or 
significantly decreased work efficiency 
 
B. Deep Dyspareunia 
None 
0 = No symptoms 
Mild 
1 = Tolerated discomfort during intercourse 
Moderate 2 = Interference of usual frequency of sexual intercourse due to pain 
Severe  
3 = Avoids, or wishes to avoid, intercourse because of pain 
 
C. Non Menstrual Pelvic Pain 
None 
0 = No symptoms 
Mild 
1 = Occasional pelvic discomfort 
Moderate 2 = Noticeable discomfort for most of cycle 
Severe  
3 = Pain persistent during cycle other than during menstruation 
 
 
D. Pelvic Tenderness (assessed by the phycician) 
None 
0 = No findings 
Mild 
1 = Minimal tenderness on palpation 
Moderate 2 = Moderate tenderness on palpation 
Severe  
3 = Exam limited due to tenderness 
 
E. Induration (assessed by the physician) 
None 
0 = No findings 
Mild 
1 = Uterus freely mobile, minimal induration in the cul-de-sac 
Moderate 2 = Significant induration in the cul-de-sac, restricted uterine mobility 
Severe  
3 = Nodular adnexa and cul-de-sac, uterus fixed 
 
Composite Pelvic Pain and Physical Sign Score (A + B + C + D + E) 
None 
 
0 
Mild 
 
1 - 2 
Moderate  
3 - 5 
 
Severe 
 
6 - 10 
Very Severe 
11 – 15 
 
* based on Biberoglu KO, Behrman SJ. Dosage aspects of danazol therapy in endometriosis: short 
term and long term effectiveness. Am J Obstet Gynecol. 1981;139:645.  
 
Total Pelvic Pain Score (A + B + C) 
None 
 
0 
Mild 
 
1 - 3 
Moderate 
4 - 6 
 
Severe
7 - 9
Total Physical Sign Score (D + E) 
None 
 
0 
Mild 
 
1 - 2 
Moderate 
3 - 4 
 
Severe
5 - 6


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ENDOMETRIOSIS HEALTH PROFILE QUESTIONNAIRE 
(EHP-30) 
 
PART 1: CORE QUESTIONNAIRE 
DURING THE LAST 4 WEEKS,  
HOW OFTEN, BECAUSE OF YOUR ENDOMETRIOSIS, HAVE YOU... 
 
Never 
Rarely 
Sometimes 
Often 
Always 
1. 
Been unable to go to social events 
because of the pain?  
 
 
 
 
 
 
2. 
Been unable to do jobs around the 
home because of the pain?  
 
 
 
 
 
 
3. 
Found it difficult to stand because 
of the pain? 
 
 
 
 
 
 
4. 
Found it difficult to sit because of 
the pain? 
 
 
 
 
 
 
5. 
Found it difficult to walk because of 
the pain? 
 
 
 
 
 
 
6. 
Found it difficult to exercise or do 
the leisure activities you would like 
to do because of the pain? 
 
 
 
 
 
 
7. 
Lost your appetite and/or been 
unable to eat because of the pain? 
 
 
 
 
 
 
 
 
 


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DURING THE LAST 4 WEEKS,  
HOW OFTEN, BECAUSE OF YOUR ENDOMETRIOSIS, HAVE YOU... 
 
Never 
Rarely 
Sometimes 
Often 
Always 
8. 
Been unable to sleep properly 
because of the pain? 
 
 
 
 
 
 
9. 
Had to go to bed/lie down because 
of the pain? 
 
 
 
 
 
 
10. Been unable to do the things you 
want to do because of the pain? 
 
 
 
 
 
 
11. Felt unable to cope with the pain? 
 
 
 
 
 
 
12. Generally felt unwell? 
 
 
 
 
 
 
13. Felt frustrated because your 
symptoms are not getting better? 
 
 
 
 
 
 
14. Felt frustrated because you are not 
able to control your symptoms? 
 
 
 
 
 
 
 
 
 


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DURING THE LAST 4 WEEKS,  
HOW OFTEN, BECAUSE OF YOUR ENDOMETRIOSIS, HAVE YOU... 
 
Never 
Rarely 
Sometimes 
Often 
Always 
15. Felt unable to forget your 
symptoms? 
 
 
 
 
 
 
16. Felt as though your symptoms are 
ruling your life? 
 
 
 
 
 
 
17. Felt your symptoms are taking 
away your life? 
 
 
 
 
 
 
18. Felt depressed? 
 
 
 
 
 
 
19. Felt weepy/tearful? 
 
 
 
 
 
 
20. Felt miserable? 
 
 
 
 
 
 
21. Had mood swings? 
 
 
 
 
 
 
22. Felt bad tempered or short 
tempered? 
 
 
 
 
 
 
 
 
 


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DURING THE LAST 4 WEEKS,  
HOW OFTEN, BECAUSE OF YOUR ENDOMETRIOSIS, HAVE YOU... 
 
Never 
Rarely 
Sometimes 
Often 
Always 
23. Felt violent or aggressive? 
 
 
 
 
 
 
24. Felt unable to tell people how you 
feel? 
 
 
 
 
 
 
25. Felt others do not understand what 
you are going through? 
 
 
 
 
 
 
26. Felt as though others think you are 
moaning? 
 
 
 
 
 
 
27. Felt alone? 
 
 
 
 
 
 
28. 
Felt frustrated as you cannot 
always wear the clothes you would 
choose? 
 
 
 
 
 
 
29. Felt your appearance has been 
affected? 
 
 
 
 
 
 
30. Lacked confidence? 
 
 
 
 
 
 
 
 
 


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PATIENT GLOBAL IMPRESSION OF CHANGE 
 
 
Farrar JT, Young Jr. JP, LaMoreaux L, Werth JL, Poole RM: Clinical importance of changes in chronic 
pain intensity measured on an 11-point numerical pain rating scale. Pain 2001; 94(2): 149-158. 
 
 
 


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PIPELLE DE CORNIER® 
 
 
 
 


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LABORATORY PARAMETERS 
 
Routine Haematology  
 
Blood Chemistry 
Haemoglobin  
 
 
Sodium  
Haematocrit 
 
 
 
Potassium 
RBC count 
 
 
 
Calcium 
WBC count 
 
 
 
Phosphate 
Neutrophils 
 
 
 
Creatinine 
Lymphocytes  
 
 
Bilirubin total 
Monocytes 
 
 
 
Indirect Bilirubin 
Eosinophils 
 
 
 
Total protein 
Basophils 
 
 
 
Albumin 
Thrombocytes  
 
 
AST 
MCV  
 
 
 
ALT 
MCH  
 
 
 
γGT 
MCHC  
 
 
 
Alkaline phosphatase 
APTT  
 
 
 
Creatine Kinase 
INR 
 
 
 
 
LDH 
PT 
 
 
 
 
HDL, LDL and total cholesterol, triglycerides 
 
 
 
 
 
Urea and uric acid 
Urinary protein dipstick 
All the above listed tests are to be performed at the frequencies indicated in APPENDIX A. 
Hormones 
E2, LH, P4, SHBG, AMH 
All above listed blood tests will be performed by a central laboratory. Please consult the central 
laboratory instructions manual for the preparation and handling of the blood samples to be drawn to 
perform these tests. 
 
 
 


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REFERENCE LIST 
1. Eskenazi B, Warner M. Epidemiology of endometriosis. Obstet Gynecol Clin North Am 
1997;24:235–58. 
2. Giudice LC. Clinical practice. Endometriosis. N Engl J Med. 2010;362:2389-98. Review. 
3. Fauconnier A, Chapron C. Endometriosis and pelvic pain: epidemiological evidence of the 
relationship and implications. Hum Reprod Update 2005;11:595–606. 
4. Dunselman GA, Vermeulen N, Becker C, et al. ESHRE guideline: management of women with 
endometriosis. Hum Reprod 2014; 29:400–12. 
5. Gao X, Outley J, Botteman M, et al. Economic burden of endometriosis. Fertil Steril. 
2006;86:1561-72. Review. 
6. Nnoaham KE, Hummelshoj L, Webster P, et al. World Endometriosis Research Foundation 
Global Study of Women's Health consortium. Impact of endometriosis on quality of life and 
work productivity: a multicenter study across ten countries. Fertil Steril. 2011;96:366-73. 
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