Conditions: Endometriosis
Keywords: Dysmenorrhea Dyspareunia Dyschezia Non-menstrual pelvic pain
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 30
Healthy volunteers: no

Brief summary:
The primary objective of this extension study is to assess the maintenance of efficacy of linzagolix administered orally once daily for up to an additional 6 months (for up to 12 months of treatment in total) in women who have already completed 6 months of linzagolix treatment at a dose of 75 mg alone or of 200 mg in combination with ABT (E2 1 mg / NETA 0.5 mg), in the management of moderate to severe endometriosis-associated pain (EAP) in women with surgically confirmed endometriosis.

Detailed description:
This is a prospective, randomized, double-blind study. Subjects who have completed the 6-month Treatment Period in 18-OBE2109-002 - Edelweiss 2 study (herein referred to as main study) will be invited to enter the present extension study. Month 6 visit of the main study is a decision point for Subjects to either end treatment and enter a post-treatment follow up (part of the main study), or to opt for a 6-month treatment extension. All subjects will receive once daily either linzagolix 75 mg alone (with ABT placebo) or 200 mg combined with ABT for 6 months. Subjects who received placebo during the main study will be randomized to either linzagolix 75 mg alone (with ABT placebo) or linzagolix 200 mg with ABT. Subjects who received active treatment during the main study will continue with the same treatment. Double-dummy design will be used in order to maintain the blinding of the study.

After end of treatment in the extension study (6-month treatment period: from Month 6 to Month 12), subjects will enter a post-treatment Follow-Up Period of 6 months with no investigational medicinal product (IMP) or - for subjects willing to continue treatment - a second extension study will be proposed.

Arms:
arm 1: None arm 2: None

Interventions: intervention 1: 75 mg linzagolix tablet intervention 2: 200 mg linzagolix tablet intervention 3: Add-back capsule (E2 1 mg / NETA 0.5 mg) intervention 4: Placebo tablet to match 75 mg linzagolix tablet intervention 5: Placebo tablet to match 200 mg linzagolix tablet intervention 6: Placebo capsule to match Add-back capsule
Intervention descriptions: intervention 1: For oral administration once daily intervention 2: For oral administration once daily intervention 3: For oral administration once daily intervention 4: For oral administration once daily intervention 5: For oral administration once daily intervention 6: For oral administration once daily

Protocol document:
Prot_002.pdf: 
19-OBE2109-005 PROTOCOL V2.0 DATED 24 AUGUST 2020 
Page 1 of 121 
 
OBSEVA CONFIDENTIAL 
CLINICAL STUDY PROTOCOL 
 
Protocol Number: 
19-OBE2109-005 
Investigational Medicinal 
Product: 
Linzagolix (OBE2109) 
Study Title: 
A double-blind randomized extension study to assess the 
long-term efficacy and safety of linzagolix in subjects with 
endometriosis-associated pain. 
Short Study Title: 
A phase 3 extension study to assess the efficacy and safety of 
linzagolix to treat endometriosis-associated pain 
Study Name: 
Edelweiss 2 extension 
Version number: 
Version 2.0 
Date: 
24 August 2020 
Replacing:  
Version 1.0 – 14 October 2019 
Study Sponsor: 
 
ObsEva S.A. 
  
 
Clinical Trial Director: 
 
 
 
 
Medical Responsible: 
 
  
 
CRO 
 
 
CRO Project Director: 
  
  
 
 
 


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OBSEVA CONFIDENTIAL 
 
VERSION HISTORY 
Amendment 
Number 
Amendment 
Date 
General / Country-Specific/ 
Site-Specific 
Amended Protocol 
version and date 
01 
24 Aug 2020 
General 
V2.0 – August 24, 2020 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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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. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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OBSEVA CONFIDENTIAL 
SPONSOR 
AND 
CONTRACT 
RESEARCH 
ORGANIZATION(S) 
SIGNATORY APPROVAL PAGE 
The below signatories have read this trial protocol and agree with its principles. They agree to carry out 
the clinical trial in compliance with this protocol, with ICH Good Clinical Practice (ICH GCP) and the 
applicable regulatory requirements. 
Sponsor: 
ObsEva S.A., 
 
 
Signature 
Date of signature 
 
 
(Clinical Trial Director) 
 
 
Signature 
 signature 
 
(Medical Responsible) 
 
 
Contract Research Organization(s): 
 
 
 
 
Signature 
 
Date of signature 
 
 
 
(Project Director) 
 
 
 
 


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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 linzagolix, 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 
PI Name: 
Institution: 
 
 
 
 


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OBSEVA CONFIDENTIAL 
1 TABLE OF CONTENTS 
1 
TABLE OF CONTENTS ........................................................................................................ 6 
2 
LIST OF FIGURES ............................................................................................................. 12 
3 
LIST OF ABBREVIATIONS ................................................................................................. 13 
4 
SYNOPSIS ....................................................................................................................... 18 
5 
BACKGROUND INFORMATION........................................................................................ 26 
5.1 
INTRODUCTION TO LINZAGOLIX ................................................................................ 26 
5.2 
ENDOMETRIOSIS ............................................................................................................. 26 
5.3 
CONVENTIONAL TREATMENT OF ENDOMETRIOSIS .............................................. 26 
5.4 
SUMMARY OF NON-CLINICAL STUDIES .................................................................... 26 
5.5 
SUMMARY OF CLINICAL STUDIES .............................................................................. 27 
5.5.1 
Pharmacokinetics/Pharmacodynamics ................................................................................ 27 
5.5.2 
Efficacy ................................................................................................................................. 29 
5.5.3 
Safety  .................................................................................................................................. 29 
5.6 
RATIONALE FOR THE CURRENT STUDY ................................................................... 32 
5.7 
SUMMARY OF OVERALL RISKS AND BENEFITS ...................................................... 32 
6 
OBJECTIVES .................................................................................................................... 33 
6.1 
EFFICACY OBJECTIVES .................................................................................................. 33 
6.1.1 
Primary ................................................................................................................................. 33 
6.1.2 
Secondary ............................................................................................................................ 33 
6.2 
SAFETY OBJECTIVES ...................................................................................................... 34 
6.3 
EXPLORATORY OBJECTIVES ........................................................................................ 34 
7 
ENDPOINTS .................................................................................................................... 34 
7.1 
EFFICACY ENDPOINTS ................................................................................................... 34 
7.1.1 
Primary ................................................................................................................................. 34 
7.1.2 
Secondary ............................................................................................................................ 34 
7.2 
SAFETY ENDPOINTS ....................................................................................................... 36 


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OBSEVA CONFIDENTIAL 
7.3 
EXPLORATORY ENDPOINTS ......................................................................................... 36 
8 
STUDY DESIGN................................................................................................................ 36 
9 
STUDY POPULATION ....................................................................................................... 38 
9.1 
SUBJECTS .......................................................................................................................... 38 
9.1.1 
Description of the target population ................................................................................... 38 
9.1.2 
Number of subjects .............................................................................................................. 38 
9.1.3 
Study region/location .......................................................................................................... 38 
9.2 
ENTRY CRITERIA ............................................................................................................. 38 
9.2.1 
Inclusion Criteria .................................................................................................................. 38 
9.2.2 
Exclusion Criteria.................................................................................................................. 39 
10 
STUDY PROCEDURES AND ASSESSMENTS ....................................................................... 40 
10.1 
GENERAL INSTRUCTIONS ............................................................................................. 40 
10.2 
OUTLINE OF STUDY PROCEDURES AND ASSESSMENTS ....................................... 41 
10.2.1 
Treatment Period ................................................................................................................. 42 
10.2.2 
Post-treatment Follow-Up Period ........................................................................................ 47 
10.3 
EFFICACY OBSERVATIONS AND MEASUREMENTS ................................................ 50 
10.3.1 
Daily eDiary .......................................................................................................................... 50 
10.3.2 
Outcome rating scales assessed at site visits ....................................................................... 53 
10.4 
SAFETY OBSERVATIONS AND MEASUREMENTS .................................................... 54 
10.4.1 
Adverse Events ..................................................................................................................... 54 
10.4.2 
Physical Examination ........................................................................................................... 55 
10.4.3 
Vital signs ............................................................................................................................. 55 
10.4.4 
Transvaginal ultrasound ....................................................................................................... 55 
10.4.5 
Endometrial biopsies ........................................................................................................... 55 
10.4.6 
Bone mineral density and DXA ............................................................................................ 57 
10.4.7 
Bone markers ....................................................................................................................... 57 
10.4.8 
Laboratory parameters ........................................................................................................ 57 
10.4.9 
Electrocardiogram ................................................................................................................ 58 
10.4.10 
Columbia-Suicide Severity Rating Scale (C-SSRS) ................................................................. 58 


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OBSEVA CONFIDENTIAL 
10.5 
LINZAGOLIX AND KP017 PLASMA LEVELS ............................................................... 58 
10.6 
CONCOMITANT MEDICATIONS AND THERAPIES .................................................... 59 
10.6.1 
Permitted Medicines ............................................................................................................ 59 
10.6.2 
Prohibited Medicines ........................................................................................................... 59 
10.6.3 
Non-Drug Therapies ............................................................................................................. 60 
10.7 
SUBJECT COMPLETION AND WITHDRAWAL ............................................................ 60 
10.7.1 
Subject Completion .............................................................................................................. 60 
10.7.2 
Subject Withdrawal .............................................................................................................. 60 
10.7.3 
Subject Replacement ........................................................................................................... 62 
11 
INVESTIGATIONAL MEDICINAL PRODUCT ....................................................................... 62 
11.1 
DESCRIPTION OF INVESTIGATIONAL MEDICINAL PRODUCTS............................ 62 
11.2 
DOSAGE AND ADMINISTRATION ................................................................................ 64 
11.3 
PACKAGING AND LABELLING ..................................................................................... 64 
11.4 
PREPARATION, HANDLING AND STORAGE .............................................................. 65 
11.5 
IMP ACCOUNTABILITY .................................................................................................. 66 
11.6 
ASSIGNMENT TO TREATMENT GROUPS .................................................................... 67 
11.7 
ASSESSMENT OF INVESTIGATIONAL MEDICINAL PRODUCT COMPLIANCE ... 67 
11.8 
METHOD OF BLINDING .................................................................................................. 67 
11.9 
EMERGENCY UNBLINDING ........................................................................................... 68 
11.10 
TREATMENT OF OVERDOSE AND MISUSE ................................................................ 68 
11.11 
OTHER SUPPLIES TO BE USED IN THE STUDY ......................................................... 68 
12 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS ........................................................ 68 
12.1 
ADVERSE EVENTS ........................................................................................................... 69 
12.1.1 
Definitions ............................................................................................................................ 69 
12.1.2 
Abnormal laboratory findings and other objective measurements..................................... 71 
12.1.3 
Baseline Medical Conditions ................................................................................................ 71 
12.1.4 
Exacerbation of endometriosis ............................................................................................ 71 
12.1.5 
Adverse Events of Special Interest ....................................................................................... 71 
12.2 
PROCEDURES FOR ELICITING, RECORDING AND REPORTING ADVERSE 
EVENTS .............................................................................................................................. 72 


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OBSEVA CONFIDENTIAL 
12.2.1 
Eliciting Adverse Events ....................................................................................................... 72 
12.2.2 
Recording of Adverse Events in the eCRF ............................................................................ 72 
12.2.3 
Reporting of Adverse Events ................................................................................................ 72 
12.3 
SERIOUS ADVERSE EVENTS ......................................................................................... 73 
12.3.1 
Definitions ............................................................................................................................ 73 
12.3.2 
SAE Urgent Reporting Procedure ......................................................................................... 74 
12.4 
REPORTING TO THE INSTITUTIONAL REVIEW BOARDS AND REGULATORY 
AUTHORITIES ................................................................................................................... 75 
12.5 
REPORTING PERIOD ........................................................................................................ 75 
12.6 
PREGNANCY AND IN UTERO DRUG EXPOSURE ...................................................... 75 
13 
DATA ANALYSIS AND STATISTICS .................................................................................... 76 
13.1 
TEST OF HYPOTHESES ................................................................................................... 76 
13.2 
SAMPLE SIZE .................................................................................................................... 77 
13.3 
RANDOMIZATION ............................................................................................................ 77 
13.4 
ANALYSIS SETS ............................................................................................................... 77 
13.5 
DATA ANALYSIS .............................................................................................................. 78 
13.5.1 
Baseline Assessment ............................................................................................................ 78 
13.5.2 
Efficacy Analysis ................................................................................................................... 78 
13.5.3 
Safety Analysis ..................................................................................................................... 79 
13.5.4 
Pharmacokinetic analysis methodology .............................................................................. 79 
13.5.5 
Pharmacodynamic analysis methodology ........................................................................... 79 
13.5.6 
Missing Data......................................................................................................................... 79 
13.6 
STUDY SPECIFIC DATA ANALYSIS ............................................................................. 79 
13.6.1 
End-of-Treatment Period Analysis ....................................................................................... 79 
13.6.2 
Post-Treatment Follow-Up Period Analysis ......................................................................... 79 
14 
STUDY ADMINISTRATION ............................................................................................... 80 
14.1 
REGULATORY AND ETHICAL CONSIDERATIONS ................................................... 80 
14.1.1 
Informed Consent ................................................................................................................ 80 
14.1.2 
Regulatory Authority Approval ............................................................................................ 80 
14.1.3 
Institutional Review Board Requirements ........................................................................... 80 


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OBSEVA CONFIDENTIAL 
14.1.4 
End of the study ................................................................................................................... 80 
14.2 
INVESTIGATOR RESPONSIBILITIES ............................................................................ 80 
14.3 
DATA MANAGEMENT ..................................................................................................... 81 
14.4 
STUDY MONITORING ..................................................................................................... 81 
14.5 
DATA MONITORING COMMITTEE ............................................................................... 81 
14.6 
SUBJECT CONFIDENTIALITY ........................................................................................ 82 
14.7 
QUALITY ASSURANCE ................................................................................................... 82 
14.8 
PROTOCOL DEVIATIONS ............................................................................................... 82 
14.9 
STUDY OR SITE DISCONTINUATION ........................................................................... 82 
14.10 
RETENTION OF ESSENTIAL STUDY DOCUMENTS ................................................... 83 
14.11 
PUBLICATION POLICY.................................................................................................... 83 


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OBSEVA CONFIDENTIAL 
15 
APPENDICES ................................................................................................................... 84 
APPENDIX A. SCHEDULE OF STUDY ASSESSMENTS – TREATMENT PERIOD........................................... 85 
APPENDIX B. SCHEDULE OF STUDY ASSESSMENTS – FOLLOW-UP PERIOD ........................................... 87 
APPENDIX C. ENDOMETRIOSIS HEALTH PROFILE QUESTIONNAIRE (EHP-30) ....................................... 88 
APPENDIX D. PROMIS FATIGUE – SHORT FORM 6A ............................................................................. 93 
APPENDIX E. HEALTH-RELATED PRODUCTIVITY QUESTIONNAIRE (HRPQ) ........................................... 94 
APPENDIX F. HEALTH RESOURCE UTILIZATION QUESTIONNAIRE (HRUQ) ............................................ 96 
APPENDIX G. PATIENT GLOBAL IMPRESSION OF CHANGE (PGIC) ....................................................... 101 
APPENDIX H. POST-TREATMENT PATIENT GLOBAL IMPRESSION OF CHANGE (PPGIC) ....................... 102 
APPENDIX I. PATIENT GLOBAL IMPRESSION OF SEVERITY (PGIS) ...................................................... 103 
APPENDIX J. SUBJECT SURGERY INTENTION QUESTIONNAIRE (SSIQ) ................................................ 104 
APPENDIX K. PHYSICIAN SURGERY INTENTION QUESTIONNAIRE (PSIQ) ............................................ 105 
APPENDIX L. EQ-5D-5L ...................................................................................................................... 106 
APPENDIX M. LABORATORY PARAMETERS ......................................................................................... 108 
APPENDIX N. PROHIBITED MEDICINES ............................................................................................... 109 
APPENDIX O. STRONG CYP3A4 INDUCERS AND INHIBITORS .............................................................. 110 
APPENDIX P. ANALGESIC CHANGE DURING TREATMENT PERIOD ...................................................... 112 
APPENDIX Q. REFERENCE LIST ............................................................................................................ 114 
APPENDIX R. C-SSRS ALREADY ENROLLED SUBJECTS ......................................................................... 115 
APPENDIX S. C-SSRS SINCE LAST VISIT ............................................................................................... 118 
 
 


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OBSEVA CONFIDENTIAL 
2 LIST OF FIGURES 
FIGURE 1 : STUDY DESIGN ............................................................................................................................................ 37 
FIGURE 2 : SCHEDULE OF VISITS .................................................................................................................................... 41 
FIGURE 3 : BIOPSY PROCESS FOR MONTH 12 VISIT ............................................................................................................ 56 
FIGURE 4 : BIOPSY PROCESS FOR THE FOLLOW-UP PERIOD VISITS ........................................................................................ 56 
FIGURE 5 : LINZAGOLIX KIT DESIGN ................................................................................................................................ 65 
 
 


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OBSEVA CONFIDENTIAL 
3 LIST OF ABBREVIATIONS 
ABT 
Add-Back Therapy 
AE 
Adverse Event 
ALT 
ALanine amino Transferase 
APTT 
Activated Partial Thromboplastin Time 
AST 
ASpartate amino Transferase 
AUC 
Area Under the Curve 
B-ALP 
Bone-specific Alkaline Phosphatase 
BMD 
Bone Mineral Density 
BMI 
Body Mass Index 
BP 
Blood Pressure 
bpm 
Beats Per minute 
°C 
Degree Celsius 
CK 
Creatine Kinase 
ClinRO 
Clinician Reported Outcome 
COC 
Combined Oral Contraceptive 
CRA 
Clinical Research Associate 
CRO 
Contract Research Organization 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CTx 
C-terminal telopeptide  
CV 
Coefficient of Variation 
CYP 
Cytochrome P 
DMC 
Data Monitoring Committee 
dPGIS 
Patient Global Impression of Severity – daily recall  
DXA 
Dual-energy X-ray Absorptiometry 
DYS 
Dysmenorrhea 
E2 
Estradiol 


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OBSEVA CONFIDENTIAL 
EAP 
Endometriosis-Associated Pain 
ECG 
ElectroCardioGram 
eCRF 
Electronic Case Report Form 
eDiary 
Electronic Diary 
EHP-30 
Endometriosis Health Profile – 30 
ePRO 
Electronic Patient Reported Outcome 
EQ-5D-5L 
EuroQol 5 Dimension 5 Level questionnaire 
EU 
European Union 
ExFU 
Extension Follow-Up 
FD 
Fixed Dose 
FDA 
Food and Drug Administration 
FSH 
Follicle-Stimulating Hormone 
GCP 
Good Clinical Practice 
γGT 
Gamma-Glutamyl Transferase 
GMP 
Good Manufacturing Practice 
HDL 
High Density Lipoprotein 
HIV 
Human Immunodeficiency Virus 
HRPQ 
Health-Related Productivity Questionnaire 
HRUQ 
Health Resource Utilization Questionnaire 
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 
Institutional Review Board 
IUD 
Intra-Uterine Device 


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OBSEVA CONFIDENTIAL 
IWRS 
Interactive Web Response System 
LDH 
Lactate DeHydrogenase 
LDL 
Low Density Lipoprotein 
LFT 
Liver Function Test 
LH 
Luteinizing Hormone 
LOQ 
Limit Of Quantification 
MCH 
Mean Corpuscular Haemoglobin 
MCHC 
Mean Corpuscular Haemoglobin Concentration 
MCV 
Mean Corpuscular Volume 
mg 
Milligram 
min 
Minute 
MME 
Morphine Milligram Equivalent 
mPGIS 
Patient Global Impression of Severity – monthly recall  
mmHg 
millimeter of mercury 
msec 
Millisecond 
NETA 
NorEThisterone Acetate 
NMPP 
Non-Menstrual Pelvic Pain 
NRS 
Numeric Rating Scale 
NSAID 
Non Steroidal Anti-Inflammatory Drug 
OAT3 
Organic Anion Transporter 3 
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 
P1NP 
Procollagen type 1 N-terminal Propeptide  
P4 
Progesterone 
PAP 
PAPanikolaou test 
PD 
PharmacoDynamic 
PGIC 
Patient Global Impression of Change 


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OBSEVA CONFIDENTIAL 
PPGIC 
Post-treatment Patient Global Impression of Change 
PGIS 
Patient Global Impression of Severity 
PK 
PharmacoKinetic 
PSF 
Pregnancy Surveillance Form 
PSIQ 
Pysician Surgery Intention Question 
PVC/Al 
PolyVinyl Chloride/Aluminum 
QC 
Quality Control 
QD 
Once daily (from the Latin Quaque Die)  
QoL 
Quality of Life 
QTc 
QT interval corrected for heart rate  
QTcF 
QT interval corrected for heart rate (QTc) using Fridericia's correction 
formula 
RBC 
Red Blood Cell 
REB 
Research Ethics Board 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SERM 
Selective Estrogen Receptor Modulator 
SHBG 
Sex Hormone-Binding Globulin 
SIN 
Subject Identification Number 
SPRM 
Selective Progesterone Receptor Modulator 
SSIQ 
Subject Surgery Intention Question 
SUSAR 
Suspected Unexpected Serious Adverse Reaction  
TD 
Titrated Dose 
TEAE(s) 
Treatment Emergent Adverse Event(s) 
TVUS 
TransVaginal UltraSound 
ULN 
Upper Limit of Normal 
US/USA 
United States/United States of America 


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OBSEVA CONFIDENTIAL 
VAS 
Visual Analogue Scale 
VRS 
Verbal Rating Scale 
WBC 
White Blood Cell 


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OBSEVA CONFIDENTIAL 
4 SYNOPSIS 
Study Title: A double-blind randomized extension study to assess the long-term efficacy and safety 
of linzagolix in subjects with endometriosis-associated pain 
Code/Name ObsEva Investigational Drug: linzagolix (OBE2109) Phase of Development: 3 
Objectives: 
The primary objective of this extension study is to assess the maintenance of efficacy of linzagolix 
administered orally once daily for up to an additional 6 months (for up to 12 months of treatment in 
total) in women who have already completed 6 months of linzagolix treatment at a dose of 75 mg 
alone or of 200 mg in combination with add-back therapy (estradiol (E2) 1 mg / norethisterone acetate 
(NETA) 0.5 mg) in the management of moderate to severe endometriosis-associated pain (EAP) in 
women with surgically confirmed endometriosis. The two co-primary efficacy endpoints will be 
clinically meaningful reduction over the last 28 days of randomized treatment up to the Month 12 
visit, along with a stable or decreased use of analgesics for EAP, for 1) dysmenorrhea (DYS) and for 
2) non menstrual pelvic pain (NMPP).  
Secondary objectives include evaluation of efficacy over the last 28 days of randomized treatment 
up to the Month 12 visit  based on the following parameters: evaluation of pain associated with sexual 
intercourse (dyspareunia) and defecation (dyschezia), difficulty of doing daily activities, analgesic 
use, assessment of subject perception of severity, change in uterine bleeding, Quality of Life (QoL) 
questionnaires, pharmacoeconomic burden of endometriosis by assessing changes in patient 
productivity, assessment of endometriosis-related number of non-study health visits, number of days 
in hospital and type of medical procedures performed during the Treatment Period. 
Safety and tolerability objectives include assessment of bone mineral density (BMD), endometrial 
health, cardiac safety including QT interval prolongation, standard laboratory safety parameters, 
gynecological assessments and adverse event (AE) frequency including specific hypoestrogenic AEs. 
Exploratory objectives include assessment of bone turnover markers and collection of 
pharmacokinetic (PK) and pharmacodynamic (PD) related data of linzagolix for a separate modelling 
exercise. 
Endpoints: 
Efficacy endpoints  
 
Primary efficacy endpoints:  
The two co-primary, composite, efficacy endpoints are clinically meaningful reduction from 
baseline to the last 28 days preceding the Month 12 visit (the 4-week period preceding Month 12 
visit), along with a stable or decreased use of analgesics for EAP, in the mean daily assessment 
of 1) DYS and of 2) NMPP, both measured on a Verbal Rating Scale (VRS) using an electronic 
diary (eDiary). 
 


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OBSEVA CONFIDENTIAL 
 
Secondary efficacy endpoints:  
 
Change from baseline to Month 12 in DYS (VRS) 
 
Change from baseline to Month 12 in NMPP (VRS) 
 
Change from baseline to Month 12 in dyschezia (Numeric Rating Scale - NRS) 
 
Change from baseline to Month 12 in overall pelvic pain (NRS) 
 
Change from baseline to Month 12 in the interference of pain with the ability to perform 
daily activities, measured using the pain dimension of the Endometriosis Health Profile-
30 (EHP-30)  
 
Change from baseline to Month 12 in dyspareunia (VRS) 
 
No analgesics use for EAP during the preceding 4-week period at each scheduled 
assessment 
 
No opiate use for EAP during the preceding 4-week period at each scheduled assessment 
 
Responder rate at scheduled visit other than Month 12 visit, for DYS and NMPP (VRS) 
 
Change from baseline to each scheduled assessment in the mean pelvic pain scores for 
DYS, NMPP and overall pelvic pain, during the previous 4-week period assessed on the 
NRS and VRS 
 
Change from baseline to each scheduled assessment in the number of days with 
moderate to severe pelvic pain during the previous 4-week period assessed on the VRS 
 
Change from baseline to each scheduled assessment in the mean worst pelvic pain score 
defined as the mean of the 5 highest daily pain scores reported during the previous 4-
week period assessed on the NRS 
 
Change from baseline to each scheduled assessment in the mean of daily dyspareunia 
scores reported during the previous 4-week period on the dyspareunia VRS  
 
Change from baseline to each scheduled assessment in the mean of daily dyschezia 
scores reported during the previous 4-week period assessed on the dyschezia NRS 
 
Change from baseline to each scheduled assessment in non-opioid, opioid and combined 
analgesic use for EAP during the previous 4-week period based on pill count in the 
eDiary 
 
Change from baseline to each scheduled assessment in opioid analgesic use for EAP as 
reported in the eDiary during the previous 4-week period based on morphine milligram 
equivalent (MME) 
 
Change from baseline to each scheduled assessment in the number of days of analgesic 
use (including any class) for EAP during the previous 4-week period as assessed in the 
eDiary 


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 
Change from baseline to each scheduled assessment in the number of days of opioid 
analgesic use for EAP during the previous 4-week period as assessed in the eDiary 
 
Change from baseline to each scheduled assessment in the number of pelvic pain-free 
days (assessed on the VRS) during the previous 4-week period  
 
Change from baseline to each scheduled assessment in ability to perform daily activities 
during the previous 4-week period, as assessed in the eDiary (daily function NRS) 
 
Change from baseline to each scheduled assessment in the number of days with no 
difficulty in doing daily activities due to EAP during the previous 4-week period as 
assessed in the eDiary (daily function NRS) 
 
Change from baseline to each scheduled assessment in the number of days when 
dyspareunia was a problem during the previous 4-week period (including days when 
sexual intercourse was avoided because of anticipation of pain) as assessed on the 
dyspareunia VRS 
 
Change from baseline to each scheduled assessment in the number of days when sexual 
intercourse was avoided because of anticipation of pain during the previous 4-week 
period as assessed on the dyspareunia VRS 
 
Change from baseline to each scheduled assessment in the number of days with uterine 
bleeding (including spotting) during the previous 4-week period measured by eDiary 
 
Change from baseline to each scheduled assessment in the number of days when school 
or work was missed due to EAP in the previous 4-week period as reported in the eDiary 
 
Change from baseline to each scheduled assessment in the number of days when the 
subject had to go to bed or lie down due to EAP in the previous 4-week period as 
reported in the eDiary 
 
Change from baseline to each scheduled assessment in the Pain, Control and 
powerlessness, Emotional well-being, Social support, Self-image dimensions and the 
Modular sexual relationship questionnaire of EHP-30 scores 
 
Change from baseline to each scheduled assessment in the Health-Related Productivity 
Questionnaire (HRPQ) scores 
 
Number of non-study endometriosis related health visits, number of days in hospital and 
type of procedures performed based on Health Resource Utilization Questionnaire 
(HRUQ) at each scheduled assessment 
 
Change from baseline to each scheduled assessment in the Physician/Subject Surgery 
Intention Question (PSIQ/SSIQ) 
 
Change from baseline to each scheduled assessment in the PROMIS Fatigue – Short 
Form 6a 
 
Change from baseline to each scheduled assessment in the EuroQoL 5-Dimension 5-
Level (EQ-5D-5L) questionnaire 


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 
Response at each scheduled assessment according to Patient Global Impression of 
Change (PGIC) (and Post-treatment Patient Global Impression of Change, PPGIC) 
 
Change from baseline to each scheduled assessment in the monthly PGIS (mPGIS) score 
Safety endpoints 
 
Change from baseline to each scheduled assessment in BMD measured by Dual-energy 
X-ray Absorptiometry (DXA) of lumbar spine (L1-L4), femoral neck, and total hip 
 
Incidence and severity of treatment emergent adverse events (TEAEs) 
 
Incidence and severity of hypoestrogenic TEAEs (hot flush) 
 
Time to the first post-treatment menses 
 
Changes in clinical laboratory assessments (hematology, biochemistry, coagulation 
parameters, hormones, lipids and urinalysis) from baseline to each scheduled assessment 
 
Any pathological changes from baseline in the endometrium as assessed by histology 
from endometrial biopsies 
 
Changes from baseline to each scheduled assessment in any other safety parameter 
including weight, vital signs, electrocardiogram (ECG), gynecological assessments and 
endometrial thickness 
Exploratory endpoints 
 
Change from baseline in bone turnover markers at each scheduled assessment 
 
PK and PD of linzagolix 
Study Design: This is a prospective, randomized, double-blind study. Subjects who have completed 
the 6-month Treatment Period in the main study (18-OBE2109-002 - Edelweiss 2) will be invited to 
enter the present extension study. Month 6 visit of the main study is a decision point for Subjects to 
either end treatment and enter a post-treatment follow up (part of the main study), or to opt for a 6-
month treatment extension. 
The extension study starts at the Month 6 visit of the main study. Subjects will be required to sign a 
specific informed consent form (ICF) for this extension study. Only subjects who have completed the 
full 6-month Treatment Period in the main study and meet the inclusion criteria will be eligible for 
entry in the extension study. 
All subjects will receive once daily either linzagolix 75 mg alone (with ABT placebo) or 200 mg 
combined with ABT for 6 months. Subjects who received placebo during the main study will be 
randomized to either linzagolix 75 mg alone (with ABT placebo) or linzagolix 200 mg with ABT. 
Subjects who received active treatment during the main study will continue with the same treatment. 
Linzagolix/placebo tablets will be provided in monthly treatment kits, packaged, labelled and 
administered in the same manner to protect the blinded nature of the trial. 


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ABT/placebo treatments will be supplied as 3-monthly kits, packaged, labelled and administered in 
the same manner to protect the blinded nature of the trial. 
After end of treatment in the extension study (6-month Treatment Period: from Month 6 to Month 12), 
subjects will enter a post-treatment Follow-Up Period of 6 months with no investigational medicinal 
product (IMP).  
The total duration of the present extension study will be 12 months. 
 
Study Population: All subjects who have completed the full 6-month Treatment Period in the main 
study and who meet the inclusion criteria will be invited to enter the extension study. 
It is estimated that up to 288 subjects will enter the extension study, assuming that 80% of the patients 
randomized in the main study will complete the study (namely 360 subjects) and that up to 80 % 
thereof will enter the extension study. 
The study will be conducted at the same investigational sites as in the main study. 
Eligibility Criteria:  
Inclusion Criteria 
To be eligible for inclusion into this extension study, the subjects must fulfil all of the following 
criteria: 
1. The subject must provide written informed consent specific to this study prior to starting the 
extension study treatment. 
2. The subject has completed the 6-month treatment in the main study. 
3. The subject is willing and able to continue to comply with the requirements of the study protocol 
for the duration of the extension study. 
4. The subject agrees to continue to use only the analgesic rescue medication permitted by the 
protocol during the Treatment and Follow-up Periods. 
5. If of childbearing potential, the subject agrees to continue to use one of the following birth 
control methods during the entire Treatment Period of the study and until 3 months after the 
end of treatment: 
a. Sexual abstinence, if this is the subject's habitual practice and/or the subject is routinely 
abstinent from heterosexual intercourse, 
b. Partner with a vasectomy with confirmed azoospermia, 
c. Double non-hormonal barrier contraception such as condom or diaphragm each 
combined with spermicide. 
 
 


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Exclusion Criteria 
To be eligible for inclusion in this extension study the subject must not meet any of the following 
criteria: 
1. The subject is pregnant or is planning a pregnancy within the duration of the study (including 
the Follow-up Period). 
2. The subject is likely to require treatment during the study with any of the medications listed 
below: 
a. GnRH antagonists 
b. GnRH agonist injections/3-month depot injections 
c. Danazol 
d. Oral contraceptives and other sex hormones 
e. Depot contraceptives 
f. Selective Progesterone Receptor Modulators (SPRMs), Selective Estrogen Receptor 
Modulators (SERMs) and aromatase inhibitors 
g. Long acting narcotics (i.e. requiring less than once daily dosing) 
h. Systemic glucocorticoid treatments for acute diseases (not depot) 
i. 
In situ copper intra-uterine device (IUD) 
j. 
In situ IUD with progestogen 
3. The subject is likely to use cannabinoids during the study. 
4.  The subject has any other clinically significant gynecologic condition identified during the main 
study on transvaginal ultrasound (TVUS), on endometrial biopsy or at the manual breast 
examination, which might interfere with the study efficacy and safety objectives. 
5.  The subject has met any of the main study discontinuation criteria including: 
a. Serum calcium level confirmed on a repeated fasting test above 2.9 mmol/L 
b. BMD decrease from baseline > 8% or a Z-score ≤ -2.5 at either femoral neck, hip or spine 
on the Month 6 DXA scan during the main study. 
c. QTcF > 500 ms or increase > 60 ms from the highest value prior to first dose during the 
main study. 
d. Any of the following elevation of hepatic enzymes: 
• ALT or AST >8xULN  
• ALT or AST >5xULN for more than 2 weeks  
• ALT or AST >3xULN and (TBL >2xULN or INR >1.5)  
• ALT or AST >3xULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%)  


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6. The subject has any condition that, in the opinion of the Investigator, constitutes a risk or a 
contraindication to the participation of the subject in this extension study, or that could interfere 
with the study objectives, conduct or assessments.  
Investigational Medicinal Product(s) (IMP): the term “Investigational Medicinal Product” (IMP) 
will refer to the ObsEva investigational drug linzagolix 75 mg tablets and 200 mg tablets, the ABT 
(E2 1 mg/NETA 0.5 mg) capsules or their matching placebos.  
Data Analysis and Statistics 
The primary objective of this extension study is to assess the maintenance of efficacy of linzagolix 
administered orally once daily for up to an additional 6 months (for up to 12 months of treatment in 
total) in the subset of subjects who are treated with linzagolix up to the time point of interest. As such, 
the focus will be on subjects who received active treatment in the main study. The assessment of 
subjects who switched from placebo in the main study to active treatment in the extension study will 
be conducted as a secondary objective. 
No formal hypothesis tests are planned for this extension study. Data will be summarized by timepoint 
for each treatment group. Subjects will be analyzed according to actual treatment received. The 
following four treatment groups will be analyzed: linzagolix 75 mg and linzagolix 200 mg with ABT 
fixed dose groups, linzagolix 75 mg and linzagolix 200 mg with ABT after 6 months of placebo 
treatment. Only subjects with assessments at both baseline and the given time points will be included 
in the summaries. Baseline values are the same as in the main study (18-OBE2109-002 - Edelweiss 2), 
i.e. data collected prior to the treatment administration in the main study. 
Efficacy analysis methodology 
Summaries will be performed using the Treatment Extension Analysis Set and the Follow-up 
Extension Analysis Set. Data from both the main study and the extension study will be summarized. 
Efficacy endpoints will be derived in the same way as in the main study. The same criterion for 
defining a subject as being a responder by having a clinically meaningful reduction in DYS and in 
NMPP, along with a stable or decreased use of analgesics for EAP, will be used as per the criteria in 
the main study. 
Safety analysis methodology 
Summaries will be performed using the Extension Safety Analysis Set and the Follow-up Extension 
Analysis Set.  
Data from both the main study and the extension study will be summarized. 
Pharmacokinetic analysis methodology 
Descriptive statistics of plasma concentrations will include mean (arithmetic and geometric) and 
standard deviation, median, 1st and 3rd quartiles, minimum, maximum, coefficient of variation (CV%) 
and number of observations. Concentrations below the limit of quantification (LOQ) will be assigned 
a value of zero. Explorative analyses of correlations between plasma concentrations and intrinsic PK 
factors such as e.g. body weight/body mass index (BMI), race, age may be performed, as appropriate, 
and will be reported separately. 


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PK analyses will be based on the Extension PK Set. 
Pharmacodynamic (and other) analysis methodology 
Pharmacodynamic parameters, such as for example estradiol and other hormones, will be summarized 
by time point for each treatment group, and listed for each subject by visit day and dose regimen. 
Where appropriate, changes from baseline will be presented. Potential PK-PD relationships may be 
investigated graphically and through statistical modeling, whilst also exploring possible covariates, 
and will be reported separately. 
Study Specific Data Analyses 
End-of-Treatment Period Analysis 
After all subjects have completed the Treatment Period, a complete analysis will be performed. This 
analysis will include all data up to the end of treatment visit. A database lock will be performed, with 
any discrepant data clarified before the lock. 
Post-Treatment Follow-up Period Analysis 
After all subjects have completed the Post-Treatment Follow-up Period, a final database lock will be 
performed followed by a second analysis. This analysis will include all data collected during the Post-
Treatment Follow-up Period. 


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5 BACKGROUND INFORMATION 
5.1 INTRODUCTION TO LINZAGOLIX 
Linzagolix is a new, orally active, non-peptide gonadotropin releasing hormone (GnRH) antagonist. It 
has been shown to significantly reduce endometriosis-associated pain (EAP) in women with surgically 
confirmed endometriosis at once daily doses between 50 and 200 mg with a good safety and tolerability 
profile. It is being developed for the long-term treatment of moderate to severe EAP. 
5.2 ENDOMETRIOSIS 
Endometriosis is a chronic disease with debilitating pelvic pain symptoms (such as dysmenorrhea, 
dyspareunia, non-menstrual pelvic pain, dyschezia) affecting quality of life and requiring long-term 
management.  
5.3 CONVENTIONAL TREATMENT OF ENDOMETRIOSIS 
First-line medical therapies for EAP such as combined oral contraceptives (COCs) and progestins, have 
limited long-term efficacy, and second-line therapies (eg, high-dose progestins, injectable depot 
formulations of GnRH receptor agonists) are effective but associated with troublesome side effects 
including progressive bone loss and severe vasomotor symptoms (1, 2). 
GnRH receptor antagonists are a new potential treatment option allowing dose-dependent reduction of 
estradiol (E2) levels alleviating EAP (3) whilst reducing the negative impact on bone mineral density 
(BMD).  
For long term use of GnRH-analogues, concurrent treatment with add-back (progestin and/or estrogen) 
hormone replacement therapy (ABT) has been shown to be effective in reducing associated BMD loss 
(4,5) and is generally recommended as part of long-term treatment with GnRH receptor agonists to 
minimize side effects.  
Linzagolix is a new, orally active, GnRH receptor antagonist. In Phase 1 and 2 studies, it was shown to 
dose-dependently suppress luteinizing hormone (LH) and E2 and to significantly reduce EAP in women 
with moderate to severe EAP, with a good safety and tolerability profile (see section 5.5.2 and 5.5.3).  
The purpose of the present study is to collect long-term (up to 12 months) data on the safety and efficacy 
of linzagolix in subjects with EAP. This is a 6-month active treatment extension study offered to all 
subjects who have completed 6-months of active or non-active treatment in study 18-OBE2109-002 
(Edelweiss 2). 
5.4 SUMMARY OF NON-CLINICAL STUDIES 
The data in the nonclinical package have shown linzagolix 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 


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but no overt toxicity. No genotoxicity or unexpected reproduction toxicology findings in rats and rabbits 
were seen.  
In conclusion, the nonclinical package supports clinical long-term dosing regimens up to 200 mg per 
day. 
5.5 SUMMARY OF CLINICAL STUDIES 
The efficacy, safety and pharmacokinetics (PK) of linzagolix were investigated by the originator 
company (Kissei Pharmaceutical Co., LTD. from Japan) in two Phase 1 studies (Study KLH1101 and 
KLH1103) in Japanese and/or Caucasian volunteers in single and multiple doses up to 400 mg, and in 
three Phase 2a studies (Studies KLH1201, KLH1202 and KLH1203) in Japanese endometriosis patients 
at doses up to 200 mg daily for up to 12 weeks. An additional Phase 2b study (KLH1204) has been 
performed in Japan. Its objective was to assess the efficacy and safety of daily doses of linzagolix 25 
mg, 50 mg, 75 mg and 100 mg for up to 24 weeks in Japanese subjects with EAP. Overall, 455 subjects 
were randomized. 
The PK and pharmacodynamics (PD) of linzagolix have been further investigated in eight Phase 1 
studies investigating the use of estrogen/progestin ABT, potential drug-drug interactions, 
bioequivalence of forumulations and the effect of linzagolix on the QT interval.  
The efficacy and safety of linzagolix have been investigated in US and European patients with moderate 
to severe EAP in a dose-ranging Phase 2b study at doses from 50 to 200 mg daily for up to 12 months 
(study 15-OBE2109-001, also known as Edelweiss).  
The efficacy and safety of linzagolix in moderate to severe EAP are also being investigated in two 
ongoing Phase 3 placebo-controlled studies: 18-OBE2109-002 (Edelweiss 2) and 18-OBE2109-003 
(Edelweiss 3). A total of 450 subjects per study are planned to be enrolled in the USA, Canada and 
Europe. Daily doses of 75 mg alone and 200 mg in combination with low dose ABT (E2 1 mg/ 
norethisterone acetate (NETA) 0.5 mg) are administered for up to 6 months. The study described herein 
is the extension of 18-OBE2109-002 (Edelweiss 2) study. The extension of 18-OBE2109-003 
(Edelweiss 3) study is described in a separate protocol. 
In addition to the endometriosis indication, two placebo-controlled Phase 3 studies (16-OBE2109-008 
and 16-OBE2109-009) assessing the efficacy and safety of linzagolix in subjects with heavy menstrual 
bleeding associated with uterine fibroids are on going. Approximately 500 subjects per study are planned 
to be enrolled in the USA and Europe. Daily doses of 100 and 200 mg of linzagolix are administered 
with or without ABT (E2 1mg/NETA 0.5mg) for up to 52 weeks.  
5.5.1 
Pharmacokinetics/Pharmacodynamics 
Linzagolix 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 linzagolix from 12.5 to 700 
mg and repeated once daily doses of 100 to 400 mg once daily for 7 days under fed and fasted conditions. 
Linzagolix was safe and well-tolerated, showed linear PK, 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 a dose-dependent suppression of E2, LH and follicle-stimulating hormone (FSH). 


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Study 17-OBE2109-001 evaluated the tolerability and PK of a single supra-therapeutic dose of 700 mg 
linzagolix, and effects of therapeutic and supratherapeutic doses of linzagolix on the QTc interval (QT 
interval corrected for heart rate). Subjects received a 200 mg dose of linzagolix (therapeutic target 
exposure), a 700 mg dose of linzagolix (supratherapeutic target exposure), a 400 mg dose of 
moxifloxacin (positive control), and placebo with an appropriate washout. Linzagolix at 700 mg was 
well tolerated. A borderline effect of linzagolix on the QTc interval was identified with prolongations 
exceeding the threshold of concern by less than 2 msec. The categorical data for QTc showed no values 
greater than 480 msec and no changes greater than 30 msec following administration of the 
supratherapeutic and therapeutic doses. Thus, based on the magnitude of the QTc prolongation, the 
observed effects are not considered to be clinically significant. 
The open-label study, KLH1103, assessed the absorption, metabolism, and excretion of linzagolix in 6 
women of non-childbearing potential. Linzagolix was the predominant component in plasma and all 
plasma metabolites were present at less than 10% of the total drug related exposure. Similarly, 
unchanged linzagolix was also a major component in urine and feces. Linzagolix was eliminated in urine 
(52%) and, to a lesser extent, in feces (38%). 
Study 16-OBE2109-011 assessed the PD and safety of linzagolix alone and combined with E2/ NETA 
ABT on E2 levels and vaginal bleeding. In this single-center, open-label, randomized, parallel-group 
study, 76 healthy premenopausal women were randomized to linzagolix (100 mg), linzagolix/ E2/ 
NETA (100 mg/0.5 mg/0.1 mg), linzagolix/ E2/ NETA (100 mg/1 mg/0.5 mg), linzagolix (200 mg) or 
linzagolix/E2/NETA (200 mg/1 mg/0.5 mg) once daily for 6 weeks. The study showed that ABT may 
be needed to prevent adverse bone impact in subjects treated at 200 mg. 
A single-center, open-label, randomized, parallel-group study (study 17-OBE2109-008) in 32 healthy 
pre-menopausal women was performed to assess whether co-administration of ABT following 4 weeks 
of high-dose linzagolix administration alone would result in improved bleeding patterns compared to 
combined linzagolix/ABT administration. Subjects were randomized to once daily linzagolix 
(200 mg)/ABT for 10 weeks or linzagolix (200 mg) for 4 weeks followed by once daily linzagolix 
(200 mg)/ABT for 6 weeks. Starting the administration of linzagolix and hormonal ABT together 
provided better bleeding control than delaying the ABT treatment start for 4 weeks. 
In a drug-drug interaction study with women of child bearing potential (Study 16-OBE2109-005), 
linzagolix did not induce CYP3A4 and there was no clinically significant food effect. In another drug-
drug interaction study (Study 17-OBE2109-006) the OATP1B1/1B3 inhibitor rifampicin (600 mg single 
dose) had no clinically relevant effects on the PK of linzagolix. Studies 18-OBE2109-006 and 18-
OBE2109-007 assessed the effect of linzagolix on the PK of CYP2C8 and OAT3 substrates. Linzagolix 
had no clinically relevant effects on the PK of OAT3 substrates and was shown to be a weak inhibitor 
of the CYP2C8 enzyme. 
A single-center, open-label, randomized, two-period cross-over study in 20 healthy pre-menopausal 
women (Study 17-OBE2109-004) aimed to demonstrate the bioequivalence of linzagolix formulation A 
(reference formulation), used in Phase 2b Edelweiss study 15-OBE2109-001, and formulation B (test 
formulation) planned to be used in the current Phase 3 extension study. After single oral administration 
of linzagolix, the test formulation was found to be bioequivalent to the reference formulation for Cmax 
and area under the curves (AUCs) of linzagolix and KP017 (metabolite). A single administration of 
linzagolix formulations A and B to healthy female participants was safe and well tolerated. 


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5.5.2 
Efficacy 
The clinical efficacy of linzagolix has been investigated in five Phase 2 studies. 
In a Phase 2 clinical study (Study KLH1201) conducted in Japan in patients with endometriosis, 50 or 
200 mg linzagolix was orally administered once daily for 8 weeks. Linzagolix improved endometriosis 
symptoms and continuously suppressed E2 in a dose-dependent manner. 
In a Phase 2 clinical study (Study KLH1202) conducted in Japan in patients with endometriosis, 50, 
100, or 200 mg linzagolix or placebo was orally administered once daily for 12 weeks. Linzagolix 
significantly reduced endometriosis pain symptoms compared with placebo. 
In a Phase 2 clinical study (Study KLH1203) conducted in Japan in patients with endometriosis, 75 or 
150 mg linzagolix was orally administered once daily for 8 weeks. Linzagolix improved endometriosis 
symptoms and continuously suppressed E2 in a dose-dependent manner. 
A Phase 2b study (KLH1204) conducted in Japan assessed the efficacy and safety of once daily doses 
of linzagolix 25 mg, 50 mg, 75 mg and 100 mg for up to 24 weeks in subjects with EAP. There was a 
dose-dependent improvement of EAP, with significant improvement compared to placebo at the 75 and 
100 mg doses. 
In a Phase 2b study (Study 15-OBE2109-001, also known as Edelweiss) conducted in US and Europe 
in patients with endometriosis, doses of 50, 75, 100, 200 mg linzagolix or placebo were administered 
orally, once daily for up to 52 weeks. Linzagolix significantly decreased EAP after 12 weeks at doses 
of 75, 100 and 200 mg and the effects were maintained or increased at Week 24. For those subjects 
continuing treatment up to Week 52, the obtained treatment effects were generally maintained until 
Week 52. Overall, the greatest improvements on all efficacy endpoints were reported at dose levels of 
75 mg and above during the main study (75 mg, 100 mg, 200 mg), as well as treatment extension (75 
mg, 100 mg).  
The 75 mg group demonstrated the ability for long-term treatment (52 weeks of continuous dosing with 
linzagolix) of a dose combining significant treatment benefit with a good safety profile and without the 
need for hormonal ABT; the 200/100 mg group is considered as a benchmark group to characterize 
efficacy and safety of a high-dose linzagolix regimen following 52 weeks of continuous dosing.   
5.5.3 
Safety 
More than 1,500 subjects were exposed to a range of doses (25, 50, 75, 100, 200, 400 mg) of linzagolix 
from 13 completed and two ongoing clinical studies. Ongoing studies include two Phase 3 studies for 
the indication of heavy menstrual bleeding associated with uterine fibroids. 
Repeated once daily dosing at up to 700 mg linzagolix was safe and well-tolerated by premenopausal 
healthy volunteers. In endometriosis patients, doses up to 200 mg once daily for up to 24 weeks of 
treatment were well tolerated. 
Hepatic impairment had no relevant effect on total plasma linzagolix exposure. In women with severe 
hepatic impairment (Child-Pugh C), 2- to 3-fold unbound mean exposures were recorded. In hepatic 
impaired subjects, a single dose of 200 mg was well tolerated. 
Renal impairment had no relevant effect on total plasma linzagolix exposure. In women with severe 
renal impairment (eGFR <30 mL/min/1.73 m2) or end-stage renal disease, approximately 2-fold 


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unbound mean exposures were recorded. In renal impaired subjects, a single dose of 200 mg was well 
tolerated. 
The expected side effects of linzagolix are disturbances of the menstrual cycle and hypoestrogenic 
adverse events (AEs) (e.g., metrorrhagia and hot flush). 
In multiple-dose studies, a dose-dependent occurrence of hot flush was observed (14.63%, 27.27%, 
27.8%, 30% and 40.7% at 50 mg, 75 mg, 100 mg, 150 mg and 200 mg linzagolix, respectively). In the 
Phase 2b Edelweiss trial (15-OBE2109-001), a moderate proportion of patients reported a dose-
dependent increase in hot flushes (at week 12, placebo: 10.9% reporting at least one hot flush; 75mg: 
18.4%; 200 mg: 42.1% - at week 24, 75 mg: 19.0%; 200 mg: 45.6%).  
Anticipated AEs are events that were not necessarily observed with linzagolix but can be anticipated 
based on the drug’s pharmacological action and/or class effects, such as: increase in liver function test 
(LFT) parameters, headache, dizziness, nausea, hyperhidrosis, blood cholesterol increased, low density 
lipoprotein increased and BMD loss. 
In few subjects, an increase in transaminase values exceeding 3>ULN (Upper Limit of Normal) was 
observed under treatment. Most often the increase in transaminase values was reversible and decreased 
spontaneously back to normal levels under treatment. Increases in transaminase values were not 
associated with increased bilirubin values. 
A borderline effect of linzagolix on the QTc interval was identified with prolongations exceeding the 
threshold of concern by less then 2 msec. The categorical data for QTc showed no values greater than 
480 msec and no changes greater than 30 msec following the supratherapeutic and therapeutic doses. 
Thus, based on the magnitude of the QTc prolongation, the observed effects are not considered to be 
clinically significant. 
The vast majority of related AEs were reported as being of “mild” or “moderate” intensity; very few 
related events were reported as being of “severe” intensity. 
In the Phase 2b Edelweiss trial (15-OBE2109-001), changes from baseline to week 24 in BMD were 
measured by dual-energy X-ray absorptiometry (DXA) scan, using central reading. Partial E2 
suppression achieved with linzagolix 75 mg was associated with a mean percent change from baseline 
in spine BMD (the site of greatest bone loss) of ‐0.8% (95% CI ‐1.57, ‐0.03) after 6 months of treatment, 
while achieving improvement in symptoms in the majority of patients. As expected, full E2 suppression 
with linzagolix 200 mg lowers BMD by more than 2.5% after 6 months of treatment, which indicates 
the need for hormonal ABT for use beyond 6 months. 
In the Phase 2b Edelweiss trial (15-OBE2109-001), following the main study, subjects willing to 
continue treatment were entered into an extension study for an additional 28 weeks of treatment, 
followed by 24 weeks of post-treatment follow-up. Subjects received either 50 mg, 75 mg, or 100 mg 
of linzagolix, once daily in accordance with the treatment received in Part B, except for those subjects 
who had been randomized to 200 mg dose, which was reduced during the extension phase to 100 mg 
daily. AEs were collected throughout the study. BMD of femoral neck, total hip, and lumbar spine were 
assessed by DXA at week 52.  
Of the 253 subjects who completed the 24 weeks of treatment in the main study, 176 subjects received 
treatment in the extension. A summary of the safety findings is below: 


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At Week 52, BMD loss was seen in the lumbar spine in all treatment groups, except for the 50 mg group. 
Mean BMD loss in the lumbar spine was below 1.5% in the 75 mg fixed dose (FD) and 100 mg groups, 
with mean percent decreases (and lower 95% CI) from baseline of -1.139% (-2.21%), and -1.399% (-
3.35%), respectively. The greatest reductions were observed in the 75 mg titrated dose (TD), 
placebo/100 mg, and 200/100 mg groups with mean percent decreases (and lower 95% CI) from baseline 
of -2.646% (-4.46%), -2.503% (-4.04%), and -2.188% (-3.59%), respectively. 
At Week 52, BMD loss was detected in the femoral neck in all treatment groups, except for the 75 mg 
FD group. Mean BMD loss was similar in the 50 mg,75 mg TD, and 100 mg groups, with mean percent 
decreases (and lower 95% CI) from baseline of -0.992% (- 1.84%), -0.843% (-2.58%), and -1.102% (-
3.10%), respectively. The greatest reduction was observed in the 200/100 mg group with a mean percent 
decrease (and lower 95% CI) from baseline of -2.592% (-4.49%). 
At Week 52, BMD loss was detected in the total hip in all treatment groups. Mean BMD loss in the total 
hip was below 1% in the placebo/100 mg, 50 mg,75 mg FD, and 100 mg groups, with mean percent 
decreases (and lower 95% CI) from baseline of -0.807% (- 1.82%), -0.411% (-1.22%), -0.297% (-
1.36%), and -0.597% (-1.61%), respectively. The greatest reductions were observed in the 200/100 mg 
and 75 mg TD groups with mean percent decreases (and lower 95% CI) from baseline of -2.025% (-
3.58%) and - 1.363% (-3.23%), respectively. 
For the lumbar spine, the site most sensitive to BMD loss, an increase in the proportion of subjects >3% 
BMD loss was reported in a dose-dependent manner across linzagolix groups at Week 52: 4.8%, 18.2%, 
23.1% and 50% for the 50 mg, 75 mg FD, 100 mg, and 200/100 mg groups.  
At Week 24, the greatest mean BMD loss was in the 200/100 mg group for the lumbar spine: -2.887% 
(-4.07%). At Week 52, after receiving 28 weeks of 100 mg linzagolix, there appeared to be no additional 
BMD loss: mean percent change from baseline of - 2.188% (-3.59%). This observation may be due to 
increased E2 levels observed after the dose was lowered from 200 mg to 100 mg at Week 24. Of note, 
a similar proportion of subjects had a decrease >3% in the 200/100 mg group at Week 24 (51.9%) and 
Week 52 (50.0%). 
Median Z scores, interquartile ranges and total ranges for femoral neck, total hip and lumbar spine at 
baseline, Week 24 and Week 52 did not change importantly over time: medians remained within the 
range of -0.20 to 0.30, 0 to 0.40, and -0.25 to 0.35 in all treatment groups for the femoral neck, total hip 
and lumbar spine, respectively. Median absolute change from baseline to Week 52 ranged from -0.10 to 
0.00, -0.10 to 0.00 and -0.20 to -0.10, respectively. 
Over the 52-week treatment period, 154/176 (87.5%) of subjects reported treatment emergent adverse 
events (TEAEs). The incidence of TEAEs was not dose-dependent across treatment groups, ranging 
from 81.8% in the 100 mg group to 93.3% in the 200/100 mg group. The majority of the TEAEs 
(616/846; 72.8%) were reported during the first 24 weeks of treatment. 
The most commonly reported TEAEs were headache (32.4%) and hot flush (28.4%). The majority of 
these events occurred during the first 24 weeks of treatment. Headaches were reported with a similar 
frequency across treatment groups, ranging from 22.2% in the 75 mg FD group to 44.8% in the 
placebo/100 mg group, with no apparent dose relationship. Conversely, the incidence of hot flushes was 
dose-dependent and increased with increasing exposure to linzagolix: 16.7% (50 mg), 20.7% (75 mg 
FD), 22.2% (75 mg TD), 24.1% (placebo/100 mg), 27.3% (100 mg), and 60.0% (200/100 mg). Of note, 
there was no worsening in the incidence of hot flushes during the treatment extension; only 2/61 hot 
flush events were reported. 


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Ten serious AEs (SAEs) were reported in nine subjects. None of the SAEs were considered as related 
to study treatment. The SAEs of ruptured ectopic pregnancy (50 mg), pelvic pain (50 mg), pneumonia 
(75 mg TD), and anxiety disorder (200/100 mg) led to subject withdrawal from treatment during the 
extension phase of the study. 
During treatment extension, 12 subjects (6.8%) reported 17 TEAEs leading to treatment withdrawal. In 
the 200/100 mg group, one subject discontinued treatment due to bone loss and one subject due to bone 
pain. In the 75 mg FD group, one subject discontinued treatment due to bone density decreased. 
There were no subjects with AST and/or ALT values >2×ULN during the treatment extension. 
Overall, there were no clinically meaningful changes from baseline in laboratory parameters, vital signs, 
physical examination, or lipid measurements including HDL cholesterol, LDL cholesterol, and 
triglycerides in any group. 
Gynecological examinations showed a small number of abnormal clinically significant results, but with 
a higher frequency noted for uterus and ovaries. At Week 24, reductions from baseline in endometrial 
thickness and uterus volume were more notable at the higher doses of linzagolix (100 mg and 200 mg) 
compared to the lower doses. This pattern was not observed at Week 52. Endometrial biopsy did not 
raise any safety concern. 
Overalll, the safety findings at the end of 52 weeks of treatment revealed no new safety issues.  Patterns 
of BMD loss were similar to the main study.  
5.6 RATIONALE FOR THE CURRENT STUDY 
Endometriosis is a chronic disease requiring long-term continuous treatment. The results of the Phase 
2b, Edelweiss study (study 15-OBE2109-001) supported the sustained efficacy and overall safety of 12-
month treatment with linzagolix in symptomatic endometriosis (see sections 5.5.2 and 5.5.3). 
In the present study, we will collect long-term (up to 12 months) data on the safety and efficacy of 
linzagolix in subjects with EAP who have completed 6 months of treatment in study 18-OBE2109-002 
(Edelweiss 2). 
5.7 SUMMARY OF OVERALL RISKS AND BENEFITS 
Linzagolix efficacy compared to placebo was demonstrated at daily doses of 75–200 mg for 3 months 
and maintenance of effect has been shown up to 6 months. 
Linzagolix was well-tolerated at these doses. The most commonly reported AEs in the Phase 2 studies 
were headache and hot flush which are related to the biological activity of linzagolix.  
Eleven pregnancies were in the Phase 2 studies. No fetal or newborn abnormalities were reported in any 
of the pregnancies. 
There were no clinically relevant findings in laboratory measurements, vital signs or electrocardiogram 
(ECG) recordings. The administration of linzagolix results in infrequent, transient, moderate and non- 
dose-related increases in transaminase levels which were not associated with changes in bilirubin levels. 
A borderline increase in QTc interval was observed in healthy volunteers which was not considered 
clinically significant. Nevertheless, all subjects in the current study will be monitored monthly with 
ECG. 


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A modest degree of BMD loss has been seen in linzagolix-treated subjects with doses below 100 mg 
QD. Clinically significant BMD loss was observed with a dose of 200 mg QD at 6 months of treatment 
and requires combined use of hormonal ABT to mitigate BMD loss. As linzagolix 200mg will be 
combined with ABT in this extension study, no major impact on BMD is expected. In addition, the 
BMD loss will be monitored during the study and subjects who experience more than 8% confirmed 
BMD loss or a Z-score ≤ -2.5 will be discontinued from treatment. Moreover, subjects will be provided 
with vitamin D and calcium supplements which they will be recommended to take. 
In addition, an independent Data Monitoring Committee (DMC) will oversee the safety of study 
subjects, including a regular review of transaminase levels, BMD values and ECG parameters. 
In conclusion, linzagolix has a favorable benefit/risk ratio and represents a potential therapy for treating 
EAP.  
The overall benefit/risk of this study was re-evaluated by ObsEva in light of the COVID-19 pandemic 
and evolving regulatory guidance. 
For subjects who could not attend their visits due to quarantine, travel restrictions, site closure or other 
unforeseen reasons, remote study visits and shipment of materials and study drugs from site to subject 
were setup, whenever feasible, based on local restrictions related to the pandemic. Sites scheduled 
telephone calls to subjects as replacement for on-site visits, to ensure continuity in patient’s safety 
monitoring, treatment and study data collection.  
6 OBJECTIVES 
6.1 EFFICACY OBJECTIVES 
6.1.1 
Primary 
The primary objective of this extension study is to assess the maintenance of efficacy of linzagolix 
administered orally once daily for up to an additional 6 months (for up to 12 months of treatment in 
total) in women who have already completed 6 months of linzagolix treatment at a dose of 75 mg alone 
or 200 mg in combination with ABT (E2 1 mg / NETA 0.5 mg) in the management of moderate to 
severe EAP in women with surgically confirmed endometriosis. The two co-primary efficacy endpoints 
will be clinically meaningful reduction over the last 28 days of randomized treatment up to the Month 
12 visit, along with a stable or decreased use of analgesics for EAP for 1) dysmenorrhea (DYS) and for 
2) non menstrual pelvic pain (NMPP). 
6.1.2 
Secondary 
Secondary objectives include evaluation of efficacy over the last 28 days of randomized treatment up to 
the Month 12 visit based on the following parameters: evaluation of pain associated with sexual 
intercourse (dyspareunia) and defecation (dyschezia), difficulty of doing daily activities, analgesic use, 
assessment of subject perception of severity, change in uterine bleeding, Quality of Life (QoL) 
questionnaires, pharmacoeconomic burden of endometriosis by assessing changes in patient 
productivity, assessment of endometriosis-related number of non-study health visits, number of days in 
hospital and type of medical procedures performed during the Treatment Period. 


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6.2 SAFETY OBJECTIVES 
Safety and tolerability objectives include assessment of BMD, endometrial health, cardiac safety 
including QT interval prolongation, standard laboratory safety parameters, gynecological assessments 
and AE frequency including specific hypoestrogenic AEs. 
6.3 EXPLORATORY OBJECTIVES 
Exploratory objectives include assessment of bone turnover markers and collection of PK and PD related 
data of linzagolix for a separate modelling exercise. 
7 ENDPOINTS 
7.1 EFFICACY ENDPOINTS 
7.1.1 
Primary 
The two co-primary, composite efficacy endpoints are clinically meaningful reduction from baseline to 
the last 28 days preceding the Month 12 visit (the 4-week period preceding Month 12 visit) along with 
a stable or decreased use of analgesics for EAP, in the mean daily assessment of 1) DYS and of 2) 
NMPP measured on a Verbal Rating Scale (VRS) using an electronic diary (eDiary).  
7.1.2 
Secondary 
The secondary endpoints include: 
 
Change from baseline to Month 12 in DYS (VRS) 
 
Change from baseline to Month 12 in NMPP (VRS) 
 
Change from baseline to Month 12 in dyschezia (Numeric Rating Scale - NRS) 
 
Change from baseline to Month 12 in overall pelvic pain (NRS) 
 
Change from baseline to Month 12 in the interference of pain with the ability to perform daily 
activities, measured using the pain dimension of the Endometriosis Health Profile-30 (EHP-30)  
 
Change from baseline to Month 12 in dyspareunia (VRS) 
 
No analgesics use for EAP during the preceding 4-week period at each scheduled assessment 
 
No opiate use for EAP during the preceding 4-week period at each scheduled assessment 
 
Responder rate at scheduled visit other than Month 12 visit, for DYS and NMPP (VRS) 
 
Change from baseline to each scheduled assessment in the mean pelvic pain scores for DYS, 
NMPP and overall pelvic pain, during the previous 4-week period assessed on the NRS and VRS 
 
Change from baseline to each scheduled assessment in the number of days with moderate to severe 
pelvic pain during the previous 4-week period assessed on the VRS 


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 
Change from baseline to each scheduled assessment in the mean worst pelvic pain score defined 
as the mean of the 5 highest daily pain scores reported during the previous 4-week period assessed 
on the NRS 
 
Change from baseline to each scheduled assessment in the mean of daily dyspareunia scores 
reported during the previous 4-week period on the dyspareunia VRS  
 
Change from baseline to each scheduled assessment in the mean of daily dyschezia scores reported 
during the previous 4-week period assessed on the dyschezia NRS 
 
Change from baseline to each scheduled assessment in non-opioid, opioid and combined analgesic 
use for EAP during the previous 4-week period based on pill count in the eDiary 
 
Change from baseline to each scheduled assessment in opioid analgesic use for EAP as reported 
in the eDiary during the previous 4-week period based on morphine milligram equivalent (MME) 
 
Change from baseline to each scheduled assessment in the number of days of analgesic use 
(including any class) for EAP during the previous 4-week period as assessed in the eDiary 
 
Change from baseline to each scheduled assessment in the number of days of opioid analgesic use 
for EAP during the previous 4-week period as assessed in the eDiary 
 
Change from baseline to each scheduled assessment in the number of pelvic pain-free days 
(assessed on the VRS) during the previous 4-week period  
 
Change from baseline to each scheduled assessment in ability to perform daily activities during 
the previous 4-week period, as assessed in the eDiary (daily function NRS) 
 
Change from baseline to each scheduled assessment in the number of days with no difficulty in 
doing daily activities due to EAP during the previous 4-week period as assessed in the eDiary 
(daily function NRS) 
 
Change from baseline to each scheduled assessment in the number of days when dyspareunia was 
a problem during the previous 4-week period (including days when sexual intercourse was avoided 
because of anticipation of pain) as assessed on the dyspareunia VRS 
 
Change from baseline to each scheduled assessment in the number of days when sexual intercourse 
was avoided because of anticipation of pain during the previous 4-week period as assessed on the 
dyspareunia VRS 
 
Change from baseline to each scheduled assessment in the number of days with uterine bleeding 
(including spotting) during the previous 4-week period measured by eDiary 
 
Change from baseline to each scheduled assessment in the number of days when school or work 
was missed due to EAP in the previous 4-week period as reported in the eDiary 
 
Change from baseline to each scheduled assessment in the number of days when the subject had 
to go to bed or lie down due to EAP in the previous 4-week period as reported in the eDiary 
 
Change from baseline to each scheduled assessment in the Pain, Control and powerlessness, 
Emotional well-being, Social support, Self-image dimensions and the Modular sexual relationship 
questionnaire of EHP-30 scores 


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 
Change from baseline to each scheduled assessment in the Health Related Productivity 
Questionnaire (HRPQ) scores 
 
Number of non-study endometriosis related health visits, number of days in hospital and type of 
procedures performed based on Health Resource Utilization Questionnaire (HRUQ) at each 
scheduled assessment 
 
Change from baseline to each scheduled assessment in the Physician/Subject Surgery Intention 
Question (PSIQ/SSIQ) 
 
Change from baseline to each scheduled assessment in the PROMIS Fatigue – Short Form 6a 
 
Change from baseline to each scheduled assessment in the EuroQoL 5-Dimension 5-Level (EQ-
5D-5L) questionnaire 
 
Response at each scheduled assessment according to Patient Global Impression of Change (PGIC) 
(and Post-treatment Patient Global Impression of Change, PPGIC) 
 
Change from baseline to each scheduled assessment in the monthly PGIS (mPGIS) score 
7.2 SAFETY ENDPOINTS 
 
Change from baseline to each scheduled assessment in BMD measured by DXA of lumbar spine 
(L1-L4), femoral neck, and total hip 
 
Incidence and severity of treatment emergent adverse events (TEAEs) 
 
Incidence and severity of hypoestrogenic TEAEs (hot flush) 
 
Time to the first post-treatment menses 
 
Changes in clinical laboratory assessments (hematology, biochemistry, coagulation parameters, 
hormones, lipids and urinalysis) from baseline to each scheduled assessment 
 
Any pathological changes from baseline in the endometrium as assessed by histology from 
endometrial biopsies 
 
Changes from baseline to each scheduled assessment in any other safety parameter including 
weight, vital signs, ECG, gynecological assessments and endometrial thickness 
7.3 EXPLORATORY ENDPOINTS 
 
Change from baseline in bone turnover markers at each scheduled assessment 
 
PK and PD of linzagolix 
8 STUDY DESIGN 
This is a prospective, randomized, double-blind study. 
Subjects who have completed the 6-month Treatment Period in 18-OBE2109-002 - Edelweiss 2 study 
(herein referred to as main study) will be invited to enter the present extension study. Month 6 visit of 


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the main study is a decision point for Subjects to either end treatment and enter a post-treatment follow 
up (part of the main study), or to opt for a 6-month treatment extension. 
The extension study starts at the Month 6 visit of the main study. Subjects will be required to sign a 
specific informed consent form (ICF) for this extension study. Only subjects who have completed the 
full 6-month Treatment Period in the main study and meet the inclusion criteria will be eligible for entry 
in the extension study.  
All subjects will receive once daily either linzagolix 75 mg alone (with ABT placebo) or 200 mg 
combined with ABT for 6 months. Subjects who received placebo during the main study will be 
randomized to either linzagolix 75 mg alone (with ABT placebo) or linzagolix 200 mg with ABT. 
Subjects who received active treatment during the main study will continue with the same treatment. 
After end of treatment in the extension study (6-month treatment period: from Month 6 to Month 12), 
subjects will enter a post-treatment Follow-Up Period of 6 months with no investigational medicinal 
product (IMP).  
The total duration of the present extension study will be 12 months. 
  
A schematic of the study design is shown in Figure 1. 
 
 
Figure 1 : Study design 
 


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All subjects will receive once daily either linzagolix 75 mg alone (with ABT placebo) or linzagolix 200 
mg combined with low dose ABT for 6 months. ABT is a combination of estradiol (E2) 1 mg and 
norethisterone acetate (NETA) 0.5 mg. 
Since linzagolix 75 mg and 200 mg tablets have a different appearance, a double-dummy design will be 
used in order to maintain the blinding of the study. 
Linzagolix/placebo tablets will be provided in monthly treatment kits, packaged, labelled and 
administered in the same manner to protect the blinded nature of the trial. 
ABT/placebo treatments will be supplied as 3-monthly kits, packaged, labelled and administered in the 
same manner to protect the blinded nature of the trial. 
Each treatment kit will be labelled with a unique kit number. Treatment kit numbers will be provided 
through IWRS.  
9 STUDY POPULATION 
9.1 SUBJECTS 
9.1.1 
Description of the target population 
All subjects who have completed the full 6-month Treatment Period in the main study and who meet 
the inclusion criteria will be offered to enter the extension study. 
9.1.2 
Number of subjects 
It is estimated that up to 288 subjects will enter the extension study, assuming that 80% of the patients 
randomized in the main study will complete the study (namely 360 subjects) and that up to 80 % thereof 
will enter the extension study. 
9.1.3 
Study region/location 
The study will be conducted at the same investigational sites as in the main study. 
9.2 ENTRY CRITERIA 
9.2.1 
Inclusion Criteria 
To be eligible for inclusion into this extension study, the subjects must fulfil all of the following 
criteria: 
1. The subject must provide a written informed consent specific to this study prior to starting the 
extension study treatment. 
2. The subject has completed the 6-month treatment in the main study. 


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3. The subject is willing and able to continue to comply with the requirements of the study 
protocol for the duration of the extension study. 
4. The subject agrees to continue to use only the analgesic rescue medication permitted by the 
protocol during the Treatment and Follow-up Periods. 
5. If of childbearing potential, the subject agrees to continue to use one of the following birth 
control methods during the entire Treatment Period of the study and until 3 months after the 
end of treatment: 
a. Sexual abstinence, if this is the subject's habitual practice and/or the subject is 
routinely abstinent from heterosexual intercourse, 
b. Partner with a vasectomy with confirmed azoospermia, 
c. Double non-hormonal barrier contraception such as condom or diaphragm each 
combined with spermicide. 
9.2.2 
Exclusion Criteria 
To be eligible for inclusion in this extension study the subject must not meet any of the following 
criteria: 
1. The subject is pregnant or is planning a pregnancy within the duration of the study (including 
the Follow-up Period). 
2. The subject is likely to require treatment during the study with any of the medications listed 
below: 
a. GnRH antagonists 
b. GnRH agonist injections/3-month depot injections 
c. Danazol 
d. Oral contraceptives and other sex hormones 
e. Depot contraceptives 
f. Selective Progesterone Receptor Modulators (SPRMs), Selective Estrogen Receptor 
Modulators (SERMs) and aromatase inhibitors 
g. Long acting narcotics (i.e. requiring less than once daily dosing) 
h. Systemic glucocorticoid treatments for acute diseases (not depot) 
i. 
In situ copper intra-uterine device (IUD) 
j. 
In situ IUD with progestogen 
3. The subject is likely to use cannabinoids during the study. 
4.  The subject has any other clinically significant gynecologic condition identified during the 
main study on transvaginal ultrasound (TVUS), on endometrial biopsy or at the manual breast 
examination, which might interfere with the study efficacy and safety objectives. 
5.  The subject has met any of the main study discontinuation criteria including: 


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a. Serum calcium level confirmed on a repeated test above 2.9 mmol/L 
b. BMD decrease from baseline > 8% or a Z-score ≤ -2.5 at either femoral neck, hip or spine 
on the Month 6 DXA scan during the main study. 
c. QTcF > 500 ms or increase > 60 ms from the highest value prior to first dose during the 
main study. 
d. Any of the following elevation of hepatic enzymes: 
 
ALT or AST >8xULN  
 
ALT or AST >5xULN for more than 2 weeks  
 
ALT or AST >3xULN and (TBL >2xULN or INR >1.5)  
 
ALT or AST >3xULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%) 
6. The subject has any condition that, in the opinion of the Investigator, constitutes a risk or a 
contraindication to the participation of the subject in this extension study or that could interfere 
with the study objectives, conduct or assessments.  
10 STUDY PROCEDURES AND ASSESSMENTS 
10.1 GENERAL INSTRUCTIONS 
The extension study starts at the Month 6 visit of 18-OBE2109-002 - Edelweiss2 study (herein referred 
to as the main study). At Month 5 visit of the main study, the subject will have been informed of the 
possibility to enter the extension study at Month 6 (if eligible) and will have been provided with a copy 
of the subject information sheet, specific to the extension study, to read prior to the Month 6 visit. 
After all Month 6 assessments have been made, if the subject is eligible, one original copy of the 
extension-specific ICF will be signed and personally dated by both the subject and the Investigator or 
legally acceptable designee. The original signed copy will be kept in the confidential investigator file 
and a copy will be given to the subject. Once the ICF is signed, the subject will be dispensed new 
treatment kits. She will take her daily dose of study medication at the study site from these newly 
dispensed kits. 
During the whole study, the subject will be identified using a Subject Identification Number (SIN) for 
all documentation and discussion. The subjects will be identified with the same SIN than in the main 
study. SINs will be made of 6 digits, as follows: 
 
1st, 2nd and 3rd digits: site identifier (100 to 999) 
 
4th, 5th and 6th digits: subject number (001 to 999) 
An electronic Case Report Form (eCRF) will be completed for all subjects who signed the ICF.  
Subjects who previously received placebo in the main study will be randomized in a 1:1 ratio to either 
linzagolix 75 mg alone (with ABT placebo) or linzagolix 200 mg with ABT. 


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Subjects who received active treatment in the main study will continue with the same treatment 
(linzagolix 75 mg alone with ABT placebo or linzagolix 200 mg with ABT). 
In order to maintain the blind, the site will not be required to perform any randomization activities. The 
kits will be automatically allocated to the corresponding patients in the IWRS upon confirmation of their 
eligibility. 
Treatment kits will be dispensed to the subjects as follows: 
- 
on Month 6 and Month 9 visits, subject will receive two kits, one for linzagolix/placebo 
(monthly kit) and one for the ABT/ABT placebo (3-monthly kit).  
- 
On Month 7, Month 8, Month 10 and Month 11 visits, subject will receive one kit only, for 
linzagolix/placebo.  
The treatment kit numbers for linzagolix/placebo and for ABT will refer to unique kits present at site 
and corresponding to the randomization allocation.  
10.2 OUTLINE OF STUDY PROCEDURES AND ASSESSMENTS 
The first visit for this extension study is combined with the Month 6 visit of the main study. Therefore, 
the Month 6 assessments from the main study will not have to be duplicated at the start of the extension 
study. The study visit schedule is depicted in Figure 2 and the schedule of assessments is detailed in 
Appendix A and Appendix B. 
 
 
Figure 2 : Schedule of Visits 
 
All visits should take place at the end of the defined period (i.e. Month 7 visit should be scheduled at 
the end of Month 7, Month 8 visit should be scheduled at the end of Month 8, etc.). One month is defined 
as 28 days/4 weeks. All visit dates are calculated from the date the patient started treatment in the main 
study (Day 1 visit of 18-OBE2109-002 Edelweiss 2):  
 
Month 7 (Day 197), Month 8 (Day 225), Month 9 (Day 253), Month 10 (Day 281), Month 11 
(Day 309) and Month 12 (Day 337) for the Treatment Period,  
 
Month 1 Extension FU (Day 365), Month 3 Extension FU (Day 421) and Month 6 Extension 
FU (Day 505) for the Follow-up Period. 


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A window of -3/+2 days is allowed for Month 7 visit, and of ± 3 days for each of the following visits 
during the Treatment Period. A window of ± 7 days/1 week is allowed for each visit scheduled during 
the Follow-Up Period. 
The timing of events is shown in the Schedule of Assessments (Appendix A and Appendix B). 
10.2.1 Treatment Period  
During the entire Treatment Period: 
 
the subject will use the same eDiary as during the main study. The eDiary should be completed 
daily, in the evening at approximately the same time, for use of provided/prescribed analgesics, 
uterine bleeding, pelvic pain, dyspareunia, dyschezia and daily function.  
 
the subject will take her daily dose of study medication at home except on the day of study visits 
where she will take her daily dose at site. There will be no IMP intake at the Month 12 visit. The 
last dose of study medication in this extension study will be the dose taken the day before Month 12 
visit. 
 
the subject will be asked to bring her eDiary and her IMP kits at each visit to the site.  
 
the subject will receive contraception counselling at each visit. 
 
the subject will be provided/prescribed a limited quantity (as per Investigator’s judgement) of 
standard doses of permitted analgesics as rescue medication for EAP for the duration of the study. 
 
the subject will receive calcium 500 to 1000 mg and vitamin D 400 IU supplementation which she 
will be advised to take daily (at least 4 hours from the intake of the study drug) until the end of the 
study. Intake should be recorded at each study visit in eCRF. 
 
AEs and concomitant medications will be recorded in the eCRF (excluding any provided/prescribed 
analgesics used for EAP will be recorded daily in the eDiary only). 
10.2.1.1 
Study visit: Month 6 (Day 169 ± 3 days) 
After all Month 6 assessments pertaining to the main study have been made and the subject has been 
confirmed to be eligible to proceed in the extension study (see section 9.2), the subject will be requested 
to sign the extension-specific ICF that she was given at the Month 5 visit. 
Note: inclusion in the extension study will not be postponed if the results of any Month 6 assessment 
are not available on the day of Month 6 visit. Subjects will be required to stop the treatment if the results 
obtained after enrollment meet the discontinuation criteria defined in Section 10.7.2.1. 
After signature of the extension-specific ICF, the subject will be dispensed new treatment kits. The 
subject will take her daily dose of study medication at the study site from these newly dispensed kits.  
The exact time of dosing (hour/minute) will be recorded in eCRF. 
In addition, the subject will: 
 
receive contraception counselling and will be given double barrier contraception (condoms with 
spermicide), if requested, to be used until 3 months after treatment end. If the subject is at risk for 


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acquiring HIV, she must be reminded to use double non-hormonal barrier contraception without 
spermicides (eg: condoms and diaphragms). 
 
be provided/prescribed a limited quantity (as per Investigator’s judgement) of standard doses of 
permitted analgesics as rescue medication for EAP for the duration of the study. 
 
receive calcium 500 to 1000 mg and vitamin D 400 IU supplementation 
Upon completion of the visit, the subject will be provided with emergency contact phone numbers and 
will be scheduled for her next visits.  
10.2.1.2 
Study visits: Month 7 (Day 197 -3/+2 days) and Month 8 (Day 225 ± 3 days) 
The following tests and evaluations will be performed : 
- 
eDiary completion compliance check  
- 
ePRO and ClinRO completion, ideally before any other procedures or assessments:  
 
at Month 7 visit: EHP-30, EQ-5D-5L, PROMIS, mPGIS, PGIC, HRUQ, HRPQ with 
mPGIS and PGIC completed last 
 
at Month 8 visit: mPGIS, PGIC, HRUQ and HRPQ with mPGIS and PGIC completed last. 
- 
Concomitant treatments recording 
- 
AE recording 
- 
Completion of the paper C-SSRS questionnaire (version for “already enrolled subjects” (see 
Appendix R) for patients responding to the C-SSRS for the first time during the study, or 
version “since last study visit” (see Appendix S) for patients for whom the C-SSRS was 
completed at the previous study visit) 
- 
IMP accountability based on blisters 
- 
ECG (at about the same time as but before the PK sample) 
- 
Vital signs (blood pressure (BP) and heart rate) 
- 
Urine pregnancy test 
- 
Urinary protein dipstick 
- 
Blood samples for haematology, coagulation parameters, chemistry, hormones (E2, LH and 
progesterone (P4))  
- 
Pre-dose PK sample (the time of study medication administration on previous 4 days and time 
of PK sampling will be recorded) 
- 
Contraception dispensing (if applicable) and counselling 
- 
Prescribe/dispense permitted analgesics as rescue medication 
- 
Dispense calcium and vitamin D supplementation 


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- 
Dispensing via IWRS of one new kit of linzagolix 
The subject will take her daily dose of study medication at the study site from the newly dispensed 
linzagolix/placebo kit, and from the ABT/placebo kit dispensed at the Month 6 visit. 
10.2.1.3 
Study visit: Month 9 (Day 253 ± 3 days) 
The following tests and evaluations will be performed: 
- 
eDiary completion compliance check 
- 
ePRO and ClinRO completion, ideally before any other procedures or assessments: EHP-30, 
EQ-5D-5L, PROMIS, mPGIS, PGIC, HRUQ, HRPQ (mPGIS and PGIC must be completed 
last) 
- 
Concomitant treatments recording 
- 
AE recording 
- 
Completion of the paper C-SSRS questionnaire (version for “already enrolled subjects” (see 
Appendix R) for patients responding to the C-SSRS for the first time during the study, or version 
“since last study visit” (see Appendix S) for patients for whom the C-SSRS was completed at 
the previous study visit) 
- 
IMP accountability based on blisters 
- 
ECG (at about the same time as but before the PK sample) 
- 
Physical examination, including weight recording 
- 
Vital signs (BP and heart rate) 
- 
Urine pregnancy test 
- 
Gynecological examination 
- 
TVUS of the uterus 
- 
Urinary protein dipstick 
- 
Fasting (overnight) blood samples for haematology, coagulation parameters, chemistry, lipids, 
hormones (E2, LH, P4 and sex hormone-binding globulin (SHBG)) and bone biomarkers 
- 
Pre-dose PK sample (the time of dose administration on previous 4 days and time of PK 
sampling will be recorded) 
- 
BMD assessed by DXA for femoral neck, hip and spine for subjects who met the following 
criterion at any site on the Month 6 DXA scan: -2.5 < Z-score ≤ -1.5 
- 
Contraception dispensing (if applicable) and counselling 
- 
Prescribe/dispense permitted analgesics as rescue medication 
- 
Dispense calcium and vitamin D supplementation 


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- 
Dispensing via IWRS of one new kit of linzagolix/placebo and one new kit of ABT/placebo 
The subject will take her daily dose of study medication at the study site from the newly dispensed kits. 
10.2.1.4 
Study visits: Month 10 (Day 281 ± 3 days) and Month 11 (Day 309 ± 3 days) 
The following tests and evaluations will be performed : 
- 
eDiary completion compliance check  
- 
ePRO and ClinRO completion, ideally before any other procedures or assessments:  mPGIS, 
PGIC, HRUQ, HRPQ with mPGIS and PGIC completed last 
- 
Concomitant treatments recording 
- 
AE recording 
- 
Completion of the paper C-SSRS questionnaire (version for “already enrolled subjects” (see 
Appendix R) for patients responding to the C-SSRS for the first time during the study, or version 
“since last study visit” (see Appendix S) for patients for whom the C-SSRS was completed at 
the previous study visit) 
- 
IMP accountability based on blisters 
- 
ECG (at about the same time as but before the PK sample) 
- 
Vital signs (BP and heart rate) 
- 
Urine pregnancy test 
- 
Urinary protein dipstick 
- 
Blood samples (fasting not required) for haematology, coagulation parameters, chemistry, 
hormones (E2, LH and P4) 
- 
Pre-dose PK sample (the time of study medication administration on previous 4 days and time 
of PK sampling will be recorded) 
- 
Contraception dispensing (if applicable) and counselling 
- 
Prescribe/dispense permitted analgesics as rescue medication 
- 
Dispense calcium and vitamin D supplementation 
- 
Dispensing via IWRS of one new kit of linzagolix/placebo 
The subject will take her daily dose of study medication at the study site from the newly dispensed 
linzagolix/placebo kit, and from the ABT/placebo kit dispensed at the Month 9 visit. 
10.2.1.5 
Study visit: Month 12 (Day 337 ± 3 days) 
The following tests and evaluations will be performed : 
- 
eDiary completion compliance check  


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- 
ePRO and ClinRO completion, ideally before any other procedures or assessments: EHP-30, 
EQ-5D-5L, PROMIS, mPGIS, PGIC, HRUQ, HRPQ, SSIQ andd PSIQ (mPGIS and PGIC must 
be completed last) 
- 
Concomitant treatments recording 
- 
AE recording 
- 
Completion of the paper C-SSRS questionnaire (version for “already enrolled subjects” (see 
Appendix R) for patients responding to the C-SSRS for the first time during the study, or version 
“since last study visit” (see Appendix S) for patients for whom the C-SSRS was completed at 
the previous study visit) 
- 
Final IMP accountability based on blisters 
- 
ECG (at about the same time as but before the PK sample) 
- 
Physical examination, including weight recording 
- 
Vital signs (BP and heart rate) 
- 
Urine pregnancy test  
- 
Gynecological examination 
- 
Manual breast examination (by palpation) 
- 
TVUS of uterus  
- 
Urinary protein dipstick 
- 
Fasting (overnight) blood samples for haematology, coagulation parameters, chemistry, lipids, 
hormones (E2, LH, P4 and SHBG) and bone biomarkers 
- 
PK sample (the time of dose administration on previous 4 days and time of PK sampling will 
be recorded) 
- 
Endometrial biopsy, unless the endometrium thickness in TVUS is ≤ 5 mm, in which case no 
endometrial biopsy will be necessary (see section 10.4.5). Appropriate photo documentation of 
the endometrium thickness is mandatory.  
- 
BMD assessed by DXA for femoral neck, hip and spine. DXA can be performed up to 10 days 
prior to the study visit which allows to get the DXA results ideally at the time of the Month 12 
study visit at the latest. 
- 
The subject will be verbally asked which treatment she believed she received during the 
Treatment Period in the extension study. The answer will be recorded in the eCRF. 
- 
Contraception dispensing (if applicable) and counselling 
- 
Prescribe/dispense permitted analgesics as rescue medication 
- 
Dispense calcium and vitamin D supplementation 


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An additional question will be asked to the subject about the burden of filling in the eDiary (0 = not at 
all a burden, 10 = very much a burden). The answer will be recorded in the eCRF. 
The Month 12 study visit constitutes the end of the Treatment Period pertaining to this extension study. 
The subject will continue in the post-treatment 6-month Follow-Up (FU) Period. 
10.2.2 Post-treatment Follow-Up Period  
Up to Month 6 Extension FU visit, the subject will continue to record on her eDiary, daily at 
approximately the same time each evening, her use of provided/prescribed analgesics, uterine bleeding, 
pelvic pain, dyspareunia, dyschezia and daily function.  
The subject will be asked to bring her eDiary at each visit to the site during the entire Follow-Up Period. 
10.2.2.1 
Study visit: Month 1 Extension FU (Month 1 ExFU)  
Month 1 ExFU visit should be scheduled on Day 365 ± 7 days after main study Day 1 (or 28 days ± 7 
days after last IMP intake for early discontinued subjects). 
The following tests and evaluations will be performed at Month 1 ExFU visit: 
- 
eDiary completion compliance check  
- 
ePRO completion, ideally before any other procedures or assessments: mPGIS and PPGIC 
(must be completed last) 
- 
Concomitant treatments recording 
- 
AE recording 
- 
Completion of the paper C-SSRS questionnaire (version for “already enrolled subjects” (see 
Appendix R) for patients responding to the C-SSRS for the first time during the study, or version 
“since last study visit” (see Appendix S) for patients for whom the C-SSRS was completed at 
the previous study visit) 
- 
ECG 
- 
Vital signs (BP and heart rate) 
- 
Urine pregnancy test and contraception dispensing and counselling 
- 
Urinary protein dipstick 
- 
Blood samples for haematology, coagulation parameters, chemistry, hormones (E2, LH and P4) 
- 
Endometrial biopsy only if diagnosis at Month 12 was different than “benign endometrium” or 
if no endometrial biopsy was done at Month 12 (see section 10.4.5).  
- 
Prescribe/dispense permitted analgesics as rescue medication 
- 
Dispense calcium and vitamin D supplementation 


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10.2.2.2 
Study visit: Month 3 Extension FU (Month 3 ExFU) 
Month 3 ExFU visit should be scheduled on Day 421 ± 7 days after Day 1 (or 84 days ± 7 days after 
last IMP intake for early discontinued subjects). 
The following tests and evaluations will be performed at Month 3 ExFU Visit: 
- 
eDiary completion compliance check 
- 
ePRO and ClinRO completion, ideally before any other procedures or assessments: EHP-30, 
EQ-5D-5L, PROMIS, mPGIS, PPGIC, HRUQ, HRPQ (mPGIS and PPGIC must be completed 
last) 
- 
Concomitant treatments recording 
- 
AE recording 
- 
Completion of the paper C-SSRS questionnaire (version for “already enrolled subjects” (see 
Appendix R) for patients responding to the C-SSRS for the first time during the study, or version 
“since last study visit” (see Appendix S) for patients for whom the C-SSRS was completed at 
the previous study visit) 
- 
ECG 
- 
Physical examination, including weight recording 
- 
Vital signs (BP and heart rate) 
- 
Urine pregnancy test and contraception counselling 
- 
Gynecological examination 
- 
Manual breast examination (by palpation) 
- 
TVUS of uterus 
- 
Urinary protein dipstick 
- 
Fasting (overnight) blood samples for haematology, coagulation parameters, chemistry, lipids, 
hormones (E2, LH and P4) and bone markers. For subjects who do not resume menses by the 
Month 3 ExFU visit, an FSH test should be performed at a local laboratory and the subject 
should be advised to consult for gynaecological evaluation. 
- 
Endometrial biopsy only if diagnosis at preceding biopsy was different than “benign 
endometrium” or if no endometrial biopsy was done at Month 12 nor at any visit after Month 
12 (see section 10.4.5).  
- 
Prescribe/dispense permitted analgesics as rescue medication 
- 
Dispense calcium and vitamin D supplementation 


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10.2.2.3 
Study visit: Month 6 Extension FU (Month 6 ExFU) – End of Follow-up visit 
Month 6 ExFU visit should be scheduled on Day 505 ± 7 days after Day 1 (or 168 days ± 7 days after 
last IMP intake for early discontinued subjects). 
The following evaluations and tests will be performed at Month 6 ExFU Visit: 
- 
eDiary completion compliance check 
- 
ePRO and ClinRO completion, ideally before any other procedures or assessments: EHP-30, 
EQ-5D-5L, PROMIS, mPGIS, PPGIC, HRUQ, HRPQ (mPGIS and PPGIC must be completed 
last) 
- 
Collection and deactivation of eDiary 
- 
Concomitant treatments recording 
- 
AE recording 
- 
Completion of the paper C-SSRS questionnaire version “since last study visit” (see Appendix 
S) for patients for whom the C-SSRS was completed at the previous study visit. 
- 
ECG 
- 
Physical examination, including weight recording 
- 
Vital signs (BP and heart rate) 
- 
Urine pregnancy test 
- 
TVUS of uterus 
- 
Endometrial biopsy if no endometrial biopsy was obtained at Month 12 nor at any visit since 
Month 12 (see section 10.4.5). If inadequate/no tissue is available for pathology evaluation, the 
biopsy should be repeated as soon as possible in the following days. 
- 
BMD assessed by DXA for femoral neck, hip and spine. This DXA can be performed ± 10 days 
from the Month 6 ExFU study visit. 
This visit constitutes the end of study participation except for subjects with a BMD decrease > 1.5% 
from the main study baseline for lumbar spine and/or > 2.5% for total hip. These subjects should have 
a repeat DXA scan 6 months later for BMD follow-up assessment.  
10.2.2.4 
Study visit: BMD Follow-up visit 
BMD Follow-up visit should be scheduled on Day 674 ± 10 days after main study Day 1 (or 168 days 
± 10 days after Month 6 ExFU visit). 
This visit is applicable only to subjects with a BMD decrease of > 1.5% from the main study baseline 
for lumbar spine and/or > 2.5% for total hip at the Month 6 ExFU visit. 
BMD of the femoral neck, hip and spine will be assessed by DXA.  


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Subjects who have ≥ 3% BMD decrease from their main study baseline at any site (femoral neck, hip or 
spine) at this visit should be referred to a bone specialist for evaluation. 
10.3 EFFICACY OBSERVATIONS AND MEASUREMENTS 
All the questionnaires described below will be completed in the eDiary by the subject and/or the site 
staff. If the subject forgets to bring her eDiary to one site visit, the completion of ePRO and ClinRO will 
be done on a site back-up device. 
10.3.1 Daily eDiary 
The subject will use the same eDiary as in the main study. If needed, she will be re-trained at Month 6 
visit by the Investigator or delegate on how to use and complete it correctly.  
The eDiary should be completed daily, in the evening at approximately the same time, during the entire 
extension study (including the Treatment and Follow-Up Periods). A daily alarm will be set up in the 
eDiary to remind the patient to complete her daily questions. In addition, appropriate email alerts will 
be sent to the site staff and to the operational team in case of missed diary entries. eDiary compliance 
will be checked remotely on an ongoing basis by a dedicated data management team and by the CRO 
and the Sponsor’s clinical operations teams. 
10.3.1.1 
Pelvic pain 
The subject’s assessment of pelvic pain will be collected daily via the eDiary using an NRS and a VRS. 
NRS: The subject will be asked to rate her worst endometriosis-associated 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-associated 
pelvic pain in the last 24 hours: 
0  
No pain. 
1  
Mild pain but I was easily able to do the things I usually do. 
2  
Moderate pain. I had some difficulty doing the things I usually do.  
3  
Severe pain. I had great difficulty doing the things I usually do.  
10.3.1.2 
Daily function (difficulty of doing daily activities) 
The subject will complete a daily questionnaire in the eDiary if she had any difficulty doing her daily 
activities in the last 24 hours on a 0–10 scale (NRS) with 0 representing no difficulty doing daily 
activities and 10 representing inability to do daily activities. 


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10.3.1.3 
Uterine bleeding 
The subject will complete a daily questionnaire in the eDiary assessing strength of uterine/vaginal 
bleeding in the last 24 hours. The strength of uterine bleeding will be assessed using the following scale: 
Please choose the category that best describes your vaginal bleeding or spotting in the last 24 hours 
None 
No bleeding nor spotting 
Spotting 
Blood loss not requiring sanitary protection (except for panty liners) 
Bleeding 
Blood loss requiring sanitary protection (tampons or pads) 
Heavy 
Bleeding 
Heavy blood loss requiring sanitary protection (tampons or pads) for example: 
• 
Need for double protection to manage menstrual bleeding 
• 
Menstrual bleeding accompanied by sensation of “gushing” or “flooding” 
• 
Soaking one pad and/or tampon or more per hour for three or more 
consecutive hours 
• 
Needing to change the tampon or pad at night or soiling bedclothes 
10.3.1.4 
Analgesic use 
The subject will report daily in the eDiary whether she has taken any provided/prescribed analgesic 
(including the dose) for her EAP during the last 24-hour period.  
Analgesic use for any other reason will be reported by the subject to the site staff and recorded in the 
eCRF. 
10.3.1.5 
Dyspareunia (pain associated with sexual intercourse) 
The subject will be asked daily about dyspareunia via the eDiary using a VRS. 
She will be asked to rate how her EAP interfered with sexual intercourse in the last 24 hours, with the 
following response options: 
 
 
 
 
 
 
0 
No pain during sexual intercourse. 
1 
I was able to tolerate the pain during sexual intercourse. 
2 
Intercourse was interrupted due to pain.  
3 
I avoided sexual intercourse because of anticipation of pain. 


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She will also be given the option to answer that she was not sexually active for reasons other than her 
endometriosis, in which case no score would be allocated. 
10.3.1.6 
Dyschezia (pain associated with defecation) 
Dyschezia will be assessed daily 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. 
10.3.1.7 
School or work missed 
The subject will be asked whether she missed school or work in the last 24 hours due to EAP. 
10.3.1.8 
Event cancelled 
The subject will be asked if she had to cancel an event in the last 24 hours due to EAP. 
Following a request from the FDA, this question was removed in protocol version 2.0 to reduce 
respondent burden and maximize the quality and completeness of clinical outcome assessment data. 
This question has been asked only to subjects who were enrolled prior to implementation of protocol 
version 2.0. 
10.3.1.9 
Sleeping or lying down during the day 
The subject will be asked whether she slept or laid down during the day in the last 24 hours due to EAP.  
10.3.1.10  Difficulty sleeping 
The subject will be asked whether she had difficulty sleeping in the last 24 hours due to EAP. 
Following a request from the FDA, this question was removed in protocol version 2.0 to reduce 
respondent burden and maximize the quality and completeness of clinical outcome assessment data. 
This question has been asked only to subjects who were enrolled prior to implementation of protocol 
version 2.0. 
10.3.1.11  Patient Global Impression of Severity – daily recall (dPGIS) 
The subject will record on a daily basis in the eDiary the severity of her endometriosis symptoms 
assessed on a 5-point scale with the following possible answers: no symptoms, very mild, mild, 
moderate, severe (see Appendix I). 
Following a request from the FDA, this assessment was removed in protocol version 2.0 to reduce 
respondent burden and maximize the quality and completeness of clinical outcome assessment data. 
This assessment has been collected only for subjects who were enrolled prior to implementation of 
protocol version 2.0. 


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10.3.2 Outcome rating scales assessed at site visits 
ePROs are self-administered questionnaires completed by the subject. ePROs completed by the subject 
during the site visits include: EHP-30, HRPQ, SSIQ, PROMIS, EQ-5D-5L, mPGIS and PGIC/PPGIC. 
ClinROs are questionnaires administered by the site staff to the subject during the site visits and 
completed by the site staff in the eDiary. ClinROs include HRUQ and PSIQ. 
During site visits, ePRO and ClinRO should be completed ideally prior to any other study procedures, 
with the mPGIS and PGIC/PPGIC being completed last (in this order). Assessments will be performed 
according to the schedule indicated in Appendix A and Appendix B.  
If needed, site personnel will be re-trained on all rating scales (ePROs, ClinROs and scales of daily 
diary) used in this study.  
10.3.2.1 
Endometriosis Health Profile-30 (EHP-30) 
The EHP-30 is a disease-specific self-administered questionnaire used to measure health related quality 
of life in women with endometriosis. The EHP-30 is composed of two parts: a core questionnaire 
containing five scales that are applicable to all women with endometriosis and a modular part containing 
six scales which do not necessarily apply to all women with endometriosis. This study will employ the 
Core EHP-30 and modular section C (Part 2) as outlined in Appendix C. 
10.3.2.2 
PROMIS Fatigue Short Form 6a14 
This questionnaire is composed of six questions to evaluate the severity of fatigue (see Appendix D). 
10.3.2.3 
Health Related Productivity Questionnaire (HRPQ) 
The HRPQ consists of nine questions measuring the impact of EAP and its treatment on work 
productivity and daily activities at home (see Appendix E). 
10.3.2.4 
Health Resource Utilization Questionnaire (HRUQ) 
The HRUQ records use of health resources (emergency room, physician visit, hospitalization, etc.) 
during the study. This includes the number of non-study health visits – the total, the reason, primary 
reason, and type of clinician for the visit; Diagnostic/therapeutic procedures performed (Hysteroscopy, 
SIS, Colposcopy, Biopsy, Ultrasound or Other) and Emergency Room/Outpatient Procedures (see 
Appendix F). 
10.3.2.5 
Patient Global Impression of Change (PGIC) 
The PGIC is used by the subject to evaluate the change in her endometriosis symptoms since initiation 
of study drug on a 7-point scale with following possible answers: very much improved, much improved, 
minimally improved, no change, minimally worse, much worse, very much worse (see Appendix G). 


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10.3.2.6 
Post-treatment Patient Global Impression of Change (PPGIC) 
Subjects will evaluate the change in their endometriosis symptoms after discontinuation of study drug 
on a 7-point scale with the following possible answers: very much improved, much improved, minimally 
improved, no change, minimally worse, much worse, very much worse (see Appendix H).  
10.3.2.7 
Patient Global Impression of Severity - monthly recall (mPGIS) 
At each study visit and up to the end of the Follow-Up Period, the subject will be asked to evaluate the 
severity of her endometriosis symptoms over the past 28 days using a 5-point scale with the following 
possible answers: no symptoms, very mild, mild, moderate, severe (see Appendix I). 
10.3.2.8 
Subject Surgery Intention Question (SSIQ) 
The SSIQ evaluates subject willingness to opt for endometriosis-related surgery if current symptoms 
continue (see Appendix J). 
10.3.2.9 
Physician Surgery Intention Question (PSIQ) 
The PSIQ evaluates physician likelihood of recommending endometriosis-related surgery(s) to the 
subject if current symptoms continue (see Appendix K). 
10.3.2.10 EQ-5D-5L 
Subjects’ health related quality of life will be measured using the EQ-5D-5L (see Appendix L). The EQ-
5D-5L essentially consists of two pages: the EQ-5D descriptive system and the EQ visual analogue scale 
(EQ VAS). 
The descriptive system comprises five dimensions: mobility, self-care, usual activities, pain/discomfort 
and anxiety/depression. Each dimension has five levels: no problems, slight problems, moderate 
problems, severe problems and extreme problems.  
The EQ VAS records the subject’s self-rated health on a vertical VAS, where the endpoints are labelled 
‘The best health you can imagine’ and ‘The worst health you can imagine’.  
10.4 SAFETY OBSERVATIONS AND MEASUREMENTS 
10.4.1 Adverse Events 
AE data will be collected continuously during the study as described in Section 12.2. 
AE data will be obtained at scheduled study visits based on physical examination, vital signs, ECG and 
biological laboratory assessments (see flowchart in Appendix A and Appendix B). 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 will be 
reported on an ongoing basis in the AE pages of the eCRF. 


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10.4.2 Physical Examination 
A complete physical examination, i.e. 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 every three 
months (i.e. at Month 9, Month 12, Month 3 ExFU and Month 6 ExFU visits). 
In addition, a manual breast examination (by palpation) will be performed at Month 12 and at Month 3 
ExFU visits. Results of the examinations will be recorded on source data files and in the eCRF. Baseline 
medical conditions (see section 12.1.3) that worsen in severity and/or frequency during the study and 
that are considered as clinically significant by the Investigator will be reported as AEs in the 
corresponding eCRF page. 
The physical examination should be performed after the ECG. 
10.4.3 Vital signs 
BP and heart rate will be measured in sitting position. 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, which was 
not pre-existing or worsened in severity and/or frequency during the study and is considered as clinically 
significant by the Investigator, an AE must systematically be reported by the Investigator in the eCRF 
AE page. The Investigator is to provide a diagnosis rather than reporting individual vital signs 
parameters whenever possible. 
BP and heart rate should be measured after performing the 12-lead ECG. 
10.4.4 Transvaginal ultrasound 
Endometrial thickness, uterus volume and abnormality (fibroids, adenomyosis, etc…) and left/right 
ovary abnormality status will be assessed by TVUS. If TVUS is not possible, abdominal ultrasound can 
be used. The printouts of the ultrasound will be interpreted and commented by the gynecologist and kept 
as source data. Results of the examination will be recorded on source data forms and in the eCRF. 
TVUS should be recommended (for cause) for subjects with heavy/suspicious bleeding. 
10.4.5 Endometrial biopsies 
At the end of the Treatment Period (i.e. at Month 12 visit), endometrial biopsy for histological 
assessment will have to be obtained for each subject  unless the endometrium thickness in TVUS is ≤ 5 
mm, in which case no endometrium biopsy will be necessary ( 
Figure 3). 


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Figure 3 : Biopsy process for Month 12 visit 
During the Follow-Up Period, the schedule for endometrial biospy is as described in 
 
Figure 4 below.  


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Figure 4 : Biopsy process for the Follow-Up Period visits 
 
The endometrial biopsies will be analyzed by a central laboratory blinded to treatment group. 
Endometrial biopsies of hyperplasia of any type will be submitted for assessment by three independent 
expert pathologists who are blinded to the treatment and to one another’s assessment. 
At any time during the study, in case of endometrial biopsy diagnosis being hyperplasia of any type 
(with or without atypia) or worse (neoplasm) for patient on treatment, the laboratory will send an alert 
to the site and the Sponsor. The medical monitor will contact the sites to discuss the proceeding in line 
with local practice. The subject will be discontinued from the treatment, will enter the follow-up period 
and will be advised to consult for gynecological evaluation and treatment. 
Biopsy should be recommended (for cause) for subjects with heavy/suspicious bleeding. Results from 
these procedures should be documented in the eCRF. 
Endometrial biopsy samples will be performed with the Pipelle de Cornier® (or equivalent), as 
described in the manual provided by the central laboratory. 


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10.4.6 Bone mineral density and DXA 
BMD of the femoral neck, total hip and lumbar spine will be assessed by DXA at the end of the 
Treatment Period (i.e. at Month 12 visit) and at the end of the Follow-Up Period (i.e. at Month 6 ExFU 
visit), under the supervision of a nominated primary technologist at the site. BMD for femoral neck, hip 
and spine will also be assessed at Month 9 for subjects who met the following criterion at any site on 
the Month 6 DXA scan: -2.5 < Z-score ≤ -1.5. 
A repeat DXA scan will be performed 6 months after the Follow-Up Period DXA for subjects with a 
BMD decrease from main study baseline > 1.5% for lumbar spine and/or > 2.5% for total hip. 
For each subject, the same DXA machine must be used for all scan acquisitions.  
All DXA scans will be read by a central imaging laboratory blinded to treatment group. There will also 
be centralized monitoring of DXA scan quality for each site including a pre-qualification phantom scan 
and a monthly review of daily quality control (QC) data.  
In the event a scan does not meet quality standards, the site will be asked to repeat the scan. A repeated 
scan will be required for each scan showing 5% or more BMD loss from baseline. 
Instructions to measure the BMD, detailed information on the centralized reading and QC and the 
stopping rules for subjects will be included in a specific imaging manual. 
10.4.7 Bone markers 
Blood samples for exploratory bone biomarkers such as, but not limited to, collagen type 1 β-carboxy-
telopeptide (CTx), procollagen 1 Intact N-Terminal (P1NP), bone-specific alkaline phosphatase (B-
ALP) and osteocalcin will be collected as part of clinical chemistry at Month 9 and Month 12 visits as 
well as at Month 3 ExFU visit. These exploratory data will not be communicated to keep the operational 
team and the sites blinded to treatment administration. 
10.4.8 Laboratory parameters 
Haematology, coagulation parameters and chemistry will be assessed at each visit during the Treatment 
Period, as well as at Month 1 ExFU and Month 3 ExFU visits. Fasting lipids will be assessed at Month 
9, Month 12 and Month 3 ExFU visits.  
E2, P4 and LH will be assessed at each visit during the treatment period, as well as at M1 ExFU and M3 
ExFU visits. Serum levels of SHBG will be assessed at Month 9 and Month 12 visits.  
Overnight fasting is required for Months 9, 12 and Month 3 ExFU visits. 
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, P4, LH and SHBG levels will be assessed by the 
Investigator/sub-Investigator. Clinically significant abnormalities compared to main study baseline 
status will be reported as AEs in the eCRF. E2, P4, LH and SHBG levels will not be communicated to 
keep the operational team and the sites blinded to treatment administration. 
The laboratory parameters are listed in Appendix M. 


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There may be some additional laboratory parameters to be analysed as requested by the medical monitor 
in order to follow-up on existing abnormalities. 
10.4.9 Electrocardiogram 
Local 12-lead ECG readings of QTcF will be performed at each visit during the entire duration of the 
study.  
ECGs should be performed prior to blood sampling, physical examination and vital signs. 
10.4.10 Columbia-Suicide Severity Rating Scale (C-SSRS) 
The C-SSRS questionnaire prospectively assesses the occurrence of treatment-emergent suicidal 
ideation and behavior. The questions will be administered by the site staff to the subject and completed 
by the site staff, using one of the following paper versions: 
- either the “already enrolled subjects” C-SSRS version, dedicated to subjects who are providing answers 
to the C-SSRS for the first time during the study (see Appendix R). 
- or the “since last study visit” C-SSRS version (see Appendix S), dedicated to subjects for whom the 
C-SSRS was completed at the previous study visit, for use at all remaining study visits. 
10.5 LINZAGOLIX AND KP017 PLASMA LEVELS 
PK blood samples will be collected from each subject at each study visit during the Treatment Period 
for determining linzagolix and KP017 plasma levels.  
At the visits where IMP intake is at site, i.e. at Months 6, 7, 8, 9, 10 and 11 visits, PK sampling will be 
performed before IMP intake. The approximate time of dose administration on the four previous days 
and time of PK sampling will be recorded in the eCRF. 
In case of early discontinuation visit, PK sampling is not required at the withdrawal visit if the subject 
had no IMP administration the day prior to the withdrawal visit. 
Details of the blood sampling process, sample handling and shipment are described separately in a 
laboratory manual provided by the central laboratory.  
10.6 CONCOMITANT MEDICATIONS AND THERAPIES 
The Investigator will record in the appropriate section of the eCRF all concomitant medications taken 
by the subject during the entire study duration. 
However, the use of provided/prescribed analgesics for EAP will be recorded solely in the eDiary. 
10.6.1 Permitted Medicines 
Any medications other than those excluded by the protocol (see section 10.6.2), 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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Analgesics: 
Only the analgesics provided/prescribed by Sponsor will be allowed during the study (Treatment and 
Follow-up Periods). Other analgesics will be prohibited. Provided/prescribed analgesics should be taken 
only when required for treatment of pain. Prophylactic use of analgesics will be prohibited. 
Permitted opioid analgesics will be prescribed and dispensed as required according to local practice. 
Subjects will be required to restrict the use of analgesics to those permitted by the protocol as listed in 
Table 1.  
Table 1: Permitted rescue analgesics 
Analgesic class 
Name and dose* 
NSAID 
ibuprofen 200 mg 
Narcotic Analgesic 
5 mg hydrocodone + 300 mg acetaminophen** 
* Use of these analgesic medications should be according to the product prescribing 
information. 
** Or local equivalent  
 
Other:  
In order to prevent or minimize possible impact on BMD, subjects will receive calcium 500 to 1000 mg 
and vitamin D 400 IU supplementation which they will be advised to take daily until the end of study. 
Intake should be recorded at each study visit in eCRF. As the interaction potential is unknown, the intake 
should be separated of at least 4 hours from the intake of the study drug. 
If necessary, the dose of calcium or vitamin D supplementation may be reduced or discontinued at the 
discretion of the Investigator. 
10.6.2 Prohibited Medicines 
Medication listed in Appendix N will be prohibited up to Month 12.  
Strong CYP3A4 inhibitors or inducers are prohibited up to end of treatment in view of the ABT 
(Appendix O). 
Linzagolix is considered to be a weak inhibitor of CYP2C8. Substrates to CYP2C8 with a narrow 
therapeutic index should be administered with caution. 
Hormonal contraception, including use of hormonal IUDs, must not be taken until 3 months after end 
of treatment.  
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. 


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10.6.3 Non-Drug Therapies 
Contraceptive use: 
For subjects of childbearing potential and requiring contraception, non-hormonal contraception is 
required until 3 months after the end of treatment. Two forms of non-hormonal contraception will be 
required e.g. condom with spermicide (if in the opinion of the Investigator a woman is at risk of 
acquiring HIV, spermicide should be avoided; condom with diaphragm may be used). Suitable condoms 
with spermicide will be provided free of charge to subjects over the duration of the study. 
Contraception is still required from 3 months after the end of the Treatment Period until the end of the 
post-treatment Follow-up Period; hormonal contraception is allowed. 
10.7 SUBJECT COMPLETION AND WITHDRAWAL 
10.7.1 Subject Completion 
A subject will be considered as a “completer” when she has completed all study procedures/visits 
according to the protocol. 
10.7.2 Subject Withdrawal  
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.  
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. 
In case of early discontinuation, the subject will be instructed to complete the relevant eDiary 
questionnaires as soon as possible upon treatment discontinuation. 
 
Withdrawal during Treatment Period: 
Subjects discontinuing participation in the study during the Treatment Period should undergo the 
procedures required at Month 12, except the DXA in case of discontinuation before Month 9 visit. These 
subjects will enter the 6-month Follow-Up Period and will continue daily eDiary recording for 6 months 
and up to Month 6 ExFU visit in order to continue to collect efficacy and safety data. 
PK sampling is not required if the subject had no IMP administration the day prior to the withdrawal 
visit. 
Withdrawal during Follow-Up Period: 


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Subjects discontinuing participation in the study during the Follow-Up Period should undergo the 
procedures required at Month 6 ExFU visit, which includes completion of all ClinRO and ePRO 
questionnaires, except the DXA in case of discontinuation before Month 3 ExFU visit. 
10.7.2.1 
Discontinuation criteria 
During the course of the study, the subject may be discontinued for the following reasons: 
- 
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 at least two phone calls and a certified letter requesting return 
receipt without response. Document in the comment section of the eCRF Exit 
Form. 
- 
Pregnancy: 
Subjects who 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 Month 3 ExFU visit, 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 12.6). 
- 
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. 
 
 
Discontinuation Rules: 
Endometrial biopsies: in case of endometrial biopsy diagnosis being an endometrial hyperplasia of 
any type or worse, the subject will have to discontinue  treatment and will be advised to consult for 
gynecological evaluation and treatment. 
Serum calcium: Subjects who have a serum calcium level on treatment above 2.9 mmol/L should 
have calcium supplements interrupted. If serum calcium level on treatment is above 3.1 mmol/L 
calcium supplements and study treatment are to be interrupted.  A repeat test of this parameter 
within 2 weeks under fasting conditions is to be performed. If the results of the repeat remain above 


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2.9 mmol/L, study treatment should definitively be discontinued and the subject should be advised 
to consult an endocrinologist for further evaluation. 
BMD loss: subjects who experience more than 8% BMD loss or a Z-score ≤ -2.5 at any site (femoral 
neck, hip or spine) will be discontinued from study treatment and will enter the Follow-Up Period. 
Liver function tests: following the Food and Drug Administration (FDA) guidance on drug-induced 
liver injury (8), subjects who have an elevation of hepatic enzymes are to be withdrawn immediately 
from treatment if: 
• ALT or AST >8xULN  
• ALT or AST >5xULN for more than 2 weeks  
• ALT or AST >3xULN and (TBL >2xULN or INR >1.5)  
• ALT or AST >3xULN with the appearance of fatigue, nausea, vomiting, right upper quadrant 
pain or tenderness, fever, rash, and/or eosinophilia (>5%)  
Withdrawn subjects will be followed up until hepatic parameters return to normal. 
ECG : subjects who have a QTcF > 500 ms or increase > 60 ms from the highest value prior to the 
first dose in the main study will have to be withdrawn from study treatment and followed up until 
return to QTcF < 480 ms or – if not reached after 3 months of treatment cessation- be referred to a 
cardiologist. They will enter the 6-month Follow-Up Period and undergo the follow-up ECGs 
according to the schedule of events. 
 
10.7.3 Subject Replacement 
Not applicable. 
11 INVESTIGATIONAL MEDICINAL PRODUCT  
11.1 DESCRIPTION OF INVESTIGATIONAL MEDICINAL PRODUCTS 
The term “Investigational Medicinal Product” (IMP) will refer to the ObsEva investigational drug 
linzagolix, the ABT (E2 1 mg/NETA 0.5 mg) or their matching placebos.  
 


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Investigational 
drug 
Investigational drug 
placebo 
ABT 
ABT 
placebo 
International 
nonproprietary name 
(INN) 
Linzagolix 
NA 
E2 and NETA 
NA 
Name of active 
ingredient 
Linzagolix 
NA 
E2 and NETA 
NA 
Form 
Film-coated 
tablet 
Film-coated  
tablet 
Capsule 
Capsule 
Strength 
75 mg and  
200 mg 
placebo for 75 mg and 
placebo for 200 mg 
1.0 mg/0.5 mg 
Placebo 
Dose or 
concentration of 
active treatment 
75 mg  
and 200 mg 
0 mg 
1.0 mg/0.5 mg 
0 mg 
Frequency and 
duration of 
administration 
Once daily for up to 6 months 
Route of 
administration 
Oral 
Manufacturer 
(Name and address) 
Patheon, Canada 
Sharp Clinical Services Inc. 
2400 Baglyos Cir, Bethlehem, 
PA 18020, United States 
Primary packaging  
PVC-PVdC/Al blister containing 
15 tablets 
PVC/Al blister containing 
7 capsules 
Secondary 
packaging (1 kit) 
4 blisters attached into a child-resistant 
wallet card* 
14 blisters in a carton box 
Storage 
Requirements 
As indicated on the study drug kit label 
*The blisters being linked together inside the wallet card, the kit is considered as a single unit and 
therefore labelling on the wallet is sufficient (individual blisters are not labelled). 
11.2 DOSAGE AND ADMINISTRATION 
Linzagolix treatments and matching placebo will be supplied as film-coated tablets for oral 
administration and given as monthly treatment kits (Figure 5). 


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ABT and corresponding placebo will be supplied as red capsules and given as 3-monthly treatment kits. 
IMP treatment will be administered once daily up to Month 12 inclusive. The subjects will have to 
swallow one tablet of linzagolix, one tablet of linzagolix placebo and one capsule of ABT or ABT 
placebo, ideally at the same time each day. 
On the day of a study visit, the subject must take the study medication at site. The site staff will record 
in the eCRF the time of study medication intake. The linzagolix/placebo tablets must be taken from the 
kits dispensed on that visit (and not from the previously dispensed kits). On Month 6 and Month 9 visits, 
ABT/placebo capsules must be taken from the kits dispensed during these visits. On Month 7, 8, 10 and 
11 visits, ABT/placebo capsules must be taken from the previously dispensed kits. 
The treatment groups are described below: 
Treatment 
group 
Daily dose Month 6 to Month 12 
Linzagolix 
active tablets 
Linzagolix 
placebo tablets 
ABT 
active capsules 
ABT 
placebo capsules 
75 mg 
1  75 mg 
1  placebo 200 mg  
None 
1 capsule 
200 mg + ABT 
1  200 mg 
1  placebo 75 mg 
1 capsule 
None 
11.3 PACKAGING AND LABELLING 
Linzagolix/placebo will be provided by the Sponsor (or delegate) as monthly kits.  
On Month 6, 7, 8, 9, 10 and 11 visits, the subject will be given a wallet card containing four blisters in 
total: 
- 
Two blisters of 15 tablets each of 200 mg linzagolix or matching placebo (corresponding to the 
grey card on Figure 5), 
- 
Two blisters of 15 tablets each of 75 mg linzagolix or matching placebo (corresponding to the 
pink card on Figure 5). 
This kit covers 30 days of treatment.  
 


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Figure 5 : Linzagolix kit design 
Each linzagolix/placebo kit will be labeled with a unique kit number from K50001 to K60000 (6-
characters). The blisters being attached into the wallet card, linzagolix/placebo kit is considered as a 
single unit and therefore labelling on the wallet is sufficient (individual blisters are not labelled). 
ABT and matching placebo will be provided by the Sponsor (or delegate) as 3-monthly kits.  
On Month 6 and 9 visits, the subject will be given a carton box containing 14 blisters of seven capsules 
each of ABT or matching placebo. This kit covers 98 days of treatment. 
Each ABT kit will be labeled with a unique kit number (different from the linzagolix kit number), from 
A50001 to A70001. 
Each kit of linzagolix/placebo or ABT/placebo will have a label including a tear-off part. The tear-off 
part containing the study number and the kit number will be placed into a drug accountability form at 
site.  
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 kit label, i.e. on the secondary packaging, will indicate at least the following items: 
 Protocol number 
 Kit number 
 Batch number 
 Storage conditions 
 Sponsor name and address 
Label examples are filed in the study file at the Investigator’s site and in the trial master file.  
11.4 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 kit label. 
The storage facility at site should be locked and temperature-controlled. 
Linzagolix and ABT must be stored at 68°F to 77°F (20°C to 25°C), excursions permitted between 59°F 
and 77°F (between 15°C and 25°C). 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. 


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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).  
11.5 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 delegate) will check for accurate delivery and 
acknowledge receipt in IWRS. A copy of acknowledgement of receipt will be retained in the 
investigator file. In case the IMP received is damaged upon delivery (including temperature 
excursion), this 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). 
 
The dispensing of the IMP will be carefully recorded on the appropriate drug accountability 
form provided by the Sponsor (or delegate) and in eCRF, 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 
o The inventory at the site of IMP delivered 
o The use of each dose by each subject (accountability to be done at each visit) 
o Dates, quantities, batch numbers and kit numbers assigned to the subject. 
o The return to the Sponsor (or delegate) or alternative disposition of used and unused 
IMP 
 
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 check on an ongoing basis the IMP accountability form and verify 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. 
11.6 ASSIGNMENT TO TREATMENT GROUPS 
Subjects who received placebo in the main study will be randomized in a 1:1 ratio to either linzagolix 
75 mg alone (with ABT placebo) or linzagolix 200 mg with ABT, as per the main study randomization 
schedule. 


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Subjects who received active treatment will continue with the same treatment (linzagolix 75 mg alone 
or linzagolix 200 mg with ABT). 
In order to maintain the blind, the site will not be required to perform any randomization activities. The 
kits will be automatically allocated in the IWRS to the corresponding patients upon confirmation of their 
eligibility. 
11.7 ASSESSMENT OF INVESTIGATIONAL MEDICINAL PRODUCT 
COMPLIANCE 
The subject will record her IMP intake daily in the eDiary. 
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.  
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.  
11.8 METHOD OF BLINDING 
The study design is double-blind for the subject, the site and the operational team. The Sponsor will be 
unblinded to active treatment groups, following analysis of Month 6 visit data of the main study (18-
OBE2109-002 - Edelweiss 2 study), but will be blinded to the treatment allocated to patients who 
previously received placebo. 
Linzagolix 75 mg and 200 mg tablets having a different appearance, a double-dummy design will be 
used in order to maintain the blinding of the study. 
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 site personnel and the subject fully blinded.  
11.9 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 nor the complete Study Team. 


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11.10 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 (200 mg per day).  
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 Sections 12.2.3 for AEs or 12.3.2 for SAEs. 
The effects of an overdose of linzagolix are unknown, but repeated once daily dosing at up to 700 mg 
linzagolix was safe and well-tolerated by premenopausal healthy volunteers, and doses up to 200 mg 
daily for 3 months were safe in endometriosis subjects (see Section 5.5.3). 
11.11 OTHER SUPPLIES TO BE USED IN THE STUDY 
A limited quantity (as per Investigator’s judgement) of standard doses of permitted analgesics will be 
provided/prescribed to the subject as rescue medication for EAP (see Section 10.6.1). These will be 
provided by the Sponsor free of charge to the subject or reimbursed.  
Electronic diaries will be provided for subjects to use. These remain the property of the Sponsor. 
Calcium 500 to 1000 mg and vitamin D 400 IU supplements will also be provided by the Sponsor free 
of charge to the subject. Intake should be separated by at least 4 hours from the intake of the study drug. 
Condoms with spermicide will also be supplied by the Sponsor free of charge to the subject. If required, 
spermicide-free condoms, latex-free condoms and diaphragms may be reimbursed to the subject. 
12 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 12.2.1). 
The safety profile of linzagolix will be assessed through the recording, reporting and analysis of baseline 
medical conditions, AEs, physical examination findings, ECGs, vital signs, laboratory tests, BMD 
assessments. 
The reporting period for AEs is described in section 12.5. 
 


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12.1 ADVERSE EVENTS 
12.1.1 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. 
Any event occurring after signature of the informed consent form 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.  
Causality assessment: 
The causality assessment of an AE to the linzagolix and/or ABT 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 
(section 6.7.1), including all amendments, is considered unexpected. 
 


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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 
Study drug is being temporarily interrupted due to AE. 
Drug (study drug) withdrawn 
Decision was made to withdraw the study drug due to AE. 
Unknown 
Unknown, not observed or not recorded. 
Not applicable 
AE started before dosing or after dosing finalized. 
12.1.2 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 main study screening visit or is assessed as having evolved since this 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. 


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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. 
12.1.3 Baseline Medical Conditions 
Medical conditions present at the Screening visit(s) in the main study, including results of the study 
screening assessments, are defined as Baseline Medical Conditions. These medical conditions should 
have been 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. 
12.1.4 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. 
12.1.5 Adverse Events of Special Interest 
Not Applicable. 
12.2 PROCEDURES FOR ELICITING, RECORDING AND REPORTING 
ADVERSE EVENTS 
12.2.1 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?  


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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. 
12.2.2 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. 
12.2.3 Reporting of Adverse Events 
Complete and accurate data on all AEs experienced for the duration of the reporting period, as defined 
in section 12.5, will be reported on an ongoing basis in the AE pages of the eCRF. 
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. 
12.3 SERIOUS ADVERSE EVENTS 
12.3.1 Definitions 
A Serious Adverse Event (SAE) is defined as any untoward medical occurrence or effect that at any 
dose: 
 


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 
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 SAEs 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 exercized 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. 
12.3.2 SAE Urgent Reporting Procedure 
If a SAE occurs from subject consent up to the end of the Follow-Up Period, or in case of study 
discontinuation, if the site becomes aware of an SAE up to four 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 11.9. 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 


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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 Life Sciences / ObsEva Pharmacovigilance 
 
E-mail:  
obsevasafety@voisinconsulting.com 
VOISIN CONSULTING will notify ObsEva Pharmacovigilance within one working day after the 
receipt of the SAE 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 one working day for urgent queries or five 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 Section 12.3.1), 
 
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). 
12.4 REPORTING TO THE 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 Institutional Review Board (IRB)Research Ethics Board) (REB) 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 IRBREB). 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 IRBREB. 
In regions/countries other than the US, reporting of events to 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 IRBREB’s 


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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 
linzagolix Investigator Brochure, and SmPC for the ABT) 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 IRBREB 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 IRBREB and maintain records of these notifications. 
12.5 REPORTING PERIOD 
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 the Month 6 
ExFU visit. 
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 has been fully processed, 
eCRF 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. 
12.6 PREGNANCY AND IN UTERO DRUG EXPOSURE 
All pregnancies that are diagnosed up to Month 3 ExFU visit 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 SAE Urgent Reporting in section 12.3.2. 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: 


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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 12.3.2 (within 24 hours of awareness of this outcome). An SAE Report form 
should be completed in addition to the PSF-part III if the subject sustains an event meeting 
seriousness criterion (e.g. abnormality for the pregnancy (spontaneous abortion, stillbirth) or 
abnormality for the birth itself (e.g. prolongation of hospitalization due to caesarean section 
complications)). In case of congenital malformation or birth defect of the child, a SAE Report 
form for the child should be completed in addition to the PSF-part III (Subject identifier = Subject 
ID – 1 for a singleton neonate). 
13 DATA ANALYSIS AND STATISTICS 
13.1 TEST OF HYPOTHESES 
No formal hypothesis tests are planned for this extension study. Data will be summarized by timepoint 
for each treatment group.   
13.2 SAMPLE SIZE 
With 150 subjects per each of the three treatment groups in the main study (450 subjects in total), the 
power was greater than 95% to reject the null hypothesis for both co-primary endpoints and 85% to 
reject all the null hypothesis for the ranked secondary endpoints. All subjects who have completed the 
full 6-month Treatment Period in the main study and who meet the inclusion criteria will be offered to 
enter the extension study. It is estimated that up to 288 subjects will enter the extension study, assuming 
that 80% of the patients randomized in the main study will complete the study (namely 360 subjects) 
and that up to 80 % thereof will enter the extension study. 
13.3 RANDOMIZATION 
Subjects who previously received placebo will be randomized in a 1:1 ratio to either linzagolix 75 mg 
alone (with ABT placebo) or linzagolix 200 mg with ABT), as per the main study randomization 
schedule. Subjects will be randomized into permutated blocks of a pre-determined length. 


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Subjects who received active treatment will continue with the same treatment (linzagolix 75 mg alone 
or linzagolix 200 mg with ABT). 
In order to maintain the blind, the site will not be required to perform any randomization activities. The 
kits will be automatically allocated to the corresponding patients in the IWRS upon confirmation of their 
eligibility. 
13.4 ANALYSIS SETS 
The following data sets will be used for the statistical analysis: 
1. Treatment Extension Analysis Set: All subjects from the main study who entered the extension 
study and received at least one dose of study drug with the exception of subjects whose Month 6 
assessments subsequently met any of the discontinuation criteria listed in section 10.7.2.1. These 
subjects will be withdrawn from study treatment and will enter the Follow-Up Period. Subjects will 
be analyzed according to randomized treatment. 
 
2. Follow-up Extension Analysis Set: All subjects from the main study who completed the 6 months 
of treatment in the extension study and who entered the Post-Treatment Follow-Up Period. Subjects 
will be analyzed according to randomized treatment. 
 
3. Extension Safety Analysis Set: All subjects randomized into the extension study who received at 
least one dose of study drug irrespective of the treatment received. Subjects will be analyzed 
according to treatment received. 
 
4. Extension Pharmacokinetic (PK) Set: all subjects who were randomized and received active study 
medication in the main study, had no major protocol deviations impacting PK throughout the main 
study or extension and with available PK data. 
 
5.  Extension Pharmacodynamic (PD) Set: all subjects who were randomized and received active 
study medication in the main study, had no major protocol deviations impacting PD throughout the 
main study or extension and with available PD data. 
 
Individual data points may also be excluded from the analysis sets. Rules for such exclusions will be 
described in the statistical analysis plan (SAP). 
13.5 DATA ANALYSIS 
The primary objective of this extension study is to assess the maintenance of efficacy of linzagolix 
administered orally once daily for up to an additional 6 months (for up to 12 months of treatment in 
total) in the subset of subjects who are treated with linzagolix up to the time point of interest. As such, 
the focus will be on subjects who received active treatment in the main study. The assessment of subjects 
who switched from placebo in the main study to active treatment in the extension study will be 
conducted as a secondary objective. 


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Subjects will be analyzed according to actual treatment received. The following four treatment groups 
will be analyzed: linzagolix 75 mg and linzagolix 200 mg with ABT fixed dose groups, linzagolix 75 
mg and linzagolix 200 mg with ABT after 6 months placebo treatment. Only subjects with assessments 
at both baseline and the given time points will be included in the summaries. Baseline values are the 
same as in the main study (18-OBE2109-002 - Edelweiss 2), i.e. data collected prior to the treatment 
administration in the main study. 
More details of the proposed statisical analyses will be described in the SAP, which will be written 
following finalization of the protocol and prior to database lock. 
13.5.1 Baseline Assessment 
Descriptive statistics will be performed on relevant baseline data and on demographic characteristics for 
each treatment group and overall. Baseline is defined as the data collected prior to the treatment 
administration in the main study. A second baseline is defined as the data collected prior to the treatment 
administration in the extension study for subjects who were in the placebo arm in the main study. There 
will be no formal comparison of baseline data, that is, no statistical hypothesis testing. 
13.5.2 Efficacy Analysis 
Summaries will be performed using the Treatment Extension Analysis Set and the Follow-up Extension 
Analysis Set. Data from both the main study and the extension study will be summarized. 
Efficacy endpoints will be derived in the same way as in the main study. The same criterion for defining 
a subject as being a responder by having a clinically meaningful reduction in DYS and in NMPP, along 
with a stable or decreased use of analgesics for EAP, will be used as per the criteria used in the main 
study. The evaluation of a stable or decreased use of analgesics will be done per the specification in 
Appendix P. 
All secondary efficacy endpoints will be summarized by descriptive statistics for each treatment group, 
for each time point, including summaries of change from baseline when applicable. 
13.5.3 Safety Analysis 
Summaries will be performed using the Extension Safety Analysis Set and the Follow-up Extension 
Analysis Set.  
Data from both the main study and the extension study will be summarized. 
13.5.4 Pharmacokinetic analysis methodology 
Descriptive statistics of plasma concentrations will include mean (arithmetic and geometric) and 
standard deviation, median, 1st and 3rd quartiles, minimum, maximum, coefficient of variation (CV%) 
and number of observations. Concentrations below the limit of quantification (LOQ) will be assigned a 
value of zero. Explorative analyses of correlations between plasma concentrations and intrinsic PK 
factors such as e.g. body weight/BMI, race, age may be performed, as appropriate, and will be reported 
separately. 
PK analyses will be based on the Extension PK Set.  


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13.5.5 Pharmacodynamic analysis methodology 
Pharmacodynamic parameters, such as for example estradiol and other hormones, will be summarized 
by time point for each treatment group, and listed for each subject by visit day and dose regimen. Where 
appropriate, changes from baseline will be presented. Potential PK-PD relationships may be investigated 
graphically and through statistical modeling, whilst also exploring possible covariates, and will be 
reported separately. 
PD analyses will be based on the Extension PD Set.  
13.5.6 Missing Data 
Summary statistics will be based on non-missing values. 
13.6 STUDY SPECIFIC DATA ANALYSIS 
13.6.1 End-of-Treatment Period Analysis 
After all subjects have completed the Treatment Period, a complete analysis will be performed. This 
analysis will include all data up to the end of treatment visit. A database lock will be performed, with 
any discrepant data clarified before the lock. 
13.6.2 Post-Treatment Follow-Up Period Analysis 
After all subjects have completed the Post-Treatment Follow-up Period, a final database lock will be 
performed, followed by a second analysis. This analysis will include all data collected during the Post-
Treatment Follow-up Period. 
14 STUDY ADMINISTRATION 
14.1 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 (9), the ICH Harmonized Tripartite Guideline for GCP and all 
applicable local regulatory requirements. 
14.1.1 Informed Consent 
Before a subject can participate in the study, she must give a written informed consent specific to the 
extension study. The informed consent process will be in accordance with ICH GCP and local regulatory 
requirements. 


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14.1.2 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. 
14.1.3 Institutional Review Board 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 IRBREB. 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 IRBREB 
approval of the study. 
14.1.4 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 the Post-Treatment Follow-Up Period. 
This provides a single and conservative definition across all study sites. 
14.2 INVESTIGATOR RESPONSIBILITIES 
The Investigator must be familiar with and conduct the study according to ICH GCP guidelines, the 
FDA Code of Regulation and applicable local laws and regulations. 
Where required by local regulations, national level coordinating Investigators may be appointed. Their 
responsibilities are outlined in a separate agreement with the Sponsor. 
14.3 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. 
14.4 STUDY MONITORING 
The Investigator must ensure that eCRFs are completed in a timely manner and must allow a Sponsor 
representative (e.g. Clinical Research Associate (CRA) or study monitor) periodical access to subject 
records and all study-related materials. The frequency of monitoring visits will be determined by factors 


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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 and 
study material if applicable. 
14.5 DATA MONITORING COMMITTEE 
The Data Monitoring Committee (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. 
14.6 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. 
14.7 QUALITY ASSURANCE 
In compliance with ICH GCP and regulatory requirements, the Sponsor, a third party acting on behalf 
of the Sponsor, regulatory agencies or IRBREB 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 
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. 


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14.8 PROTOCOL DEVIATIONS 
A protocol deviation is any noncompliance with the clinical trial protocol or ICH GCP requirements. It 
is the responsibility of the site Investigator to use continuous vigilance to identify and report deviations. 
All deviations must be addressed in study source documents and reported to the reviewing IRBREB per 
their policies. The site Investigator is responsible for knowing and adhering to the reviewing IRBREB 
requirements. 
All Protocol Deviations will be reported to the Sponsor and documented in the monitoring report. These 
will be classified as minor or major based on their effect on the right, safety or well-being of the subjects 
and/or the quality and integrity of the data, and the final rating of all deviations will be confirmed prior 
to database lock. 
14.9 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 IRBREB.  
Where required by local regulations, the Sponsor (or delegate) will be responsible for informing the 
IRBREB of study or site discontinuation. In such cases, all study data and unused IMP must be returned 
to the Sponsor. 
14.10 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, IRBREB 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. 
14.11 PUBLICATION POLICY 
ObsEva registers clinical trials (Phase I – IV) wherever and whenever mandatory on publicly accessible 
websites (e.g.: www.clinicaltrials.gov ; www.clinicaltrialsregister.eu), including posting the trial design, 
population, and study details as required. 
ObsEva posts the outcome of clinical trials on the required medium(a), within required timelines, 
regardless of the nature of the outcome. 


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OBSEVA CONFIDENTIAL 
ObsEva shares information on the outcome of clinical trials with the Principal/Coordinating 
Investigators of trials in the form of a final report synopsis, regardless of the trial outcome. 
ObsEva duly communicates to stakeholders all relevant information arising from research activities 
related to products developed by the company, at any point and during any phase of the development of 
a product and the entire life-cycle of an ObsEva product. 
Registration, reporting and communication of clinical trial results, results and/or outcome of non-clinical 
research are subject to mandatory preliminary review and authorization by the relevant ObsEva 
functions, prior to disclosure. 
 
 


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15 APPENDICES 
APPENDIX A. SCHEDULE OF STUDY ASSESSMENTS – TREATMENT PERIOD........................................... 85 
APPENDIX B. SCHEDULE OF STUDY ASSESSMENTS – FOLLOW-UP PERIOD ........................................... 87 
APPENDIX C. ENDOMETRIOSIS HEALTH PROFILE QUESTIONNAIRE (EHP-30) ....................................... 88 
APPENDIX D. PROMIS FATIGUE – SHORT FORM 6A ............................................................................. 93 
APPENDIX E. HEALTH-RELATED PRODUCTIVITY QUESTIONNAIRE (HRPQ) ........................................... 94 
APPENDIX F. HEALTH RESOURCE UTILIZATION QUESTIONNAIRE (HRUQ) ............................................ 96 
APPENDIX G. PATIENT GLOBAL IMPRESSION OF CHANGE (PGIC) ....................................................... 101 
APPENDIX H. POST-TREATMENT PATIENT GLOBAL IMPRESSION OF CHANGE (PPGIC) ....................... 102 
APPENDIX I. PATIENT GLOBAL IMPRESSION OF SEVERITY (PGIS) ...................................................... 103 
APPENDIX J. SUBJECT SURGERY INTENTION QUESTIONNAIRE (SSIQ) ................................................ 104 
APPENDIX K. PHYSICIAN SURGERY INTENTION QUESTIONNAIRE (PSIQ) ............................................ 105 
APPENDIX L. EQ-5D-5L ...................................................................................................................... 106 
APPENDIX M. LABORATORY PARAMETERS ......................................................................................... 108 
APPENDIX N. PROHIBITED MEDICINES ............................................................................................... 109 
APPENDIX O. STRONG CYP3A4 INDUCERS AND INHIBITORS .............................................................. 110 
APPENDIX P. ANALGESIC CHANGE DURING TREATMENT PERIOD ...................................................... 112 
APPENDIX Q. REFERENCE LIST ............................................................................................................ 114 
APPENDIX R. C-SSRS ALREADY ENROLLED SUBJECTS ......................................................................... 115 
APPENDIX S. C-SSRS SINCE LAST VISIT ............................................................................................... 118 


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Appendix A. Schedule of study assessments – Treatment Period 
 
Schedule of study assessments – Treatment Period 
Timing1  
Treatment Period 
M62  
M7 
M8 
M9 
M10 
M11 
M12 
Informed Consent 
x 
 
 
 
 
 
 
Inclusion-Exclusion criteria 
x 
 
 
 
 
 
 
Physical examination (including weight) 
x 
 
 
x 
 
 
x 
Columbia-Suicide Severity Rating Scale 
x 
x 
x 
x 
x 
x 
x 
ECG3  
x 
x 
x 
x 
x 
x 
x 
Vital signs 
x 
x 
x 
x 
x 
x 
x 
Urine pregnancy test 
x 
x 
x 
x 
x 
x 
x 
Endometrium TVUS 
x 
 
 
x 
 
 
x 
Gynecological examination 
x 
 
 
x 
 
 
x 
Endometrial biopsy 
x4  
 
 
 
 
 
 x4  
Manual breast examination 
x 
 
 
 
 
 
x 
Clinical laboratory & urinary protein dipstick 
x5  
x 
x 
x5  
x 
x 
x5  
BMD by DXA 
x 
 
 
x6  
 
 
x 
Adverse events 
x 
x 
x 
x 
x 
x 
x 
Concomitant medication 
x 
x 
x 
x 
x 
x 
x 
Contraceptive dispensing and counselling 
x 
x 
x 
x 
x 
x 
x 
Permitted analgesic prescribing/dispensing 
x 
x 
x 
x 
x 
x 
x 
Vitamin D and calcium dispensing 
x 
x 
x 
x 
x 
x 
x 
Subject eDiary completion check 
x 
x 
x 
x 
x 
x 
x 
 
1  All visits should take place at the end of the defined period (i.e. M7 visit should be scheduled at the end of Month 7, M8 visit should be 
scheduled at the end of Month 8, etc.). All visit dates should be calculated from the date of Day 1 visit (in the main study). A month is 
defined as 28 days/4 weeks. Visits should be scheduled ± 3 days (-3/+ 2 days for Month 7 visit) from the calculated date. 
2  All Month 6 assessments except informed consent and inclusion/exclusion criteria would have been performed as part of the main study 
(18-OBE2109-002 - Edelweiss 2). 
3  ECG should be performed at about the same time but before the PK sample  
4  If endometrium thickness in TVUS is ≤ 5 mm, no endometrial biopsy will be necessary. 
5  Overnight fasting is required. 
6  Only for subjects who met the following criterion at any site on the M6 DXA scan: -2.5 < Z-score ≤ -1.5 
 
 


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Schedule of study assessments – Treatment Period (cont’d) 
 
Schedule of study assessments – Treatment Period 
Timing1  
Treatment Period 
M62  
M7 
M8 
M9 
M10 
M11 
M12 
IMP accountability 
x 
x 
x 
x 
x 
x 
x 
Dispense linzagolix/placebo kit 
x 
x 
x 
x 
x 
x 
 
Dispense ABT/placebo kit 
x 
 
 
x 
 
 
 
EHP-30, EQ-5D-5L and PROMIS3  
x 
x 
 
x 
 
 
x 
mPGIS, PGIC, HRUQ and HRPQ3  
x 
x 
x 
x 
x 
x 
x 
SSIQ and PSIQ3  
x 
 
 
 
 
 
x 
Blood sample for PK4  
x 
x 
x 
x 
x 
x 
x 
E2, LH, P4 
x 
x 
x 
x 
x 
x 
x 
SHBG 
x 
 
 
x 
 
 
x 
Bone biomarkers 
x 
 
 
x 
 
 
x 
 
1  All visits should take place at the end of the defined period (i.e. M7 visit should be scheduled at the end of Month 7, M8 visit should be 
scheduled at the end of Month 8, etc.). All visit dates should be calculated from the date of Day 1 visit (in the main study). A month is 
defined as 28 days/4 weeks. Visits should be scheduled ± 3 days from the calculated date. 
2  All Month 6 assessments except informed consent and inclusion/exclusion criteria would have been performed as part of the main study. 
3  ClinROs (PSIQ and HRUQ) will be administered to the subject by the site staff and the responses will be filled in the eDiary. ePROs (EHP-30, 
EQ-5D-5L, PROMIS, PGIS, PGIC, HRPQ and SSIQ) will be filled in by the subject in the eDiary. 
4  PK samples should be taken after the ECG and before the daily dose of IMP. 
 


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Appendix B. Schedule of study assessments – Follow-up Period 
 
Schedule of study assessments – Extension Follow-up Period 
Timing1  
M1 
ExFU 
M3 
ExFU 
M6 
ExFU 
Concomitant medication 
x 
x 
x 
Adverse events 
x 
x 
x 
Columbia-Suicide Severity Rating Scale 
x 
x 
x 
ECG 
x 
x 
x 
Physical examination (including weight) 
 
x 
x 
Vital signs 
x 
x 
x 
Gynecological examination 
 
x 
 
Manual breast examination 
 
x 
 
Endometrium TVUS 
 
x 
x 
Endometrial biopsy 
x2  
x2  
x2  
Clinical laboratory & urinary protein dipstick 
x 
x4  
 
Subject eDiary completion check 
x 
x 
x 
Subject eDiary collection and deactivation 
 
 
x 
EHP-30, EQ-5D-5L, PROMIS, HRUQ, HRPQ 
 
x 
x 
mPGIS and PPGIC  
x 
x 
x 
BMD by DXA 
 
 
x5  
E2, LH, P4 
x 
x 
 
FSH at local laboratory for subjects that do not resume menses at M3 
ExFU visit 
 
x 
 
Bone biomarkers 
 
x 
 
Permitted analgesic prescribing/dispensing 
x 
x 
 
Vitamin D and calcium dispensing 
x 
x 
 
Urine pregnancy test and contraceptive dispensing and counselling 
x 
x 
x 
 
1  All follow-up study visits should take place at the end of the defined period (i.e. M1 ExFU visit should be scheduled at the end of the first 
month of follow-up, M3 ExFU visit should be scheduled at the end of the third month of follow-up, etc.). A month is defined as 28 days/4 
weeks. Visits should be scheduled ± 7 days from the calculated date. 
2  Endometrium biopsy will be taken only if diagnosis at preceding visit was different than “benign endometrium” or if no endometrial 
biopsy was done at M12 nor at any visit since M12. 
3  An end-of-study biopsy is mandatory if no endometrium biopsy was obtained at M12 nor at any of the subsequent visits. 
4  Overnight fasting is required. 
5  Subjects with a BMD decrease from main study baseline of > 1.5% for lumbar spine and/or > 2.5% for total hip at M6 ExFU visit will have 
an additional DXA scan 6 months later. 


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Appendix C. Endometriosis Health Profile questionnaire (EHP-30) 
 
Final English (US) EHP-30 + Section C 
© Copyright, Oxford University Innovation Limited 2001. All Rights Reserved. 
The authors, being Professor Crispin Jenkinson, Professor Stephen Kennedy and Dr. Georgina Jones, 
have asserted their moral rights. 
 
PART 1: CORE QUESTIONNAIRE 
 
DURING THE LAST 4 WEEKS,  
BECAUSE OF YOUR ENDOMETRIOSIS, HOW OFTEN 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 
house 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? 
 
 
 
 
 
 
 


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DURING THE LAST 4 WEEKS,  
BECAUSE OF YOUR ENDOMETRIOSIS, HOW OFTEN HAVE YOU... 
 
Never 
Rarely 
Sometimes 
Often 
Always 
7. 
Lost your appetite and/or been unable 
to eat because of the pain? 
 
 
 
 
 
 
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 
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,  
BECAUSE OF YOUR ENDOMETRIOSIS, HOW OFTEN 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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OBSEVA CONFIDENTIAL 
 
DURING THE LAST 4 WEEKS,  
BECAUSE OF YOUR ENDOMETRIOSIS, HOW OFTEN HAVE YOU... 
 
Never 
Rarely 
Sometimes 
Often 
Always 
23. 
Felt violent or aggressive? 
 
 
 
 
 
 
24. 
Felt unable to tell others how you feel?  
 
 
 
 
 
25. 
Felt others do not understand what you 
are going through? 
 
 
 
 
 
 
26. 
Felt as though others think you are 
whining? 
 
 
 
 
 
 
27. 
Felt alone? 
 
 
 
 
 
 
28. 
Felt frustrated that you cannot always 
wear the clothes you would choose? 
 
 
 
 
 
 
29. 
Felt your appearance has been 
affected? 
 
 
 
 
 
 
30. 
Lacked confidence? 
 
 
 
 
 
 
 
 
 


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OBSEVA CONFIDENTIAL 
 
PART 2: MODULAR QUESTIONNAIRE CORRESPONDING TO SEXUAL RELATIONSHIPS  
 
DURING THE LAST 4 WEEKS,  
BECAUSE OF YOUR ENDOMETRIOSIS, HOW OFTEN HAVE YOU... 
 
Never 
Rarely Sometimes 
Often 
Always 
1. 
Experienced pain during or 
after intercourse? 
If not applicable,  
please check here 
 
 
 
 
 
 
 
2. 
Felt worried about having 
intercourse because of the 
pain? 
If not applicable,  
please check here 
 
 
 
 
 
 
 
3. 
Avoided intercourse because of 
the pain? 
If not applicable,  
please check here 
 
 
 
 
 
 
 
4. 
Felt guilty about not wanting to 
have intercourse? 
If not applicable,  
please check here 
 
 
 
 
 
 
 
5. 
Felt frustrated because you 
cannot enjoy intercourse? 
If not applicable,  
please check here 
 
 
 
 
 
 
 
 
 


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OBSEVA CONFIDENTIAL 
 
Appendix D. PROMIS Fatigue – Short Form 6a 
 
This scale is formally known as PROMIS Item Bank v1.0 – Fatigue – Short Form 6a. The questions 
and the response categories included in this scale are presented below. 
 
 
Please respond to each question or statement by marking one box per row. 
 
 
During the past 7 
days… 
Not at all 
A little bit 
Somewhat 
Quite a bit 
Very much 
1 
I feel fatigued 
□ 
□ 
□ 
□ 
□ 
2 
I have trouble starting 
things because I am 
tired 
□ 
□ 
□ 
□ 
□ 
 
In the past 7 days… 
 
 
 
 
 
3 
How run-down did you 
feel on average? 
□ 
□ 
□ 
□ 
□ 
4 
How fatigued were you 
on average? 
□ 
□ 
□ 
□ 
□ 
5 
How much were you 
bothered by your fatigue 
on average? 
□ 
□ 
□ 
□ 
□ 
6 
To what degree did your 
fatigue interfere with 
your physical 
functioning? 
□ 
□ 
□ 
□ 
□ 
 
Scoring Rules: 
The mapping of the response categories is as follows: 
1 = Not at all; 2 = A little bit; 3 = Somewhat; 4 = Quite a bit; 5 = Very much 
Assessment will be based on the sum of the individual scores across the six questions (possible scores 6 to 30, 6 = not at all, 
30 = very much). Missing data will not be imputed. 
 
 


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Appendix E. Health-Related Productivity Questionnaire (HRPQ) 
 


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Appendix F. Health Resource Utilization Questionnaire (HRUQ) 
 (To be completed by Site Staff) 
Subject number: ___________________________ 
Study Visit (please ensure to tick 1 visit only):  
Treatment period 
☐ Month 7 
☐ Month 8 
☐ Month 9  
☐ Month 10  
☐ Month 11 
☐ Month 12 
Follow-up period 
☐ Month 3 ExFU  
☐ Month 6 ExFU  
Date of Assessment:  __________________________________________ 
 
Instructions to complete:  
At each scheduled on-site visit in the Treatment Period (Month 6 through Month 12) and at Month 3 
ExFU and Month 6 ExFU visits in the Follow-up period, please ask if the subject saw a non-study 
health care practitioner since her last scheduled on-site visit for a routine/general health care visit that 
is not associated with an adverse event. 
Only record below the health care visits with non-study health care practitioners. Any visits associated 
with Adverse Events should be recorded on the AE eCRF form only (do not record below). 
 
*********** 
 
 


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Question 1 
Since the subject's last scheduled study on-site visit, has she seen a non-study health care practitioner 
(e.g., physician, nurse practitioner, physician assistant, dentist, physical therapist) for a 
routine/general health care visit that is not associated with an adverse event? 
☐ No  
☐ Yes   
If Yes, please complete the questions 2 and 3 below. 
Question 2 
a. Select the type of non-study health care practitioner who saw the subject.  
b. Indicate if it was at an office or a clinic (includes a hospital outpatient visit) 
c. Indicate the number of times the subject was seen by each practitioner. 
Types of non-study health care 
practitioner who saw the subject 
(check all that apply) 
Type of facility  
Number of times 
subject was seen by 
this non-study health 
care practitioner 
 
Office 
Clinic 
Office 
Clinic 
☐ AUDIOLOGIST 
☐ 
☐ 
 
 
☐ ALLERGIST 
☐ 
☐ 
 
 
☐ CARDIOLOGIST 
☐ 
☐ 
 
 
☐ DENTIST 
☐ 
☐ 
 
 
☐ DERMATOLOGIST 
☐ 
☐ 
 
 
☐ ENDOCRINOLOGIST 
☐ 
☐ 
 
 
☐ ENT 
☐ 
☐ 
 
 
☐ FAMILY PHYSICIAN 
☐ 
☐ 
 
 
☐ GASTROENTEROLOGIST 
☐ 
☐ 
 
 
☐ GYNECOLOGIST 
☐ 
☐ 
 
 
☐ HEMATOLOGIST 
☐ 
☐ 
 
 
☐ HEPATOLOGIST 
☐ 
☐ 
 
 
☐ IMMUNOLOGIST 
☐ 
☐ 
 
 
☐ INFECTIOUS DISEASE SPECIALIST 
☐ 
☐ 
 
 


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OBSEVA CONFIDENTIAL 
☐ INTERNAL MEDICINE SPECIALIST 
☐ 
☐ 
 
 
☐ INTERNIST 
☐ 
☐ 
 
 
☐ MEDICAL GENETICIST 
☐ 
☐ 
 
 
☐ NEPHROLOGIST 
☐ 
☐ 
 
 
☐ NEUROSURGEON 
☐ 
☐ 
 
 
☐ NURSE 
☐ 
☐ 
 
 
☐ NURSE PRACTITIONER 
☐ 
☐ 
 
 
☐ OCCUPATIONAL THERAPIST 
☐ 
☐ 
 
 
☐ OPHTHALMOLOGIST 
☐ 
☐ 
 
 
☐ ORTHOPEDIC SURGEON 
☐ 
☐ 
 
 
☐ OPTOMETRIST 
☐ 
☐ 
 
 
☐ PHYSIATRIST 
☐ 
☐ 
 
 
☐ PHYSICAL THERAPIST 
☐ 
☐ 
 
 
☐ PLASTIC SURGEON 
☐ 
☐ 
 
 
☐ PODIATRIST 
☐ 
☐ 
 
 
☐ PSYCHOLOGIST 
☐ 
☐ 
 
 
☐ PULMONOLOGIST 
☐ 
☐ 
 
 
☐ RADIOLOGIST  
☐ 
☐ 
 
 
☐ REPRODUCTIVE ENDOCRINOLOGIST  
☐ 
☐ 
 
 
☐ RHEUMATOLOGIST 
☐ 
☐ 
 
 
☐ SURGEON 
☐ 
☐ 
 
 
☐ UROLOGIST 
☐ 
☐ 
 
 
☐ UNKNOWN 
☐ 
☐ 
 
 
☐ OTHER HEALTH CARE PRACTITIONER 
(specify type): 
☐ 
☐ 
 
 
 
 


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Question 3 
Did the Subject have any diagnostic or therapeutic procedures performed by a non-study health care 
practitioner since the last scheduled study on-site visit? 
☐ No  
 
☐ Yes   
If Yes, complete question 4 below. 
Question 4 
a. Select the type of diagnosis/therapeutic procedures performed by non-study health care 
practitioner who saw the subject.  
b. Indicate the number of times the diagnosis/therapeutic procedures were performed. 
Diagnostic/Therapeutic Procedure  
(check all that apply) 
Number of times the procedure was 
performed 
Ultrasound Scan 
☐ 
 
Physical Examination 
☐ 
 
Vital Signs 
☐ 
 
MRI 
☐ 
 
CT Scan 
☐ 
 
X-Ray 
☐ 
 
Biopsy and Histologic Examination 
☐ 
 
Pelvic Exam 
☐ 
 
Urine Test 
☐ 
 
Blood Test 
☐ 
 
Hysteroscopy 
☐ 
 
SIS ( Saline infusion Sonohysterography) 
☐ 
 
Colposcopy 
☐ 
 
Other (specify): 
 
☐ 
 
 
 


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Question 5 
Has the patient spent any nights as a hospital in-patient since the last visit? 
☐ No  
 
☐ Yes  
If Yes, how many nights did they spend in hospital? 
 
 


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Appendix G. Patient Global Impression of Change (PGIC) 
 
 
 


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Appendix H. Post-treatment Patient Global Impression of Change 
(PPGIC) 
 
 
“Overall, how have your endometriosis symptoms 
changed since you stopped taking the study drug?” 
 
 
 
 


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Appendix I. Patient Global Impression of Severity (PGIS) 
 
Daily recall (dPGIS) 
 
Monthly recall (mPGIS) 
Overall, how would you describe your 
endometriosis symptoms in the last 24 hours? 
 
Overall, how would you describe your 
endometriosis symptoms over the past 28 
days? 
 
 
 
 
 
 


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Appendix J. Subject Surgery Intention Questionnaire (SSIQ) 
 
1. How likely are you to consider having laparoscopic surgery to treat your endometriosis if your 
symptoms continue as they are now? 
The SSIQ evaluates subject likelihood of considering endometriosis-related surgeries if current 
symptoms continue, with possible scores from 0 to 10, 
0 = not at all, 10 = very likely. 
 
 


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Appendix K. Physician Surgery Intention Questionnaire (PSIQ) 
 
1. How likely are you to recommend laparoscopic surgery to treat this patient's endometriosis if her 
symptoms continue as they are now? 
The PSIQ evaluates physician likelihood of recommending endometriosis-related surgeries to the 
subject if current symptoms continue, with possible scores from 0 to 10, 
0 = not at all, 10 = very likely. 
 
 


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Appendix L. EQ-5D-5L 
EQ-5D-5L English US version 
© EuroQol Research Foundation. EQ-5D™ is a trade mark of the EuroQol Research Foundation 
 
Please tap the ONE box that best describes your health TODAY. 
 
 


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Please tap on the scale to indicate how your health is TODAY. 


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Appendix M.  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, total cholesterol, and LDL/HDL ratio,  
 
 
 
 
 
triglycerides 
 
 
 
 
 
Glucose 
 
 
 
 
 
Urea and uric acid 
Urinary protein dipstick 
Hormones 
E2, LH, P4, SHBG 
All the above listed tests are to be performed at the frequencies indicated in Appendix A and Appendix 
B. 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. 
Bone markers 
Blood samples for exploratory bone biomarkers such as, but not limited to, collagen type 1 β-carboxy-
telopeptide (CTx), procollagen 1 Intact N-Terminal (P1NP), bone-specific alkaline phosphatase (B-
ALP) and osteocalcin will be collected as part of clinical chemistry.  
 


19-OBE2109-005 PROTOCOL V2.0 DATED 24 AUGUST 2020 
 
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Appendix N. Prohibited medicines 
 
 
GnRH antagonists 
 
GnRH agonist injections/3-month depot injections 
 
Danazol 
 
Oral contraceptives and other sex hormones 
 
Depot contraceptives 
 
Selective Progesterone Receptor Modulators (SPRMs), Selective Estrogen Receptor 
Modulators (SERMs) and aromatase inhibitors 
 
Long acting narcotics (i.e. requiring less than once daily dosing) 
 
Systemic glucocorticoid treatments for acute diseases (not depot) 
 
Medical (prescribed) marijuana 
 
In situ copper intra-uterine device (IUD) 
 
In situ IUD with progestogen 
 


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Appendix O. Strong CYP3A4 Inducers and Inhibitors 
 
The presented lists are indicative and should not be considered exhaustive. 
 
Strong CYP3A4 inducers prohibited up to end of treatment in view of the add-back treatment: 
 
Carbamazepine 
Enzalutamide 
Mitotane 
Phenytoin 
Rifampin 
St. John’s Wort 
 
Strong CYP3A4 inhibitors prohibited up to end of treatment in view of the add-back treatment: 
 
Boceprevir 
clarithromycin 
Cobicistat 
Conivaptan 
danoprevir and ritonavir 
diltiazem 
elvitegravir and ritonavir 
grapefruit juice 
idelalisib 
indinavir and ritonavir 
itraconazole 
ketoconazole 
lopinavir and ritonavir 
nefazodone 
nelfinavir 


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OBSEVA CONFIDENTIAL 
paritaprevir and ritonavir and (ombitasvir and/or dasabuvir) 
posaconazole 
ritonavir 
saquinavir and ritonavir 
telaprevir 
tipranavir and ritonavir 
troleandomycin 
voriconazole 
 
 


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OBSEVA CONFIDENTIAL 
Appendix P. Analgesic change during Treatment Period 
Use of No Analgesics at Baseline* 
Analgesic used during 
Screening* 
Analgesic dose status at end of 
study 
Assessment of Change  
None 
None 
Stable/Decrease  
Narcotic analgesic and/or 
ibuprofen is started 
Increase 
Use of Only Ibuprofen at Baseline* 
Analgesic uses at Baseline* 
Analgesic dose status at end of 
study 
Assessment of Change 
ibuprofen 
Dose stopped, decreases, or is 
stable 
Stable/Decrease 
Dose increases by 15% or more 
Increase 
Narcotic analgesic is 
substituted or added 
Increase 
Use of Only Narcotic Analgesic at Baseline* 
Analgesic uses at Baseline* 
Analgesic dose status at end of 
study 
Assessment of Change  
Narcotic analgesic 
Dose stopped, decreases, or is 
stable 
Stable/Decrease  
Dose stopped and ibuprofen 
substituted (any dose) 
Stable/Decrease 
Dose decreases and ibuprofen 
added (any dose) 
Stable/Decrease 
 
Dose stable and ibuprofen 
added (any dose) 
Increase 
Dose increases by 15% or more 
Increase 
Use of Ibuprofen and Narcotic Analgesic at Baseline* 
Analgesic uses at Baseline* 
Analgesic dose status at end of 
study 
Assessment of Change  
ibuprofen + narcotic analgesic 
Ibuprofen dose stops + narcotic 
analgesic use stops, decreases, 
or is stable** 
Stable/Decrease 


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OBSEVA CONFIDENTIAL 
Ibuprofen use stops + narcotic 
analgesic dose increases by 
more than 15% 
Increase 
Ibuprofen dose decreases + 
narcotic analgesic use stops, 
decreases, or is stable** 
Stable/Decrease 
Ibuprofen dose decreases + 
narcotic analgesic dose 
increases by more than 15% 
Increase 
Ibuprofen dose stable + 
narcotic analgesic use 
stops, decreases, or is stable** 
Stable/Decrease 
Ibuprofen dose stable + 
narcotic analgesic dose 
increases by more than 15% 
Increase 
 
Ibuprofen dose increases by 
more than 15% + narcotic 
analgesic use stops 
Stable/Decrease 
 
Ibuprofen dose increases by 
more than 15% + narcotic 
analgesic dose decreases 
Stable/Decrease 
Ibuprofen dose increases by 
more than 15% + narcotic 
analgesic dose is stable** 
Increase 
Ibuprofen dose increases by 
more than 15% + narcotic 
analgesic dose increases by 
15% or more 
Increase 
 
*Screening and Baseline are defined as the screening and baseline visits in the main study. 
**Stable =Dose is the same as the screening dose or increases by less than 15% of the screening dose. 
In addition, a subject can increase the monthly total dose of analgesics by one pill of analgesic (either 
ibuprofen or narcotic) and still be considered stable. 
 
 
 


19-OBE2109-005 PROTOCOL V2.0 DATED 24 AUGUST 2020 
 
Page 115 of 121 
 
OBSEVA CONFIDENTIAL 
 
Appendix Q. Reference List  
1. 
Dunselman GA, Vermeulen N, Becker C, Calhaz-Jorge C, D'Hooghe T, De Bie B, et al. 
ESHRE guideline: management of women with endometriosis. Hum Reprod. 2014;29(3):400-
12. 
2. 
Ferrero S, Barra F, Leone Roberti Maggiore U. Current and Emerging Therapeutics for the 
Management of Endometriosis. Drugs. 2018 Jul;78(10):995-1012. 
3. 
Ezzati M, Carr BR. Elagolix, a novel, orally bioavailable GnRH antagonist under investigation 
for the treatment of endometriosis-related pain. Womens Health (Lond Engl ). 2015;11(1):19-
28. 
4. 
Lee DY, Park HG, Yoon BK, Choi D. Effects of different add-back regimens on 
hypoestrogenic problems by postoperative gonadotropin-releasing hormone agonist treatment 
in endometriosis. Obstet Gynecol Sci. 2016;59(1):32-8. 
5. 
Farmer JE, Prentice A, Breeze A. Gonadotrophin-releasing hormone analogues for 
endometriosis: bone mineral density. Cochrane Database Syst Rev. 2003(4):CD001297. 
6. 
Surrey E, Taylor HS, Giudice L, Lessey BA, Abrao MS, Archer DF, et al. Long-Term 
Outcomes of Elagolix in Women With Endometriosis: Results From Two Extension Studies. 
Obstet Gynecol. 2018 Jul;132(1):147-160. 
7. 
AbbVie. Orilissa: Prescribing information. 2018. 
8. 
FDA. Guidance for Industry - Drug-Induced Liver Injury: Premarketing Clinical Evaluation. 
2009. 
9. 
World Medical A. World Medical Association Declaration of Helsinki: ethical principles for 
medical research involving human subjects. JAMA. 2013;310(20):2191-4. 
 
 


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Appendix R. C-SSRS Already Enrolled Subjects 
 
 
 
 
 


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Appendix S. C-SSRS Since Last Visit 
 
 
 
 


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OBSEVA CONFIDENTIAL 
 
 
 


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OBSEVA CONFIDENTIAL 
 

SAP_003.pdf: 
     Statistical Analysis Plan Template 
Sponsor:  
ObsEva 
Protocol:  
19-OBE2109-005 
Document Version No.:  
1.0 
Document Date: 
18-MAY-2021 
 
 
 CRS-BS-TP-000005 V 1.0  
 
Page 1 of 66 
Cytel Confidential: This is a controlled document and shall not be changed, saved, copied or reproduced by any unauthorized 
person.  
 
 
Protocol 19-OBE2109-005 
 
A Phase 3 extension study to assess the long-term efficacy and safety of of linzagolix in subjects with 
endometriosis-associated pain. 
Protocol Number: 
(Version Date) 
19-OBE2109-005 
Version 2.0, 24 August 2020 
Name of Test Drug: 
Linzagolix (OBE2109) 
Phase: 
3 
Methodology: 
Randomized, double-blind, placebo-controlled 
Sponsor: 
ObsEva S.A. 
 
 
 
 
Sponsor Representative: 
 
 
Document Date: 
18 May 2021 
Document Version: 
Version 1.0 
 
 
 
 


     Statistical Analysis Plan  
Sponsor:  
ObsEva 
 
Protocol: 
19-OBE2109-005 
Document Version No.: 
1.0 
Document Date: 
18-MAY-2021 
 
CRS-BS-TP-000005 V 1.0 
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SIGNATURE PAGE 
Protocol Title: 
A double-blind randomized extension study to assess the 
long-term efficacy and safety of linzagolix in subjects with 
endometriosis-associated pain. 
Sponsor: 
ObsEva S.A. 
 
 
 
 
Protocol Number: 
18-OBE2109-005 
Document Date/Version: 
18 May 2021 / Version 1.0 
Cytel, Inc. Author: 
 
 
 
 
 
 
 
 


     Statistical Analysis Plan  
Sponsor:  
ObsEva 
 
Protocol: 
19-OBE2109-005 
Document Version No.: 
1.0 
Document Date: 
18-MAY-2021 
 
CRS-BS-TP-000005 V 1.0 
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Sponsor Approval 
By signing this document, I acknowledge that I have read the document and approve of the planned 
statistical analyses described herein.  I agree that the planned statistical analyses are appropriate for this 
study, are in accordance with the study objectives, and are consistent with the statistical methodology 
described in the protocol, clinical development plan, and all applicable regulatory guidance’s and 
guidelines. 
I have discussed any questions I have regarding the contents of this document with the biostatistical 
author. 
I also understand that any subsequent changes to the planned statistical analyses, as described herein, 
may have a regulatory impact and/or result in timeline adjustments.  All changes to the planned analyses 
will be described in the clinical study report (CSR). 
Sponsor Signatory: 
  
 
 
 
 
 
 
 
 
Sponsor Signatory: 
  
 
 
 
 
 
 
 


     Statistical Analysis Plan  
Sponsor:  
ObsEva 
 
Protocol: 
19-OBE2109-005 
Document Version No.: 
1.0 
Document Date: 
18-MAY-2021 
 
CRS-BS-TP-000005 V 1.0 
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person. 
TABLE OF CONTENTS 
 
1. 
INTRODUCTION AND OBJECTIVES OF ANALYSIS .................................................................. 10 
1.1. 
INTRODUCTION ............................................................................................................................. 10 
1.2. 
OBJECTIVES OF STATISTICAL ANALYSIS ......................................................................................... 10 
2. 
STUDY DESIGN ................................................................................................................... 12 
2.1. 
SYNOPSIS OF STUDY DESIGN......................................................................................................... 12 
2.2. 
RANDOMIZATION METHODOLOGY .............................................................................................. 14 
2.3. 
STOPPING RULES AND UNBLINDING ............................................................................................. 14 
2.3.1. 
STOPPING RULES ......................................................................................................... 14 
2.3.2. 
UNBLINDING ............................................................................................................... 16 
2.4. 
STUDY PROCEDURES ..................................................................................................................... 16 
2.5. 
EFFICACY, PHARMACOKINETIC, AND SAFETY VARIABLES ............................................................. 21 
2.5.1. 
EFFICACY VARIABLES ................................................................................................... 21 
2.5.2. 
PHARMACOKINETIC VARIABLES .................................................................................. 21 
2.5.3. 
SAFETY VARIABLES ...................................................................................................... 21 
2.5.4. 
EXPLORATORY VARIABLES .......................................................................................... 21 
3. 
SUBJECT POPULATIONS ...................................................................................................... 22 
3.1. 
ANALYSES SETS DEFINITIONS ........................................................................................................ 22 
3.2. 
PROTOCOL VIOLATIONS ................................................................................................................ 24 
4. 
STATISTICAL METHODS ...................................................................................................... 25 
4.1. 
SAMPLE SIZE JUSTIFICATION ......................................................................................................... 25 
4.2. 
GENERAL STATISTICAL METHODS AND DATA HANDLING ............................................................ 25 
4.2.1. 
GENERAL METHODS .................................................................................................... 25 
4.2.2. 
COMPUTING ENVIRONMENT ...................................................................................... 26 
4.2.3. 
METHODS OF POOLING DATA .................................................................................... 26 
4.2.4. 
ADJUSTMENTS FOR COVARIATES ............................................................................... 26 


     Statistical Analysis Plan  
Sponsor:  
ObsEva 
 
Protocol: 
19-OBE2109-005 
Document Version No.: 
1.0 
Document Date: 
18-MAY-2021 
 
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4.2.5. 
MULTIPLE COMPARISONS/MULTIPLICITY ................................................................... 26 
4.2.6. 
SUBPOPULATIONS....................................................................................................... 26 
4.2.7. 
WITHDRAWALS, DROPOUTS, LOSS TO FOLLOW-UP ................................................... 26 
4.2.8. 
MISSING, UNUSED, AND SPURIOUS DATA .................................................................. 27 
4.2.9. 
TVUS DATA .................................................................................................................. 31 
4.2.10. 
VISIT WINDOWS .......................................................................................................... 32 
4.2.11. 
BASELINE DEFINITIONS ............................................................................................... 34 
4.2.12. 
LAST EXTENSION TREATMENT ADMINISTRATION DATE, END OF 
EXTENSION STUDY DATE AND PERIOD DEFINITIONS .................................................. 34 
4.3. 
INTERIM ANALYSES ....................................................................................................................... 34 
4.4. 
SUBJECT DISPOSITION ................................................................................................................... 35 
4.5. 
DEMOGRAPHIC AND BASELINE CHARACTERISTICS ....................................................................... 35 
4.5.1. 
DEMOGRAPHICS ......................................................................................................... 36 
4.5.2. 
BASELINE DISEASE CHARACTERISTICS ......................................................................... 36 
4.5.3. 
MEDICAL HISTORY....................................................................................................... 37 
4.5.4. 
ENDOMETRIOSIS HISTORY .......................................................................................... 37 
4.6. 
EFFICACY EVALUATION ................................................................................................................. 37 
4.7. 
PHARMACOKINETIC EVALUATIONS .............................................................................................. 38 
4.8. 
SAFETY ANALYSES ......................................................................................................................... 38 
4.8.1. 
EXTENT OF TREATMENT EXPOSURE AND COMPLIANCE ON THE 
EXTENSION STUDY ...................................................................................................... 38 
4.8.2. 
ADVERSE EVENTS ........................................................................................................ 39 
4.8.3. 
BONE MINERAL DENSITY (BMD) BY DXA..................................................................... 41 
4.8.4. 
LABORATORY DATA..................................................................................................... 42 
4.8.5. 
VITAL SIGNS AND PHYSICAL EXAMINATIONS .............................................................. 43 
4.8.6. 
ELECTROCARDIOGRAM ............................................................................................... 44 
4.8.7. 
CONCOMITANT MEDICATIONS ................................................................................... 44 
4.8.8. 
TRANSVAGINAL ULTRASOUND (TVUS) ........................................................................ 45 


     Statistical Analysis Plan  
Sponsor:  
ObsEva 
 
Protocol: 
19-OBE2109-005 
Document Version No.: 
1.0 
Document Date: 
18-MAY-2021 
 
CRS-BS-TP-000005 V 1.0 
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4.8.9. 
OTHER EXAMINATIONS ............................................................................................... 45 
4.8.10. 
COLUMBIA-SUICIDE SEVERITY RATING SCALE (C-SSRS) .............................................. 46 
4.9. 
EXPLORATORY ANALYSES .............................................................................................................. 47 
5. 
CHANGES TO PLANNED ANALYSES ...................................................................................... 48 
6. 
REFERENCES ...................................................................................................................... 49 
7. 
CLINICAL STUDY REPORT APPENDICES ................................................................................ 50 
7.1. 
APPENDIX A: MAPPING RULES FOR EDIARY DATA ........................................................................ 51 
7.2. 
APPENDIX B: STATISTICAL TABLES/FIGURES/LISTINGS TO BE GENERATED .................................. 58 
 
LIST OF IN-TEXT TABLES 
Table 
Page 
Table 1 Schedule of Assessments – Extension Treatment Period ............................................................. 17 
Table 2 Schedule of study assessments - Extension Follow-up Period ..................................................... 19 
Table 3 Theoretical Visit Dates in Extension Treatment Period ............................................................... 33 
Table 4 Theoretical Visit Dates in Extension Follow-up Period ............................................................... 33 
Table 5 Mapping Rules for 
 Device ............................................................................................ 51 
Table 6 Mapping Rules for Signant Health Device ................................................................................... 55 
 
 


     Statistical Analysis Plan  
Sponsor:  
ObsEva 
 
Protocol: 
19-OBE2109-005 
Document Version No.: 
1.0 
Document Date: 
18-MAY-2021 
 
CRS-BS-TP-000005 V 1.0 
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person. 
 
ABBREVIATIONS 
Abbreviation 
Definition 
ABT 
Add-back therapy 
AE 
Adverse events 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
ATC 
Anatomic Therapeutic class 
AUC 
Area under the concentration versus time curve 
AUC0-24 
Area under the concentration versus time curve from time 0 to the end 
of the dosing interval 24 hours later, calculated using linear trapezoid 
rule 
BMD 
Bone Mineral Density 
BMI 
Body Mass Index 
CDF 
Cumulative Distribution Function 
CI 
Confidence Interval 
ClinRO 
Clinician Reported Outcome 
CM 
Concomitant Medication 
CSR 
Clinical study report 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CV 
Coefficient of Variation 
DXA 
Dual-energy X-ray absorptiometry 
DYS 
Dysmenorrhea 
E2 
Estradiol 
EAP 
Endometriosis Associated Pain 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EHP-30 
30-Item Endometriosis Health Profile 
ePRO 
Electronic Patient Reported Outcome 
EQ-5D-5L 
EuroQOL 5-Dimension 5-Level 


     Statistical Analysis Plan  
Sponsor:  
ObsEva 
 
Protocol: 
19-OBE2109-005 
Document Version No.: 
1.0 
Document Date: 
18-MAY-2021 
 
CRS-BS-TP-000005 V 1.0 
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person. 
Abbreviation 
Definition 
FU 
Follow-up 
GCP 
Good Clinical Practice 
GGT 
Gamma Glutamyl Transferase 
Gnrh 
Gonadotropin releasing hormone 
HDL 
High-density lipoprotein 
HRPQ 
Health Related Productivity Questionnaire 
HRUQ 
HealthCare Resource Utilization Questionnaire 
ICH 
International Conference on Harmonisation 
IDMC 
Independent Data Monitoring Committee 
IMP 
Investigational Medicinal Product 
INR 
International Normalized Ratio 
IRB 
Investigational Review Board 
ITT 
Intent-to-treat 
IWRS 
Interactive Web Response System 
LDL 
Low density lipoprotein 
LH 
Luteinizing hormone 
LOQ 
Limit of Quantification 
mB&B 
Biberoglu & Behrman 
MedDRA 
Medical Dictionary for Regulatory Activities 
MME 
Morphine Milligram Equivalent 
mmHg 
Millimeters of mercury 
mPGIS 
Monthly Patient Global Impression of Severity 
Ms 
Millisecond 
NETA 
Norethisterone acetate 
NMPP 
Non-Menstrual Pelvic Pain 
NRS 
Numeric Rating Scale 
NSAIDS 
Non-steroidal anti-inflammatory drugs 
OR 
Odds-ratio 
P4 
Progesterone 
PD 
Pharmacodynamic 


     Statistical Analysis Plan  
Sponsor:  
ObsEva 
 
Protocol: 
19-OBE2109-005 
Document Version No.: 
1.0 
Document Date: 
18-MAY-2021 
 
CRS-BS-TP-000005 V 1.0 
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person. 
Abbreviation 
Definition 
PGIS 
Patient Global Impression of Severity 
PGIC 
Patient Global Impression of Change 
PK 
Pharmacokinetic 
PP 
Per Protocol Set 
PPGIC 
Post-treatment Global Impression of Change 
PPV 
Pelvic Pain Verbal Rating Scale 
PROMIS 
Patient Reported Outcomes Measurement Information System 
PSIQ 
Physician Surgery Intention Question 
QOL 
Quality of Life 
Qt 
Qt interval 
Qtc 
Corrected Qt interval 
Qtcf 
Corrected Qt interval Fridericia 
REB 
Research Ethics Board 
ROC 
Receiver operating characteristic 
SAP 
Statistical analysis plan 
SHBG 
Sex hormone-binding globulin 
SOC 
System Organ Class 
SSIQ 
Subject Surgery Intention Question 
TBL 
Total Bilirubin 
TVUS  
TransVaginal UltraSound 
ULN 
Upper Limit of Normal 
VRS 
Verbal Rating Scale 


     Statistical Analysis Plan  
Sponsor:  
ObsEva 
 
Protocol: 
19-OBE2109-005 
Document Version No.: 
1.0 
Document Date: 
18-MAY-2021 
 
CRS-BS-TP-000005 V 1.0 
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person. 
1. 
INTRODUCTION AND OBJECTIVES OF ANALYSIS 
1.1. 
Introduction 
This is a prospective, randomized, double-blind study. Subjects who had completed the 6-month 
Treatment Period in the main study (18-OBE2109-002 - Edelweiss 2) were invited to enter the extension 
study. Month 6 visit of the main study was a decision point for Subjects to either end treatment and enter 
a post-treatment follow up period (part of the main study), or to opt for a 6-month treatment extension.  
 
The extension study started at the Month 6 visit of the main study. Subjects were required to sign a 
specific informed consent form (ICF) for this extension study. Only subjects who have completed the full 
6-month Treatment Period in the main study and met the inclusion criteria were eligible for entry in the 
extension study.  
All subjects were to receive once daily either linzagolix 75 mg alone (with ABT placebo) or 200 mg 
combined with ABT for 6 months. Subjects who received placebo during the main study were randomized 
to either linzagolix 75 mg alone (with ABT placebo) or linzagolix 200 mg with ABT. Subjects who received 
active treatment during the main study were to continue with the same treatment.  
1.2. 
Objectives of Statistical Analysis 
Following the early termination of the main study (18-OBE2109-002), this extension study was early 
terminated as well and due to the number of subjects randomized being substantially lower than the 
target number if the study had been fully enrolled, this statistical analysis plan (SAP) is focused on the 
safety analysis and all safety and efficacy data will be presented in listings. Consequently, this SAP is 
designed to outline the methods to be used in the analysis of study data to answer the safety and 
tolerability objectives.  
The primary objective of this extension study was to assess the maintenance of efficacy of linzagolix 
administered orally once daily for up to an additional 6 months (for up to 12 months of treatment in 
total) in women who had already completed 6 months of linzagolix treatment at a dose of 75 mg alone 
or of 200 mg in combination with add-back therapy (estradiol (E2) 1 mg / norethisterone acetate (NETA) 
0.5 mg) in the management of moderate to severe endometriosis-associated pain (EAP) in women with 
surgically confirmed endometriosis. The two co-primary efficacy endpoints were clinically meaningful 
reduction over the last 28 days of randomized treatment up to the Month 12 visit, along with a stable or 
decreased use of analgesics for EAP, for 1) dysmenorrhea (DYS) and for 2) non menstrual pelvic pain 
(NMPP).  
 


     Statistical Analysis Plan  
Sponsor:  
ObsEva 
 
Protocol: 
19-OBE2109-005 
Document Version No.: 
1.0 
Document Date: 
18-MAY-2021 
 
CRS-BS-TP-000005 V 1.0 
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Secondary objectives included evaluation of efficacy over the last 28 days of randomized treatment up 
to the Month 12 visit based on the following parameters: evaluation of pain associated with sexual 
intercourse (dyspareunia) and defecation (dyschezia), difficulty of doing daily activities, analgesic use, 
assessment of subject perception of severity, change in uterine bleeding, Quality of Life (QoL) 
questionnaires, pharmacoeconomic burden of endometriosis by assessing changes in patient 
productivity, assessment of endometriosis-related number of non-study health visits, number of days in 
hospital and type of medical procedures performed during the Treatment Period.  
 
Safety and tolerability objectives included assessment of bone mineral density (BMD), endometrial 
health, cardiac safety including QT interval prolongation, standard laboratory safety parameters, 
gynecological assessments and adverse event (AE) frequency including specific hypoestrogenic AEs.  
 
Exploratory objectives included assessment of bone turnover markers and collection of pharmacokinetic 
(PK) and pharmacodynamic (PD) related data of linzagolix for a separate modelling exercise.  
Populations for analysis, data handling rules, statistical methods, and formats for data presentation are 
provided.  The statistical analyses and summary tabulations described in this SAP will provide the basis 
for the results sections of the clinical study report (CSR) for this trial. 
This SAP will also outline any differences in the currently planned analytical objectives relative to those 
planned in the study protocol. 
 


     Statistical Analysis Plan  
Sponsor:  
ObsEva 
 
Protocol: 
19-OBE2109-005 
Document Version No.: 
1.0 
Document Date: 
18-MAY-2021 
 
CRS-BS-TP-000005 V 1.0 
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2. 
STUDY DESIGN 
2.1. 
Synopsis of Study Design 
This was a prospective, randomized, double-blind study. Subjects who completed the 6-month Treatment 
Period in the main study (18-OBE2109-002 - Edelweiss 2) were invited to enter the present extension 
study. Month 6 visit of the main study was a decision point for Subjects to either end treatment and enter 
a post-treatment follow up (part of the main study), or to opt for a 6-month treatment extension.  
 
The extension study started at the Month 6 visit of the main study. Subjects were required to sign a 
specific informed consent form (ICF) for this extension study. Only subjects who completed the full 6-
month Treatment Period in the main study and met the inclusion criteria were eligible for entry in the 
extension study. 
  
All subjects received once daily linzagolix 75 mg alone (with ABT placebo) or 200 mg combined with ABT 
for 6 months. Subjects who received placebo during the main study were randomized in a 1:1 ratio to 
either linzagolix 75 mg alone (with ABT placebo) or linzagolix 200 mg with ABT. Subjects who received 
active treatment during the main study continued with the same treatment.  
Linzagolix/placebo tablets were provided in monthly treatment kits, packaged, labelled and administered 
in the same manner to protect the blinded nature of the trial.  
ABT/placebo treatments were supplied as 3-monthly kits, packaged, labelled and administered in the 
same manner to protect the blinded nature of the trial. 
  
After end of treatment in the extension study (6-month Treatment Period: from Month 6 to Month 12), 
subjects entered a post-treatment Follow-Up Period of 6 months with no investigational medicinal 
product (IMP).  
The total duration of the present extension study was to be 12 months.  
 
 


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A schematic of the study design is shown in Figure 1. 
 
 
 
 
 
 
 
 
 
 
 
Figure 1: Study design 


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Two analyses were planned: one after all subjects completed the Treatment Period and one after all 
subjects completed the Post-Treatment Follow-up Period. However, due to the early termination of the 
study, one summary and report of the data will be performed and will be focused on the safety results 
from all subjects regardless of treatment duration.  
2.2. 
Randomization Methodology 
Subjects who previously received placebo were randomized in a 1:1 ratio to either linzagolix 75 mg alone 
(with ABT placebo) or linzagolix 200 mg with ABT), as per the main study randomization schedule. 
Subjects were randomized into permutated blocks of a pre-determined length. 
Subjects who received active treatment continued with the same treatment (linzagolix 75 mg alone or 
linzagolix 200 mg with ABT).  
In order to maintain the blind, the sites were not required to perform any randomization activities. The kits 
were automatically allocated to the corresponding patients in the IWRS upon confirmation of their 
eligibility. 
2.3. 
Stopping Rules and Unblinding 
2.3.1. 
Stopping Rules 
Subjects were informed that they had the right to withdraw from the study at any time, without prejudice 
to their medical care, and that they were not obliged to state the reason(s). Any withdrawal must be fully 
documented in the eCRF exit form.  
The Investigator may have withdrawn a subject at any time if this was 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 was to be ended 
prematurely without asking for her consent.  
In addition, an Independent Data Monitoring Committee (IDMC) regularly reviewed safety data and made 
recommendations concerning the continuation, modification or termination of the study. 
 
Discontinuation criteria  
During the course of the study, the subject may have been discontinued for the following reasons: 
-  Adverse Event 
- Subject’s request 


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- Protocol Violation 
- Lost to Follow-up 
- Pregnancy 
- Other 
Details are provided in the Protocol. 
 
Discontinuation Rules during the Treatment Period:  
Endometrial biopsies: in case of an endometrial biopsy diagnosis of endometrial hyperplasia of any type 
or worse, the subject was to discontinue study treatment (and was not eligible to enter the extension 
study) and was to be advised to undergo gynecological evaluation and treatment. 
Serum calcium: Subjects with a serum calcium level on treatment above 2.9 mmol/L was to 
have calcium supplements interrupted. If serum calcium level on treatment was above 3.1 mmol/L, 
calcium supplements and study treatment were to be interrupted.  A repeat test of this parameter within 
2 weeks under fasting conditions was to be performed. If the results of the repeat remained above 2.9 
mmol/L, study treatment was to be discontinued and the subject was to be advised to consult an 
endocrinologist for further evaluation. 
Bone mineral density loss: subjects who experienced more than 8% BMD loss or a Z-score ≤ -2.5 at any 
site (femoral neck, hip or spine) were to be discontinued from study treatment and were to enter the 
follow-up period (they were not eligible to enter the extension study). 
Liver function tests: following the Food and Drug Administration (FDA) guidance on drug-induced liver 
injury, subjects who had an elevation of hepatic enzymes were to be withdrawn immediately from 
treatment if: 
• 
ALT or AST >8xULN  
• 
ALT or AST >5xULN for more than 2 weeks  
• 
ALT or AST >3xULN and (TBL >2xULN or INR >1.5)  
• 
ALT or AST >3xULN with the appearance of fatigue, nausea, vomiting, right upper quadrant pain 
or tenderness, fever, rash, and/or eosinophilia (>5%)  
Withdrawn subjects were to be followed up until hepatic parameters returned to normal. 
ECG : subjects with a QTcF > 500 ms or increase > 60 ms from the highest value prior to first dose were 
to be withdrawn from study treatment and followed up until return to QTcF < 480 ms or – if not reached 
after 3 months of treatment cessation- be referred to a cardiologist. They were to enter the 6-month 
Follow-Up Period and undergo follow-up ECGs according to the schedule of events. 


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2.3.2. 
Unblinding 
 
The study design was double-blind for the subject, the clinical site and the operational team. The Sponsor 
was planned to be unblinded to active treatment groups, following the analysis of Month 6 visit data 
from the main study (18-OBE2109-002 - Edelweiss 2 study), but was to be blinded to the treatment 
allocated to patients who had previously received placebo.  
A database lock was to be performed prior to unblinding of treatment. 
Following the early termination of the studies (main and extension), the lock was to be performed at the 
same time for the main and extension studies, and the unblinding done for all subjects for both studies. 
2.4. 
Study Procedures 


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The schedule of assessments, as outlined in the study protocol, is provided in Table 1 and Table 2. 
Table 1 Schedule of Assessments – Extension Treatment Period 
Schedule of study assessments – Extension Treatment Period 
Timing1  
Treatment Period 
M62  
M7 
M8 
M9 
M10 
M11 
M12 
Informed Consent 
x 
 
 
 
 
 
 
Inclusion-Exclusion criteria 
x 
 
 
 
 
 
 
Physical examination (including weight) 
x 
 
 
x 
 
 
x 
Columbia-Suicide Severity Rating Scale 
x 
x 
x 
x 
x 
x 
x 
ECG3  
x 
x 
x 
x 
x 
x 
x 
Vital signs 
x 
x 
x 
x 
x 
x 
x 
Urine pregnancy test 
x 
x 
x 
x 
x 
x 
x 
Endometrium TVUS 
x 
 
 
x 
 
 
x 
Gynecological examination 
x 
 
 
x 
 
 
x 
Endometrial biopsy 
x4  
 
 
 
 
 
 x4  
Manual breast examination 
x 
 
 
 
 
 
x 
Clinical laboratory & urinary protein dipstick 
x5  
x 
x 
x5  
x 
x 
x5  
BMD by DXA 
x 
 
 
x6  
 
 
x 
Adverse events 
x 
x 
x 
x 
x 
x 
x 
Concomitant medication 
x 
x 
x 
x 
x 
x 
x 
1  All visits should take place at the end of the defined period (i.e. M7 visit should be scheduled at the end of Month 7, M8 visit should be 
scheduled at the end of Month 8, etc.). All visit dates should be calculated from the date of Day 1 visit (in the main study). A month is defined 
as 28 days/4 weeks. Visits should be scheduled ± 3 days (-3/+ 2 days for Month 7 visit) from the calculated date. 
2  All Month 6 assessments except informed consent and inclusion/exclusion criteria would have been performed as part of the main study (18-
OBE2109-002 - Edelweiss 2). 
3  ECG should be performed at about the same time but before the PK sample  
4  If endometrium thickness in TVUS is ≤ 5 mm, no endometrial biopsy will be necessary. 
5  Overnight fasting is required. 
6  Only for subjects who met the following criterion at any site on the M6 DXA scan: -2.5 < Z-score ≤ -1.5 


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Schedule of study assessments – Extension Treatment Period (cont’d)  
Timing1  
Treatment Period 
M62  
M7 
M8 
M9 
M10 
M11 
M12 
Contraceptive dispensing and counselling 
x 
x 
x 
x 
x 
x 
x 
Permitted analgesic prescribing/dispensing 
x 
x 
x 
x 
x 
x 
x 
Vitamin D and calcium dispensing 
x 
x 
x 
x 
x 
x 
x 
Subject eDiary completion check 
x 
x 
x 
x 
x 
x 
x 
IMP accountability 
x 
x 
x 
x 
x 
x 
x 
Dispense linzagolix/placebo kit 
x 
x 
x 
x 
x 
x 
 
Dispense ABT/placebo kit 
x 
 
 
x 
 
 
 
EHP-30, EQ-5D-5L and PROMIS3  
x 
x 
 
x 
 
 
x 
mPGIS, PGIC, HRUQ and HRPQ3  
x 
x 
x 
x 
x 
x 
x 
SSIQ and PSIQ3  
x 
 
 
 
 
 
x 
Blood sample for PK4  
x 
x 
x 
x 
x 
x 
x 
E2, LH, P4 
x 
x 
x 
x 
x 
x 
x 
SHBG 
x 
 
 
x 
 
 
x 
Bone biomarkers 
x 
 
 
x 
 
 
x 
1  All visits should take place at the end of the defined period (i.e. M7 visit should be scheduled at the end of Month 7, M8 visit should be 
scheduled at the end of Month 8, etc.). All visit dates should be calculated from the date of Day 1 visit (in the main study). A month is defined 
as 28 days/4 weeks. Visits should be scheduled ± 3 days from the calculated date. 
2  All Month 6 assessments except informed consent and inclusion/exclusion criteria would have been performed as part of the main study. 
3  ClinROs (PSIQ and HRUQ) will be administered to the subject by the site staff and the responses will be filled in the eDiary. ePROs (EHP-30, 
EQ-5D-5L, PROMIS, PGIS, PGIC, HRPQ and SSIQ) will be filled in by the subject in the eDiary. 
4  PK samples should be taken after the ECG and before the daily dose of IMP. 


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Table 2 Schedule of study assessments - Extension Follow-up Period 
Schedule of study assessments – Extension Follow-up Period 
Timing1  
M1 ExFU 
M3 ExFU 
M6 ExFU 
Concomitant medication 
x 
x 
x 
Adverse events 
x 
x 
x 
Columbia-Suicide Severity Rating Scale 
x 
x 
x 
ECG 
x 
x 
x 
Physical examination (including weight) 
 
x 
x 
Vital signs 
x 
x 
x 
Gynecological examination 
 
x 
 
Manual breast examination 
 
x 
 
Endometrium TVUS 
 
x 
x 
Endometrial biopsy 
x2  
x2  
x2  
Clinical laboratory & urinary protein dipstick 
x 
x4  
 
Subject eDiary completion check 
x 
x 
x 
Subject eDiary collection and deactivation 
 
 
x 
EHP-30, EQ-5D-5L, PROMIS, HRUQ, HRPQ 
 
x 
x 
mPGIS and PPGIC  
x 
x 
x 
BMD by DXA 
 
 
x5  
1  All follow-up study visits should take place at the end of the defined period (i.e. M1 ExFU visit should be scheduled at the end of the first 
month of follow-up, M3 ExFU visit should be scheduled at the end of the third month of follow-up, etc.). A month is defined as 28 days/4 
weeks. Visits should be scheduled ± 7 days from the calculated date. 
2  Endometrium biopsy will be taken only if diagnosis at preceding visit was different than “benign endometrium” or if no endometrial biopsy 
was done at M12 nor at any visit since M12. 
3  An end-of-study biopsy is mandatory if no endometrium biopsy was obtained at M12 nor at any of the subsequent visits. 
4  Overnight fasting is required. 
5  Subjects with a BMD decrease from main study baseline of > 1.5% for lumbar spine and/or > 2.5% for total hip at M6 ExFU visit will have an 
additional DXA scan 6 months later. 
 


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Schedule of study assessments – Extension Follow-up Period 
Timing1  
M1 
ExFU 
M3 
ExFU 
M6 
ExFU 
E2, LH, P4 
x 
x 
 
FSH at local laboratory for subjects that do not resume menses at M3 
ExFU visit 
 
x 
 
Bone biomarkers 
 
x 
 
Permitted analgesic prescribing/dispensing 
x 
x 
 
Vitamin D and calcium dispensing 
x 
x 
 
Urine pregnancy test and contraceptive dispensing and counselling 
x 
x 
x 
1  All follow-up study visits should take place at the end of the defined period (i.e. M1 ExFU visit should be scheduled at the end of the first 
month of follow-up, M3 ExFU visit should be scheduled at the end of the third month of follow-up, etc.). A month is defined as 28 days/4 
weeks. Visits should be scheduled ± 7 days from the calculated date. 


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2.5. 
Efficacy, Pharmacokinetic, and Safety Variables 
2.5.1. 
Efficacy Variables 
The efficacy variables planned in the protocol, will not be analyzed due to the early study termination 
and the low number of subjects randomized. 
 
2.5.2. 
Pharmacokinetic Variables 
 
The pharmacokinetic variables planned in the protocol, will not be analyzed due to the early study 
termination and the low number of subjects randomized. 
 
2.5.3. 
Safety Variables 
Safety endpoints include:  
- 
Change from baseline to each scheduled assessment in BMD measured by DXA of lumbar spine 
(L1-L4), femoral neck, and total hip 
- 
Incidence and severity of treatment emergent adverse events (TEAEs) 
- 
Incidence and severity of hypoestrogenic TEAEs (hot flush) 
- 
Changes in clinical laboratory assessments (hematology, biochemistry, coagulation parameters, 
hormones, lipids and urinalysis) from baseline to each scheduled assessment 
- 
Any pathological changes from baseline in the endometrium as assessed by histology from 
endometrial biopsies 
- 
Changes from baseline to each scheduled assessment in any other safety parameter including 
weight, vital signs, ECG, gynecological assessments and endometrial thickness 
Safety analyses are described in Section 4.8. 
Note that the endpoint “Time to the first post-treatment menses” was initially planned in the protocol, 
but will not be described in this SAP, because the study was stopped prematurely and all subjects couldn’t 
be followed to evaluate this endpoint. 
 
2.5.4. 
Exploratory Variables 
The exploratory variables planned in the protocol, will not be analyzed due to the early study termination 
and the low number of subjects randomized. 


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3. 
SUBJECT POPULATIONS 
3.1. 
Analyses Sets Definitions 
The following data sets will be used for the statistical analysis:  
 
Extension Safety Analysis Set: All subjects randomized who entered the extension study and received at 
least one dose of study drug in the extension study irrespective of the treatment received. Subjects will 
be analyzed according to treatment received  
Follow-up Extension Safety Analysis Set: All subjects randomized who entered the extension study and 
who entered the drug free extension follow-up period. Subjects will be analyzed according to treatment 
received.  
The actual treatment for the extension study will be derived as follows, based on daily e-diary IMP intake 
data: 
Subjects received a different kit of active linzagolix for each month, and a different kit for add-back or 
placebo for each 3-month period. 
The number of days with one pink tablet, one grey tablet and one red capsule taken based on e-diary 
IMP intake data for each treatment will be computed. Data from “Today” will be used primarily. If data 
from today is missing, data from “Yesterday” of the following day will be considered. If the e-diary is not 
completed for a day (neither “Today” nor “Yesterday” of following day), it will be assumed that  no drug 
was taken on that day. 
Further rules are as follows: 
- 
Treatment administration errors: 
o If a subject received placebo with placebo ABT on more than 50% of days (even if it is not 
planned), then the actual treatment group will be placebo with placebo ABT for the 
extension period. 
o Otherwise, the active treatment (combined with add-back or placebo add-back) with the 
most days taken will be assigned for the extension period. 
o If the number of days is equal for two treatments groups containing active treatment, 
then LGX 200 mg with ABT will be assigned for the extension period.  
- 
If a subject discontinued, only data received up to discontinuation will be used. 
All analyses for the extension study will be described according to the combined treatment group based 
on the treatment on the main study and the extension study.  


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For combined planned treatment groups, the planned treatment during the main study and the planned 
treatment during the extension study comprise the following four combined planned treatment groups: 
 
Placebo / LGX 75 mg: for subjects randomized to placebo in the main study and randomized to 
LGX 75 mg in the extension study 
 
Placebo / LGX 200 mg + ABT: for subjects randomized to placebo in the main study and 
randomized to LGX 200 mg + ABT in the extension study 
 
LGX 75 mg: for subjects randomized to LGX 75 mg in the main study and continued with the same 
treatment in the extension study 
 
LGX 200 mg + ABT: for subjects randomized to LGX 200 mg + ABT in the main study and continued 
with the same treatment in the extension study 
 
For the combined actual treatment groups, the actual treatment during the main study and the actual 
treatment during the extension study comprise the following four combined actual treatment groups. It 
is possible that the derived actual treatment group will not correspond to any of the combined planned 
treatment groups; thus the combined actual treatment group will be derived as follows: 
Actual treatment  
Main study 
Actual treatment 
Extension study 
Combined 
actual treatment 
group 
Combination planned in the protocol 
Placebo   
LGX 75 mg  
Placebo / LGX 75 mg  
Placebo   
LGX 200 mg + ABT 
Placebo / LGX 200 mg + ABT 
LGX 75 mg  
LGX 75 mg  
LGX 75 mg  
LGX 200 mg + ABT 
LGX 200 mg + ABT 
LGX 200 mg + ABT 
Combination not planned in the protocol (but possible with treatment administration errors) 
Placebo 
Placebo 
Placebo / LGX 75 mg  
LGX 75 mg  
Placebo 
LGX 75 mg  
LGX 200 mg + ABT 
Placebo 
LGX 200 mg + ABT 


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LGX 75 mg  
LGX 200 mg + ABT 
LGX 75 mg  
LGX 200 mg + ABT 
LGX 75 mg  
LGX 200 mg + ABT 
3.2. 
Protocol Violations 
A protocol deviation is any noncompliance with the clinical trial protocol or International Conference on 
Harmonization Good Clinical Practice (ICH GCP) requirements. It was the responsibility of the site 
investigator to use continuous vigilance to identify and report deviations. All deviations were to be 
addressed in study source documents and reported to the reviewing IRB/REB per their policies. The site 
investigator was responsible for knowing and adhering to the reviewing IRB/REB requirements.  
All Protocol Deviations were to be reported to the Sponsor and documented in the monitoring report. 
These will be classified as minor or major based on their effect on the right, safety or well-being of the 
subjects and/or the quality and integrity of the data. The following deviations will be considered as major: 
 
Non-compliance with inclusion criteria 2 
 
Non-compliance with exclusion criteria 2; 3; 4; 5; 6 
 
IP Dispensing error; 
 
Randomisation code broken 
 
The final rating of all deviations will be confirmed prior the unblinding. The final protocol deviation 
file (formatted as a Microsoft Excel file) will be provided to Cytel. 
Major protocol deviations will be summarized by category and by treatment group on the Extension 
Safety Analysis Set. 
All protocol deviations will be presented in the data listings. 
 


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4. 
STATISTICAL METHODS 
4.1. 
Sample Size Justification 
With a planned sample size of 150 subjects per each of the three treatment groups in the main study 
(450 subjects in total), the power was to be greater than 95% to reject the null hypothesis for both co-
primary endpoints and 85% to reject all the null hypothesis for the ranked secondary endpoints. All 
subjects who completed the full 6-month Treatment Period in the main study and who met the inclusion 
criteria were to be offered to enter the extension study. It was estimated that up to 288 subjects would 
enter the extension study, assuming that 80% of the patients randomized in the main study would 
complete the study (~ 360 subjects) and that up to 80 % thereof would enter the extension study.  
4.2. 
General Statistical Methods and Data Handling  
4.2.1. 
General Methods 
All output will be incorporated into Microsoft Excel or Word files, sorted and labeled according to the 
International Conference on Harmonisation (ICH) recommendations, and formatted to the appropriate 
page size(s). 
Tabulations will be produced for appropriate demographic, baseline, and safety parameters.   
The analyses will be performed on 4 treatment groups (taking into account the treatment taken in the 
main study): 
 
linzagolix 75 mg / linzagolix 75 mg 
 
linzagolix 200 mg with ABT / linzagolix 200 mg with ABT 
 
Placebo / linzagolix 75 mg (subject receiving placebo in main study and treated with linzagolix 75 
mg in extension study) 
 
Placebo / linzagolix 200 mg with ABT (subject receiving placebo in main study and treated with 
linzagolix 200 mg with ABT in extension study) 
 
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, including for change from baseline when applicable. The baseline mean will be calculated 
for all subjects based on the Safety Set. For Bone Mineral Density, a baseline mean will also be calculated 
for each visit using the baseline data for the subset of subjects who attended that visit, such that the 
same subjects contribute to the mean for the visit and the mean for the corresponding baseline values. 


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Summary statistics will be based primarily on non-missing values. For ordered categorical data and 
nominal data, absolute counts and relative frequencies (in %) will be calculated.  
Raw and derived data will be listed. 
 
4.2.2. 
Computing Environment 
All descriptive statistical analyses will be performed using SAS statistical software (Version 9.4), unless 
otherwise noted.  Medical History and adverse events will be coded MedDRA version 23.0.  Concomitant 
medications will be coded using World Health Organization (WHO) Drug Dictionary B3 – Mar 2019.  
 
4.2.3. 
Methods of Pooling Data 
Not applicable to the present study. 
 
4.2.4. 
Adjustments for Covariates 
Not Applicable 
 
4.2.5. 
Multiple Comparisons/Multiplicity 
No formal hypothesis tests are planned for this extension study. Data will be summarized by timepoint 
for each treatment group. 
 
4.2.6. 
Subpopulations 
Not Applicable.  
 
4.2.7. 
Withdrawals, Dropouts, Loss to Follow-up 
In general, there will be no substitutions made to accommodate missing data points due to withdrawals, 
dropouts and loss to follow-up.  All data recorded in the CRF will be included in data listings that will 
accompany the clinical study report.   
In case of early discontinuation, the subject was to be instructed to complete the relevant eDiary 
questionnaires as soon as possible upon treatment discontinuation.  
 


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Withdrawal during treatment period:  
Subjects discontinuing participation in the study during the Treatment Period were to undergo the 
procedures required at Month 12, except the DXA in case of discontinuation before Month 9 visit. These 
subjects were to enter the 6-month Follow-Up Period and were to continue daily eDiary recording for 6 
months and up to the Month 6 ExFU visit in order to continue to collect efficacy and safety data.  
PK sampling was not required if the subject had no IMP administration the day prior to the withdrawal 
visit.  
 
Withdrawal during follow-up period: 
Subjects discontinuing participation in the study during the Follow-Up Period were to undergo the 
procedures required at the Month 6 ExFU visit, which included completion of all ClinRO and ePRO 
questionnaires, except for DXA scans in subjects who discontinued before the Month 3 ExFU visit.  
 
4.2.8. 
Missing, Unused, and Spurious Data 
 
4.2.8.1. 
Adverse events and Concomitant Medication Missing Dates 
Imputation of missing/partial AE and CM dates will be done only to identify treatment-emergent AEs. 
AE onset dates: 
- 
Partially missing AE onset dates will be imputed as follows: 
o When only Day is missing:  
 
If Month & Year of the onset date are the same as Month & Year of the first 
administration date, the imputed onset date will be imputed as the minimum of 
the first administration date and the AE resolution date (imputed if needed). 
 
Else if the subject entered the Extension Study and Month & Year is the same as 
Month & Year of the first administration date in Extension, the imputed onset 
date will be imputed as the minimum of the first administration date in Extension 
and the AE resolution date (imputed if needed). 
 
Otherwise, the missing day will be replaced by “1” 
o When Day & Month are missing:  
 
If the subject entered the Extension Study and if Year of the onset date is the 
same as Year of the first administration date in Extension, the imputed onset 


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date will be imputed as the minimum of the first administration date in Extension 
and the AE end date (imputed if needed). 
 
Else if Year of the onset date is the same as Year of the first administration date, 
the imputed onset date will be imputed as the minimum of the first 
administration date and the AE end date (imputed if needed). 
 
Otherwise, the missing Day & Month will be replaced by “01 JAN.” 
- 
Completely missing AE onset dates will be imputed as follows: 
o If the subject entered the Extension, the AE onset date will be imputed by the first 
administration date in Extension and the AE will be considered as treatment-emergent, 
unless the end date of the AE (imputed if needed) or the end year of the AE (if day and 
month are missing) is entered and is before the first administration date in Extension.  
o If the subject did not enter the Extension, or if the end of the AE is before the first 
administration date in Extension, the AE onset date will be imputed by the first 
administration date and the AE will be considered as treatment-emergent, unless the 
end date of the AE (imputed if needed) or the end year of the AE (if day and month are 
missing) is entered and is before the first administration date. If the end date is before 
the first administration date, the AE will not be considered as treatment-emergent. 
 
AE end dates 
- 
If Day only is missing, incomplete end dates will be replaced by the last day of the month, if not 
resulting in a date later than the date of the subject's death or date of study discontinuation. In 
the latter case, the date of death/date of study discontinuation will be used to impute the 
incomplete end date. 
- 
If Day & Month are missing, Day & Month will be replaced by 31DEC, if not resulting in a date 
later than the date of the subject's death or date of study discontinuation. In the latter case, the 
date of death/ date of study discontinuation will be used to impute the incomplete end date. 
- 
In all other cases the incomplete end date will not be imputed. 
 
Concomitant Medications dates 
Partially missing dates for prior and concomitant medications and procedures will be imputed. Of note, 
imputation of missing/partial dates will be done only to identify the treatment period assignment. 
- 
End date: Missing day will be imputed as the last day of the month, and missing month will be 
imputed by December, if not resulting in a date later than the date of the subject's death or date 


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of study discontinuation In the latter case, the date of death/date of study discontinuation will 
be used to impute the incomplete end date. 
- 
Start date: Missing day will be imputed as the first day of the month, and missing month will be 
imputed by January.  
- 
If the start date is completely missing, then: 
o If the end date is prior to the date of first administration of the study drug, then the 
medication is considered as prior 
o If the end date is prior to the date of last administration of the study drug, then the 
medication is considered as prior and concomitant 
o If the end date is completely missing or after the date of last administration of the study 
drug, then the medication is considered as prior, concomitant and post. 
 
Following imputation of the dates,  the concomitant medications will be assigned to the main study 
and/or the extension study according to imputed start and end dates. Note that a concomitant 
medication starts before the first IMP administration in the main study and stops during the extension 
study will be assigned to both studies. 
 
4.2.8.2. 
eDiary Devices Data Cleaning 
Due to eDiary system errors, mapping rules are defined for data cleaning, as described in Appendix E in 
Section 7.1.  
In addition, the following rules are defined for handling of duplicate records: 
- 
A change of eDiary device vendor (
 vendor to Signant Health vendor) occurred during 
the study.  
- 
Some subjects may have entered data in the two different devices during the transition period. 
In case of duplicates results on the same day for daily diaries or on the same visit for monthly 
questionnaires, data from the new vendor (Signant Health) will be used for analysis.  
- 
In case of duplicates within the same device, the first record (with earliest date/time) should be 
used for analysis. 
Additional rules to specific e-diary domains will be applied: 
Analgesic use data: 
- 
Analgesic use data from “Today” will be used primarily.  If data from ”Today” is missing, data 
from “Yesterday” of the following day will be considered 


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IMP Intake Data: 
- 
IMP Intake data from “Today” will be used primarily.  If data from ”Today” is missing, data from 
“Yesterday” of the following day will be considered 
 device specific rules 
NOTE: by design, when a subject is completing a questionnaire (daily or monthly) on a 
 device, 
the device automatically saves all answers provided by the subject as soon as recorded, unless subject 
uses the “previous” button to come back to already answered question(s) within the questionnaire and 
changes her answer(s) prior to finishing the questionnaire.  
There are several triggering questions in the study questionnaires: the next question(s) to be presented 
to the subject will depend on the answer chosen by the subject to the current question. 
Due to device functioning, when an answer to a triggering question has been changed by subject (using 
previous button), the device keeps subsequent answer(s) to the previously triggered question(s), even if 
this/these question(s) is/are no longer relevant considering the new answer to the triggering question. 
The agreed rules consider the last entry made by the subject i.e. the entry that would have not allowed 
her to provide additional data or to modify data for the sub-questions  (in contrast to the 
 device, 
with the Signant Health device, the intermediate answers are not saved and will not be present in the 
database; the agreed rules are aligned with this functioning).  
 
Analgesic use data: 
- 
If answer to question “Did you take any provided/prescribed analgesic for your endometriosis 
related pain?” is “Yes” or empty but the number of ibuprofen intakes and narcotic analgesics 
intakes are both 0, it will be considered that no analgesic was used on that day. 
- 
If answer to question “Did you take any provided/prescribed analgesic for your endometriosis 
related pain?” is “Yes” or empty, but question to Ibuprofen intake is “No” and the number of 
ibuprofen intakes is not zero, it will be considered that no ibuprofen was used on that day. The 
same rule will be applied for narcotic analgesics. 
- 
If answer to question “Did you take any provided/prescribed analgesic for your endometriosis 
related pain?” is “No” and the number of ibuprofen intakes and narcotic analgesics intakes are 
not 0, it will be considered that no analgesic was used on that day and following answers will be 
ignored. 
- 
If answer to “Did you take any provided/prescribed analgesic for your endometriosis related 
pain?” is “No” and answer to question Ibuprofen intake is “Yes”, but the number of Ibuprofen 
intakes is 0, it will be considered that no ibuprofen was used on that day. The same rule will be 
applied for narcotic analgesics. 


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Dyspareunia VRS Data: 
- 
when question “Did you have any sexual intercourse?” is answered “No, I was not sexually active 
for reasons other than my endometriosis” or “No, I avoided sexual intercourse because of 
anticipation of pain” and there is an answer to question “How did your endometriosis related 
pain interfere with sexual intercourse?”, only the “No” answer will be considered.  
- 
when question “Did you have any sexual intercourse?” is blank and there is an answer to question 
“How did your endometriosis related pain interfere with sexual intercourse?”, consider that 
“Yes” was answered to “Did you have any sexual intercourse”.  
HRUQ Data: 
- 
when answer to triggering question 1 is “No” and at least one answer to question 2 to  6 (any 
answer different from 0) is present, ignore answer 2-6 in the analysis 
- 
when answer to triggering question 7 is “No” and at least one answer to questions 8 to 9 (any 
answer different from 0) is present, ignore answers 8-9 in the analysis 
- 
For questions 8-9, consider the number of times whatever the answer provided for “procedures” 
(ie if it is NO include number of times if different than 0) 
HRPQ Data: 
- 
When answer to question 9 is different than “endometriosis symptoms or its treatment(s) forced 
me to work part-time when I wanted to work full-time” and question 9bis is different than 0, ignore 
answer 9bis in the analysis. 
- 
When answer to question 9 is different than “endometriosis symptoms or its treatment(s) kept me 
from having a job when I wanted to work full-time” and question 9ter is different than 0, ignore 
answer 9ter in the analysis. 
- 
When answer to question 9 is different than “endometriosis symptoms or its treatment(s) kept me 
from having a job when I wanted to work part-time” and question 9quater is different than 0, ignore 
answer 9quater in the analysis 
 
4.2.9. 
TVUS data 
If the depth recorded for a TVUS of uterus is 0 mm, the depth and the volume should be considered as 
missing (i.e., the assessment was done in 2 dimensions instead of 3 dimensions). 
 


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4.2.10. 
Visit Windows 
For all analyses except for the DXA assessments and the diary questionnaires, the visits as collected in 
the eCRF will be used.  
All visit dates are calculated from the date the patient started treatment in the main study (Day 1 visit of 
18-OBE2109-002 Edelweiss 2). 
 
DXA data 
Visit windows rules for DXA assessments will be the following: 
- 
The DXA assessment at Month 6 will be derived as the first non-missing DXA assessment with 
acceptable quality (accepted=”Yes”) and dated between Month 6 theoretical date (=Day 169) -
28 days and Month 6 theoretical date + 28 days. 
- 
The DXA assessment at Month 9 will be derived as the first non-missing DXA assessment with 
acceptable quality (accepted=”Yes”) and dated between Month 9 theoretical date (=Day 253) -
28 days and Month 9 theoretical date + 28 days. 
- 
The DXA assessment at Month 12 will be derived as the first non-missing DXA assessment with 
acceptable quality (accepted=”Yes”) and dated between Month 12 theoretical date (=Day 337 in 
the main study) -28 days and Month 12 theoretical date + 28 days. 
- 
The DXA assessment at Month 6 Extension Follow-Up will be derived in the same way as the DXA 
assessment at Month 6. Theoretical date of Month 6 Extension Follow-up is 168 days after Month 
12 theoretical date or after treatment discontinuation. 
 
Other safety data: 
For other safety data, data from early discontinuation should be compared to theoretical visits dates. 
Only assessments within the window of theoretical date +/-14 days will be used for analyses, if it is 
planned to have a such assessment at this visit and no other assessment is in the window. If a subject 
discontinued in the extension treatment period, date will be compared to the theoretical visit dates in 
extension treatment period as described in Table 3. If a subject discontinued in the extension follow-up 
period, date will be compared to the theoretical visit dates in extension Follow-up period from Table 4.  
For unscheduled safety assessments, if the assessment occurs within a window of theoretical date +/- 14 
days for a planned eCRF visit for which it was planned per protocol to have such assessment, and no 
assessment was done for that visit, the assessment will be assigned to that visit. If the assessment is 
equally distant from two eCRF visits with no corresponding safety assessment, the assessment will be 
assigned to the next visit. 


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For biopsy, DXA assessment or laboratory assessment, if an assessment has been assigned in external 
data to a follow-up visit of the main study for subjects who entered in the extension study, the visit of 
assessment should be reassigned with the same rules described above for unscheduled safety 
assessment. 
Table 3 Theoretical Visit Dates in Extension Treatment Period 
Visit 
Theoretical Date 
Month 6 
Day 169 
Month 7 
Day 197 
Month 8 
Day 225 
Month 9 
Day 253 
Month 10 
Day 281 
Month 11 
Day 309 
Month 12 
Day 337 
Table 4 Theoretical Visit Dates in Extension Follow-up Period 
Visit 
Theoretical Date 
Month 1 ExFU 
Month 12 or treatment discontinuation date + 28 
Month 3 ExFU 
Month 12 date or treatment discontinuation date 
+ 84 
Month 6 ExFU 
Month 12 date or treatment discontinuation date 
+ 168 
 
 
 


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4.2.11. 
Baseline Definitions 
The baseline will be described in two ways: 
 
Main Baseline, defined in the Statistical Analysis Plan of the main study and calculated according 
to first dose of IMP taken during the main Study. 
 
Second Baseline (named Baseline 2), defined as the last assessment before the first active dose 
of IMP during the extension study. The baseline 2 will be calculated only for the subjects who are 
in the placebo arm (actual arm) in the main study. 
 
4.2.12. 
Last extension treatment administration date, End of extension Study date and Period 
definitions 
The last extension treatment administration date will be defined as the date from the treatment 
termination reported in the extension period eCRF page. If this date is missing, the last date with a drug 
intake in the eDiary that is inferior or equal to Month 12 visit or the last available date with a drug intake 
in the eDiary if the subject discontinued the extension treatment will be used. 
For subjects who entered the extension, the end of the extension study date will be the last assessment 
date in the extension study defined as last assessment recorded in the eCRF (excluding end date of 
adverse events and concomitant medications) or ediary date. 
Note:  
 
For summaries by visit (efficacy or safety), the Month 6 assessments will be included in the main 
study analyses. For Adverse Events, Concomitant Medications and Daily diaries data collected on 
the Month 6 date will be part of the extension for subjects entering the extension study, and will 
be part of the main Follow-up period for subjects entering the main study follow-up period. 
 
For Adverse Events, Concomitant Medications and Daily diaries, data collected on the Month 12 
date will be part of the Extension Follow-up period for subjects entering the Extension follow-up 
period. 
The extension treatment period will be defined as Month 6 up to (Month 12 date -1) or treatment 
discontinuation date. 
The extension follow-up period will be defined as the Month 12 date or (treatment discontinuation 
date+1) up to the extension follow-up end date (for subjects who entered the extension follow-up). 
4.3. 
Interim Analyses 
Not applicable 


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4.4. 
Subject Disposition 
A tabulation of subject disposition will be presented by treatment group and overall, for randomized 
subjects in the main study, including : 
 
Number of subjects randomized in the main study, 
 
Number of subjects who completed the main treatment period until Month 6 
 
Number of subjects who signed consent form for the extension study,  
 
Number of subjects who discontinued the study between informed consent for extension study 
and the first day of study drug in extension period,  
 
Number of subjects who received at least one dose of study drug in the extension study,  
 
Number of subjects who completed the extension treatment period until Month 12 
 
Number of subjects who discontinued the extension treatment period prior to Month 12, and 
reasons for extension treatment discontinuation 
 
Number of subjects who entered the extension follow-up period 
 
Number of subjects who discontinued the extension follow-up period, and reasons for the 
extension follow-up period discontinuation 
 
Number of subjects who completed the extension study (complete the extension treatment 
period and the extension follow-up period) 
 
The number of subjects included in the extension study by country and by site will be also provided. 
The number in each subject population for analysis will be presented by treatment group and overall, for 
Extension Safety Analysis Set. The number of subjects who completed each visit of the extension study 
will be summarized by treatment group and overall, for the Extension Safety Analysis Set. 
The following listings will be presented: 
- 
Study completion information, including the reason for premature study withdrawal, if applicable; 
- 
Inclusion/exclusion criteria; 
- 
Subject inclusion in each of the analysis sets (Extension Safety Analysis Set and Follow-up Extension 
Safety Set) and reasons for exclusion 
4.5. 
Demographic and Baseline Characteristics 
Baseline, demographic and medical history information will be analyzed by treatment group and overall, 
for the Extension Safety Analysis Set.  


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No formal statistical comparisons will be performed. 
 
4.5.1. 
Demographics 
Demographics and baseline characteristics recorded at baseline in the main study will be summarized by 
treatment group and overall using descriptive statistics.   
Demographics and baseline data include Age (years), Gender, Ethnicity, Race, Height (cm), Weight (kg), 
Body Mass Index (kg/m2), Systolic Blood Pressure (mmHg), Diastolic Blood Pressure (mmHg), Heart Rate 
(beats/minute), QTc interval (Fridericia) (ms). 
BMI is auto-calculated, defined as: Weight (kg)/(Height(m)*Height(m)). 
Demographic and Baseline data will be provided in data listings. 
 
4.5.2. 
Baseline Disease Characteristics 
For the 4 treatment groups (as detailed in section 4.2.1), the following parameters, recorded at baseline 
in the main study, will be calculated as described in section 4.5.2 of the SAP of the main study. 
 
Baseline Dysmenorrhea (DYS) 
 
Baseline Non-Menstrual Pelvic Pain (NMPP) 
 
Baseline analgesic use. 
 
The average duration of the two baseline menstrual cycles (days)  
 
The number and percentage of subjects with Normal, Abnormal, Abnormal clinically significant 
(or Not Assessable) results for Physical Examination, Gynecological Examination, Breast 
Examination, Mammography, Endometrial Biopsy and PAP Smear assessments at baseline. 
 
Transvaginal ultrasound data (i.e., presence of ovarian endometrioma with a diameter of 7 cm 
or greater, uterus length, width, and depth in mm and corresponding calculated uterine volume 
in cm3 (using the prolate ellipsoid formula [L x H x W x 0.523]), endometrium thickness in mm, 
and presence of any uterus, left ovary or right ovary abnormality). 
Only for subjects receiving Placebo in the main study, these baseline characteristics will be described as 
the definition of the second baseline (section 4.2.11 of this SAP): 
 
The number and percentage of subjects with Normal, Abnormal, Abnormal clinically significant 
(or Not Assessable) results for Physical Examination, Gynecological Examination, Breast 
Examination, Mammography (if required), Endometrial Biopsy (if required), for baseline 2. 


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 
Baseline 2 Transvaginal ultrasound data (i.e., presence of ovarian endometrioma with a diameter 
of 7 cm or greater, uterus length, width, and depth in mm and corresponding calculated uterine 
volume in cm3 (using the prolate ellipsoid formula [L x H x W x 0.523]), endometrium thickness 
in mm, and presence of any uterus, left ovary or right ovary abnormality). 
Baseline Disease Characteristics will be reported in listings. 
 
4.5.3. 
Medical History 
Medical history, recorded at baseline in the main study, will be summarized by System Organ Class and 
Preferred Term using the Medical Dictionary for Regulatory Activities (MedDRA), by treatment group and 
overall. 
Medical history will be summarized by subject incidence rates; therefore, a subject contributes only once 
to the count for a given medical history (SOC or preferred term). 
Medical history will be reported in a listing.  
 
4.5.4. 
Endometriosis History 
For the 4 treatment groups (as detailed in section 4.2.1), the following parameters, recorded at baseline 
in the main study, will be calculated as described in section 4.5.2 of the SAP of the main study. 
Time since first medical diagnosis/treatment, first surgical diagnosis and most recent surgical diagnosis 
in years defined as (randomization date – date of diagnosis)/365.25 will be summarized. 
Presence within 2 months before screening and ongoing symptoms at baseline of the main study for the 
following symptoms will be summarized, by treatment group and overall: Dyspareunia, Dyschezia, 
Dysuria, Adenomyosis, Rectovaginal endometriosis nodes. 
Endometriosis History will be reported in a listing. 
4.6. 
Efficacy Evaluation 
Following the early termination of the study and due to the number of subjects randomized being 
substantially lower than the target number if the study had been fully enrolled, no efficacy analyses are 
planned. 
Efficacy data from eDiaries, eCRF, quality of life questionnaires and other ePROs questionnaires will be 
reported in listings. 


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4.7. 
Pharmacokinetic Evaluations 
Following the early termination of the study and due to the number of subjects randomized being 
substantially lower than the target number if the study had been fully enrolled, no pharmacokinetic 
analysis is planned. 
4.8. 
Safety Analyses 
Safety analyses will be conducted using the Extension Safety Analysis Set.   
 
4.8.1. Extent of treatment exposure and compliance on the extension study 
 
4.8.1.1. 
Extent of treatment exposure in the extension study 
Duration of treatment (weeks) will be summarized for each treatment group. Duration is defined as: 
[(date of last extension treatment administration as described in section 4.2.12) - (date of first 
administration in extension as collected in eCRF) +1] / 7. 
Time on extension study (weeks) will be summarized for each treatment group, defined as: [(end of 
extension study date as described in section 4.2.12) – (date of first administration in extension as 
collected in eCRF) +1.]/7 
Exposure data will be reported in listings. 
 
4.8.1.2. 
Compliance in the extension study 
Lingazolix/Placebo Grey blister (200 mg or matching placebo), Lingazolix/Placebo Pink blister (75 mg or 
matching placebo) and Add-back therapy compliances from the study treatment accountability page will 
be summarized on the extension treatment period by treatment group. 
If Lingazolix/Placebo and Add-back therapy compliances from accountability data are missing, 
compliance will be computed from daily diary data:  
Compliance will be computed as the number of days with pink tablet/grey tablet/red capsule taken *100 
divided by the number of days in the period (Month 12 visit date/discontinuation date - Month 6 visit 
date ). Data from “Today” will be used primarily. If data from today is missing, date from “Yesterday” will 
be considered. If the e-diary is not completed for a day (neither “Today” nor “Yesterday), it will be 
assumed that no drug was taken on that day. 
 Study treatment overdose and misuse will be reported in a listing. 


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Compliance will be reported in a listing. 
 
4.8.2. 
Adverse Events 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) and 
displayed in tables and listings using System/Organ/Class (SOC) and Preferred Term. 
Analyses of adverse events will be performed for those events that are considered treatment emergent 
(TEAEs), where treatment emergent is defined as AEs with a start date on or after the first dose of 
extension study drug through 30 days after discontinuation of study drug or Month 12 visit date, or any 
event that was present at Month 6 but worsened in intensity or was subsequently considered drug-
related by the investigator through the end of the extension study.  
Adverse Event tables will be presented for the following periods: Month 6 to Month 12 (Extension 
treatment period) and Month 12 to Month 6 ExFU (Extension follow-up period) as defined in section 
4.2.12. 
Adverse events starting more than 30 days after end of treatment will be considered as post-treatment 
AE. 
For each of these 2 study periods, an overall summary table will be prepared presenting, by treatment 
group, the number and percentage of subjects with  
 
any AE, 
 
any TEAE,   
 
any post-treatment AE (displayed only for the Extension follow-up period), 
 
Severe TEAE, 
 
any TEAE assessed by the Investigator as related to Linzagolix ((definite, probable, or possible 
relationship),  
 
any TEAE assessed by the Investigator as related to add-back therapy ((definite, probable, or 
possible relationship),  
 
any TEAE leading to permanent discontinuation of IMP,  
 
any serious adverse event (SAE), 
 
any serious treatment emergent adverse event (Serious TEAE), 
 
any serious treatment emergent adverse event (SAE) related to Linzagolix, 
 
any serious treatment emergent adverse event (SAE) related to add-back therapy,  
 
any fatal TEAE (where outcome is “Fatal”) 


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In these tabulations, each subject will contribute only once (i.e., via the most related occurrence or the 
most intense occurrence) to each of the incidence rates in the descriptive analysis, regardless of the 
number of episodes experienced. 
Adverse events are summarized by subject incidence rates, therefore, in any tabulation, a subject 
contributes only once to the count for a given adverse event (SOC or preferred term). 
The number and percentage of subjects with any treatment-emergent adverse event will be summarized 
by treatment group and by SOC and PT.   
If serious TEAEs are observed in the study, the number and percentage of subjects with any non-serious 
treatment-emergent adverse event will be summarized by treatment group.   
Serious TEAE, TEAE assessed by the Investigator as related to treatment (definite, probable, or possible 
relationship), TEAE leading to permanent discontinuation of IMP, TEAE leading to permanent 
discontinuation of IMP leading to death and post-treatment AE will be only listed due to the low number 
of subjects included in the extension study. 
The number of events will be also displayed for summaries on TEAE and for analysis of TEAE and non-
serious TEAE by SOC and PT. 
The ongoing status of each Adverse Event will be derived based on Adverse Event Outcome as the 
following: 
AE Outcome 
AE Ongoing Status 
Fatal 
No 
Not recovered/not resolved 
Yes 
Recovering/resolving 
Yes 
Recovered/resolved 
No 
Recovered/resolved with sequelae 
No 
Unknown 
Unknown 
Missing 
Missing 
The ongoing status collected in eCRF will be ignored. 
No formal hypothesis-testing analysis of adverse events incidence rates will be performed.   


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All adverse events occurring on study will be listed in subject data listings. 
By-subject listings also will be provided for the following: Treatment Emergent Adverse event, serious 
Treatment Emergent adverse events; Treatment Emergent adverse events leading to permanent 
discontinuation of IMP and leading to permanent discontinuation of IMP leading to death.  
 
4.8.3. 
Bone Mineral Density (BMD) by DXA 
BMD of femoral neck, total hip and lumbar spine will be assessed by DXA at Baseline, Month 9 (if 
required) Month 12 and Month 6 of the extension follow-up (if required). Unacceptable DXA assessments 
(accepted=”No”) will not be summarized (hip, spine and femur considered separately). 
In case of repeated values due to BMD loss ≥5%, the initial scan will be used in summaries. Initial and 
repeated scan values will be reported in the listings. 
Calibrated values will be used if available, otherwise initial values will be considered. 
BMD, expressed as both absolute values and Z-scores will be summarized at each visit in terms of actual 
values, changes from baseline, changes from baseline 2 (only for the subjects who are in the placebo arm 
in the main study) for each anatomic location. For absolute values only, percent change from baseline, 
percent changes from baseline 2 (only for the subjects who are in the placebo arm in the main study) and 
95% confidence interval for the mean percent change from baseline and for the mean percent change 
from baseline 2  within each group will be produced at each time point. 
The definition of both baselines are described in section 4.2.11.  
Percent change from baseline and percent change from baseline 2 to Month 9, Month 12 and Month 6 
extension follow-up will be described and will also be summarized in categories of percentage with the 
following classes: 
• 
No change or increase, 
• 
Decrease ≤ 3%, 
• 
Decrease > 3% and ≤ 5%, 
• 
Decrease > 5% and ≤ 7%, 
• 
Decrease > 7% and ≤ 8%, 
• 
Decrease > 8%. 
All data will be listed. 
 


     Statistical Analysis Plan  
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4.8.4. 
Laboratory Data 
Clinical laboratory values will be expressed using conventional SI units. 
Hematology, coagulation parameters, chemistry and lipids were assessed at screening and at each visit 
during the extension treatment period (from M7 to M12), as well as at the M1 ExtFU and M3 ExtFU visits.  
E2, progesterone (P4) and LH were assessed at each visit during the extension treatment period (from 
M6 to M12), as well as at M1 ExtFU and M3 ExtFU visits. 
Serum levels of sex hormone-binding globulin (SHBG) were assessed on Month 6, Month 9 and Month 
12 visits.  
Blood samples were to be analyzed by the central laboratory. Due to the covid-19 situation, some 
samples may be collected by local laboratories.  
For Hematology, coagulation parameters, chemistry and lipids, the actual value, change from baseline 
and change from baseline 2 (only for the subjects who are in the placebo arm in the main study) will be 
summarized for each visit for each treatment group. In the event of repeated values, the last non-missing 
value per study day/time will be used. 
Evaluation of shifts for changes from baseline and for changes from baseline 2 (only for the subjects who 
are in the placebo arm in the main study) to all visits according to the normal ranges with categories 
“Low”, “Normal”, “High” and according to normal/abnormal/abnormal clinically significant information 
collected otherwise, will be provided.  
For Liver Function Test (LFT) parameters (ALT, AST, ALP, total bilirubin, direct bilirubin, indirect bilirubin, 
GGT, LDH, albumin and Creatine Kinase), evaluation of shifts for changes from baseline will be extended 
by the worst (highest) on-treatment value (including unscheduled assessments) according to the normal 
ranges with categories “Low”, “Normal”, “High” will be provided.  
For the lipid panel (Triglycerides, HDL, LDL, Total Cholesterol, LDL/HDL ratio), the percent change from 
baseline and the percent change from baseline 2 (only for the subjects who are in the placebo arm in the 
main study) to each on-study visit will also be summarized. 
For serum levels of P4, SHBG and LH, only the actual values at each time point will be summarized. Note: 
in the event of repeated values, the last non-missing value per study day/time will be used. 
Note that no serum levels of E2 is measured for subjects in extension study due to the early termination 
study. 
For P4, since P4 above 10 nMol/L may suggest luteal activity and hence ovulation, the proportion of 
subjects with P4 >10.0 nMol/L at least once from Month 6 to Month 12 will also be provided in tables. 
The number and percentage of subjects with cholesterol values in the following categories 
 
LDL ≥ 160 mg/dL  


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 
LDL ≥ 190 mg/dL  
 
HDL < 40 mg/dL  
will be reported at each visit. 
Shift tables from baseline and shift tables from baseline 2 (only for the subjects who are in the placebo 
arm in the main study) to each visit will be provided for the following LDL and Triglycerides categories 
(after rounding to integer values if necessary). 
LDL: 
 
0: ≤ 130 mg/dL 
 
1: 131 to 159 mg/dL 
 
2: 160 to 189 mg/dL 
 
3: ≥ 190 mg/dL 
Triglycerides: 
 
0: ≤ 150 mg/dL 
 
1: 151 to 300 mg/dL 
 
2: 301 to 500 mg/dL 
 
3: 501 to 1000 mg/dL 
 
4: >1000 mg/dL 
 
All laboratory data will be provided in data listings. Day 1 Serum levels of the anti-müllerian hormone 
(AMH) and fasting glucose will be included in the listings. 
 
A subset listing will be presented for all abnormal clinically significant laboratory values. 
 
4.8.5. 
Vital Signs and Physical Examinations 
Vital signs include: Height (cm), Weight (kg), Body Mass Index, Systolic Blood Pressure (mmHg), Diastolic 
Blood Pressure (mmHg) and Heart Rate (beats/min). 
Height is assessed at Screening (main study); Weight is assessed at Month 6, Month 9, Month 12, as well 
as at M3 ExtFU and M6 ExtFU visits. Other Vital Signs are assessed at every monthly visit during the 
extension treatment period and at Month 1, 3 and 6 from the extension follow-up period. 
Physical Examination was to be assessed Month 6, Month 9, Month 12, as well as at M3 ExtFU and M6 
ExtFU visits.  


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The actual value, change from baseline and change from baseline 2 (only for the subjects who are in the 
placebo arm in the main study) for each on-study evaluation will be summarized by treatment group for 
vital signs.   
By-subject listings of vital sign measurements will be presented in data listings. 
Physical examination results at each time point will be summarized by treatment group; Shifts from 
Baseline and shift from baseline 2 (only for the subjects who are in the placebo arm in the main study) in 
physical examination findings to each on study visit will also be presented.   
All physical examination findings will be presented in a data listing. 
 
4.8.6. 
Electrocardiogram 
 
Local 12-lead ECG readings of QTcF are performed at every monthly visit during the extension treatment 
period, as well as Months 1,3 and 6 from the extension follow-up period. 
Baseline will be defined as the highest QTcF value prior to first dose of the main study. 
Baseline 2 will be defined as the highest QTcF value prior to first active dose of the extension study from 
screening to Month 6 (only for subjects in the placebo arm of the main study). 
The actual value, change from baseline and change from baseline 2 (only for the subjects who are in the 
placebo arm in the main study) of ECG results will be summarized descriptively, as well as the number 
and percent of subjects with normal, abnormal and clinically significant abnormal results at each study 
visit by treatment group. 
All ECG data for each subject will be provided in data listings. 
 
4.8.7. 
Concomitant Medications 
Concomitant medications will be coded using the WHO Drug dictionary. Frequencies and percentages 
will be presented for each treatment group and overall by the first level anatomical main (ATC 1) group 
and preferred name. 
All medications administered between the date of the Month 6 visit and the date of the last dose of 
extension study drug, inclusive, (i.e., all medications starting or ongoing during the time interval) are 
concomitant to the extension treatment period.  
Concomitant medications tables will be presented for the following periods: Month 6 to Month 12 
(Extension treatment period) and Month 12 to Month 6 ExFU (Extension follow-up period) as defined in 
section 4.2.12. 


     Statistical Analysis Plan  
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The use of prior and concomitant medications will be included in a by-subject data listing. 
 
4.8.8. 
Transvaginal Ultrasound (TVUS) 
TVUS was to be performed at Month 6, Month 9, Month 12, as well as Month 3 and Month 6 of Extension 
Follow-up period. 
The actual value, change from baseline and change from baseline 2 (only for subjects in the placebo arm 
in the main study) will be summarized by treatment group for uterus length, width, and depth in mm and 
corresponding uterine volume in cm3, endometrium thickness in mm. 
The number and percentage of subjects with ovarian endometrioma with a diameter of 7 cm or greater, 
and development of any uterus, left ovary or right ovary abnormality over time will be presented by 
treatment group. 
All TVUS data for each subject will be provided in data listings. 
 
4.8.9. 
Other Examinations 
4.8.9.1. 
Endometrial biopsy 
Biopsies for histological assessment were obtained for each subject at the following timepoints:   
- 
Month 6 or one at Month 12 if endometrium thickness via TVUS is > 5 mm  
- 
Month 1 ExtFU, 3 ExtFU, or 6 ExtFU if not obtained at Month 12 or if the preceding biopsy diagnosis 
is different than “benign endometrium”  
On biopsies with a primary diagnostic 1 either “hyperplasia” or “Malignant Endometrial Neoplasm”, a 
second read should be done at other visit than screening. For hyperplasia diagnostic, in case of multiple 
readings of the same sample, the most severe diagnostics will be selected for the statistical analysis, 
considering the following order, from less severe to more severe: simple without atypia hyperplasia < 
simple with atypia hyperplasia < complex without atypia hyperplasia < complex with atypia hyperplasia. 
For Malignant Endometrial Neoplasm, we assume that there will be no difference on diagnostic between 
the readings. 
Biopsies with a primary diagnostic 1 “Benign Endometrium” will be analyzed in the classification “Benign 
Endometrium without Hyperplasia or Atypia”. 
A summary at each time point will be performed (number and percentage of subjects with normal, 
abnormal, not assessable).  


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Biopsy assessment will be summarized by classification (primary diagnosis 1) and primary diagnoses 
(diagnoses 2, 3 and 4) at each visit. Subjects will be counted only once for classification (primary diagnosis 
1) and a subject could be in several diagnoses (e.g. if for example diagnoses 2 and 3 are fulfilled).  
Possible results by classification (primary diagnosis 1) and primary diagnoses (diagnoses 2, 3 and 4) are: 
- 
Benign Endometrium without Hyperplasia or Atypia: Proliferative, Atrophic, Metaplastic Changes, 
Secretory, Indeterminate, Inactive, Polyp, Endometritis, Menstrual phase, Other 
- 
Hyperplasia: Simple with Atypia, Simple without Atypia, Complex with Atypia, Complex without 
Atypia 
Malignant Endometrial Neoplasm: Carcinoma, Sarcoma, Other Malignant. 
Endometrial biopsy results, including multiple readings, will be reported in listings. 
4.8.9.2. 
Gynecological and Breast examination 
Gynecological Examination was to be assessed at Month 6, Month 9 and Month 12, as well as Month 3 
of the extension Follow-Up period.  
Breast examination (by palpation) was to be performed at Month 6 and Month 12, as well as Month 3 of 
the extension Follow-Up period.  
A summary at each time point will be performed (number and percentage of subjects with normal, 
abnormal, abnormal significant) for Gynecological and Breast Examinations.  
Results will also be reported in listings. 
 
4.8.10. 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
The C-SSRS questionnaire prospectively assess the occurrence of treatment-emergent suicidal ideation 
and behavior.  
Subjects completed: 
- either the “Baseline” C-SSRS version, capturing lifetime history of suicidal ideation and behavior, for 
subjects who were still in screening period in the main study,  
- or the “already enrolled subjects” C-SSRS version, for subjects already enrolled in the Extension study, 
and who were providing answers to the C-SSRS for the first time during the study 
- the “since last study visit” C-SSRS version, dedicated to subjects for whom the C-SSRS was completed at 
the previous study visit, for use at all remaining study visits. 
The “Baseline” C-SSRS version was to be completed during Screening, or at Day 1 if not done during 
Screening. 


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The following C-SSRS data will be summarized by time point (baseline “Lifetime” or Prior to Study Entry, 
“Since Study Start” and each post-baseline time point): 
  
The number of subjects experiencing the following, at any time post-baseline in the extension study, 
will be summarized from Month 6 up to Month 12. 
- 
Any suicidal ideation or behavior 
- 
Emergence of suicidal ideation. 
- 
Worsening of suicidal ideation. 
- 
Emergence of suicidal behavior. 
Any suicidal ideation or behavior is defined as an answer “Yes” for at least one of five questions for 
suicidal ideation or for at least one of five questions for suicidal behavior. 
Emergence of suicidal ideation/behavior is defined as having no suicidal ideation/behavior at baseline 
and having reported any type of suicidal ideation/behavior at any time post-baseline (including “Since 
Study Start” answers).   
Worsening of suicidal ideation is defined to occur when the most severe suicidal ideation rating since 
study start at any time post-baseline is more severe than its rating at baseline.  If data of suicidal ideation 
or behavior is missing at baseline then the subject will not be included in summaries of emergence or 
worsening of suicidal ideation or behavior. The “already enrolled subjects” C-SSRS version (“Prior to Entry 
Study”) will be used as baseline for subjects already randomized at the time of protocol amendment 3 
implementation. 
Same analysis will be repeated on the extension follow-up period. 
 
4.9. 
Exploratory Analyses 
Bone turnover markers will be listed on the Extension Safety Analysis Set.   
 


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5. 
CHANGES TO PLANNED ANALYSES 
Following the early termination of the study and due to the number of subjects randomized being really 
less than the target number if the study had been fully enrolled, the analyses planned in the protocol on 
efficacy and pharmacokinetic assessments have been removed and only listings (if data available) for 
these assessments will be displayed. The statistical analysis plan (SAP) will be focused on the safety 
analysis. 
For safety endpoints, the endpoint “Time to the first post-treatment menses” was initially planned in the 
protocol, but will not be described in this SAP, because the study was stopped prematurely and all 
subjects couldn’t be followed to evaluate this endpoint. 
 


     Statistical Analysis Plan  
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6. 
REFERENCES 
Not applicable 


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7. 
CLINICAL STUDY REPORT APPENDICES 
 
 
 


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7.1. 
Appendix A: Mapping rules for ediary data 
Table 5 Mapping Rules for 
 Device 
Cas
e # 
impacte
d visit 
Patient status 
Schedul
e of 
 daily 
diary 
impact 
on data 
Cytel action on IMP 
intake data 
Cytel action on 
Menstrual data 
Cytel 
mapping 
cut off date 
(from eCRF) 
1 
Month 6 
patient was included in 
EXT 
remain
ed in 
MAIN 
TREAT
MENT 
(due to 
Covid 
remote 
visit or 
to site 
error in 
diary 
comple
tion)  
data 
present 
in the 
Main 
datasets 
should be 
considere
d for the 
analysis 
of the 
extension 
study 
mapping 
n/a 
from 
MAIN 
TREAT to 
EXT 
TREAT 
First IMP intake 
in EXT 


     Statistical Analysis Plan  
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2 
Month 6 
patient was included in 
EXT 
resched
uled to 
MAIN 
FU (due 
to site 
error in 
diary 
comple
tion)  
data 
present 
in the 
Main 
datasets 
should be 
considere
d for the 
analysis 
of the 
extension 
study 
n/a - missing in final 
DB 
n/a 
from 
MAIN FU 
to EXT 
TREAT 
First IMP intake 
in EXT 
3 
Month 6 
patient entered MAIN 
FU 
resched
uled to 
EXT 
TREAT
MENT 
(site 
error in 
diary 
comple
tion)  
data 
present 
in the 
Extension 
datasets 
should be 
considere
d for the 
analysis 
of the 
Main 
study 
"Is the subject 
eligible to the 6 
months treatment 
free follow-up?" is 
YES --> delete 
answers to YIMPI 
and IMPI 
n/a 
from EXT 
TREAT to 
MAIN FU 
MONTH 6 visit 
date 


     Statistical Analysis Plan  
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Protocol: 
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4 
Month 6 
patient entered MAIN 
FU 
remain
ed in 
MAIN 
TREAT
MENT 
(due to 
Covid 
remote 
visit or 
to site 
error in 
diary 
comple
tion)  
Data 
regarding 
IMP 
intake 
will be 
present 
for this 
period   
"Is the subject 
eligible to the 6 
months treatment 
free follow-up?" is 
YES --> delete 
answers to YIMPI 
and IMPI 
n/a 
n/a - 
remain in 
MAIN DB 
MONTH 6 visit 
date 
5 
Month 6 
whatever status: 
DUPLICATE ENTRIES 
patient 
entered 
diary 
data in 
both 
Main 
and 
Extensi
on 
studies 
each 
day 
duplicate
s data will 
be 
present 
across 
the 
datasets 
CASE by CASE review - 
 cleaning needed 


     Statistical Analysis Plan  
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6 
Day 1 
patient entered MAIN 
TREATMENT 
remain
ed in 
SCREEN
ING 
(due to 
site 
error in 
diary 
comple
tion) 
Data 
regarding 
IMP 
intake 
will not 
be 
present 
for this 
period 
and data 
regarding 
menstrua
l periods 
will be 
present  
n/a - missing in final 
DB 
delete the answers 
to “is it your 
Menstrual period?” 
and start date 
questions, if any 
n/a - 
remain in 
MAIN DB 
First IMP intake 
in MAIN 
 
 
 


     Statistical Analysis Plan  
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Protocol: 
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Document Version No.: 
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Table 6 Mapping Rules for Signant Health Device 
Cas
e # 
impacted 
visit 
Patient 
status 
Schedule of 
Signant Health 
daily diary 
impact on 
data 
Cytel action on 
IMP intake data 
Cytel action on 
Menstrual data 
Cytel 
mapping 
cut off date 
(from eCRF) 
1 
Month 6 
patient was 
included in 
EXT 
remained in 
MAIN 
TREATMENT 
(due to Covid 
remote visit or 
to site error in 
diary 
completion)  
data present 
in the Main 
datasets 
should be 
considered for 
the analysis of 
the extension 
study 
mapping 
n/a 
from MAIN 
TREAT to 
EXT TREAT 
First IMP 
intake in EXT 
2 
Month 6 
patient was 
included in 
EXT 
rescheduled to 
MAIN FU (due 
to site error in 
diary 
completion)  
data present 
in the Main 
datasets 
should be 
considered for 
the analysis of 
the extension 
study 
n/a - missing in 
final DB 
n/a 
from MAIN 
FU to EXT 
TREAT 
First IMP 
intake in EXT 
3 
Month 6 
patient 
entered 
MAIN FU 
rescheduled to 
EXT 
TREATMENT 
(site error in 
data present 
in the 
Extension 
datasets 
should be 
delete answers to 
Yesterday IMP 
intake and to 
Today IMP intake if 
any 
n/a 
from EXT 
TREAT to 
MAIN FU 
MONTH 6 visit 
date 


     Statistical Analysis Plan  
Sponsor:  
ObsEva 
 
Protocol: 
19-OBE2109-005 
Document Version No.: 
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diary 
completion)  
considered for 
the analysis of 
the Main 
study 
4 
Month 6 
patient 
entered 
MAIN FU 
remained in 
MAIN 
TREATMENT 
(due to Covid 
remote visit or 
to site error in 
diary 
completion)  
Data regarding 
IMP intake will 
be present for 
this period   
delete answers to 
Yesterday IMP 
intake and to 
Today IMP intake if 
any 
n/a 
n/a - 
remain in 
MAIN DB 
MONTH 6 visit 
date 
5 
Day 1 
patient 
entered 
MAIN 
TREATMENT 
remained in 
SCREENING 
(due to site 
error in diary 
completion) 
Data regarding 
IMP intake will 
not be present 
for this period 
and data 
regarding 
menstrual 
periods will be 
present  
n/a - missing in 
final DB 
delete the 
answers to “is it 
your Menstrual 
period?” and 
start date 
questions, if any 
n/a - 
remain in 
MAIN DB 
First IMP 
intake in MAIN 
6 
Any 
Monthly 
visit of 
the Main 
patient in 
MAIN 
TREATMENT 
Set-up in 
screening 
period (due to 
site error in 
Data regarding 
IMP intake will 
not be present 
for this period 
n/a - missing in 
final DB 
delete the 
answers to “is it 
your Menstrual 
period?” and 
n/a - 
remain in 
MAIN DB 
First IMP 
intake in MAIN 


     Statistical Analysis Plan  
Sponsor:  
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Protocol: 
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Treatmen
t period 
diary 
completion) 
and data 
regarding 
menstrual 
periods will be 
present  
start date 
questions, if any 


     Statistical Analysis Plan  
Sponsor:  
ObsEva 
 
Protocol: 
19-OBE2109-005 
Document Version No.: 
1.0 
Document Date: 
18-MAY-2021 
 
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7.2. 
Appendix B: Statistical Tables/Figures/Listings to be Generated 
Section 14.1 Demographic Data and Subject Characteristics 
 
Table 14.1.1 Patients included in the extension study by Country and Site - Included in the 
extension study 
 
Table 14.1.2 Patient Disposition by treatment group – Randomized Subjects 
 
Table 14.1.3 Analysis Sets – Extension Safety Analysis Set 
 
Table 14.1.4 Number of Subjects by Visit - Extension Safety Analysis Set 
 
Table 14.1.4 Major Protocol Deviations – Extension Safety Analysis Set 
 
Table 14.1.5 Demographic and Baseline Characteristics – Extension Safety Analysis Set 
 
Table 14.1.6.1 Baseline Disease Characteristics: Menstrual Cycles and Pain – Extension 
Safety Analysis Set 
 
Table 14.1.6.2 Disease Characteristics before the first active dose of IMP: Menstrual Cycles 
and Pain – Extension Safety Analysis Set – subset of subjects who are in the placebo arm 
(actual arm) in the main study 
 
Table 14.1.7.1 Baseline Disease Characteristics: Transvaginal Ultrasound – Extension Safety 
Analysis Set 
 
Table 14.1.7.2 Disease Characteristics before the first active dose of IMP: Transvaginal 
Ultrasound – Extension Safety Analysis Set – subset of subjects who are in the placebo arm 
(actual arm) in the main study 
 
Table 14.1.8.1 Other Baseline examinations – Extension Safety Analysis Set 
 
Table 14.1.8.2 Other Baseline examinations before the first active dose of IMP – Extension 
Safety Analysis Set – subset of subjects who are in the placebo arm (actual arm) in the main 
study 
 
Table 14.1.9 Medical History – Extension Safety Analysis Set 
 
Table 14.1.10 Endometriosis History – Extension Safety Analysis Set 
 
Table 14.1.11.1 Exposure and Compliance to Study Treatment – Extension Safety Analysis 
Set 
 
 


     Statistical Analysis Plan  
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Section 14.3.1 Adverse Events 
 
Table 14.3.1.1.1 Summary of Treatment-Emergent Adverse Events from Month 6 to Month 
12 – Extension Safety Analysis Set 
 
Table 14.3.1.1.2 Summary of Treatment-Emergent Adverse Events from Month 12 to Month 
6 ExFU - Follow-up Extension Safety Analysis Set 
 
Table 14.3.1.2.1 Treatment-Emergent Adverse Events by MedDRA SOC and Preferred Term 
from Month 6 to Month 12 – Extension Safety Analysis Set 
 
Table 14.3.1.2.2 Treatment-Emergent Adverse Events by MedDRA SOC and Preferred Term 
from Month 12 to Month 6 ExFU – Follow-up Extension Safety Analysis Set 
 
Table 14.3.1.3.1 Non-Serious Treatment-Emergent Adverse Events by MedDRA SOC and 
Preferred Term from Month 6 to Month 12 – Extension Safety Analysis Set (if applicable) 
 
Table 14.3.1.3.2 Non-Serious Treatment-Emergent Adverse Events by MedDRA SOC and 
Preferred Term from Month 12 to Month 6 ExFU – Follow-up Extension Safety Analysis Set 
(if applicable) 
Section 14.4 Other Safety Data 
 
Table 14.4.1.1.1 Bone Mineral Density (BMD) by Dual-Energy X-ray Absorptiometry (DXA) 
from Month 7 up to Month 6 Extension Follow-up – Extension Safety Analysis Set 
 
Table 14.4.1.2.1 Bone Mineral Density (BMD) by Dual-Energy X-ray Absorptiometry (DXA) - 
Category of Percent Change from Month 7 up to Month 6 Extension Follow-up – Extension 
Safety Analysis Set 
 
Table 14.4.1.3.1 Bone Mineral Density (BMD) by Dual-Energy X-ray Absorptiometry (DXA) Z-
scores from Month 7 up to Month 6 Extension Follow-up – Extension Safety Analysis Set 
 
Table 14.4.2.1 Hematology Parameters by Visit from Month 7 up to Month 6 Extension 
Follow-up – Extension Safety Analysis Set 
 
Table 14.4.2.2 Hematology Parameters - Shifts from Baseline Based on Clinical Findings from 
Month 7 up to Month 6 Extension Follow-up – Extension Safety Analysis Set 
 
Table 14.4.2.3 Hematology Parameters - Shifts from Baseline 2* based on Clinical Findings 
from Month 7 up to Month 6 Extension Follow-up – Extension Safety Analysis Set – subset of 
subjects who are in the placebo arm (actual arm) in the main study 
 
Table 14.4.2.4 Hematology Parameters - Shifts from Baseline Based on Normal Ranges from 
Month 7 up to Month 6 Extension Follow-up – Extension Safety Analysis Set 


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 
Table 14.4.2.5 Hematology Parameters - Shifts from Baseline 2* based on Clinical Findings 
from Month 7 up to Month 6 Extension Follow-up – Extension Safety Analysis Set – subset of 
subjects who are in the placebo arm (actual arm) in the main study 
 
Table 14.4.3.1 Coagulation Parameters by Visit from Month 7 up to Month 6 Extension 
Follow-up – Extension Safety Analysis Set See shell for Table 14.4.2.1. 
 
Table 14.4.3.2 Coagulation Parameters - Shifts from Baseline Based on Clinical Findings from 
Month 7 up to Month 6 Extension Follow-up – Extension Safety Analysis Set 
 
Table 14.4.3.3 Coagulation Parameters - Shifts from Baseline 2* based on Clinical Findings 
from Month 7 up to Month 6 Extension Follow-up – Extension Safety Analysis Set – subset of 
subjects who are in the placebo arm (actual arm) in the main study 
 
Table 14.4.3.4 Coagulation Parameters - Shifts from Baseline Based on Normal Ranges from 
Month 7 up to Month 6 Extension Follow-up – Extension Safety Analysis Set See shell for 
Table 14.4.2.4. 
 
Table 14.4.3.5 Coagulation Parameters - Shifts from Baseline 2* based on Clinical Findings 
from Month 7 up to Month 6 Extension Follow-up – Extension Safety Analysis Set – subset of 
subjects who are in the placebo arm (actual arm) in the main study 
 
Table 14.4.4.1 Chemistry Parameters by Visit from Month 7 up to Month 6 Extension Follow-
up – Extension Safety Analysis Set See shell for Table 14.4.2.1. 
 
Table 14.4.4.2 Chemistry Parameters - Shifts from Baseline Based on Clinical Findings from 
Month 7 up to Month 6 Extension Follow-up – Extension Safety Analysis Set 
 
Table 14.4.4.3 Chemistry Parameters - Shifts from Baseline 2* based on Clinical Findings 
from Month 7 up to Month 6 Extension Follow-up – Extension Safety Analysis Set – subset of 
subjects who are in the placebo arm (actual arm) in the main study 
 
Table 14.4.4.4 Chemistry Parameters - Shifts from Baseline Based on Normal Ranges from 
Month 7 up to Month 6 Extension Follow-up – Extension Safety Analysis Set 
 
Table 14.4.4.5 Chemistry Parameters - Shifts from Baseline 2* based on Clinical Findings 
from Month 7 up to Month 6 Extension Follow-up – Extension Safety Analysis Set – subset of 
subjects who are in the placebo arm (actual arm) in the main study 
 
Table 14.4.5.1 Lipids by Visit from Month 7 up to Month 6 Extension Follow-up – Extension 
Safety Analysis Set See shell for Table 14.4.2.1. 


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 
Table 14.4.5.2 Lipids - LDL and HDL Categories by Visit from Month 7 up to Month 6 
Extension Follow-up – Extension Safety Analysis Set 
 
Table 14.4.5.3 Lipids - Shifts from Baseline Based on LDL Categories from Month 7 up to 
Month 6 Extension Follow-up – Extension Safety Analysis Set 
 
Table 14.4.5.5 Lipids - Shifts from Baseline 2* Based on LDL Categories from Month 7 up to 
Month 6 Extension Follow-up – Extension Safety Analysis Set – subset of subjects who are in 
the placebo arm (actual arm) in the main study 
 
Table 14.4.5.6 Lipids - Shifts from Baseline Based on Triglycerides Categories from Month 7 
up to Month 6 Extension Follow-up – Extension Safety Analysis Set 
 
Table 14.4.5.7 Lipids - Shifts from Baseline 2* Based on Triglycerides Categories from Month 
7 up to Month 6 Extension Follow-up – Extension Safety Analysis Set – subset of subjects 
who are in the placebo arm (actual arm) in the main study 
 
Table 14.4.5.8 Lipids Parameters - Shifts from Baseline Based on Clinical Findings from 
Month 7 up to Month 6 Extension Follow-up – Extension Safety Analysis Set 
 
Table 14.4.5.9 Lipids Parameters - Shifts from Baseline 2* based on Clinical Findings from 
Month 7 up to Month 6 Extension Follow-up – Extension Safety Analysis Set – subset of 
subjects who are in the placebo arm (actual arm) in the main study 
 
Table 14.4.5.10 Lipids Parameters - Shifts from Baseline Based on Normal Ranges from 
Month 7 up to Month 6 Extension Follow-up – Extension Safety Analysis Set 
 
Table 14.4.5.11 Lipids Parameters - Shifts from Baseline 2* based on Clinical Findings from 
Month 7 up to Month 6 Extension Follow-up – Extension Safety Analysis Set – subset of 
subjects who are in the placebo arm (actual arm) in the main study 
 
Table 14.4.6.1 Serum levels of P4, SHGB and LH from Month 7 up to Month 6 Extension 
Follow-up – Extension Safety Analysis Set 
 
Table 14.4.6.3 Proportions of Subjects with P4 at Least once >10.0 nMol/L from Month 6 to 
Month 12 – Extension Safety Analysis Set 
 
Table 14.4.7.1 Vital Signs by Visit from Month 7 up to Month 6 Extension Follow-up – 
Extension Safety Analysis Set 
 
Table 14.4.8.1 Physical Examination Findings from Month 9 up to Month 6 Extension Follow-
up – Extension Safety Analysis Set 
 
Table 14.4.8.2 Physical Examination Findings - Shifts from Baseline from Month 9 up to 
Month 6 Extension Follow-up – Extension Safety Analysis Set 


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 
Table 14.4.8.3 Physical Examination Findings - Shifts from Baseline 2* from Month 9 up to 
Month 6 Extension Follow-up – Extension Safety Analysis Set – subset of subjects who are in 
the placebo arm (actual arm) in the main study 
 
Table 14.4.9.1 ECG - QTcF by Visit from Month 7 up to Month 6 Extension Follow-up – 
Extension Safety Analysis Set 
 
Table 14.4.9.2 ECG Findings from Month 7 up to Month 6 Extension Follow-up – Extension 
Safety Analysis Set 
 
Table 14.4.10.1 Gynecological Examination Findings by Visit from Month 9 up to Month 6 
Extension Follow-up – Extension Safety Analysis Set 
 
Table 14.4.11.2 Breast Examination Findings by Visit from Month 9 up to Month 6 Extension 
Follow-up – Extension Safety Analysis Set 
 
Table 14.4.12.1 Endometrial Biopsy Findings by visit from Month 12 up to Month 6 
Extension Follow-up – Extension Safety Analysis Set 
 
Table 14.4.12.2 Endometrial Biopsy Diagnosis by Classification and Primary Diagnosis from 
Month 12 up to Month 6 Extension Follow-up – Extension Safety Analysis Set 
 
Table 14.4.13.1 Concomitant Medications From Month 6 to Month 12 – Extension Safety 
Analysis Set 
 
Table 14.4.13.2 Concomitant Medications From Month 12 to Month 6 Extension Follow-up– 
Follow-up Extension Safety Analysis Set 
 
Table 14.4.14.1 Transvaginal Ultrasound: Uterus Length, Width, Depth, uterine Volume and  
 
Thickness by Visit from Month 9 up to Month 6 Extension Follow-up – Extension Safety 
Analysis Set 
 
Table 14.4.14.2 Transvaginal Ultrasound: Ovaries assessment by Visit from Month 9 up to 
Month 6 Extension Follow-up – Extension Safety Analysis Set 
 
Table 14.4.15.1 Suicide-related Treatment Emergent Events (C-SSRS) from Month 7 up to 
Month 12 – Extension Safety Analysis Set 
 
Table 14.4.15.2 Suicide-related Events (C-SSRS) from Month 1 ExFU to Month 6 ExFU – 
Follow-up Extension Safety Analysis Set 
Post-text Listings 
 
Listing 16.1.7 Randomization scheme and codes (patient identification and treatment) – 
Extension Safety Analysis Set 


     Statistical Analysis Plan  
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 
Listing 16.2.1.1 Subject Disposition and Study Termination Information – Part A - Extension 
Safety Analysis Set 
 
Listing 16.2.1.2 Subject Disposition and Study Termination Information – Part B – Extension 
Safety Analysis Set 
 
Listing 16.2.2.1 Inclusion Criteria – Extension Safety Analysis Set 
 
Listing 16.2.2.2 Exclusion Criteria – Extension Safety Analysis Set 
 
Listing 16.2.2.3 Protocol Deviations – Extension Safety Analysis Set 
 
Listing 16.2.3.1 Analysis Sets – Extension Safety Analysis Set 
 
Listing 16.2.3.2 Subjects with actual treatment not corresponding to any of the planned 
treatment groups – Extension Safety Analysis Set 
 
Listing 16.2.4.1 Demographic and Baseline Information – Extension Safety Analysis Set 
 
Listing 16.2.4.2 Menstrual Cycle – Extension Safety Analysis Set 
 
Listing 16.2.4.3 Biberoglu & Behrman at Screening – Extension Safety Analysis Set 
 
Listing 16.2.4.4 Pelvic Pain Scores and Analgesic Use at Baseline – Extension Safety Analysis 
Set 
 
Listing 16.2.4.5 Endometriosis History – Extension Safety Analysis Set 
 
Listing 16.2.4.6 Medical History – Extension Safety Analysis Set 
 
Listing 16.2.5.1 Dispensing and Study Treatment Administration – Extension Safety Analysis 
Set 
 
Listing 16.2.5.2 Study Treatment Overdose and Misuse – Extension Safety Analysis Set 
 
Listing 16.2.5.3 Treatment Compliance – Extension Safety Analysis Set 
 
Listing 16.2.6.1 Daily Diary – Endometriosis pelvic pain and analgesic use – Extension Safety 
Analysis Set 
 
Listing 16.2.6.2 Daily Diary – Daily function, daily difficulties, and other pains – Extension 
Safety Analysis Set 
 
Listing 16.2.6.3 Monthly severity questions – Extension Safety Analysis Set 
 
Listing 16.2.6.4 EHP-30 Questionnaire over Time – Extension Safety Analysis Set 
 
Listing 16.2.6.5 HRPQ Questionnaire over Time – Extension Safety Analysis Set 


     Statistical Analysis Plan  
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 
Listing 16.2.6.6 HRUQ Questionnaire over Time – Non-study endometriosis related health 
visits – Extension Safety Analysis Set 
 
Listing 16.2.6.7 HRUQ Questionnaire over Time – Diagnostic or therapeutic procedures - 
Extension Safety Analysis Set 
 
Listing 16.2.6.8 HRUQ Questionnaire over Time – Nights in Hospital - Extension Safety 
Analysis Set 
 
Listing 16.2.6.9 Physician and Subject Surgery Intention Question over Time - Extension 
Safety Analysis Set 
 
Listing 16.2.6.10 PROMIS Fatigue Questionnaire over Time - Extension Safety Analysis Set 
 
Listing 16.2.6.11 EQ-5D-5L Questionnaire over Time - Extension Safety Analysis Set 
 
Listing 16.2.6.12 Patient Global Impression of Change over Time - Extension Safety Analysis 
Set 
 
Listing 16.2.6.13 Patient Global Impression of Severity over Time - Extension Safety Analysis 
Set 
 
Listing 16.2.7.1 All Adverse Events by Subject and MedDRA SOC/ PT and Verbatim Term -
Extension Safety Analysis Set 
 
Listing 16.2.7.2 Treatment Emergent Adverse Events by Subject and MedDRA SOC/ PT and 
Verbatim Term - Extension Safety Analysis Set 
 
Listing 16.2.7.3 Related Treatment Emergent Adverse Events by Subject and MedDRA SOC/ 
PT and Verbatim Term - Extension Safety Analysis Set 
 
Listing 16.2.7.4 Serious Treatment Emergent Adverse Events by Subject and MedDRA SOC/ 
PT and Verbatim Term - Extension Safety Analysis Set 
 
Listing 16.2.7.5 Treatment-Emergent Adverse Events Leading to Discontinuation by Subject 
and MedDRA SOC/ PT and Verbatim Term - Extension Safety Analysis Set 
 
Listing 16.2.7.6 Treatment-Emergent Adverse Events Leading to Death by Subject and 
MedDRA SOC/ PT and Verbatim Term - Extension Safety Analysis Set 
 
Listing 16.2.7.7 Post-Treatment Adverse Events and MedDRA SOC/ PT and Verbatim Term - 
Extension Safety Analysis Set 
 
Listing 16.2.8.1.1 Central Laboratory Hematology - Extension Safety Analysis Set 


     Statistical Analysis Plan  
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 
Listing 16.2.8.1.1 Central Laboratory Hematology: Abnormal Clinically Significant Values - 
Extension Safety Analysis Set 
 
Listing 16.2.8.2.1 Central Laboratory: Coagulation - Extension Safety Analysis Set 
 
Listing 16.2.8.2.2 Central Laboratory Coagulation: Abnormal Clinically Significant Values - 
Extension Safety Analysis Set 
 
Listing 16.2.8.3.1 Central Laboratory: Chemistry - Extension Safety Analysis Set 
 
Listing 16.2.8.3.2 Central Laboratory Chemistry: Abnormal Clinically Significant Values - 
Extension Safety Analysis Set 
 
Listing 16.2.8.4.1 Central Laboratory: Lipids - Extension Safety Analysis Set 
 
Listing 16.2.8.4.2 Central Laboratory Lipids: Abnormal Clinically Significant Values - Extension 
Safety Analysis Set 
 
Listing 16.2.8.5.1 Central Laboratory: Hormones - Extension Safety Analysis Set 
 
Listing 16.2.8.5.2 Central Laboratory Hormones : Abnormal Clinically Significant Values - 
Extension Safety Analysis Set 
 
Listing 16.2.8.6 Urinary Protein Dipstick / Urinary Pregnancy Test - Extension Safety Analysis 
Set 
 
Listing 16.2.9.1 Vital Signs - Extension Safety Analysis Set 
 
Listing 16.2.9.2 Physical Examination - Extension Safety Analysis Set 
 
Listing 16.2.9.3 Transvaginal Ultrasound - Extension Safety Analysis Set 
 
Listing 16.2.9.4  Gynecological Examination - Extension Safety Analysis Set 
 
Listing 16.2.9.5  Breast Examination - Extension Safety Analysis Set 
 
Listing 16.2.9.6 PAP Smear - Extension Safety Analysis Set 
 
Listing 16.2.9.7 Prior Medications - Extension Safety Analysis Set 
 
Listing 16.2.9.8 Prior Interventional Surgeries/Procedures for Endometriosis/ Endometriosis 
Symptoms – Extension Safety Analysis Set 
 
Listing 16.2.9.9 Concomitant Medications - Extension Safety Analysis Set 
 
Listing 16.2.9.10 Bone Mineral Density (BMD) by Dual-Energy X-ray Absorptiometry (DXA) - 
Extension Safety Analysis Set 
 
Listing 16.2.9.11 Endometrial Biopsy - Extension Safety Analysis Set 


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 
Listing 16.2.9.12 lead ECG - Extension Safety Analysis Set 
 
Listing 16.2.9.13  CSSR-S – Extension Safety Analysis Set 
 
Listing 16.2.9.14  Bone Turnover Markers – Extension Safety Analysis Set 
 


18-OBE2109-005 (Edelweiss 5) - Statistical
Analysis Plan - Version 1.0 - 20210518
Final Audit Report
2021-05-20
Created:
2021-05-20
By:
Status:
Signed
Transaction ID:
CBJCHBCAABAA-vxsoOv1nq1ejaMBVmOVXrvT_oCUGcgm
"18-OBE2109-005 (Edelweiss 5) - Statistical Analysis Plan - Ver
sion 1.0 - 20210518" History