Clinical trial NCT03992846
Conditions: Endometriosis
Keywords: Dysmenorrhea Dyspareunia Dyschezia Non-menstrual pelvic pain
Sponsor: Kissei Pharmaceutical Co., Ltd.
Start date: 2019-06-13; Completion date: 2022-04-01
Enrollment: 486 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective of this study is to demonstrate the efficacy and safety of linzagolix administered orally once daily for 3 months at a dose of 75 mg alone or of 200 mg in combination with add-back hormone replacement therapy (ABT: estradiol (E2) 1 mg / norethisterone acetate (NETA) 0.5 mg) versus placebo, in the management of moderate to severe endometriosis-associated pain (EAP).

Detailed description:
This is a prospective, randomized, double-blind, placebo-controlled study to demonstrate the efficacy and safety of linzagolix administered orally once daily at doses of 75 mg alone and 200 mg in combination with low dose ABT (E2 1 mg/NETA 0.5 mg) versus placebo in the management of moderate to severe EAP in 450 women.

Eligible subjects who have completed the 6-month treatment period may enter a separate extension study for 6 additional months of active treatment (no placebo control). Subjects who do not continue in the extension study will enter a 6 month treatment-free follow-up phase.

Arms: arm 1: None arm 2: None arm 3: 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 documents:
Prot_002.pdf: 
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OBSEVA CONFIDENTIAL 
CLINICAL STUDY PROTOCOL 
 
Protocol Number: 
18-OBE2109-003 
EudraCT Number: 
2019-000283-26 
Investigational Medicinal 
Product: 
Linzagolix (OBE2109) 
Study Title: 
A Phase 3 multicenter, randomized, double-blind, placebo-
controlled, clinical study to assess the efficacy and safety of 
linzagolix in subjects with moderate to severe endometriosis-
associated pain. 
Short Study Title: 
A phase 3 study to confirm the efficacy and safety of 
linzagolix to treat endometriosis-associated pain. 
Study Name: 
Edelweiss 3 
Version number: 
Version 4.0 
Date: 
27 July20 
Replacing:  
Version 3.0 – 25 June 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 
March 28, 2019 
General 
V2.0 – March 28, 2019 
02 
June 25, 2019 
General 
V3.0 – June 25, 2019 
03 
July 27, 2020 
General 
V4.0 – July 27, 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 
of signature 
 
(Clinical Trial Director) 
 
Signature 
 signature 
 
(Medical Responsible) 
 
 
Contract Research Organization(s): 
 
 
Signature 
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 ................................................................................................ 7 
2 
LIST OF FIGURES ...................................................................................................... 13 
3 
LIST OF ABBREVIATIONS ....................................................................................... 14 
4 
SYNOPSIS .................................................................................................................... 19 
5 
BACKGROUND INFORMATION .............................................................................. 32 
5.1 
INTRODUCTION TO LINZAGOLIX ................................................................................ 32 
5.2 
ENDOMETRIOSIS ............................................................................................................. 32 
5.3 
CONVENTIONAL TREATMENT OF ENDOMETRIOSIS .............................................. 32 
5.4 
SUMMARY OF NON-CLINICAL STUDIES .................................................................... 33 
5.4.1 
Non-Clinical Pharmacology .................................................................................................. 33 
5.4.2 
Non-Clinical Pharmacokinetics and Toxicology.................................................................... 34 
5.4.3 
Non-clinical summary .......................................................................................................... 35 
5.5 
SUMMARY OF CLINICAL STUDIES .............................................................................. 35 
5.5.1 
Pharmacokinetics/Pharmacodynamics ................................................................................ 35 
5.5.2 
Efficacy ................................................................................................................................. 37 
5.5.3 
Safety 37 
5.6 
RATIONALE FOR THE CURRENT STUDY ................................................................... 38 
5.7 
SUMMARY OF OVERALL RISKS AND BENEFITS ...................................................... 39 
6 
OBJECTIVES ............................................................................................................... 40 
6.1 
EFFICACY OBJECTIVES .................................................................................................. 40 
6.1.1 
Primary ................................................................................................................................. 40 
6.1.2 
Secondary ............................................................................................................................ 40 
6.2 
SAFETY OBJECTIVES ...................................................................................................... 41 
6.3 
EXPLORATORY OBJECTIVES ........................................................................................ 41 
7 
ENDPOINTS ................................................................................................................. 41 
7.1 
EFFICACY ENDPOINTS ................................................................................................... 41 


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7.1.1 
Primary ................................................................................................................................. 41 
7.1.2 
Secondary ............................................................................................................................ 41 
7.2 
SAFETY ENDPOINTS ....................................................................................................... 43 
7.3 
EXPLORATORY ENDPOINTS ......................................................................................... 44 
8 
STUDY DESIGN........................................................................................................... 44 
9 
STUDY POPULATION ................................................................................................ 46 
9.1 
SUBJECTS .......................................................................................................................... 46 
9.1.1 
Description of the target population ................................................................................... 46 
9.1.2 
Number of subjects .............................................................................................................. 46 
9.1.3 
Study region/location .......................................................................................................... 46 
9.2 
ENTRY CRITERIA ............................................................................................................. 46 
9.2.1 
Inclusion Criteria .................................................................................................................. 46 
9.2.2 
Exclusion Criteria.................................................................................................................. 47 
10 
STUDY PROCEDURES AND ASSESSMENTS .......................................................... 50 
10.1 
GENERAL INSTRUCTIONS ............................................................................................. 50 
10.2 
OUTLINE OF STUDY PROCEDURES AND ASSESSMENTS ....................................... 52 
10.2.1 
Screening Period – Screening visit ....................................................................................... 52 
10.2.2 
Treatment period ................................................................................................................. 55 
10.2.3 
Follow-up period without treatment for subjects not entering the extension study .......... 60 
10.3 
EFFICACY OBSERVATIONS AND MEASUREMENTS ................................................ 63 
10.3.1 
Modified Biberoglu and Behrman questionnaire ................................................................ 63 
10.3.2 
Daily diary ............................................................................................................................ 64 
10.3.3 
Outcome rating scales assessed at site visits ....................................................................... 66 
10.4 
SAFETY OBSERVATIONS AND MEASUREMENTS .................................................... 70 
10.4.1 
Adverse Events ..................................................................................................................... 70 
10.4.2 
Physical Examination ........................................................................................................... 70 
10.4.3 
Vital signs ............................................................................................................................. 71 
10.4.4 
Transvaginal ultrasound ....................................................................................................... 71 
10.4.5 
Endometrial biopsies ........................................................................................................... 71 


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10.4.6 
Bone mineral density and DXA ............................................................................................ 73 
10.4.7 
Bone markers ....................................................................................................................... 73 
10.4.8 
Laboratory parameters ........................................................................................................ 73 
10.4.9 
Electrocardiogram ................................................................................................................ 74 
10.4.10 
Columbia-Suicide Severity Rating Scale (C-SSRS) ................................................................. 74 
10.5 
LINZAGOLIX AND KP017 PLASMA LEVELS ............................................................... 74 
10.6 
CONCOMITANT MEDICATIONS AND THERAPIES .................................................... 75 
10.6.1 
Permitted Medicines ............................................................................................................ 75 
10.6.2 
Prohibited Medicines ........................................................................................................... 76 
10.6.3 
Non-Drug Therapies ............................................................................................................. 77 
10.7 
SUBJECT COMPLETION AND WITHDRAWAL ............................................................ 77 
10.7.1 
Subject Completion .............................................................................................................. 77 
10.7.2 
Subject Withdrawal .............................................................................................................. 77 
10.7.3 
Subject Replacement ........................................................................................................... 79 
11 
INVESTIGATIONAL MEDICINAL PRODUCT ....................................................... 80 
11.1 
DESCRIPTION OF INVESTIGATIONAL MEDICINAL PRODUCTS............................ 80 
11.2 
DOSAGE AND ADMINISTRATION ................................................................................ 81 
11.3 
PACKAGING AND LABELLING ..................................................................................... 82 
11.4 
PREPARATION, HANDLING AND STORAGE .............................................................. 83 
11.5 
IMP ACCOUNTABILITY .................................................................................................. 83 
11.6 
ASSIGNMENT TO TREATMENT GROUPS .................................................................... 84 
11.7 
ASSESSMENT OF INVESTIGATIONAL MEDICINAL PRODUCT COMPLIANCE ... 84 
11.8 
METHOD OF BLINDING .................................................................................................. 85 
11.9 
EMERGENCY UNBLINDING ........................................................................................... 85 
11.10 
TREATMENT OF OVERDOSE AND MISUSE ................................................................ 85 
11.11 
OTHER SUPPLIES TO BE USED IN THE STUDY ......................................................... 86 
12 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS ....................................... 86 
12.1 
ADVERSE EVENTS ........................................................................................................... 86 
12.1.1 
Definitions ............................................................................................................................ 86 


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12.1.2 
Abnormal laboratory findings and other objective measurements..................................... 88 
12.1.3 
Baseline Medical Conditions ................................................................................................ 88 
12.1.4 
Exacerbation of endometriosis ............................................................................................ 89 
12.1.5 
Adverse Events of Special Interest ....................................................................................... 89 
12.2 
PROCEDURES FOR ELICITING, RECORDING AND REPORTING ADVERSE 
EVENTS .............................................................................................................................. 89 
12.2.1 
Eliciting Adverse Events ....................................................................................................... 89 
12.2.2 
Recording of Adverse Events in the eCRF ............................................................................ 89 
12.2.3 
Reporting of Adverse Events ................................................................................................ 90 
12.3 
SERIOUS ADVERSE EVENTS ......................................................................................... 90 
12.3.1 
Definitions ............................................................................................................................ 90 
12.3.2 
SAE Urgent Reporting Procedure ......................................................................................... 91 
12.4 
REPORTING TO THE INSTITUTIONAL REVIEW BOARDS AND REGULATORY 
AUTHORITIES ................................................................................................................... 92 
12.5 
REPORTING PERIOD ........................................................................................................ 92 
12.6 
PREGNANCY AND IN UTERO DRUG EXPOSURE ...................................................... 93 
13 
DATA ANALYSIS AND STATISTICS ........................................................................ 94 
13.1 
TEST OF HYPOTHESES ................................................................................................... 94 
13.2 
SAMPLE SIZE .................................................................................................................... 95 
13.3 
RANDOMIZATION ............................................................................................................ 95 
13.4 
ANALYSIS SETS ............................................................................................................... 95 
13.5 
DATA ANALYSIS .............................................................................................................. 96 
13.5.1 
Baseline Assessment ............................................................................................................ 97 
13.5.2 
Primary Efficacy Analysis ...................................................................................................... 97 
13.5.3 
Secondary Efficacy Analysis ................................................................................................. 98 
13.5.4 
Additional Efficacy Analysis ................................................................................................ 101 
13.5.5 
Safety Analysis ................................................................................................................... 101 
13.5.6 
Pharmacokinetic analysis methodology ............................................................................ 102 
13.5.7 
Pharmacodynamic analysis methodology ......................................................................... 102 
13.5.8 
Missing Data....................................................................................................................... 103 


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13.6 
STUDY SPECIFIC DATA ANALYSIS ........................................................................... 103 
13.6.1 
Responder Threshold Analysis ........................................................................................... 103 
13.6.2 
End-of-Treatment Period Analysis ..................................................................................... 103 
13.6.3 
Treatment Free Follow-Up Period Analysis ....................................................................... 103 
14 
STUDY ADMINISTRATION..................................................................................... 104 
14.1 
REGULATORY AND ETHICAL CONSIDERATIONS ................................................. 104 
14.1.1 
Informed Consent .............................................................................................................. 104 
14.1.2 
Regulatory Authority Approval .......................................................................................... 104 
14.1.3 
Institutional Review Board Requirements / Independent Ethics Committee .................... 104 
14.1.4 
End of the study ................................................................................................................. 104 
14.2 
INVESTIGATOR RESPONSIBILITIES .......................................................................... 105 
14.3 
DATA MANAGEMENT ................................................................................................... 105 
14.4 
STUDY MONITORING ................................................................................................... 105 
14.5 
DATA MONITORING COMMITTEE ............................................................................. 105 
14.6 
SUBJECT CONFIDENTIALITY ...................................................................................... 106 
14.7 
QUALITY ASSURANCE ................................................................................................. 106 
14.8 
PROTOCOL DEVIATIONS ............................................................................................. 106 
14.9 
STUDY OR SITE DISCONTINUATION ......................................................................... 106 
14.10 
RETENTION OF ESSENTIAL STUDY DOCUMENTS ................................................. 107 
14.11 
PUBLICATION POLICY.................................................................................................. 107 


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15 
APPENDICES ............................................................................................................. 108 
APPENDIX A. SCHEDULE OF STUDY ASSESSMENTS – SCREENING AND TREATMENT PERIODS ............ 109 
APPENDIX B. SCHEDULE OF STUDY ASSESSMENTS – FOLLOW-UP PERIOD ......................................... 114 
APPENDIX C. MODIFIED BIBEROGLU & BEHRMAN SYMPTOM SEVERITY SCALE* ............................... 117 
APPENDIX D. ENDOMETRIOSIS HEALTH PROFILE QUESTIONNAIRE (EHP-30) ..................................... 119 
APPENDIX E. PROMIS FATIGUE – SHORT FORM 6A ........................................................................... 124 
APPENDIX F. HEALTH-RELATED PRODUCTIVITY QUESTIONNAIRE (HRPQ) ......................................... 125 
APPENDIX G. HEALTH RESOURCE UTILIZATION QUESTIONNAIRE (HRUQ) .......................................... 128 
APPENDIX H. PATIENT GLOBAL IMPRESSION OF CHANGE (PGIC) ....................................................... 133 
APPENDIX I. POST-TREATMENT PATIENT GLOBAL IMPRESSION OF CHANGE (PPGIC) ....................... 134 
APPENDIX J. PATIENT GLOBAL IMPRESSION OF SEVERITY (PGIS) ...................................................... 135 
APPENDIX K. SUBJECT SURGERY INTENTION QUESTIONNAIRE (SSIQ) ................................................ 136 
APPENDIX L. PHYSICIAN SURGERY INTENTION QUESTIONNAIRE (PSIQ) ............................................ 137 
APPENDIX M. EQ-5D-5L ...................................................................................................................... 138 
APPENDIX N. LABORATORY PARAMETERS ......................................................................................... 141 
APPENDIX O. ANALGESIC CHANGE DURING TREATMENT PERIOD ...................................................... 142 
APPENDIX P. STRONG CYP3A4 INDUCERS AND INHIBITORS .............................................................. 144 
APPENDIX Q. REFERENCE LIST ............................................................................................................ 146 
APPENDIX R. BASELINE C-SSRS .......................................................................................................... 148 
APPENDIX S. C-SSRS ALREADY ENROLLED SUBJECTS ......................................................................... 151 
APPENDIX T. C-SSRS SINCE LAST VISIT ............................................................................................... 154 
 
 


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OBSEVA CONFIDENTIAL 
2 LIST OF FIGURES 
FIGURE 1 : STUDY DESIGN ...................................................................................................................................... 45 
FIGURE 2 : SCHEDULE OF VISITS ............................................................................................................................ 52 
FIGURE 3 : BIOPSY PROCESS FOR MONTH 6 STUDY VISIT ........................................................................................ 71 
FIGURE 4 : BIOPSY PROCESS FOR THE FOLLOW-UP PERIOD VISITS........................................................................... 72 
FIGURE 5 : LINZAGOLIX/PLACEBO KIT DESIGN ....................................................................................................... 82 
 


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OBSEVA CONFIDENTIAL 
3 LIST OF ABBREVIATIONS 
ABT 
Add-Back Therapy 
AE 
Adverse Event 
Al 
Aluminum 
ALT 
ALanine amino Transferase 
APTT 
Activated Partial Thromboplastin Time 
AMH 
Anti-Müllerian Hormone 
AST 
ASpartate amino Transferase 
AUC 
Area Under the Curve 
AUC (24hr) 
Area Under the plasma concentration time Curve from time 0 to 24hr post-
dose 
AUC0-∞ 
Area Under the Curve from time 0 to infinite time 
AUC0-t 
Area Under the Curve from time 0 to the last measurable time 
AUCτ 
Area Under the Curve to the end of the dosing period 
BMD 
Bone Mineral Density 
BMI 
Body Mass Index 
BP 
Blood Pressure 
Bpm 
Beats Per minute 
°C 
Degree Celsius 
CDF 
Cumulative Distribution Function 
CK 
Creatine Kinase 
ClinRO 
Clinician Reported Outcome 
Cm 
Centimeter(s) 
COC 
Combined Oral Contraceptive 
CRA 
Clinical Research Associate 
CRO 
Contract Research Organization 
C-SSRS 
Columbia-Suicide Severity Rating Scale 


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OBSEVA CONFIDENTIAL 
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 
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 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FU 
Follow-Up 
FSH 
Follicle-Stimulating Hormone 
G 
Gram(s) 
GCP 
Good Clinical Practice 
γGT 
Gamma-Glutamyl Transferase 
GGT 
Gamma-Glutamyl Transpeptidase 
GMP 
Good Manufacturing Practice 
hGnRH 
human Gonadotropin Releasing Hormone 
HDL 
High Density Lipoprotein 


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OBSEVA CONFIDENTIAL 
HIV 
Human Immunodeficiency Virus 
Hr 
hour 
HRPQ 
Health Related Productivity Questionnaire 
HRUQ 
Health Resource Utilization Questionnaire 
IB 
Investigator Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IMP 
Investigational Medicinal Product 
INN 
International Nonproprietary Name 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IUD 
Intra-Uterine Device 
IWRS 
Interactive Web Response System 
Kg 
Kilogram(s) 
L 
Liter(s) 
LDH 
Lactate DeHydrogenase 
LDL 
Low Density Lipoprotein 
LEEP 
Loop Electrosurgical Excision Procedure 
LFT 
Liver Function Test 
LH 
Luteinizing Hormone 
LOQ 
Limit Of Quantification 
mB&B 
Modified Biberoglu & Behrman 
MCH 
Mean Corpuscular Haemoglobin 
MCHC 
Mean Corpuscular Haemoglobin Concentration 
MCV 
Mean Corpuscular Volume 
Mg 
Milligram(s) 


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Min 
Minute(s) 
mL 
Milliliter(s) 
MME 
Morphine Milligram Equivalent 
mPGIS 
Patient Global Impression of Severity – monthly recall  
mmHg 
millimeter of mercury 
msec 
Millisecond 
nmol 
Nanomole(s) 
NETA 
NorEThisterone Acetate 
NMPP 
Non-Menstrual Pelvic Pain 
NOAEL 
No Observed Adverse Effect level 
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 
PharmacoDynamics 
PDF 
Probability Density Function 
PGIC 
Patient Global Impression of Change 
PPGIC 
Post-treatment Patient Global Impression of Change 
PGIS 
Patient Global Impression of Severity 
PK 
Pharmacokinetic 
PP 
Per Protocol 
PSF 
Pregnancy Surveillance Form 
PSIQ 
Pysician Surgery Intention Question 


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OBSEVA CONFIDENTIAL 
PT 
Prothrombin Time 
PVC/Al 
PolyVinyl Chloride/Aluminum 
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 
ROC 
Receiver Operating Characteristic 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SERM 
Selective Estrogen Receptor Modulator 
SIN 
Subject Identification Number 
SPRM 
Selective Progesterone Receptor Modulator 
SHBG 
Sex Hormone-Binding Globulin 
SLE 
Systemic Lupus Erythematosus 
SSIQ 
Subject Surgery Intention Question 
SUSAR 
Suspected Unexpected Serious Adverse Reaction  
T1/2 
Elimination half-life 
TEAE(s) 
Treatment Emergent Adverse Event(s) 
TVUS 
TransVaginal UltraSound 
ULN 
Upper Limit of Normal 
US/USA 
United States/United States of America 
VAS 
Visual Analogue Scale 
VRS 
Verbal Rating Scale 
WBC 
White Blood Cell 
WHO 
World Health Organization 


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OBSEVA CONFIDENTIAL 
4 SYNOPSIS 
Study Title: A Phase 3, multicenter, randomized, double-blind, placebo-controlled, clinical study to 
assess the efficacy and safety of linzagolix in subjects with moderate to severe endometriosis-
associated pain. 
Code/Name ObsEva Investigational Drug: linzagolix (OBE2109) Phase of Development: 3 
Objectives: 
The primary objective of this study is to demonstrate the efficacy and safety of linzagolix 
administered orally once daily for up to 3 months at a dose of 75 mg alone or of 200 mg in 
combination with add-back hormone replacement therapy (ABT: estradiol (E2) 1 mg / norethisterone 
acetate (NETA) 0.5 mg) versus placebo, while under randomized treatment, 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 3 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 persistence of efficacy over the last 28 days of 
randomized treatment up to the Month 6 visit, 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) 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 3 visit (the 4-week period preceding Month 3 
visit) or, for subjects who discontinue randomized treatment prior to the Month 3 visit, to the last 
28 days of randomized treatment,  , 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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 
Secondary efficacy endpoints:  
 
Ranked secondary efficacy endpoints (in the order of the endpoints to be tested): 
 
Change from baseline to Month 6 in DYS (VRS) 
 
Change from baseline to Month 6 in NMPP (VRS) 
 
Change from baseline to Month 6 in dyschezia (Numeric Rating Scale - NRS) 
 
Change from baseline to Month 6 in overall pelvic pain (NRS) 
 
Change from baseline to Month 6 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 6 in dyspareunia (VRS) 
 
No analgesics use for EAP during the preceding 4-week period at Month 6 
 
No opiate use for EAP during the preceding 4-week period at Month 6 
 
Additional secondary efficacy endpoints : 
 
Clinically meaningful reduction at scheduled visits other than Month 3 for DYS and 
NMPP  
 
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) 


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 
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 
 
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) 


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 
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 
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, placebo-controlled study to 
demonstrate the efficacy and safety of linzagolix administered orally once daily at doses of 75 mg 
alone and 200 mg in combination with low dose ABT (E2 1 mg/NETA 0.5 mg) versus placebo in the 
management of moderate to severe EAP in women with surgically confirmed endometriosis. 
The study starts with an approximately 3-month screening period during which subjects will receive 
no study drug. Eligibility will be confirmed based on data collected during the screening period. After 
randomization, a 6-month Treatment Period will follow. Subjects will be randomized to one of the 
three treatment groups: 
1. Linzagolix 75 mg  
2. Linzagolix 200 mg combined with ABT  
3. Placebo  


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Randomization will be conducted via an interactive web response system (IWRS) in a 1:1:1 ratio. There 
will be no stratification. 
At 6 months, BMD change will be assessed via DXA measurement. Eligible subjects who have 
completed the 6-month treatment period may enter a separate extension study for 6 additional months 
of active treatment (no placebo control). In this extension study, subjects who previously received 
placebo will be randomly switched to one of the two active treatments (75 mg alone or 200 mg + 
ABT). Subjects who received active treatment will continue with the same treatment. 
Subjects who decline to participate to or do not qualify for the extension study and who were exposed 
to at least 3 months of treatment will enter a 6-month drug-free follow-up. At the end of the 6-month 
follow-up period, subjects with a BMD decrease from baseline of >1.5% for lumbar spine and >2.5% 
for total hip will have an additional DXA scan 6 months later. Subjects who discontinue treatment 
prior to Month 3 will not enter the follow-up period.  
The main analysis will be performed after 6 months of treatment and will include all of the subjects’ 
data up to Month 6. 
The study will last on average 15 months; 3-month Screening Period, 6-month Treatment Period and 
6-month Follow-up (with 1 month being defined as 28 days/4 weeks). The duration excludes any 
washout period. 
All subjects will receive once daily either linzagolix 75 mg alone or 200 mg combined with ABT or 
placebo for 6 months. Linzagolix or its corresponding placebo will be supplied as tablets for oral 
administration. ABT or its corresponding placebo will be supplied as capsules for oral administration.  
Linzagolix/placebo treatments 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. Blinded treatment kit numbers corresponding to each subject’s 
randomized treatment will be provided through an IWRS. 
Study Population: The target population will be premenopausal women aged 18 to 49 years inclusive 
at screening, with surgically and, if available, histologically confirmed pelvic endometriosis and with 
moderate to severe EAP. They must not be planning to become pregnant and must agree to use double 
non-hormonal barrier contraception from screening until 3 months after the end of treatment. From 3 
months after the end of treatment to the end of the drug-free follow-up period, contraception is still 
mandatory but hormonal contraception is allowed. 
Four hundred and fifty (450) randomized subjects are planned in total (approximately 150 subjects per 
group). It is expected that the screen failure rate will be around 60%. Therefore, approximately 1125 
subjects will be screened in order to randomize 450 subjects into the study.  
The study will be conducted in approximately 100 investigational sites in the Unites States (US) and 
Europe. Additional sites will be identified, qualified and activated in case of recruitment issues. 
Recruitment will be competitive between countries and sites. 
Eligibility Criteria:  


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Inclusion Criteria 
To be eligible for inclusion into this study, the subject must fulfill all of the following criteria: 
1. The subject must provide written informed consent prior to any study related procedures. 
2. The subject must be a female subject aged 18 years to 49 years inclusive. 
3. The subject must have had her most recent surgical and – if available – histological diagnosis 
of pelvic endometriosis (laparoscopy, laparotomy, vaginal fornix or other biopsy) up to 10 years 
before screening. 
4. The subject must agree to the washout intervals for prohibited therapies (if applicable). 
5. The subject must agree to switch from her usual analgesic rescue medication to only those 
permitted by the protocol during the Screening, Treatment and Follow-up Period. 
6. The subject has moderate to severe EAP during the screening period defined as: 
a. At the screening visit, a score of at least 2 for DYS and at least 2 for NMPP for the 
previous month assessed with the modified Biberoglu & Behrman (mB&B) scale. 
b. Over two full menstrual cycles (i.e. from day 1 of the first menstruation going over two 
spontaneous menstrual cycles up to the day before the next menstruation i.e. the third 
menstruation) finishing just before the baseline visit: 
i. Mean overall pelvic pain scores of at least 4 on the 0–10 NRS over the 5 days 
with the highest score for each cycle separately, i.e. required for both cycles; 
ii. At least two days with “moderate” or “severe” pain on the 0–3 VRS for pelvic 
pain over the days with uterine bleeding for each cycle separately, i.e. required 
for both cycles; 
iii. At least two days with “moderate” or “severe” pain on the 0–3 VRS for pelvic 
pain over the days without uterine bleeding for each cycle separately, i.e. 
required for both cycles. 
7. The subject is compliant with eDiary completion i.e. has completed at least 75% of days during 
the screening period. 
8. The subject has regular menstrual cycles and the total length of the two screening menstrual 
cycles should be between 42 and 76 days inclusive. 
9. The subject has a Body Mass Index (BMI) ≥ 18 kg/m2 at the screening visit. 
10. If of childbearing potential, the subject agrees to use one of the following birth control methods 
during the Screening Period, 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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11. If of non-childbearing potential, the subject must have had tubal ligation sterilization at least 
two months before the screening visit. 
12. The subject is ≥ 40 years of age at the screening visit has a normal mammogram within 1 year 
before randomization. 
13. The subject must be able to communicate well with the Investigator and research staff and to 
comply with the requirements of the study protocol. 
Exclusion Criteria 
To be eligible for inclusion in this study the subject must not meet any of the following criteria: 
1. The subject is pregnant or breast feeding or is planning a pregnancy within the duration of the 
Treatment Period of the study. 
2. The subject is less than 6 months postpartum or 3 months post-abortion/miscarriage at the time 
of entry into the screening period. 
3. The subject has a surgical history of: 
a. Hysterectomy,  
b. Bilateral oophorectomy, 
c. Vagotomy, bowel resection or any surgical procedure (including gastric surgery) that 
might interfere with gastrointestinal motility, pH, or absorption, 
d. Any major abdominal surgery (including laparotomy for endometriosis) within 6 
months or any interventional surgery for endometriosis performed within a period of 2 
months before screening, or the subject is scheduled for a surgical abdominal procedure 
during the course of the study. 
4. The subject had a tubal sterilization which was performed with ESSURE™. 
5. The subject had endometrial ablation resulting in amenorrhea. 
6. The subject has at least one ovarian endometrioma with a diameter of 7 cm or greater. 
7. The subject is likely to require treatment during the study OR received treatment within a 
specified period prior to screening with any of the medications listed below: 
a. 
Gonadotropin releasing hormone (GnRH) antagonists 
3 months 
b. 
GnRH agonist injections/3-month depot injections 
3/6 months 
c. 
Danazol 
3 months 
d. 
Oral contraceptives and other sex hormones 
1 month 
e. 
Depot contraceptives 
10 months 
f. 
Selective Progesterone Receptor Modulators (SPRMs), Selective 
Estrogen Receptor Modulators (SERMs) and aromatase inhibitors 
3 months 
g. 
Long acting narcotics (i.e. requiring less than once daily dosing) 
1 day 
h. 
Systemic glucocorticoid treatments for acute diseases (not depot) 
1 month 


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i. 
Medical (prescribed) marijuana 
1 week 
j. 
In situ copper intra-uterine device (IUD) 
1 day 
k. 
In situ IUD with progestogen 
1 month 
8. The subject is likely to use cannabinoids during the study washout, screening or treatment 
period. 
9.  The subject has required more than 2 weeks of continuous use of a narcotic analgesics for 
treatment of EAP within 6 months prior to Screening. 
10. The subject received strong CYP3A4 inducers or inhibitors that (might potentially) interact 
with ABT within 1 month prior to randomization. 
11. The subject has a contra-indication to ABT including: 
a. Active deep vein thrombosis, pulmonary embolism, or history of these conditions; 
b. Active or recent (e.g. within the past year) arterial thromboembolic disease (e.g. stroke, 
myocardial infarction); 
c. Known, suspected, or history of breast cancer; 
d. Known or suspected estrogen-dependent neoplasia;  
e. Known protein C, protein S, or antithrombin deficiency, or other known thrombophilia 
disorders, including Factor V Leiden; 
f. Migraine with aura; 
g. History of porphyria; 
h. Known hypersensitivity to the ingredients. 
12. The subject has a history of or current systemic glucocorticoid therapy for treatment of chronic 
diseases (e.g. Systemic Lupus Erythematosus (SLE), rheumatic arthritis). Inhaled 
glucocorticoids for e.g. asthma are not considered systemic glucocorticoids. 
13. The subject did not respond to prior treatment with GnRH agonists or GnRH antagonists for 
endometriosis. 
14. The subject has alanine aminotransferase (ALT), aspartate aminotransferase (AST), total 
bilirubin levels or gamma-glutamyl transpeptidase (GGT) level ≥ 2 times the upper limit of 
normal and indicative of potential liver damage at Screening or Day 1 (subjects with 
abnormalities at Day 1 will be withdrawn from study at reception of the results). 
15. The subject has clinically significant abnormal ECG, or ECG with QT interval corrected for 
heart rate (QTc) using Fridericia's correction formula (QTcF) > 450 msec at Screening or Day 
1 (prior to dosing). 
16. The subject has a known positive human immunodeficiency virus (HIV) or viral Hepatitis 
serology. 
17. The subject has abnormal uterine bleeding of undiagnosed cause. 


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18. The subject had/has clinically significant findings from a Papanikolaou (PAP) smear test 
performed within the past 12 months or at the screening visit which will require surgical 
intervention (e.g. Loop electrosurgical excision procedure (LEEP) or cervical conization). 
19. The subject has chronic pelvic pain that, in the opinion of the Investigator, is not caused by 
endometriosis and requires chronic analgesic or other chronic therapy which would interfere 
with the assessment of EAP (e.g., interstitial cystitis, presumptive adenomyosis, fibroids, non-
endometriosis-related pelvic adhesive disease, post-tubal ligation or irritable bowel syndrome).  
20. The subject has any other clinically significant gynecological condition identified during 
screening transvaginal ultrasound (TVUS) or endometrial biopsy which might interfere with 
the study efficacy and safety objectives (e.g. endometritis, endometrial hyperplasia). However, 
uterine fibroids (as long as uterus size ≤ 12 weeks, i.e. equivalent gestational weeks) and 
adenomyosis are allowed provided they do not interfere with the assessment of EAP (see 
previous criterion). 
21. The subject has any known condition, including findings in the medical history or in the 
screening assessments, which in the opinion of the Investigator constitutes a risk or a 
contraindication to the participation of the subject in the trial or that could interfere with the 
trial objectives, conduct or evaluation. 
22. The subject has a history of, or known, osteoporosis, hyperparathyroidism or other metabolic 
bone disease. 
a. Screening DXA results of the lumbar spine (L1–L4), femoral neck, or total hip BMD 
showing a Z-score ≤ –1.5  
b. Any condition that would interfere with obtaining adequate DXA measurements (e.g. 
weight [> 300 pounds or 136 kg], history of spinal surgery, spinal hardware, severe 
scoliosis) 
c. Intercurrent bone disease 
d. History of hip fracture 
e. History of pathologic or compression fractures 
f. History of bilateral hip replacement 
23. The subject has a mental condition rendering her unable to understand the nature, scope and 
possible consequences of the study, or evidence of an uncooperative attitude. 
24. The subject has current problem with alcohol or drug abuse (including painkiller abuse).  
25. The subject has been administered with any experimental drug in the 12 weeks before screening. 
26. The subject has calcium level above the upper limit of normal range at screening, which is 
confirmed on repeat fasting testing at Screening. 
27. The subject has a history of, or active malignancy (with or without systemic chemotherapy) 
(except treated basal carcinoma of the skin which is not an exclusion criterion). 
28. The subject has a history of attempted suicide and/or a history of, or known major psychiatric 
disorders that are not well controlled.  


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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 
Descriptive statistics will be performed on relevant screening and baseline data (i.e. data collected 
prior to the treatment administration) and on demographic characteristics for each treatment group and 
overall. There will be no formal comparison of baseline data, that is, no statistical hypothesis testing. 
All statistical hypothesis tests and confidence intervals will be two sided. To maintain an overall type 
I error rate of 0.05, as there are two linzagolix versus placebo comparisons, Bonferoni corrected p-
values will be produced (raw p-values will be multiplied by two prior to comparing to 0.05), along 
with corresponding 97.5% confidence intervals.  
Each linzagolix group will need to demonstrate a statistically significant difference for both co-primary 
endpoints in order for the group to be considered more efficacious than placebo, thus maintaining the 
overall type I error rate of 0.05.  
For each linzagolix group that is statistically significantly more efficacious than placebo for the co-
primary endpoints, a fixed-sequence testing strategy shall be used within the group to test the ranked 
secondary endpoints, so as to maintain the family-wise type I error rate. 
Primary Efficacy Analysis 
The primary efficacy analysis aims to estimate the effect of linzagolix versus placebo on DYS and 
NMPP over the last 28 days up to and including the Month 3 visit or, for subjects who discontinue 
randomized treatment prior to the Month 3 visit, over the last 28 days of randomized treatment. Use 
of analgesic medication for EAP will be included in the responder definition. A responder for the co-
primary endpoints needs to demonstrate both a reduction in pain (DYS or NMPP, depending on the 
endpoint) and a stable or decreased use of analgesics for EAP. Anyone who does not meet both of 
these criteria will be defined as a non-responder. 
For each of the co-primary endpoints, the criterion for defining a subject as a responder over the last 
28 days of randomized treatment up to the Month 3 visit will include a reduction of X or greater from 
baseline in pain, where X will be determined using appropriate anchors as described below, as well as 
a stable or decreased use of analgesics for EAP. 
Mean pelvic pain scores for DYS and for NMPP will be calculated by averaging over the 
corresponding 28 calendar days immediately prior to and including the day of the Month 3 visit. DYS 
will use days with uterine bleeding, defined as those days on which the subject records any uterine 
bleeding or spotting in the subject eDiary; NMPP will use days with no uterine bleeding. If a subject's 
mean score for DYS is undefined numerically because her daily eDiary reports indicate that she did 
not experience uterine bleeding on any days during the 28 calendar day time period, then the mean 
score for DYS will be set equal to zero (which reflects the absence of any DYS during that reporting 
time period). For subjects who discontinue treatment prior to Month 3, the last available observations 
prior to discontinuation will be used, in order to estimate the treatment effect of while under treatment, 
that is the 28 calendar days immediately prior to and including the last dose date. The baseline mean 
overall pelvic pain scores for DYS and NMPP will be calculated by averaging over the two complete 


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menstrual cycles during screening, which may not be exactly 28 days each. For both DYS and NMPP, 
responses of "No pain," "Mild pain," "Moderate pain," and "Severe pain" will be assigned a score of 
0, 1, 2, and 3, respectively. 
For the assessment of a stable or decreased use of analgesics for EAP, the analgesic use for any defined 
period will be based on the mean of the total pill count for each class of rescue analgesics 
(endometriosis-associated). The total pill count for each class of rescue analgesic is the sum of the pill 
count of the corresponding class of rescue analgesic, as reported in the eDiary during the time period 
of interest. The baseline analgesic use will be calculated as the mean of daily pill count of analgesics 
over the two complete menstrual cycles during screening. For purposes of determining a stable or 
decreased use of analgesics, the averaging will be done over the same calendar days as used for the 
pelvic pain scores. The evaluation of a stable or decreased use of analgesics will be done according to 
a pre-defined set of rules. 
The analysis of each co-primary endpoint will be conducted using a logistic regression model, with 
treatment group as the main effect (three values) and including the baseline pain score as a covariate. 
Individual linzagolix versus placebo treatment group comparisons will be made using the same logistic 
regression model. 
An additional analysis of the co-primary endpoints will be conducted to estimate the effect of treatment 
policy rather than that of while on treatment. A reference based multiple imputation approach will be 
used for subjects who discontinue the study prior to Month 3. Further details will be provided in the 
Statistical Analysis Plan (SAP). 
Responder Thresholds analysis:  
For each of the co-primary endpoints, the criterion for defining a subject as a responder over the last 
28 days of randomized treatment up to the Month 3 visit will be a reduction of X or greater from 
baseline in pain. The threshold for response in the responder analysis (i.e., the value of X) will be 
chosen to represent a clinically meaningful reduction in pain and may not be the same for each 
endpoint. The threshold will be determined based on separate analyses of overall mean change using 
the mPGIS at Month 3 as an anchor. A 2-point improvement in the mPGIS will be used to define 
responders for the primary analysis. Response categories of “very mild” and “mild” will be collapsed 
into one category prior to the analyses. Monthly questions specific to DYS, NMPP, overall pelvic pain, 
dyschezia, dyspareunia and daily function will be used as separate anchors, PGIC as an anchor, 
Cumulative Distribution Function (CDF) and Probability Density Function (PDF) curves, and 
Receiver Operating Characteristic (ROC) analyses will be used as supportive analyses. The thresholds 
have been estimated in an analysis of DYS and NMPP data from the Phase 2b Edelweiss study and 
will be re-estimated in this study, calculated based on the blinded Month 3 data. The final responder 
thresholds, taking into account the previous estimates from phase 2b, will be included in the final SAP 
prior to breaking the blind after Month 6. Based on the results from the Phase 2b Edelweiss study, it 
is expected that the responder thresholds will be in the range of a 0.7 to 1.25 point (40% to 50%) 
reduction in pain in the 4-point VRS for a 2-point improvement, and of a 0.25 to 0.75 point (20% to 
30%) reduction in pain in the 4-point VRS for a 1-point improvement. The numerical thresholds for 
DYS are expected to be larger than those for NMPP.    
Secondary Efficacy Analysis 


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In order to estimate the treatment effect of while under treatment, endpoints that are collected daily 
using the eDiary will be based on the 28 calendar days immediately prior to and including the day of 
the corresponding visit, or the 28 calendar days immediately prior to and including the last dose date 
for subjects who discontinue treatment prior to the visit in question. Corresponding baseline values 
will be calculated based on the two complete menstrual cycles during screening, which may not be 
exactly 28 days each. 
The value for other endpoints is defined as the value at the corresponding visit, or the last completed 
assessment prior to and including the last dose date for subjects who discontinue treatment prior to the 
visit in question. 
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. As with the 
primary analysis, individual linzagolix versus placebo treatment group comparisons will be made. 
In general, between-group comparisons for continuous endpoints will be analyzed via analysis of co-
variance, with the baseline value as a covariate. Between-group comparisons for binary endpoints will 
be analyzed via logistic regression. Between-group comparisons for ordinal categorical data will be 
analyzed using a Mantel-Haenszel test, or using Koch’s method when there is also a baseline covariate. 
Full details describing the derivation and analyses of each secondary endpoint will be provided in the 
SAP. 
Safety analysis 
The safety and tolerability profile will be assessed versus baseline conditions and differences between 
treatment groups and descriptive statistics will be produced for both values and change from baseline, 
where applicable.  
Extent of exposure and compliance will be evaluated.  
Concomitant medications will be summarized using the World Health Organization (WHO) Drug 
Dictionary with frequencies and percentages for each treatment group. All medications administered 
between the date of the first dose and the end of the study will be included. 
An analysis of the TEAEs will be done. AEs will be summarized using the Medical Dictionary for 
Regulatory Activities (MedDRA) tabulated by preferred term and system organ class. TEAEs will be 
summarized with frequencies and percentages for each treatment group. Tabulations by severity and 
drug-relatedness will also be made. 
Laboratory parameters values will be summarized for each visit for each treatment group including 
within-group changes from baseline.  
BMD values and corresponding Z-scores will be summarized at baseline and at Month 6 for each 
treatment group, using the observed data. The within-group percent changes from baseline for BMD 
values will also be summarized, including 2-sided 95% confidence intervals. Categorical summaries 
of percent change from baseline will also be produced. The percent changes from baseline to Month 6 
will be compared between each of the linzagolix groups and the placebo group via analysis of co-
variance with treatment group as the main effect (three values) and including the baseline as a 
covariate. 


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Pharmacokinetic and pharmacodynamic analyses 
Plasma concentrations of linzagolix and 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. 
PK/PD analyses will be reported separately. 


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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 an estrogen-dependent gynecological condition, defined as the presence of 
endometrium-like tissue outside the uterus. It is one of the most common gynecological diseases (1). 
The condition is predominantly found in women in their reproductive years and disappears 
spontaneously after menopause. A chronic, inflammatory reaction, induced by the ectopic endometrial 
cells, results in a variety of pain symptoms including dysmenorrhea (DYS), dyspareunia, chronic pelvic 
pain, dysuria and dyschezia (2, 3). 
5.3 CONVENTIONAL TREATMENT OF ENDOMETRIOSIS 
The principal objective in treating endometriosis is symptom-relief management. Treatment options for 
women with EAP are diverse and consist of analgesic therapies, hormonal therapies, conservative or 
minimal invasive surgery, or a combination of these (3). Hormonal therapies aim at inhibition of 
ovulation, prevention of cyclic endometrium growth, and abolition of menstruation through 
achievement of a stable steroid hormone milieu, based on the concept that the response of the eutopic 
and ectopic endometrium is substantially similar (4, 5). 
Combined oral contraceptives (COCs), although not approved for the treatment of EAP, are often used 
as initial therapy. Their intake results in anovulation, reduction of menstrual blood flow, decidualization 
of endometriotic lesions, down regulation of cell proliferation and enhanced apoptosis in the 
endometrium (6). However, over time many women on COCs no longer have adequate pain relief and 
require second-line therapy (7).  
Progestin monotherapy can be efficacious for the reduction in EAP as it induces anovulation and a 
hypoestrogenic state via suppression of pituitary gonadotropin release. Progestins also have direct 
effects on the endometrium, causing decidualization of eutopic and ectopic endometrium leading to 
atrophy of the endometriotic implants (8). However, progestin monotherapy is often associated with 
breakthrough bleeding, alterations in mood, weight gain, and breast tenderness (9). 
Other therapies with proven efficacy for the treatment of EAP are often limited by undesirable side 
effects. For example, GnRH agonists lead through a constant stimulation of the GnRH receptor at the 
pituitary level to its desensitization and ultimately to suppression of ovulation and reduced serum 
estrogen levels; thus their use is associated with significant hypoestrogenic side-effects. Short-term 
effects include menopausal symptoms such as hot flush, vaginal dryness, loss of libido and emotional 
lability and their long-term use is limited to 6 months without hormonal add-back therapy (ABT) by 


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substantial bone mineral density (BMD) reduction (10). In addition, GnRH-agonists are administered 
as depot products which lack flexibility in case of side effects. 
For longer term use of GnRH-analogues, concurrent treatment with add-back (progestin and/or estrogen) 
hormone replacement therapy has been shown to be effective in reducing associated BMD loss (11). 
ABT is generally recommended as part of initial treatment with GnRH agonists to minimize side effects.  
Randomized trial data comparing 12-month GnRH agonist treatment with and without ABT showed 
durable suppression of endometriosis symptoms and minimal impact on BMD with the addition of daily 
5 mg norethisterone acetate (NETA) alone or in combination with estrogen (11). ABT is considered 
mandatory for women requiring GnRH agonist retreatment / treatment expected to go beyond 6 months. 
In a prospective cohort study comparing four different regimens of ABT, the add-back regimen 
containing 1 mg estradiol (E2) and 0.5 mg NETA demonstrated the best efficacy in terms of quality of 
life, hypoestrogenism-associated symptoms, and BMD (12).  
GnRH antagonists are a new potential treatment option that is hypothesized to allow dose-dependent 
control of E2 levels reducing endometriosis implants and EAP (12). Partial or complete suppression of 
E2 is possible depending on the dose (13). Partial suppression with elagolix 150 mg once daily was 
demonstrated to reduce EAP significantly while having limited impact on BMD and therefore allowing 
for up to 2 years administration (14). A higher dose of elagolix 200 mg twice a day for 6 months led to 
nearly full suppression of E2, better reduction of EAP but significant reduction of BMD which limits 
treatment to 6 months (14). 
Linzagolix is a new, orally active, non-peptide GnRH antagonist. In a Phase 2b placebo-controlled dose-
ranging study, 75 mg linzagolix given once daily for 6 months partially suppressed E2 and significantly 
decreased EAP with limited effect on BMD. A dose of 200 mg given once daily for 6 months suppressed 
E2 to menopausal levels (< 20 pg/mL), significantly decreased EAP, with better efficacy for some 
symptoms such as DYS and dyspareunia, but as expected, significantly reduced BMD at 6 months.  
Daily doses of 75 and 200 mg linzagolix have been chosen to be developed further for the treatment of 
EAP in order to provide dosing optionality to achieve both partial and complete E2 suppression. 
However, due to the significant BMD loss observed with 200 mg linzagolix, this dose will be developed 
in combination with concomitant estrogen/progestogen ABT. 
The purpose of this study is to evaluate the safety, tolerability and efficacy of linzagolix in women with 
EAP. It is a Phase 3, randomized, double-blind, placebo-controlled study to demonstrate the superior 
efficacy of once daily oral 75 mg linzagolix and of once daily oral 200 mg linzagolix in combination 
with ABT on the reduction of EAP in women with surgically confirmed endometriosis. 
5.4 SUMMARY OF NON-CLINICAL STUDIES 
5.4.1 
Non-Clinical Pharmacology 
Linzagolix shows potent affinity for the GnRH receptors in different species particularly the human 
GnRH (hGnRH) receptor and acts as an antagonist in vitro (hGnRH Ki=27.4nM). The affinity of KP017, 
the main metabolite of linzagolix, to the hGnRH receptor was shown to be 4.4 fold lower (Ki=127 nM). 
Specific effects on the endometrium were observed during in vivo studies, with linzagolix acting through 
suppression of estrogen dependent endometrial proliferation in a rat autograft endometriosis model. 


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Safety pharmacology studies, including a comprehensive set of cardiovascular ion channels, did not 
show any adverse effects on the central nervous, respiratory or cardiovascular system at exposures 
significantly exceeding those that would be used in a clinical setting. 
5.4.2 
Non-Clinical Pharmacokinetics and Toxicology  
5.4.2.1 
Pharmacokinetics 
Linzagolix was rapidly and completely absorbed after oral dosing with exposures increasing in a 
generally dose-proportional manner. The volumes of distribution and plasma clearance were low. 
Linzagolix is highly bound to plasma proteins (>95%) across a range of species with no concentration 
dependent changes. In human plasma, the major binding protein for linzagolix was albumin. It does not 
exhibit blood partitioning.  
Tissue distribution of radiolabeled linzagolix was widespread; there was no indication of unusual 
distribution or accumulation to tissues. Radioactivity was also detected in fetal tissues and milk.  
The major route of biotransformation of linzagolix was the oxidative O-demethylation to KP017 
(produced via CYP2C9 metabolism) which was observed in hepatocytes of all tested species. The in 
vivo metabolic pathway of linzagolix in mice, rats and monkeys was comparable to the in vitro data. 
Excretion of radioactivity from radiolabeled linzagolix was predominantly via feces in both rats and 
monkeys. 
Pharmacokinetic (PK) interaction studies in vitro indicated that drugs possibly co-administered in 
clinical settings (non steroidal anti-inflammatory drugs - NSAIDs) did not affect the plasma protein 
binding of linzagolix.  
5.4.2.2 
Toxicology 
Overall, the toxicological profile of linzagolix from repeated-dose toxicity studies was dominated by 
the consequences of its pharmacological activity as a GnRH receptor antagonist. During pivotal 
toxicology studies, dose levels of 200 and 10 mg/kg/day linzagolix were shown to be the no observed 
adverse effect level (NOAEL) in the main toxicology species rat (26-week daily oral administration) 
and monkey (39-week daily oral administration), respectively, and resulted in therapeutic indices (based 
on total / unbound exposure) for a human dose of 200 mg/day of 6.7 / 4.6 and 0.8 / 3.6, respectively.  
Reproductive toxicity studies, especially fertility studies and embryo-foetal development studies in 
rabbits, were limited in dose by the anti-GnRH effects of linzagolix preventing conception or leading to 
total litter loss. The effects of linzagolix on conception were reversible, and rabbit embryo-foetal studies 
showed expected pharmacological activity and no adverse reprotoxic/teratogenic effect. 
No effect on pre- and postnatal development of the offspring exposed during embryo-fetal development 
and lactation was recorded. 
Linzagolix was not genotoxic nor phototoxic. 
A 26-week carcinogenicity study in transgenic TgRasH2 mice showed no evidence of any linzagolix-
induced carcinogenicity. 


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5.4.3 
Non-clinical summary 
Taken together, 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 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 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 PD of linzagolix have been further investigated in six 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 are being 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).  
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. A total of 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 luteinizing hormone (LH), follicle-stimulating hormone (FSH) 
and E2. 
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 


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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 heart rate corrected QT 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 pharmacodynamics (PD) and safety of linzagolix alone and 
combined with E2/ NETA add-back hormone replacement therapy 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. Additional drug-drug interaction studies 
(Studies 18-OBE2109-006 and 18-OBE2109-007) showed linzagolix to have no effect on OAT3 
substrate benzylpenicillin and to increase the exposure to CYP2C8 substrate repaglinide. Linzagolix is 
considered 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 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 conducted in Japan in patients with endometriosis (Study KLH1201), 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 conducted in Japan in patients with endometriosis (Study KLH1202), 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 conducted in Japan in patients with endometriosis (Study KLH1203), 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 an ongoing Phase 2b study conducted in US and Europe in patients with endometriosis (Study 15-
OBE2109-001, also known as Edelweiss), 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 24 weeks. 
5.5.3 
Safety 
More than 1,500 subjects were exposed to different doses (25, 50, 75, 100, 200, 400 mg) of linzagolix 
from 12 completed and 3 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 
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) (metrorrhagia and hot flush). 
In the Phase 2b Edelweiss trial, 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 


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greatest bone loss) of ‐0.8% (95% CI ‐1.57, ‐0.03) after 6 months of treatment, while achieving 
improvement of the conditions in the majority of patients. As expected, full E2 suppression with 
linzagolix 200 mg lowers BMD by more than 2.5%, which indicates the need for a low dose ABT for 
use beyond 6 months. 
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, a moderate proportion of patients reported a dose-dependent increase in hot 
flush (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 adverse events (AE) 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 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 under treatment up to normal. These increased transaminase values were not associated 
with increased bilirubin values. 
A borderline effect of linzagolix on the heart rate corrected QT 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; only very 
few related events were reported as being of “severe” intensity. 
5.6 RATIONALE FOR THE CURRENT STUDY 
Linzagolix has been shown to suppress LH and E2 dose dependently and to significantly reduce EAP in 
women with moderate to severe EAP with a good safety and tolerability profile.  
In the dose-ranging study (15-OBE2109-001), daily doses of 75, 100 and 200 mg linzagolix for 12 
weeks significantly reduced EAP compared to placebo, whereas daily doses of 50 mg led to a reduction 
which was not significantly different than placebo. The effects of daily doses of 75, 100 and 200 mg 
were maintained or increased at 24 weeks. For overall pelvic pain, 49%, 62%, 56% and 56% of subjects 
responded (30% reduction in pelvic pain) to the doses of 50, 75, 100 and 200 mg linzagolix compared 
to 35% in placebo. For DYS, 43%, 68%, 69%, 79% of subjects responded to the dose of 50 mg, 75 mg, 
100 mg and 200 mg, respectively, compared to 29% in placebo. For NMPP, 37%, 46%, 59%, 62% and 
48% of subjects responded to the doses of 50, 75, 100 and 200 mg linzagolix, respectively, compared 
to 37% in placebo. Suppression of E2 was dose dependent with partial suppression achieved with once 
daily 75 mg dose and complete suppression with once daily 200 mg dose. Mean percent (95% CI, P 
value) BMD changes for lumbar spine from baseline to week 24 in the 50, 75, 100 and 200 mg dose 
groups were 0.137% (-0.83, -1.11, P=.777), 0.798% (-1.57, -0.03, P=.042), -1.365% (-2.14, -0.59, 
P<.001), -2.602% (-3.56, -1.65, P<.001). BMD of femoral neck and total hip showed a similar pattern 
but with generally smaller changes from baseline.  


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Based on the clinically and statistically very significant results of the dose-ranging study, two doses 
have been chosen for Phase 3 confirmatory registration studies: 75 mg alone and 200 mg in combination 
with hormone ABT (E2 1 mg/NETA 0.5 mg).  
The two doses are chosen to provide two different long-term treatment options for women suffering 
from endometriosis: one dose providing a significant pain control for the majority of patients whilst 
maintaining E2 at levels above 20 pg/mL, which will mitigate a major impact on bone mineral density 
and one high dose requiring administration with hormone ABT (E2 1 mg/NETA 0.5 mg) achieving a 
better symptom control for some patients by providing complete E2 suppression but limiting the impact 
on bone mineral density due to the addition of ABT. 
The study is double-blind and placebo-controlled which is considered the gold standard to prove efficacy 
of new medicines, in particular if potential advantages over alternative therapies lie in areas other than 
efficacy (15).  For this reason, a placebo-controlled study is required by some regulatory authorities to 
support the registration of a product. In this study, the placebo control is restricted to 6 months after 
which all subjects will be offered active treatment (while maintaining the double-blind) for a further 6 
months in a separate extension study. Of note, all subjects are allowed to use rescue analgesics for 
endometriosis-associated pain during the study. All subjects will enter a 6-month post-treatment follow-
up, except for subjects who discontinued treatment prior to completing 3 months of treatment; those 
subjects will be directly discontinued from the study.  
5.7 SUMMARY OF OVERALL RISKS AND BENEFITS 
Endometriosis is an underserved gynecologic condition and one of the most common gynecological 
diseases (1). It is characterized by pain symptoms including DYS, dyspareunia, chronic pelvic pain, 
dysuria and dyschezia. Medical options are still limited and new treatment options are warranted. 
Linzagolix is a new oral GnRH antagonist which has been shown significantly to reduce EAP via dose 
dependent suppression of LH, FSH and E2. This has included clinically meaningful improvements in 
DYS, NMPP, dyschezia and dyspareunia. 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 have been observed in the Phase 2 studies. No fetal or newborn abnormalities were 
reported in any of these 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 not 
dose-related increases in transaminase levels which were not associated with any change 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. 
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 ABT to mitigate BMD loss. 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 


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discontinued from treatment and will not be eligible to enter the extension study. In addition, subjects 
will be provided with vitamin D and calcium supplements which they will be recommended to take. 
In conclusion, linzagolix has a favorable benefit/risk ratio and represents a potentially useful 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. 
The trial was not completely stopped; rather, ObsEva implemented a temporary hold on recruitment in 
order to ensure patient safety.  Therefore, ObsEva believes the hold had no potential effect on the 
benefit/risk balance for subjects. 
Respecting national recommendations, as the COVID-19 pandemic situation improves and after careful 
assessment of risks and benefits, the Sponsor will decide on a site by site basis, when to resume screening 
and randomization for this study. 
For randomized subject who could not attend her 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 study is to demonstrate the efficacy and safety of linzagolix administered 
orally once daily for up to 3 months at a dose of 75 mg alone or of 200 mg in combination with ABT 
(E2 1 mg / NETA 0.5 mg) versus placebo, while under randomized treatment, 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 3 visit along with a stable or decreased use of analgesics for EAP for 1) DYS and for 
2) NMPP. 
6.1.2 
Secondary 
Secondary objectives include evaluation of persistence of efficacy over the last 28 days of randomized 
treatment up to the Month 6 visit, 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 


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of endometriosis related number of non-study health visits, number of days in hospital and type of 
medical procedures performed during the Treatment Period. 
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 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 3 visit (the 4-week period preceding Month 3 visit) or, for subjects 
who discontinue randomized treatment prior to the Month 3 visit, to the last 28 days of randomized 
treatment, 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 
7.1.2.1 
Ranked secondary efficacy endpoints 
Ranked secondary efficacy endpoints (in the order of the endpoints to be tested) are: 
 
Change from baseline to Month 6 in DYS (VRS) 
 
Change from baseline to Month 6 in NMPP (VRS) 
 
Change from baseline to Month 6 in dyschezia (Numeric Rating Scale - NRS) 
 
Change from baseline to Month 6 in overall pelvic pain (NRS) 
 
Change from baseline to Month 6 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 6 in dyspareunia (VRS) 
 
No analgesics use for EAP during the preceding 4-week period at Month 6 


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 
No opiate use for EAP during the preceding 4-week period at Month 6 
7.1.2.2 
Additional secondary efficacy endpoints 
Additional secondary efficacy endpoints include: 
 
Clinically meaningful reduction at scheduled visits other than Month 3 for DYS and NMPP  
 
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 
 
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 


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 
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 
 
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 


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 
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, placebo-controlled study to demonstrate the efficacy 
and safety of linzagolix administered orally once daily at doses of 75 mg alone and 200 mg in 
combination with low dose ABT (E2 1 mg/NETA 0.5 mg) versus placebo in the management of 
moderate to severe EAP in women with surgically confirmed endometriosis. 
The study starts with an approximately 3-month screening period during which subjects will receive 
no study drug. Eligibility will be confirmed based on data collected during the screening period. After 
randomization, a 6-month Treatment Period will follow. Subjects will be randomized to one of the 
three treatment groups: 
1. Linzagolix 75 mg  
2. Linzagolix 200 mg combined with ABT  
3. Placebo  
Randomization will be conducted via an interactive web response system (IWRS) in a 1:1:1 ratio. There 
will be no stratification. 
At 6 months, BMD change will be assessed via DXA measurement. Eligible subjects who have 
completed the 6-month treatment period may enter a separate extension study for 6 additional months 
of active treatment (no placebo control). In this extension study, subjects who previously received 
placebo will be randomly switched to one of the two active treatments (75 mg alone or 200 mg + 
ABT). Subjects who received active treatment will continue with the same treatment. 
Subjects who decline to participate to or do not qualify for the extension study and who were exposed 
to at least 3 months of treatment will enter a 6-month drug-free follow-up. At the end of the 6-month 
follow-up period, subjects with a BMD decrease from baseline of >1.5% for lumbar spine and/or 
>2.5% for total hip will have an additional DXA scan 6 months later. Subjects who discontinue 
treatment prior to Month 3 will not enter the follow-up period.  
The main analysis will be performed after 6 months of treatment and will include all of the subjects’ 
data up to Month 6. 
The study will last on average 15 months; 3-month Screening Period, 6-month Treatment Period and 
6-month Follow-up (with 1 month being defined as 28 days/4 weeks). The duration excludes any 
washout period. 


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It is expected that only few subjects will have to enter the second 6-month follow-up period to have 
a DXA scan.  
A schematic of the study design is shown in Figure 1. 
 
Figure 1 : Study design 
 
All subjects will receive once daily either linzagolix 75 mg alone (with ABT placebo) or linzagolix 
200 mg combined with low dose ABT, or placebo (linzagolix placebo with ABT placebo) for 6 months. 
ABT is a combination of estradiol (E2) 1 mg and norethisterone acetate (NETA) 0.5 mg. Linzagolix 
or its corresponding placebo will be supplied as tablets for oral administration. ABT or its 
corresponding placebo will be supplied as capsules for oral administration.  
Linzagolix/placebo treatments 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. 
Blinded treatment kit numbers corresponding to each subject’s randomized treatment will be provided 
through an IWRS. 


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9 STUDY POPULATION 
9.1 SUBJECTS 
9.1.1 
Description of the target population 
The target population will be premenopausal women aged 18 to 49 years inclusive at screening, with 
surgically and, if available, histologically confirmed pelvic endometriosis and with moderate to severe 
EAP. 
They must not be planning to become pregnant and must agree to use double non-hormonal barrier 
contraception from screening until 3 months after the end of treatment. From 3 months after the end of 
treatment to the end of the drug-free follow-up period, contraception is still mandatory but hormonal 
contraception is allowed. 
9.1.2 
Number of subjects 
Four hundred and fifty (450) randomized subjects are planned in total (approximately 150 subjects per 
group). It is expected that the screen failure rate will be around 60%. Therefore, approximately 1125 
subjects will be screened in order to randomize 450 subjects into the study.  
9.1.3 
Study region/location 
The study will be conducted in approximately 100 investigational sites in the Unites States (US) and 
Europe. Additional sites will be identified, qualified and activated in case of recruitment issues. 
Recruitment will be competitive between countries and sites. 
9.2 ENTRY CRITERIA 
9.2.1 
Inclusion Criteria 
1. The subject must provide written informed consent prior to any study related procedures. 
2. The subject must be a female subject aged 18 years to 49 years inclusive. 
3. The subject must have had her most recent surgical and – if available – histological diagnosis 
of pelvic endometriosis (laparoscopy, laparotomy, vaginal fornix or other biopsy) up to 10 
years before screening. 
4. The subject must agree to the washout intervals for prohibited therapies (if applicable). 
5. The subject must agree to switch from her usual analgesic rescue medication to only those 
permitted by the protocol during the Screening, Treatment and Follow-up Period. 
6. The subject has moderate to severe EAP during the screening period defined as: 
a. At the screening visit, a score of at least 2 for DYS and at least 2 for NMPP for the 
previous month assessed with the modified Biberoglu & Behrman (mB&B) scale. 


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b. Over two full menstrual cycles (i.e. from day 1 of the first menstruation going over 
two spontaneous menstrual cycles up to the day before the next menstruation i.e. the 
third menstruation) finishing just before the baseline visit: 
i. Mean overall pelvic pain scores of at least 4 on the 0–10 NRS over the 5 days 
with the highest score for each cycle separately, i.e. required for both cycles; 
ii. At least two days with “moderate” or “severe” pain on the 0–3 VRS for pelvic 
pain over the days with uterine bleeding for each cycle separately, i.e. required 
for both cycles; 
iii. At least two days with “moderate” or “severe” pain on the 0–3 VRS for pelvic 
pain over the days without uterine bleeding for each cycle separately, i.e. 
required for both cycles. 
7. The subject is compliant with eDiary completion i.e. has completed at least 75% of days during 
the screening period. 
8. The subject has regular menstrual cycles and the total length of the two screening menstrual 
cycles should be between 42 and 76 days inclusive. 
9. The subject has a Body Mass Index (BMI) ≥ 18 kg/m2 at the screening visit. 
10. If of childbearing potential, the subject agrees to use one of the following birth control methods 
during the Screening Period, 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. 
11. If of non-childbearing potential, the subject must have had tubal ligation sterilization at least 
two months before the screening visit. 
12. The subject is ≥ 40 years of age at the screening visit has a normal mammogram within 1 year 
before randomization. 
13. The subject must be able to communicate well with the Investigator and research staff and to 
comply with the requirements of the study protocol. 
9.2.2 
Exclusion Criteria 
To be eligible for inclusion in this study the subject must not meet any of the following criteria: 
1. The subject is pregnant or breast feeding or is planning a pregnancy within the duration of the 
Treatment Period of the study. 
2. The subject is less than 6 months postpartum or 3 months post-abortion/miscarriage at the time 
of entry into the screening period. 
3. The subject has a surgical history of: 


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a. Hysterectomy,  
b. Bilateral oophorectomy, 
c. Vagotomy, bowel resection or any surgical procedure (including gastric surgery) that 
might interfere with gastrointestinal motility, pH, or absorption, 
d. Any major abdominal surgery (including laparotomy for endometriosis) within 6 
months or any interventional surgery for endometriosis performed within a period of 
2 months before screening, or the subject is scheduled for a surgical abdominal 
procedure during the course of the study. 
4. The subject had a tubal sterilization which was performed with ESSURE™. 
5. The subject had endometrial ablation resulting in amenorrhea. 
6. The subject has at least one ovarian endometrioma with a diameter of 7 cm or greater. 
7. The subject is likely to require treatment during the study OR received treatment within a 
specified period prior to screening with any of the medications listed below: 
a. GnRH antagonists 
3 months 
b. GnRH agonist injections/3-month depot injections 
3/6 months 
c. Danazol 
3 months 
d. Oral contraceptives and other sex hormones 
1 month 
e. Depot contraceptives 
10 months 
f. Selective Progesterone Receptor Modulators (SPRMs), 
Selective Estrogen Receptor Modulators (SERMs) and 
aromatase inhibitors 
3 months 
g. Long acting narcotics (i.e. requiring less than once daily 
dosing) 
1 day 
h. Systemic glucocorticoid treatments for acute diseases 
(not depot) 
1 month 
i. 
Medical (prescribed) marijuana 
1 week 
j. 
In situ copper intra-uterine device (IUD) 
1 day 
k. In situ IUD with progestogen 
1 month 
8.  The subject is likely to use cannabinoids during the study washout, screening or treatment 
period. 
9.  The subject has required more than 2 weeks of continuous use of a narcotic analgesics for 
treatment of EAP within 6 months prior to Screening. 
10. The subject received strong CYP3A4 inducers or inhibitors that (might potentially) interact 
with ABT within 1 month prior to randomization. 
11. The subject has a contra-indication to ABT including: 
a. Active deep vein thrombosis, pulmonary embolism, or history of these conditions; 


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b. Active or recent (e.g. within the past year) arterial thromboembolic disease (e.g. stroke, 
myocardial infarction); 
c. Known, suspected, or history of breast cancer; 
d. Known or suspected estrogen-dependent neoplasia;  
e. Known protein C, protein S, or antithrombin deficiency, or other known thrombophilia 
disorders, including Factor V Leiden; 
f. Migraine with aura; 
g. History of porphyria; 
h. Known hypersensitivity to the ingredients. 
12. The subject has a history of or current systemic glucocorticoid therapy for treatment of chronic 
diseases (e.g. Systemic Lupus Erythematosus (SLE), rheumatic arthritis). Inhaled 
glucocorticoids for e.g. asthma are not considered systemic glucocorticoids. 
13. The subject did not respond to prior treatment with GnRH agonists or GnRH antagonists for 
endometriosis. 
14. The subject has alanine aminotransferase (ALT), aspartate aminotransferase (AST), total 
bilirubin levels or gamma-glutamyl transpeptidase (GGT) level ≥ 2 times the upper limit of 
normal and indicative of potential liver damage at Screening or Day 1 (subjects with 
abnormalities at Day 1 will be withdrawn from study at reception of the results). 
15. The subject has clinically significant abnormal ECG, or ECG with QTc using Fridericia's 
correction formula (QTcF) > 450 msec at Screening or Day 1 (prior to dosing). 
16. The subject has a known positive human immunodeficiency virus (HIV) or viral Hepatitis 
serology. 
17. The subject has abnormal uterine bleeding of undiagnosed cause. 
18. The subject had/has clinically significant findings from a Papanikolaou (PAP) smear test 
performed within the past 12 months or at the screening visit which will require surgical 
intervention (e.g. Loop electrosurgical excision procedure (LEEP) or cervical conization). 
19. The subject has chronic pelvic pain that, in the opinion of the Investigator, is not caused by 
endometriosis and requires chronic analgesic or other chronic therapy which would interfere 
with the assessment of EAP (e.g., interstitial cystitis, presumptive adenomyosis, fibroids, non-
endometriosis-related pelvic adhesive disease, post-tubal ligation or irritable bowel 
syndrome).  
20. The subject has any other clinically significant gynecological condition identified during 
screening transvaginal ultrasound (TVUS) or endometrial biopsy which might interfere with 
the study efficacy and safety objectives (e.g. endometritis, endometrial hyperplasia). However, 
uterine fibroids (as long as uterus size ≤ 12 weeks, i.e. equivalent gestational weeks) and 
adenomyosis are allowed provided they do not interfere with the assessment of EAP (see 
previous criterion). 
21. The subject has any known condition, including findings in the medical history or in the 
screening assessments, which in the opinion of the Investigator constitutes a risk or a 


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contraindication to the participation of the subject in the trial or that could interfere with the 
trial objectives, conduct or evaluation. 
22. The subject has a history of, or known, osteoporosis, hyperparathyroidism or other metabolic 
bone disease. 
a. Screening DXA results of the lumbar spine (L1–L4), femoral neck, or total hip BMD 
showing a Z-score ≤ –1.5  
b. Any condition that would interfere with obtaining adequate DXA measurements (e.g. 
weight [> 300 pounds or 136 kg], history of spinal surgery, spinal hardware, severe 
scoliosis) 
c. Intercurrent bone disease 
d. History of hip fracture 
e. History of pathologic or compression fractures 
f. History of bilateral hip replacement 
23. The subject has a mental condition rendering her unable to understand the nature, scope and 
possible consequences of the study, or evidence of an uncooperative attitude. 
24. The subject has current problem with alcohol or drug abuse (including painkiller abuse).  
25. The subject has been administered with any experimental drug in the 12 weeks before screening. 
26. The subject has calcium level above the upper limit of normal range at screening, which is 
confirmed on repeat fasting testing at Screening. 
27. The subject has a history of, or active malignancy (with or without systemic chemotherapy) 
(except treated basal carcinoma of the skin which is not an exclusion criterion). 
28. The subject has a history of attempted suicide and/or a history of, or known major psychiatric 
disorders that are not well controlled. 
10 STUDY PROCEDURES AND ASSESSMENTS 
10.1 GENERAL INSTRUCTIONS 
Before the start of the study, each subject will be provided with a subject information leaflet giving 
details on the Investigational Medicinal Product (IMP), study procedures and potential risks and they 
will also be informed verbally by the Investigator or legally acceptable designee of the overall 
requirements of the study. They will be instructed that they can obtain further information from the 
Investigator at any time and that they are free to withdraw their consent and to discontinue their 
participation in the project at any time without prejudice. 
If the subject is willing to participate in the study, she will be requested to give written informed consent 
prior to conducting any of the study screening procedures, after being given sufficient time to consider 
her participation and the opportunity to ask for further details. One original copy of the consent form 
will be signed and personally dated by both the subject and the Investigator or legally acceptable 


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designee. The original signed copy will be kept in the confidential investigator file and a copy will be 
given to the subject. 
The subject will be asked if she authorizes the Investigator to notify her general practitioner of her 
participation in the trial. 
Upon signature of the Informed Consent Form (ICF), each subject will be assigned a Subject 
Identification Number (SIN) through an IWRS. 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) 
During the whole study, the subject will be identified using the SIN for all documentation and 
discussion. The SIN assigned to a subject in this way must only be used for that subject. 
Should a subject drop out from the study, the SIN will not be re-allocated. 
Screen failures may be re-screened at a later date with the Sponsor’s approval if it is believed that the 
reason for excluding them initially is no longer applicable. Any re-screened subject will be assigned a 
new SIN through an IWRS and all the screening information will be collected again. All screening 
procedures should be repeated except endometrial biopsy collection (if done during the preceding 6 
months of re-screening), PAP smear (if done during the preceding 12 months of re-screening), DXA (if 
done during the preceding 3 months of randomization) and mammogram (if done during the preceding 
12 months of randomization). 
An electronic Case Report Form (eCRF) will be completed for all subjects who signed the ICF.  
For screen failed subjects, the following information will be collected at a minimum: Informed Consent, 
Demographics, AEs and reason for screen failure. 
When a subject has been found to be eligible for the study, she will be randomized to one of the three 
treatment groups in a 1:1:1 ratio (approximately 150 subjects per treatment group) as shown in Figure 
1. 
Randomization will be done according to a computer-generated list. Treatment assignments will be 
obtained via IWRS according to the randomization list. The subject will be allocated a randomization 
number and treatment kit numbers via IWRS. The randomization number allocated to the subject will 
allow any unblinded study personnel to identify the treatment group to which the subject is randomized.  
Treatment kits will be dispensed to the subjects as follows: 
- 
on Day 1 and Month 3 visits, subject will receive two kits, one for linzagolix/placebo (monthly 
kit) and one for the ABT/placebo (3-monthly kit).  
- 
On Month 1, Month 2, Month 4 and Month 5 visits, subject will receive one kit only, for 
linzagolix/placebo.  
The treatment kit numbers for linzagolix/placebo and ABT/placebo will refer to unique kits present at 
site and corresponding to the randomization allocation.  


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10.2 OUTLINE OF STUDY PROCEDURES AND ASSESSMENTS 
All post-baseline visits should take place at the end of the defined period (i.e. Month 1 visit should be 
scheduled at the end of Month 1, Month 2 visit should be scheduled at the end of Month 2, etc.). One 
month is defined as 28 days/4 weeks. Post-baseline visit dates are calculated from Day 1 visit date :  
- 
Month 1 (Day 29), Month 2 (Day 57), Month 3 (Day 85), Month 4 (Day 113), Month 5 
(Day 141) and Month 6 (Day 169) for the Treatment Period,  
- 
Month 1 FU (Day 197), Month 2 FU (Day 225), Month 3 FU (Day 253), Month 4 FU (Day 
281), Month 5 FU (Day 309) and Month 6 FU (Day 337) for the Follow-up Period. 
A window of ± 3 days is allowed for each visit scheduled during the treatment period. A window of ± 7 
days/1 week is allowed for each visit scheduled during the follow-up period. The visit schedule is 
illustrated in Figure 2 below:  
 
Figure 2 : Schedule of Visits 
 
The timing of events is shown in the Schedule of Assessments (Appendix A and Appendix B). 
10.2.1 Screening Period – Screening visit  
The subject will be informed of the study objectives and overall requirements, and written informed 
consent will be obtained before performing any study-specific procedures that are not standard of care. 
The subject will be considered as included into the study after the ICF is signed and dated by the subject 
and the Investigator or legally acceptable designee. 
For subjects who require washout for oral contraceptives, or other sex hormones, or GnRH 
antagonists/agonists (provided that the reason for discontinuing the previous GnRH-antagonist is not 
lack of efficacy), a period of up to 3 months will be allowed between signing the ICF and starting the 
collection of pain assessments in eDiary during the screening period. The screening period must cover 


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two full menstrual cycles and will last about 3 months. During the screening period, the subject will be 
seen up to three times if not all screening assessments could be performed at the first screening visit 
(e.g. the endometrial biopsy must be performed after day 7 of the menstrual cycle). 
During the screening period the following study screening assessments will be completed (see Schedule 
of Assessments in Appendix A): 
- 
Demographic data, height and weight 
- 
Medical and surgical history including concomitant diseases (and especially presence of 
rectovaginal endometriosis and adenomyosis), previous medication, obstetric/gynecological 
history and history of endometriosis including diagnosis and previous treatments for 
endometriosis. 
- 
Assessment of DYS, dyspareunia and NMPP with the mB&B scale (see Appendix C). Answers 
will be captured in eCRF. 
- 
Completion of the paper C-SSRS questionnaire “Baseline” version specific for subjects under 
screening (see Appendix R) 
- 
ECG 
- 
Physical examination 
- 
Vital signs (blood pressure (BP) and heart rate) 
- 
Urine pregnancy test  
- 
TVUS of uterus and ovaries to measure endometrial thickness, to rule out any clinically 
significant gynecological conditions which might interfere with the study efficacy and safety 
objectives and to confirm that the subject has no ovarian endometrioma ≥ 7 cm in diameter 
- 
Gynecological examination, including the mB&B scale (see Appendix C) clinical signs 
reporting (pelvic tenderness and pelvic induration) 
- 
Endometrial biopsy (should be performed at least 7 days after the first day of menstruation and 
sent for central assessment). If no tissue is available, the biopsy should be repeated as soon as 
possible in the following days. In case of multiple (at least two including the initial one) and 
unsuccessful attempts to get sufficient endometrial tissue, the subject is allowed to be 
randomized without any screening endometrial biopsy under the following conditions: 
a. the investigator confirms and documents in source that the subject has no signs of 
suspected endometrium malignancy (e.g. abnormal bleeding profile).  
b. The investigator and subject agree that at end of treatment all necessary actions will be 
taken to get a sufficient endometrium sample (e.g. short anaesthesia, if necessary). 
c. The medical monitor of the study approves the inclusion of the subject. 
The endometrial biopsy is not required for subjects having performed an endometrial biopsy 
within the past 6 months of the screening visit, which shows no endometrium hyperplasia of 
any type or adenocarcinoma and for which slides are available for current study assessment 
through retrospective central laboratory reading. 


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- 
PAP smear 
A screening PAP smear is not required for subjects in whom a PAP smear was performed within 
the 12 months prior to the screening visit and which results indicate no clinically significant 
abnormalities requiring surgical intervention (e.g. LEEP or cervical conization) and are 
available for source document verification.  
- 
Manual breast examination by palpation (and mammography if applicable: subject ≥ 40 years 
of age at screening should have performed a mammogram within 12 months before 
randomization) 
- 
Blood samples for haematology, coagulation parameters, chemistry and lipids assessments 
- 
Urinary protein dipstick. 
- 
Contraception dispensing and counselling 
- 
BMD assessed by DXA for femoral neck, hip and spine. The DXA scans will be read centrally. 
To avoid unnecessary exposure to X-ray it is recommended to perform this procedure towards 
the end of the screening period (when all other Inclusion/Exclusion criteria are already met), 
but at least 2 weeks prior to the baseline visit to allow enough time to get the DXA results for 
eligibility confirmation at the time of the baseline visit at the latest. 
The subject will receive double barrier contraception (condoms with spermicide) if requested. If the 
subject is at risk for acquiring HIV, she must be instructed to use double non-hormonal barrier 
contraception without spermicides (eg: condoms and diaphragms). 
In addition, a limited quantity (as per Investigator’s judgement) of permitted analgesics will be 
provided/prescribed to the subject at the screening visit to cover the screening period. 
The subject will be given an eDiary with a user manual to take home and will be trained by the 
Investigator or delegate on how to use and complete it correctly. Subject eDiary completion should be 
started on the day of screening visit (after completion of washout period when applicable). The eDiary 
should be completed daily, in the evening at approximately the same time, for use of provided/prescribed 
analgesics, uterine bleeding (including start of menstruation), pelvic pain, dyspareunia, dyschezia and 
daily function. The eDiary screening assessments should cover at least two full menstrual cycles (from 
day 1 of the first menstruation going over two spontaneous menstrual cycles up to the day before the 
next menstruation i.e. the third menstruation).  
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 the operational 
team. 
Any concomitant medications taken after signature of informed consent will be recorded in the eCRF 
(excluding any provided/prescribed analgesics used for EAP which will be recorded daily in the eDiary). 
Any AE occurring after signature of informed consent will be recorded in the eCRF. 
The subject will be asked to return to the site and bring her eDiary between the first and seventh day 
(inclusive) of her next menstrual period (the period after the 2 screening full menstrual cycles) for the 
Day 1 visit. Final assessment of her eligibility will be performed, including calculation of the baseline 


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scores for pelvic pain collected via the eDiary. The baseline mean pelvic pain scores will be calculated 
using the data collected during the screening period over two full, spontaneous menstrual cycles.  
If for logistical reasons beyond her control, the subject is unable to come to the clinic for Day 1 within 
the acceptable time window (1st to 7th day inclusive of the cycle) then the subject will be allowed to start 
Day 1 in the following cycle (again on the 1st to 7th day of the cycle). In this case, the eligibility 
assessments should be assessed based on the first two cycles only. However, the eDiary recording should 
be continued daily during the third cycle. 
Note that in exceptional cases, the Day 1 visit may occur between Day 8 and Day 12 of the third or 
fourth cycle but only upon prior approval by the sponsor. In that case, the subject should do a urine 
pregnancy test at her home 1 week after the Day 1 visit to ensure she is not pregnant. The subject should 
communicate (e.g., via phone) results of the test to the site for recording into the source medical file. 
10.2.2 Treatment period 
From Day 1 to Month 6, the subject should record daily in her eDiary, at approximately the same time 
each evening, the following questionnaires: IMP intake, use of provided/prescribed analgesics, uterine 
bleeding, pelvic pain, dyspareunia, dyschezia and daily function.  
During the entire treatment period, the subject will be asked to bring her eDiary and her IMP kits at each 
visit to the site.  
10.2.2.1 
Baseline visit: Day 1 
If the subject has successfully completed all screening assessments and is between the first and seventh 
day (inclusive) of her menstruation, she will go to the investigational site for the following evaluations 
and tests before drug administration: 
- 
eDiary eligibility data review 
- 
ePRO and ClinRO completion, ideally before any other procedures or assessments: EHP-
30, HRPQ, HRUQ, PSIQ, SSIQ, PROMIS, EQ-5D-5L, specific monthly severity questions, 
mPGIS (anchors must be completed last) 
- 
Completion of the paper C-SSRS questionnaire “Baseline” version, if not already completed 
during screening period (see Appendix R) 
- 
Screening DXA results review 
- 
Screening lab results review 
- 
Screening endometrial biopsy results review (randomization will not be postponed if the 
results of the endometrial biopsy performed during the screening period are not available 
on Day 1) 
- 
Previous and concomitant treatments recording 
- 
AE recording 
- 
ECG 


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- 
Vital signs (BP and heart rate) 
- 
Urine pregnancy test 
- 
Urinary protein dipstick 
- 
Fasting (overnight) blood samples for haematology, coagulation parameters, chemistry, 
lipids, glucose, hormones and bone biomarkers, prior to the first administration of study 
treatment, and after confirmation of the subject’s eligibility (considering the invasive nature 
of this procedure). 
Upon confirmation of inclusion/exclusion criteria, the subject will be randomized to one of the three 
treatment groups and will be provided with the study drugs (1 kit of linzagolix/placebo and 1 kit of 
ABT/placebo) and provided/prescribed with permitted analgesics as well as vitamin D and calcium 
supplements. The subject will be instructed on how to take the study drugs and analgesics, and advised 
to take the provided vitamin D and calcium daily. The subject will be provided/prescribed as necessary 
with analgesics and vitamin D/calcium supplements at each subsequent visit to cover requirements until 
the end of the follow-up period. 
The subject will take her first dose of study medication at the study site. The exact time of dosing 
(hour/minute) will be recorded in eCRF. 
After drug administration, the following procedures will be performed: 
- 
ECG at about the same time as but before the post-dose PK sample 
- 
Post-dose PK sample taken at least 1.5 h after treatment administration. The exact time of 
dosing and of PK sampling (hour/minute) will be recorded in the eCRF. 
- 
Contraception dispensing (if applicable) and counselling 
The subject will receive double barrier contraception (condoms with spermicide) if requested. If the 
subject is at risk for acquiring HIV, she will be instructed to use double non-hormonal barrier 
contraception without spermicides (condoms and diaphragms). 
Upon completion of the visit, the subject will be provided with emergency contact phone numbers and 
will be scheduled for her next visits.  
For the whole duration of the treatment period, 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. 
10.2.2.2 
Study visits: Month 1 (Day 29 -3/+2 days) and Month 2 (Day 57 ± 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 1 visit: EHP-30, HRPQ, HRUQ, PROMIS, EQ-5D-5L, mPGIS, PGIC 
 
at Month 2 visit: HRPQ, HRUQ, mPGIS, PGIC 


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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 S) for patients responding to the C-SSRS for the first time during the study, or 
version “since last study visit” (see Appendix T) 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 for haematology, coagulation parameters, chemistry, lipids, hormones 
(overnight fasting required at Month 1 visit only) 
- 
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 
- 
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 baseline visit. 
10.2.2.3 
Study visit: Month 3 (day 85 ± 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, 
HRPQ, HRUQ, PROMIS, EQ-5D-5L, specific monthly severity questions, mPGIS, PGIC 
completion (anchors must be completed last) 
- 
Concomitant treatments recording 
- 
AE recording 
- 
Completion of the paper C-SSRS questionnaire (version for “already enrolled subjects” (see 
Appendix S) for patients responding to the C-SSRS for the first time during the study, or version 
“since last study visit” (see Appendix T) for patients for whom the C-SSRS was completed at 
the previous study visit) 
- 
IMP accountability based on blisters 


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- 
ECG (at about the same time as but before the PK sample) 
- 
Physical examination 
- 
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 and bone biomarkers 
- 
Pre-dose PK samples (the time of dose administration on previous 4 days and time of PK 
sampling will be recorded) 
- 
Contraception dispensing (if applicable) and counselling 
- 
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. 
10.2.2.4 
Study visits: Month 4 (day 113 ± 3 days) and Month 5 (day 141 ± 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: HRPQ, 
HRUQ, mPGIS, PGIC completion (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 S) for patients responding to the C-SSRS for the first time during the study, or version 
“since last study visit” (see Appendix T) 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 for haematology, coagulation parameters, chemistry, lipids, hormones 


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- 
Pre-dose PK samples (the time of dose administration on previous 4 days and time of PK 
sampling will be recorded) 
- 
Contraception dispensing (if applicable) and counselling 
- 
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 3 visit. 
At Month 5 visit, the subject will be informed of the possibility to enter the extension study at Month 6 
(if eligible) and will be provided with a copy of the subject information sheet to read prior to the Month 
6 visit. 
10.2.2.5 
Study visit: Month 6 (day 169 ± 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, 
HRPQ, HRUQ, PSIQ, SSIQ, PROMIS, EQ-5D-5L, specific monthly severity questions, 
mPGIS, PGIC completion (anchors must be completed last) 
- 
Concomitant treatments recording 
- 
AE recording 
- 
Completion of the paper C-SSRS questionnaire (version for “already enrolled subjects” (see 
Appendix S) for patients responding to the C-SSRS for the first time during the study, or version 
“since last study visit” (see Appendix T) 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 and bone biomarkers 


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- 
Pre-dose PK samples (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 6 
study visit at the latest, knowing that subjects who experience more than 8% BMD loss or a Z-
score ≤ -2.5 will not be eligible to enter the extension study. 
- 
The subject will be verbally asked which treatment she believed she received during the blinded 
Treatment Period. The answer will be recorded in the eCRF. 
- 
Contraception dispensing (if applicable) and counselling 
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. 
Study visit Month 6 constitutes the end of the Treatment Period. 
The subject – if eligible - will be proposed to enter the extension study. If she is willing to participate, 
she will have to provide written consent. If she does not wish to enter the extension study or if she does 
not qualify for the extension, she will continue in the treatment-free follow-up period. 
10.2.3 Follow-up period without treatment for subjects not entering the extension study  
Up to Month 6 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. 
10.2.3.1 
Study visit: Month 1 FU  
M1 FU visit should be scheduled on Day 197 ± 7 days after 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 FU visit: 
- 
eDiary completion compliance check  
- 
ePRO completion, ideally before any other procedures or assessments: mPGIS and PPGIC 
- 
Concomitant treatments recording 
- 
AE recording 
- 
Completion of the paper C-SSRS questionnaire (version for “already enrolled subjects” (see 
Appendix S) for patients responding to the C-SSRS for the first time during the study, or version 


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“since last study visit” (see Appendix T) 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 counselling 
- 
Urinary protein dipstick 
- 
Blood samples for haematology, coagulation parameters, chemistry, lipids, hormones 
- 
Endometrial biopsy only if diagnosis at Month 6 was different than “benign endometrium” or if 
no endometrial biopsy was done at Month 6 (see section 10.4.5).  
10.2.3.2 
Study visits: Month 2 FU, Month 4 FU and Month 5 FU 
Month 2 FU visit should be scheduled on Day 225 ± 7 days after Day 1 (or 56 days ± 7 days after last 
IMP intake for early discontinued subjects). 
Month 4 FU visit should be scheduled on Day 281 ± 7 days after Day 1 (or 112 days ± 7 days after last 
IMP intake for early discontinued subjects). 
Month 5 FU visit should be scheduled on Day 309 ± 7 days after Day 1 (or 140 days ± 7 days after last 
IMP intake for early discontinued subjects). 
The following tests and evaluations will be performed at Month 2 FU, Month 4 FU and Month 5 FU 
visits: 
- 
eDiary completion compliance check 
- 
ePRO completion, ideally before any other procedures or assessments: mPGIS and PPGIC 
- 
Concomitant treatments recording 
- 
AE recording 
- 
Completion of the paper C-SSRS questionnaire (version for “already enrolled subjects” (see ) 
for patients responding to the C-SSRS for the first time during the study, or version “since last 
study visit” (see Appendix T) for patients for whom the C-SSRS was completed at the previous 
study visit) 
- 
Urine pregnancy test and contraception counselling (at Month 2 FU visit only) 
- 
Endometrial biopsy only if diagnosis at preceding biopsy was different than “benign 
endometrium” or if no endometrial biopsy was done at Month 6 nor at any visit since Month 6 
(see section 10.4.5).  
10.2.3.3 
Study visit Month 3 FU 
Month 3 FU visit should be scheduled on Day 253 ± 7 days after Day 1 (or 84 days ± 7 days after last 
IMP intake for early discontinued subjects). 


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The following tests and evaluations will be performed at Month 3 FU Visit: 
- 
eDiary completion compliance check 
- 
ePRO and ClinRO completion, ideally before any other procedures or assessments: EHP-30, 
HRPQ, HRUQ, PROMIS, EQ-5D-5L, mPGIS, PPGIC completion (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 S) for patients responding to the C-SSRS for the first time during the study, or version 
“since last study visit” (see Appendix T) for patients for whom the C-SSRS was completed at 
the previous study visit) 
- 
ECG 
- 
Physical examination 
- 
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 and bone markers. For subjects that do not resume menses at Month 3 FU visit, a 
FSH test should be performed at local laboratory and the subjects should be advised to consult 
for a gynaecological evaluation. 
- 
Endometrial biopsy only if diagnosis at preceding biopsy was different than “benign 
endometrium” or if no endometrial biopsy was done at Month 6 nor at any visit since Month 6 
(see section 10.4.5).  
10.2.3.4 
Study visit: Month 6 FU – End of Follow-up visit 
Month 6 FU visit should be scheduled on Day 337 ± 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 FU Visit: 
- 
ePRO and ClinRO completion, ideally before any other procedures or assessments: EHP-30, 
HRPQ, HRUQ, PROMIS, EQ-5D-5L, mPGIS, PPGIC completion (mPGIS and PPGIC must be 
completed last) 
- 
Collection and deactivation of eDiary 


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- 
Concomitant treatments recording 
- 
AE recording 
- 
Completion of the paper C-SSRS questionnaire version “since last study visit” (see Appendix 
T) for patients for whom the C-SSRS was completed at the previous study visit. 
- 
ECG 
- 
Physical examination, including weight recording 
- 
Urine pregnancy test 
- 
TVUS of uterus 
- 
Endometrialm biopsy if no endometrial biopsy was obtained at Month 6 nor at any visit since 
Month 6 (see section 10.4.5). If no tissue is available, 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 FU study visit. 
This visit constitutes the end of study participation except for subjects with a BMD decrease from 
baseline > 1.5% for lumbar spine and/or > 2.5% for total hip who should have a repeat DXA scan 6 
months later for a BMD follow-up assessment.  
10.2.3.5 
Study visit: BMD Follow-up visit 
BMD Follow-up visit should be scheduled on Day 505 ± 10 days after Day 1 (or 168 days ± 10 days 
after M6 FU visit). 
This visit is applicable only to subjects with a BMD decrease from baseline > 1.5% for lumbar spine 
and/or > 2.5% for total hip at M6 FU visit. 
BMD will be assessed by DXA for femoral neck, hip and spine.  
Subjects who have ≥ 3% BMD decrease at any site (femoral neck, hip or spine) at this visit should be 
referred to a bone specialist. 
10.3 EFFICACY OBSERVATIONS AND MEASUREMENTS 
All the questionnaires described below except the mB&B scale 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 Modified Biberoglu and Behrman questionnaire 
Endometriosis pain will be assessed at screening by subject using the mB&B scale (see Appendix C). 


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10.3.2 Daily diary 
The subject will be given an eDiary with a user manual to take home and will be trained by the 
Investigator or delegate on how to use and complete it correctly. Subject eDiary completion should be 
started on the day of screening visit (after completion of washout period when applicable).  
The eDiary should be completed daily, in the evening at approximately the same time. 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. 
10.3.2.1 
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.  
10.3.2.2 
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. 
10.3.2.3 
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) 


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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 
Subject will be asked additional questions to identify the first day of her menstrual periods during the 
Screening Period. 
10.3.2.4 
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. 
10.3.2.5 
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: 
 
 
 
 
 
 
She will be given as well the option to answer that she was not sexually active for reasons other than 
her endometriosis, in which case no score would be allocated. 
10.3.2.6 
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. 
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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10.3.2.7 
School or work missed 
The subject will be asked whether she missed school or work in the last 24 hours due to EAP. 
10.3.2.8 
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 is removed in protocol version 4.0 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 implementation of protocol version 4.0. 
10.3.2.9 
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.  
10.3.2.10  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 is removed in protocol version 4.0 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 implementation of protocol version 4.0. 
10.3.2.11  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 J). 
Following a request from the FDA, this assessment is removed in protocol version 4.0 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 implementation of protocol 
version 4.0. 
10.3.3 Outcome rating scales assessed at site visits 
ePROs are self-administered questionnaires completed by the subject. ePROs completed by the subject 
during the site visit include: specific monthly severity questions (i.e monthly dysmenorrhea question, 
monthly non-menstrual pelvic pain question, monthly overall pelvic pain question, monthly difficulty 
in doing daily activities question, monthly dyschezia question, monthly dyspareunia question), EHP-30, 
HRPQ, SSIQ, PROMIS, EQ-5D-5L, mPGIS and PGIC/PPGIC. 
ClinROs are questionnaires administered by the site staff to the subject and completed by the site staff 
in the eDiary. ClinROs include monthly dyspareunia question, HRUQ and PSIQ. 
Specific monthly severity questions (monthly dysmenorrhea question, monthly non-menstrual pelvic 
pain question, monthly overall pelvic pain question, monthly difficulty in doing daily activities question, 


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monthly dyschezia question, monthly dyspareunia question), mPGIS, and PGIC/PPGIC will be used as 
anchors to estimate meaningful change and deriving responder thresholds. 
During site visits, ePROs and ClinROs should be completed ideally prior to any other study procedures, 
with the anchors being completed last.. Assessments will be performed at the visits as indicated in 
Appendix A and Appendix B.  
Prior to the start of the study, site personnel will be trained on all rating scales (ePROs, ClinROs and 
scales of daily diary) used in this study. The training will be provided at the investigator meeting and/or 
site initiation visit. The objective of this training is to establish uniformity across subjects and sites in 
completion of these rating instruments.  
10.3.3.1 
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 D. 
10.3.3.2 
PROMIS Fatigue Short Form 6a14 
This questionnaire is composed of six questions to evaluate the severity of fatigue (see Appendix E). 
10.3.3.3 
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 F). 
10.3.3.4 
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 G). 
10.3.3.5 
Patient Global Impression of Change (PGIC) 
The PGIC is used by the subjects to evaluate the change in their 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 H). 
10.3.3.6 
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 I).  


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10.3.3.7 
Patient Global Impression of Severity - monthly recall (mPGIS) 
At each study visit from Day 1 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 J). 
10.3.3.8 
Subject Surgery Intention Question (SSIQ) 
The SSIQ evaluates subject willingness to opt for endometriosis-related surgery if current symptoms 
continue (see Appendix K). 
10.3.3.9 
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 L). 
10.3.3.10 EQ-5D-5L 
Subjects’ health related quality of life will be measured using the EQ-5D-5L (see Appendix M). 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’.  
10.3.3.11 Specific Monthly severity questions 
The monthly severity questions specific to DYS, NMPP, overall pelvic pain, difficulty in doing daily 
activities, dyschezia and dyspareunia will be used as separate anchors to determine what constitutes a 
meaningful within-patient score change in the respective assessment. 
10.3.3.11.1 Monthly dysmenorrhea question 
At Day 1, Month 3 and Month 6 study visits, the subject will be asked to evaluate the severity of her 
dysmenorrhea over the past 28 days using a 5-point scale with the following possible answers: no pain, 
very mild, mild, moderate, severe. 
Subject’s answer to the question “How would you describe your menstrual pelvic pain (on any days 
of vaginal bleeding or spotting) over the past 28 days?” will be collected via the eDiary. 
Not all subjects will have this assessment completed as it was added during the study course as a protocol 
amendment. 


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10.3.3.11.2 Monthly non-menstrual pelvic pain question 
At Day 1, Month 3 and Month 6 study visits, the subject will be asked to evaluate the severity of her 
non-menstrual pelvic pain over the past 28 days using a 5-point scale with the following possible 
answers: no pain, very mild, mild, moderate, severe. 
Subject’s answer to the question “How would you describe your non-menstrual pelvic pain (on any 
days with no vaginal bleeding nor spotting) over the past 28 days?” will be collected via the eDiary. 
Not all subjects will have this assessment completed as it was added during the study course as a protocol 
amendment. 
10.3.3.11.3 Monthly overall pelvic pain question 
At Day 1, Month 3 and Month 6 study visits, the subject will be asked to evaluate the severity of her 
overall pelvic pain over the past 28 days using a 5-point scale with the following possible answers: no 
pain, very mild, mild, moderate, severe. 
Subject’s answer to the question “How would you describe your overall pelvic pain (menstrual and 
non-menstrual) over the past 28 days?” will be collected via the eDiary. 
Not all subjects will have this assessment completed as it was added during the study course as a protocol 
amendment. 
10.3.3.11.4 Monthly difficulty in doing daily activities question 
At Day 1, Month 3 and Month 6 study visits, the subject will be asked to evaluate how much has her 
endometriosis-related pain caused her difficulty in performing her daily activities over the past 28 days 
using a 5-point scale with the following possible answers: No difficulty, slight difficulty, mild difficulty, 
moderate difficulty, severe difficulty. 
Subject’s answer to the question “How much has your endometriosis-related pain caused you difficulty 
in performing your daily activities over the past 28 days?” will be collected via the eDiary. 
Not all subjects will have this assessment completed as it was added during the study course as a protocol 
amendment. 
10.3.3.11.5 Monthly dyschezia question 
At Day 1, Month 3 and Month 6 study visits, the subject will be asked to evaluate the severity of her 
dyschezia over the past 28 days using a 5-point scale with the following possible answers: no pain, very 
mild, mild, moderate, severe. 
Subject’s answer to the question “Overall, how would you describe any endometriosis-related pain 
during defecation (bowel movement) over the past 28 days?” will be collected via the eDiary. 
Not all subjects will have this assessment completed as it was added during the study course as a protocol 
amendment. 
10.3.3.11.6 Monthly dyspareunia question 
The question will be administered and completed in the eDiary using the mB&B scale for Deep 
Dyspareunia, at Day 1, Month 3 and Month 6 study visits. 


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The subject will first report, directly in the eDiary, if she had any sexual intercourse over the past 28 
days.  
If she didn’t have any sexual intercourse over the past 28 days, she will report whether she avoided 
sexual intercourse mainly because of anticipation of pain during intercourse, with the following possible 
answers: Yes, No. 
If she had any sexual intercourse over the past 28 days, her overall experience of pain with intercourse 
over the previous 28 days will be asked by the site staff and graded using the mB&B scale for Deep 
Dyspareunia: 
None 
 
0 = No symptoms 
Mild 
 
1 = Tolerated discomfort during intercourse 
Moderate 
2 = Interference of usual frequency of sexual intercourse due to pain 
Severe   
3 = Avoids, or wishes to avoid, intercourse because of pain 
Not all subjects will have this assessment completed as it was added during the study course as a protocol 
amendment. 
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). 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. 
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 at scheduled 
visits. In addition, a manual breast examination (by palpation) will be performed at Screening, Month 6 
and Month 3 FU visits. Results of the examinations will be recorded on source subject data file and in 
the eCRF. Baseline medical conditions (see section 12.1.3) that do 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. 


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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 of 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 print-outs 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 least two endometrial biopsies for histological assessment will have to be obtained for each subject: 
 
One at screening (unless an endometrial biopsy was performed within the past 6 months of the 
screening visit, which shows no endometrial hyperplasia of any type or adenocarcinoma and for 
which slides are available for current study assessment through retrospective central laboratory 
reading. 
 
One at Month 6 if endometrium thickness on TVUS is > 5 mm (see Figure 3) 
 
One at Month 1 FU, 2 FU, 3 FU, 4 FU, 5 FU or 6 FU if not obtained at Month 6 or if the 
preceding biopsy diagnosis is different than “benign endometrium” but is not “malignant” or 
not “hyperplasia” (see Figure 4)  
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.  
 
Figure 3 : Biopsy process for Month 6 study visit 


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Figure 4 : Biopsy process for the follow-up period visits 
 
Screening endometrial biopsy should be performed at least 7 days after the first day of menstruation and 
sent for central assessment. If no tissue is available, the biopsy should be repeated as soon as possible 
in the following days. In case of multiple (at least two including the initial one) and unsuccessful 
attempts to get sufficient endometrial tissue, the subject is allowed to be randomized without any 
screening endometrial biopsy under the following conditions:  
a. The investigator confirms and documents in source that the subject has no signs of suspected 
endometrium malignancy (e.g. abnormal bleeding profile). 
b. The investigator and subject agree that at end of treatment all necessary actions will be taken to 
get a sufficient endometrium sample (e.g. short anaesthesia, if necessary). However, it should 
be noted that for subjects who discontinue the study and complete less than 3 months of 
treatment an end-of-study biopsy is not required. 
c. The medical monitor of the study approves the inclusion of the subject. 


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If there is a subsequent clinically significant finding in the biopsy, the subject will be withdrawn 
immediately 
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 patients 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, (and will not be eligible to enter 
the extension study), will enter the follow-up period (unless she is discontinued prior to Month 3 visit) 
and will be advised to consult for a 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. 
10.4.6 Bone mineral density and DXA 
BMD of femoral neck, total hip and lumbar spine will be assessed by DXA, under the supervision of a 
nominated primary technologist at the site. 
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 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. 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, chemistry, lipids, glucose and hormones will be assessed from 
blood samples. Haematology, coagulation parameters, chemistry and lipids will be assessed at screening 
and at each visit during the treatment period, as well as at M1 FU and M3 FU visits. E2, progesterone 
(P4) and LH will be assessed at each visit during the treatment period (not at screening visit), as well as 
at M1 FU and M3 FU visits. Serum levels of the anti-müllerian hormone (AMH) and fasting glucose 
will be assessed on Day 1 only. Serum levels of the sex hormone-binding globulin (SHBG) will be 
assessed on Day 1 and Month 3 and Month 6 visits.  


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Overnight fasting is required for Day 1, Months 1, 3 and 6, and Month 3 FU 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, SHBG, P4, LH and bone marker levels will be assessed by 
the Investigator/sub-investigator and clinically significant abnormalities compared to screening/baseline 
status will be reported as AEs in the eCRF. E2, SHBG, P4 and LH levels will not be communicated to 
keep the operational team and the sites blinded to treatment administration. 
The laboratory parameters are listed in Appendix N. 
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 the scheduled visits.  
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 assess 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 “Baseline” C-SSRS version, dedicated to subjects under screening, capturing lifetime history 
of suicidal ideation and behavior (see Appendix R) 
- or the “already enrolled subjects” C-SSRS version, dedicated to randomized subjects who are 
providing answers to the C-SSRS for the first time during the study (see Appendix S) 
- the “since last study visit” C-SSRS version (see Appendix T), 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 for determining linzagolix and KP017 plasma 
levels. 
On Day 1, blood samples for PK assessment will be taken at least 1.5 h post-first dose.  
During the treatment period, on days of site visits at Months 1, 2, 3, 4 and 5), the subject will be asked 
to take the dose of IMP at site, after a pre-dose PK sampling. 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.  


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Details of 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 study, from the date of signature of informed consent and for the whole 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. 
Analgesics: 
Only the analgesics provided/prescribed by sponsor will be allowed during the Screening, Treatment 
and Follow-up Period. 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 
 
Local equivalent Narcotic Analgesics: 
Austria 
tramadol 37.5mg + paracetamol 325mg  
Bulgaria 
tramadol 37.5mg + paracetamol 325mg 
Czech Republic 
codeine 30mg 


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paracetamol 500 mg+ codeine 30 mg 
tramadol 37.5mg + paracetamol 325mg 
France 
paracetamol 500 mg+ codeine 30 mg 
tramadol 37.5mg + paracetamol 325mg 
Hungary 
paracetamol 500 mg+ codeine 30 mg 
codeine 30mg 
tramadol 37.5mg + paracetamol 325mg 
Poland 
tramadol 37.5mg + paracetamol 325mg 
Romania 
codeine 30mg 
paracetamol 500 mg+ codeine 30 mg 
Spain 
paracetamol 500 mg+ codeine 30 mg  
tramadol 37.5mg + paracetamol 325mg 
Ukraine 
N/A  
 
Other:  
In order to prevent or minimize possible impact on bone mineral density, 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 exclusion criteria (see section 9.2.2) will be prohibited up to Month 6.  
To consider a subject who is currently taking any prohibited therapies for potential inclusion in this 
study, the Investigator must ensure that the subject has sufficient washout time prior to screening (see 
Section 10.2.1). 
Strong CYP3A4 inhibitors or inducers are prohibited up to end of treatment in view of the ABT 
(Appendix P). 
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 hormonal IUD must be stopped following ICF signature until 3 
months after end of treatment.  


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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. 
10.6.3 Non-Drug Therapies 
Contraceptive use: 
For subjects of childbearing potential and requiring contraception, non-hormonal contraception is 
required from beginning of screening period 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. 
After 3 months after the end of the Treatment Period until the end of the Follow-up Period, contraception 
is still required but 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 she is 
supposed to follow 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. 
Subjects who did not receive the study drug will be withdrawn from the study and no further study 
procedures will be performed. 
Withdrawal during treatment period: 
Subjects who discontinue between Day 1 and Month 3 should undergo the procedures required at Month 
6 (except the DXA scan and the endometrial biopsy if a biopsy was obtained at screening) and will not 
enter the 6-month follow-up period. 


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Subjects discontinuing the study treatment between Month 3 and Month 6 should undergo the 
procedures required at Month 6. These subjects will enter a 6-month follow-up period and will continue 
daily eDiary recording for 6 months and up to Month 6 FU visit in order to continue to collect efficacy 
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: 
Subjects discontinuing participation in the study during the follow-up period should undergo the 
procedures required at Month 6 FU visit, which includes completion of all ClinRO and ePRO 
questionnaires, except the DXA in case of discontinuation before Month 3 FU 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 that have been exposed to study treatment and who become pregnant 
during the Treatment Period will be immediately withdrawn from treatment. 
Pregnancies that have been exposed to study treatment and occurred up to 
Month 3 FU 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 at Day 1: Subjects presenting with ALT, AST, GGT or total bilirubin ≥ 2 ULN 
should be discussed with the Sponsor and may have to discontinue study treatment if these results are 
indicative of liver involvement.  


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Subjects presenting with a clinically significant finding in the biopsy sample collected at screening and 
who have completed Day 1, will have to discontinue study treatment. 
Subjects who have a serum calcium level at Day 1 above 2.9 mmol/L and who have completed Day 1, 
should have calcium supplements interrupted. If serum calcium level at Day 1 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 2.9 
mmol/L, study treatment should definitively be discontinued and the subject should be advised to consult 
an endocrinologist for further evaluation. 
Discontinuation Rules during the Treatment Period: 
Endometrial biopsies: in case of endometrial biopsy diagnosis being an endometrial hyperplasia of any 
type or worse, the subject will have to discontinue the treatment (and will not be eligible to enter the 
extension study) and will be advised to consult for a 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 2.9 mmol/L, study 
treatment should definitively be discontinued and the subject should be advised to consult an 
endocrinologist for further evaluation. 
Bone mineral density 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 (they will not be eligible to enter the extension study). 
 
Liver function tests: following the Food and Drug Administration (FDA) guidance on drug-induced 
liver injury (17), 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 first dose 
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. 
10.7.3 Subject Replacement 
Discontinued subjects who did not receive the study drug may be replaced. 


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Additional subjects may be recruited due to  subjects who were discontinued due to ALT, AST, GGT 
or total bilirubin ≥ 2 times the upper limit of normal at Day 1, or due to a clinically significant biopsy 
finding at Day 1 (treatment start), or due to high calcium level at Day 1. 
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.  
 
Investigational 
product 
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 
Capsules 
Capsules 
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 


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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 and corresponding placebo treatments will be supplied as film-coated tablets for oral 
administration and given as monthly treatment kits (Figure 5). 
ABT and corresponding placebo will be supplied as red capsules and given as 3-monthly treatment kits. 
IMP treatment will start on Day 1 and will be administered once daily up to the day preceding the Month 
6 visit . The subjects will have to swallow two tablets of linzagolix/placebo and one capsule of 
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, after the PK blood sample 
collection, except on Day 1 visit where the study medication must be taken before the PK blood sample 
collection (at least 1.5 h before). 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 Day 1 and Month 3 visits, ABT/placebo capsules must be taken from 
the kits dispensed during these visits. On Month 1, 2, 4 and 5 visits, ABT/placebo capsules must be 
taken from the previously dispensed kits. 
The treatment groups are described below: 
Treatment 
group 
Daily dose Day 1 to Month 6 
 
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 
1  200 mg 
1  placebo 75 mg 
1 capsule 
None 
Placebo 
None 
1  placebo 75 mg  
AND 
1  placebo 200 
mg  
None 
1 capsule 


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11.3 PACKAGING AND LABELLING 
Study drug (linzagolix/placebo) will be provided by the sponsor (or delegate) as monthly kits.  
On Day 1, Month 1, Month 2, Month 3, Month 4 and Month 5 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.  
 
Figure 5 : Linzagolix/placebo kit design 
Each linzagolix kit will be labeled with a unique kit number starting from B00001, B00002, B00003, 
etc. (6-characters). The blisters being attached into the wallet card, linzagolix 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 Day 1 and Month 3 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), 
starting from N00001, N00002, N00003 etc. 
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 


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 Kit number 
 Batch number 
 Expiry date (for Europe only) 
 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. 
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. 
 
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) 


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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 
Prior to the start of the study, a randomization list and 2 treatment kit lists (one for linzagolix/placebo, 
one for ABT/placebo) will be generated by a designated statistician from the sponsor or delegate to be 
transmitted to the assigned clinical packaging organization for labelling and to a fully integrated IWRS. 
The IWRS will provide the kit numbers, which will correspond to the linzagolix/placebo and 
ABT/placebo kit numbers.  
Subjects will be randomized to one of three treatment groups in a 1:1:1 ratio. There will be no 
stratification. 
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 
(linzagolix/placebo, ABT/placebo), in order to allow the assessment of compliance with study treatment.  
The decision to withdraw a non-compliant subject from the study will be discussed between the 
Investigator and the sponsor. A blind review meeting will take place prior to unblinding. Subjects with 
poor compliance and other significant protocol violations may be excluded from the Per Protocol 
Analysis Set. 
During the entire study period, the study monitor will perform drug accountability and the assessment 
of compliance with study treatment by checking both opened and unopened IMP packages, as well as 
empty blisters.  


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11.8 METHOD OF BLINDING 
The study design is double blind. Linzagolix/placebo treatments 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.  
The randomization list will be secured in a computer file with restricted access to only the designated 
personnel including those responsible for labelling and handling the study medication until the study 
database is locked and ready to be unblinded. 
Every effort will be done to keep the Investigator, the subject and the sponsor study personnel fully 
blinded. Individual E2, SHBG, P4, LH, bone marker levels and PK data will not be communicated to 
them. 
Post-randomization eDiary bleeding data will remain blinded to the Investigator, the operational team 
and to the sponsor study personnel.  
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. 
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 single and repeated doses of up to 400 mg 
were shown to be safe in a Phase 1 single and multiple ascending dose study, and doses up to 200 mg 
daily for 3 months were safe in endometriosis subjects (see Section 5.5.3). 


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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. These will be provided by the sponsor 
free of charge to the subject or reimbursed.  
Electronic diaries will be provided for subjects use. These remain the property of the sponsor. 
Condoms with spermicide as well as calcium and vitamin D supplements will also be provided by the 
sponsor free of charge to the subject. If required, spermicide-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. 
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. 
Events occurring prior to first IMP administration in the study are not considered AEs per se, but an 
event that could be due to the disease or specific circumstances. For monitoring purposes, any event 
occurring after signature of the informed consent form, as assessed by the Investigator, should be 
reported on an AE form or an SAE form, as appropriate. In case of AE reporting prior to IMP intake, an 
assessment should be performed whether an event constitutes rather a baseline medical condition (e.g. 
Gilbert’s disease - to be reported on the “medical history page of the eCRF”) or an AE. 
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”. 


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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. 
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: 


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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 screening visit or is assessed as having evolved since the screening visit. 
2. The abnormality is a Serious Adverse Event. 
3. The abnormality results in discontinuation of the IMP. 
4. The abnormality requires medical intervention or concomitant therapy. 
The Investigator must initial and date each laboratory report/eCRF page and note directly on the 
report/eCRF page whether or not each out-of-range laboratory result is clinically significant. The 
outcome of this assessment will be reported using an AE or SAE form, as appropriate. 
When reporting an abnormal finding for laboratory parameters or other objective measurements on the 
AE page of the eCRF, a clinical diagnosis should be recorded rather than the abnormal value itself, if 
available (for example, “anaemia” rather than “decreased red blood cell count”). 
For all of these AEs, whether or not related to the treatment, the laboratory test(s) will be followed-up 
as appropriate. 
12.1.3 Baseline Medical Conditions 
Medical conditions present at the Screening visit(s), including results of the study screening 
assessments, are defined as Baseline Medical Conditions. These medical conditions should be 
adequately documented on the “medical history page of the eCRF”. Baseline Medical Conditions that 
worsen in severity or frequency during the study should be recorded and reported as AEs. 


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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?  
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).  


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 
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: 
 
results in death, 
i.e. the AE causes or contributes to the death. 
 
is life-threatening, 
i.e. the AE places the subject at immediate risk of death; it does not refer to AE which 
hypothetically might have caused death if it were more severe. 
 
requires inpatient hospitalization or prolongation of existing hospitalization, 
i.e. the AE requires at least an overnight admission or prolongs a hospitalization beyond the 
expected length of stay. Hospital admissions for surgery planned before study entry, for social 
reasons, for any elective surgery (i.e. plastic surgery) or for normal disease management 
(including treatment adjustment) are NOT to be considered as SAE according to this criterion.. 
 
results in persistent or significant disability / incapacity, 
i.e. the AE resulted in a substantial disruption of the subject’s ability to conduct normal 
activities. 
 
is a congenital anomaly / birth defect, 
i.e. an adverse outcome in a child or fetus of a subject exposed to the IMP before conception or 
during pregnancy. 


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 
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 4 weeks post study treatment discontinuation, 
regardless of relationship and expectedness, the Investigator is to take prompt and appropriate 
therapeutic action, if necessary, to protect the safety of study subjects and report such SAE as following. 
For blinded studies, refer to section 10.9. for instructions related to emergency unblinding. 
The Investigator must notify VOISIN CONSULTING (acting on behalf of ObsEva 
Pharmacovigilance) WITHIN 24 HOURS of awareness of a new SAE or of new information on a 
previously reported SAE (= follow-up). 
To do so, the Investigator must complete a SAE report and any specific eCRF pages if justified by the 
protocol e.g. AE, medical history, concomitant medication eCRF pages and blinded and anonymized 
copies of any other supporting source documents such as lab reports, hospital discharge letter/report, 
etc. ), sign it and send it directly to Voisin Consulting by e-mail using the dedicated e-mail address 
specified below: 
 
Name/Title:  
Voisin Consulting Life Sciences / ObsEva Pharmacovigilance 
 
E-mail:  
obsevasafety@voisinconsulting.com 
VOISIN CONSULTING will notify ObsEva Pharmacovigilance within 1 working day after the receipt 
of the SAE form report or follow-up information, using the same reporting forms. 
The SAE follow-up observation period, for the concerned subjects, will be jointly decided by the 
Investigator or one of the co-investigators (in case of Investigator’s absence) and the sponsor.  
In addition, the Investigator must respond to any request for follow-up information or questions 
regarding the SAE the sponsor may have, within 1 working day for urgent queries or 5 working days 
for normal queries. SAE will be followed until the Investigator and ObsEva agree that the event is 
satisfactorily documented and resolved/stabilized. 
For any new SAE, the following minimum information is required as initial notification: 
 
Clear identification of the Investigator/Reporter with full contact information or site number, 
 
Subject identification details (study number, site number, subject’s unique study identification 
number and date of birth), 
 
IMP(s) administration details (dose and dates), 


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 
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 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 IRB/IEC 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 IRB/IEC). The sponsor will be responsible, through their US Agent, for notifying the 
FDA of any SUSAR, and the sponsor or designee is responsible for notifying the Central IRB/IEC. 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 IRB/IEC’s 
approval/favourable opinion to continue the trial”. In particular and in line with respective regulations, 
the sponsor will inform the Investigator of AEs that are both serious and unexpected (i.e. as per the 
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 IRB/IEC 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 IRB/IEC 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 M6 FU visit. 
Events occurring during the screening period (i.e between ICF signature and Day 1 visit) must be 
recorded in the eCRFs using the AE form (and SAE form if appropriate) until the date the subject is 
determined to be a screening failure. Beyond that date, only serious or medically relevant protocol-
related events will be followed-up. 
A last batch of queries will be sent after last study visit if remaining ongoing/unknown outcomes of 
reported AEs are pending. After the last batch of queries with all collected data has been fully processed, 


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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 
However, all pregnancies that are diagnosed up to M3 FU 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: 
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 criteria (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 form for 
the child should be completed in addition to the PSF-part III (Subject identifier = Subject ID – 1 
for a singleton neonate). 


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13 DATA ANALYSIS AND STATISTICS 
13.1 TEST OF HYPOTHESES 
All statistical hypothesis tests and confidence intervals will be two sided. To maintain an overall type I 
error rate of 0.05, as there are two linzagolix versus placebo comparisons, Bonferoni corrected p-values 
will be produced (raw p-values will be multiplied by two prior to comparing to 0.05), along with 
corresponding 97.5% confidence intervals. 
The two co-primary efficacy endpoints will be clinically meaningful reduction (see section 13.5.2) over 
the last 28 days of randomized treatment up to the Month 3 visit (the 4-week period preceding Month 3 
visit) from baseline in the mean daily assessment of DYS and of NMPP measured on a VRS, along with 
a stable or decreased use of analgesics for EAP. 
The primary objective will be assessed by testing the following two-sided hypotheses for each co-
primary endpoint, for each linzagolix group versus placebo separately: 
Null hypothesis (H0): There is no difference in the odds of subjects meeting the primary endpoint for 
the active treatment group compared to placebo, that is, the odds ratio (OR) equals 1. 
H0: OR =1 
Alternative hypothesis (H1): There is a difference in the odds of subjects meeting the primary endpoint 
for the active treatment group compared to placebo, that is, the OR is not equal to 1. 
H1: OR ≠ 1 
Where odds are equal to the proportion of subjects meeting the endpoint divided by proportion of 
subjects not meeting the endpoint. 
Each linzagolix group will need to demonstrate a statistically significant difference for both co-primary 
endpoints in order for the group to be considered more efficacious than placebo, thus maintaining an 
overall type I error rate of 0.05.  
For each linzagolix group that is statistically significantly more efficacious than placebo for the co-
primary endpoints, a fixed-sequence testing strategy shall be used within the group to test the ranked 
secondary endpoints as ordered in Section 7.1.2.1, so as to maintain the family-wise type I error rate. 
That is, the comparison for each linzagolix group versus placebo for each ranked endpoint will only be 
declared statistically significant different if the raw p-value multiplied by two is less than or equal to 
0.05 for that endpoint and for all preceding endpoints for that dose versus placebo.  
Response rates for DYS and NMPP pain at each visit will be analyzed to evaluate the changes in pain 
over time, with nominal bonferroni corrected p-values used in the comparisons of treatment groups at 
each visit. These are supportive analyses and will primarily be considered as descriptive. The analyses 
do not form part of the fixed-sequence strategy being used for the ranked secondary endpoints and will 
not be fully controlled for an overall type I error rate. However, to maintain consistency with the primary 
and secondary analyses, Bonferroni corrections will be used due to there being two linzagolix versus 
placebo comparisons for each endpoint / time point. 


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13.2 SAMPLE SIZE 
The planned sample size for this study is 150 subjects per treatment group (450 subjects in total).  
An overall two-sided type I error of 0.05 will be used. As there are two linzagolix versus placebo 
comparisons, Bonferoni corrected p-values will be produced (raw p-values will be multiplied by two 
prior to comparing to 0.05). The planned sample size takes into account the hierarchical, fixed sequence 
testing of the ranked secondary endpoints as well as the co-primary endpoints. The assumptions used 
for the sample size calculations are based on analyses of clinically meaningful reduction in pain with a 
stable or decreased use of analgesics from the Phase 2b Edelweiss study. Calculations were performed 
using East® 6.5 software. 
One hundred and fifty (150) subjects per treatment group will provide a power greater than 95% to reject 
the null hypothesis for both co-primary endpoints for either treatment group, assuming a placebo 
response rate of 14.6% and an active treatment response rate of 48.6% (75 mg, Edelweiss result) or 
64.7% (200 mg, Edelweiss result) for DYS, and a placebo response rate of 18.8% and an active treatment 
response rate of 42.1% (75 mg, Edelweiss result; the response rate for 200 mg in Edelweiss was lower 
but was inconsistent with the other doses and also the other timepoints for the same dose and so has not 
been used) for NMPP. In addition, 150 subjects per treatment group provides 85% power to reject all 
the ranked secondary endpoints based on the observed results from the placebo and 200 mg treatment 
group in the Edelweiss study.  
The values used for the sample size calculations assume that this is what would be seen on average when 
under treatment including taking into account any subjects who might withdraw from treatment early 
and therefore the calculations do not need to be further adjusted for dropouts.  
13.3 RANDOMIZATION 
Randomization will be performed via a centralized IWRS. Subjects will be randomized on Day 1 to one 
of three treatment groups in a 1:1:1 ratio for linzagolix 75 mg, linzagolix 200 mg with ABT and placebo. 
Subjects will be randomized into permutated blocks of a pre-determined length. 
Subjects participating in the extension phase and who are in the placebo treatment group will be 
randomized at Month 6 visit to either linzagolix 75 mg or linzagolix 200 mg with ABT in a 1:1 ratio. 
Subjects participating in the extension phase and who are in the linzagolix treatment groups will remain 
on the same dose that they were taking at the end of Month 6 and will undergo a dummy randomization 
in order to maintain the blind.  
13.4 ANALYSIS SETS 
The following data sets will be used for the statistical analysis: 
1. Safety Set: All randomized subjects who received at least one dose of double-blind study drug 
irrespective of the treatment received. Subjects will be analyzed according to treatment 
received. 


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2. Full Analysis Set (FAS): All randomized subjects who received at least one dose of double-
blind study drug irrespective of the treatment received. This is the same as the Safety Set, but 
for the FAS subjects will be analyzed according to randomized treatment. 
3. Per Protocol (PP) Set: All randomized subjects who completed the six months of treatment 
excluding those identified as having major protocol deviations that could potentially affect the 
efficacy assessments up to Month 6. Subjects will be analyzed according to randomized 
treatment. 
4. Follow-up (FU) Set: All randomized subjects who completed the six months of treatment and 
entered the drug free follow-up period. Subjects will be analyzed according to randomized 
treatment. 
5. Pharmacokinetic (PK) Set: all subjects who received active study medication, had no major 
protocol deviations impacting PK and with available PK 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), including, where appropriate, time windows for various 
safety and efficacy analyses. In general, analyses of efficacy will be conducted using the FAS and PP 
sets, analyses of safety will be conducted using the Safety Set and analyses of PK will be conducted 
using the PK Set.  
A sub-group analysis will be performed for the secondary endpoint of dyspareunia as described in 
Section 13.5.3.5. Additional pre-planned sub-group analyses will be described in the SAP. 
13.5 DATA ANALYSIS 
More details of the proposed statistical analyses will be documented in the SAP, which will be written 
following finalization of the protocol and prior to the blinded responder threshold analysis of the Month 
3 data. The SAP will then be updated prior to unblinding and analysis of the data up to Month 6, in order 
to incorporate the results of the blinded responder threshold analysis. 
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 FAS. A baseline mean will also be calculated for each visit using the 
baseline data for the subset of patients who attend that visit, such that the same subjects contribute to 
the mean for the visit and the mean for the corresponding baseline values. 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. As appropriate, time windows for various safety and 
efficacy analyses will be defined in the SAP. 
This study will be conducted at approximately 100 study sites, resulting in only a few subjects per site 
on average. Subjects from all sites will be pooled and no adjustment for sites will be carried out in the 
statistical analyses. 
The number of subjects randomized, who received at least one dose of study drug, who completed the 
study and who prematurely discontinued will be calculated overall and for each site by treatment group, 
as well as for all subjects combined. Premature discontinuation of study drug will be summarized for 


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each treatment group, as well as for all subjects combined, with frequencies and percentages overall and 
by reason for discontinuation for all randomized subjects. 
Raw and derived data will be listed.  
13.5.1 Baseline Assessment 
Descriptive statistics will be performed on relevant screening and baseline data (i.e. data collected prior 
to the treatment administration) and on demographic characteristics for each treatment group and 
overall. There will be no formal comparison of baseline data, that is, no statistical hypothesis testing. 
13.5.2 Primary Efficacy Analysis 
The primary efficacy analysis aims to estimate the effect of linzagolix versus placebo on DYS and 
NMPP over the last 28 days  up to and including the Month 3 visit or, for subjects who discontinue 
randomized treatment prior to the Month 3 visit, over the last 28 days of randomized treatment. Use of 
analgesic medication for EAP will be included in the responder definitions. A responder for each of the 
co-primary endpoints needs to demonstrate both a reduction in pain (DYS or NMPP, depending on the 
endpoint) and a stable or decreased use of analgesics for EAP. Anyone who does not meet both of these 
criteria will be defined as a non-responder. 
The primary efficacy analysis will be conducted using the FAS. 
For each of the co-primary endpoints, the criterion for defining a subject as a responder over the last 28 
days of randomized treatment up to the Month 3 visit will include a reduction of X or greater from 
baseline in pain, where X will be determined using appropriate anchors as described below, as well as 
a stable or decreased use of analgesics for EAP. 
Mean pelvic pain scores for DYS and for NMPP will be calculated by averaging over the corresponding 
28 calendar days immediately prior to and including the day of the Month 3 visit. DYS will use days 
with uterine bleeding, defined as those days on which the subject records any uterine bleeding or spotting 
in the subject eDiary; NMPP will use days with no uterine bleeding. If a subject's mean score for DYS 
is undefined numerically because her daily eDiary reports indicate that she did not experience uterine 
bleeding on any days during the 28 calendar day time period, then the mean score for DYS will be set 
equal to zero (which reflects the absence of any DYS during that reporting time period). For subjects 
who discontinue treatment prior to Month 3, the last available observations prior to discontinuation will 
be used, in order to estimate the treatment effect of while under treatment, that is the 28 calendar days 
immediately prior to and including the last dose date (or fewer if treatment is stopped less than 4 weeks 
after randomization). The baseline mean overall pelvic pain scores for DYS and NMPP will be 
calculated by averaging over the two complete menstrual cycles during screening, which may not be 
exactly 28 days each. For both DYS and NMPP, responses of "None," "Mild," "Moderate," and "Severe" 
will be assigned a score of 0, 1, 2, and 3, respectively. 
For the assessment of a stable or decreased use of analgesics for EAP, the analgesic use for any defined 
period will be based on the mean of the total pill count for each class of rescue analgesics (endometriosis-
associated). The total pill count for each class of rescue analgesic is the sum of the pill count of the 
corresponding class of rescue analgesic, as reported in the eDiary during the time period of interest. The 
baseline analgesic use will be calculated as the mean of daily pill count of analgesics over the two 
complete menstrual cycles during screening. For purposes of determining a stable or decreased use of 


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analgesics, the averaging will be done over the same calendar days as used for the pelvic pain scores. 
The evaluation of a stable or decreased use of analgesics will be done per the specification in Appendix 
O. 
The analysis of each co-primary endpoint will be conducted using a logistic regression model, with 
treatment group as the main effect (three values) and including the baseline pain score as a covariate. 
Individual linzagolix versus placebo treatment group comparisons will be made using the same logistic 
regression model. 
Responder threshold analysis: 
For each of the co-primary endpoints, the criterion for defining a subject as a responder over the last 28 
days of randomized treatment up to the Month 3 visit will be a reduction of X or greater from baseline 
in pain. The threshold for response in the responder analysis (i.e., the value of X) will be chosen to 
represent a clinically meaningful reduction in pain and may not be the same for each endpoint. The 
threshold will be determined based on separate analyses of overall mean change using the mPGIS at 
Month 3 as an anchor. A 2-point improvement in the mPGIS will be used to define responders for the 
primary analysis. Response categories of “very mild” and “mild” will be collapsed into one category 
prior to the analyses. Monthly questions specific to DYS, NMPP, overall pelvic pain, dyschezia, 
dyspareunia and daily function will be used as separate anchors. PGIC as an anchor, Cumulative 
Distribution Function (CDF) and Probability Density Function (PDF) curves, and Receiver Operating 
Characteristic (ROC) analyses will be used as supportive analyses. The thresholds have been estimated 
in an analysis of DYS and NMPP data from the Phase 2b Edelweiss study and will be re-estimated in 
this study, calculated based on the blinded Month 3 data. As with the under treatment efficacy analysis, 
for subjects who discontinue treatment prior to Month 3, the 28 calendar days immediately prior to and 
including the last dose date will be used, along with the closest time matched PGIS and PGIC. The final 
response thresholds taking into account the previous estimates from phase 2b will be included in the 
final SAP prior to breaking the blind after Month 6. Based on the results from the Phase 2b Edelweiss 
study, it is expected that the responder threshold will be in the range of a 0.7 to 1.25 point (40% to 50%) 
reduction in pain in the 4-point VRS for a 2-point improvement and a 0.25 to 0.75 point (20% to 30%) 
reduction in pain in the 4-point VRS for a 1-point improvement. The numerical thresholds for DYS are 
expected to be larger than those for NMPP. 
13.5.3 Secondary Efficacy Analysis 
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. As with the primary 
analysis, individual linzagolix versus placebo treatment groups comparisons will be made. 
13.5.3.1 
Change from baseline to Month 6 in DYS (VRS) / NMPP (VRS) 
Mean pelvic pain scores for DYS and for NMPP for each subject will be calculated in the same way as 
for the primary endpoints. The change from baseline to Month 6 (the last 28 days of randomized 
treatment up to the Month 6 visit, or the 28 calendar days immediately prior to and including the last 
dose date for subjects who discontinue treatment prior to Month 6) in DYS using the VRS, and the 
change from baseline to Month 6 (the last 28 days of randomized treatment up to the Month 6 visit, or 
the 28 calendar days immediately prior to and including the last dose date for subjects who discontinue 


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treatment prior to Month 6) in NMPP (VRS), will be analyzed via analysis of co-variance with treatment 
group as the main effect (three values) and including the baseline pain score as a covariate.  
13.5.3.2 
Change from baseline to Month 6 in dyschezia (NRS) 
Mean dyschezia scores for each subject will be calculated by averaging over the corresponding 28 
calendar days immediately prior to and including the day of the Month 6 visit (or the 28 calendar days 
immediately prior to and including the last dose date for subjects who discontinue treatment prior to 
Month 6). The baseline mean dyschezia score will be calculated by averaging over the two complete 
menstrual cycles during screening. The change from baseline to Month 6 in dyschezia using the NRS 
will be analyzed via analysis of co-variance with treatment group as the main effect (three values) and 
including the baseline pain score as a covariate. 
13.5.3.3 
Change from baseline to Month 6 in overall pelvic pain (NRS) 
The change from baseline to Month 6 (the last 28 days of randomized treatment up to the Month 6 
visit, or the 28 calendar days immediately prior to and including the last dose date for subjects who 
discontinue treatment prior to Month 6) in overall pelvic pain using the NRS will be analyzed the 
same way as for dyschezia. 
13.5.3.4 
Change from baseline to Month 6 in the interference of pain with the ability to perform 
daily activities, measured using the pain dimension of the EHP-30  
The EHP-30 pain dimension consists of 11 items each addressing the effect of pain on various activities 
and each assessed on a 5-point scale (0=Never through to 4=Always). The EHP-30 Pain Impact Domain 
comprises the following items : 
During the last 4 weeks, because of your endometriosis, how often have you... 
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? 
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? 
It shall be scored as per the user manual, resulting in a score on a scale from 0 (best possible health 
status) to 100 (worst possible health status). The change from baseline to Month 6 (the last 28 days of 
randomized treatment up to the Month 6 visit) in ability to perform daily activities, measured using the 
pain dimension of the EHP-30 will be analyzed via analysis of co-variance with treatment group as the 
main effect (three values) and including the baseline pain score as a covariate.  


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13.5.3.5 
Change from baseline to Month 6 in dyspareunia (VRS) 
The responses to the daily dyspareunia questions will be scored as follows. Responses where the subject 
was not sexually active for reasons other than their endometriosis will not be included in the analysis. 
 
Response 
Score 
No pain during sexual intercourse. 
0 
I was able to tolerate the pain during sexual intercourse. 
1 
Intercourse was interrupted due to pain.  
2 
I avoided sexual intercourse because of anticipation of pain.  
3 
 
Mean dyspareunia scores for each subject will be calculated by averaging over the corresponding 28 
calendar days immediately prior to and including the day of the Month 6 visit (or the 28 calendar days 
immediately prior to and including the last dose date for subjects who discontinue treatment prior to 
Month 6). The baseline mean dyspareunia score will be calculated by averaging over the two complete 
menstrual cycles during screening.  
Dyspareunia scores will be summarized using the FAS and for the sub-group of subjects who have a 
mean dyspareunia score > 1 at baseline. The statistical analysis of dyspareunia will only use the sub-
group of subjects in order to estimate the effect of treatment on such subjects. It is anticipated that this 
will be around 60% to 70% of the randomized subjects. This is a baseline assessment and does not 
influence the blinded, randomized treatment group. As per section 13.1, the type I error is maintained 
due to using fixed-sequence testing strategy. The change from baseline to Month 6 in dyspareunia will 
be analyzed via analysis of co-variance with treatment group as the main effect (three values) and 
including the baseline pain score as a covariate. 
13.5.3.6 
No analgesics use / no opiate use for EAP during the preceding 4-week period at 6 
months 
The analysis of the proportion of subjects reporting no analgesic use for EAP, and the proportion of 
subjects reporting no opiate use for EAP, during the preceding 4-week period at 6 months will be 
conducted using a logistic regression model, with treatment group as the main effect (three values). 
In addition to analyzing the absence of analgesic use for EAP, the amount used for each 4-week  period 
will be summarized, including the change from baseline. As it is likely that more than one opioid will 
be used (opioid analgesic may be different depending on countries), the amount of opioid used will be 
converted to morphine milligram equivalents (MME) in order to better quantify the actual amount of 
opioids used by subjects.  


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13.5.4 Additional Efficacy Analysis 
Endpoints that are collected daily using the eDiary will be based on the 28 calendar days immediately 
prior to and including the day of the corresponding visit, or the 28 calendar days immediately prior to 
and including the last dose date for subjects who discontinue treatment prior to the visit in question (or 
fewer if treatment is stopped less than 4 weeks after randomization), in order to estimate the treatment 
effect of while under treatment. Corresponding baseline values will be calculated based on the two 
complete menstrual cycles during screening, which may not be exactly 28 days each. 
The values for other endpoints are defined as the value at the corresponding visit, or the closest 
completed assessment to the last dose date for subjects who discontinue treatment prior to the visit in 
question. 
An additional analysis of the co-primary endpoints will be conducted that considers all subjects who 
prematurely discontinue the study treatment before the Month 3 visit as non-responders. These are 
composite endpoints that estimate the proportion of subjects with clinically meaningful reduction in 
pain, a stable or decreased use of rescure medication and who complete 3 months of treatment.  
An additional analysis of the co-primary endpoints will be also conducted to estimate the effect of 
treatment policy rather than that of while on treatment. A reference based multiple imputation approach 
will be used for subjects who discontinue the study prior to Month 3. Further details will be provided in 
the SAP. 
All exploratory efficacy endpoints will be summarized by descriptive statistics for each treatment group, 
for each time point, including summaries of change from baseline when applicable. Individual linzagolix 
versus placebo treatment group comparisons will be made. 
In general, between group comparisons for continuous endpoints will be analyzed via analysis of (co)-
variance. Between-group comparisons for binary endpoints will be analyzed via logistic regression. 
Between-group comparisons for ordinal categorical data will be analyzed using a Mantel-Haenszel test, 
or using Koch’s method when there is also a baseline covariate. Full details describing the derivation 
and analyses of each exploratory endpoint will be provided in the SAP. 
Sub-group analyses based on demographic and baseline characteristics will be performed for each co-
primary endpoint and select secondary endpoints, and will be specified in the SAP. 
13.5.5 Safety Analysis 
The safety and tolerability profile will be assessed versus baseline conditions and differences between 
treatment groups and descriptive statistics will be produced for both values and change from baseline, 
where applicable.  
Extent of exposure and compliance to treatment will be evaluated.  
Concomitant medications will be summarized using the World Health Organization (WHO) Drug 
Dictionary with frequencies and percentages for each treatment group. All medications administered 
between the date of the first dose of study drug and the date of the last dose of study drug, inclusive, 
(i.e., all medications starting or ongoing during the time interval) will be included. Thus, all medications 
with an end date prior to the first study drug dose will be excluded from the summary table. 


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An analysis of the TEAEs will be done. AEs will be summarized using the Medical Dictionary for 
Regulatory Activities tabulated by (MedDRA) dictionary preferred term and system organ class. TEAEs 
will be summarized with frequencies and percentages for each treatment group. TEAEs are defined as 
AEs with a start date on or after the first dose of study drug. Adverse events starting more than 30 days 
following discontinuation of study drug will not be included in summaries of TEAEs but will be 
summarized separately as post-treatment AEs. Tabulations by severity and drug-relatedness will also be 
made. 
Laboratory parameters values will be summarized for each visit for each treatment group including 
within-group changes from baseline. Evaluation of shifts for changes from baseline according to the 
normal range will be provided. 
BMD values and corresponding Z-scores will be summarized at baseline and at Month 6 for each 
treatment group, using the observed data. The within-group percent changes from baseline for BMD 
values will also be summarized, including 2-sided 95% confidence intervals. Categorical summaries of 
percent change from baseline will also be produced. The percent changes from baseline to Month 6 will 
be compared between each of the linzagolix groups and the placebo group via analysis of co-variance 
with treatment group as the main effect (three values) and including the baseline as a covariate. Sub-
group analyses based on demographic and baseline characteristics will be performed for BMD, and will 
be specified in the SAP.The Safety Analysis Set shall be used when summarizing safety data. 
13.5.6 Pharmacokinetic analysis methodology 
PK sample analysis will be performed using a validated assay. The analyses have to be performed 
unblinded by the analytical laboratory. The analyst may be aware of the subject number, sampling time 
and dose group.  
For descriptive statistics of plasma concentrations mean (arithmetic and geometric), standard deviation, 
median, 1st and 3rd quartiles, minimum, maximum, coefficient of variation (CV%) and number of 
observations will be provided. Concentrations below the limit of quantification (LOQ) will be assigned 
a value of zero. Explorative analyses of correlations between plasma concentrations and intrinsic PK 
factors such as e.g. body weight/BMI, race, age will be performed, as appropriate, and will be reported 
separately.  
PK analyses will be based on the PK Set.  
13.5.7 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. Possible PK-PD relationships may be investigated 
graphically and through statistical modeling, whilst also exploring possible covariates, and will be 
reported separately. 


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13.5.8 Missing Data 
Summary statistics will be based primarily on non-missing values. The planned statistical analyses aim 
to estimate the efficacy of linzagolix versus placebo whilst under randomized treatment and therefore 
lack of data after treatment discontinuation will not be considered as missing for these analyses.  
Subjects who cannot be assessed as a responders or not for the co-primary efficacy endpoints, e.g. due 
to lack of enough on treatment pain data will be considered as non-responders. In addition, for endpoints 
assessing the numeric change from baseline, such subjects will be assigned a change from baseline of 
zero. It is expected that very few subjects will be affected by these rules. 
As additional analyses, in order to estimate the effect of treatment policy, a reference based multiple 
imputation approach will be used for the co-primary endpoints for subjects who discontinue the study 
early under the assumption that the efficacy of the linzagolix treated subjects gradually transitions to 
that observed in the placebo subjects.  
There may be missing data during the screening period and whilst under treatment, for example, missed 
days of completing the eDiary. The primary analyses will use observed data only in such cases provided 
that a minimum number of completed daily edairy entries are available. This effectively assumes that 
the individual values such as daily eDiary assessments (observed or not) are independent of being 
missing.  
Further details on the handling of missing values and the methods and planned sensitivity analyses to 
check the robustness of the analysis results under alternative assumptions with regards to missing data 
will be provided in the SAP. 
13.6 STUDY SPECIFIC DATA ANALYSIS 
13.6.1 Responder Threshold Analysis 
An analysis will be performed using the blinded Month 3 data to determine the criterion for defining a 
subject as a responder for each co-primary and secondary endpoint, as described in section 13.5.2.  
13.6.2 End-of-Treatment Period Analysis 
After all subjects have completed the Treatment Period (Month 6), a complete analysis will be 
performed. This analysis will include all data up to the Month 6 visit. A database lock will be performed 
prior to unblinding of treatment, and any discrepant data will be clarified before the lock. Since this end-
of-treatment-period analysis is the only and final analysis of the primary and ranked secondary 
endpoints, no additional adjustment of alpha-level is necessary beyond that described in section 13.1. 
The results for the Treatment Period will be summarized and described in an integrated Clinical Study 
Report. 
13.6.3 Treatment Free Follow-Up Period Analysis 
A 6 months follow-up period without treatment is planned after the 6 months Treatment Period, or after 
the optional extension study. 


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Analyses of the follow-up period data for subjects not entering the extension study will be reported in 
an addendum to the integrated Clinical Study Report. 
After the Treatment period (Month 6), the Sponsor will be unblinded to the subject’s treatment allocation 
but treatment allocation will remain blinded up to the end of the follow-up period for the Investigator, 
the subject and the CRAs. 
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 (18), 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 written informed consent. The informed 
consent process will be in accordance with ICH GCP and local regulatory requirements. 
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 / Independent Ethics Committee  
Before initiation of the study at a given site, written approval of the protocol, ICF and any information 
presented to potential subjects must be obtained from the appropriate Institutional Review Board (IRB)/ 
Independent Ethics Committee (IEC). If any amendments to any of these documents occur during the 
study, notification or written approval as appropriate must be obtained prior to their implementation. 
The Investigator is responsible for ensuring that these actions occur.  
Where required by local regulations, the sponsor (or its delegate) is responsible for ensuring IRB/IEC 
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 drug-free follow-up period. This 
provides a single and conservative definition across all study sites. 


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14.2 INVESTIGATOR RESPONSIBILITIES 
The Investigator must be familiar with and conduct the study according to ICH GCP guidelines, the 
FDA Code of Regulation or the EU Clinical Trial Directive and applicable local laws and regulations. 
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. CRA or study monitor) periodical access to subject records and all study-related 
materials. The frequency of monitoring visits will be determined by factors such as the design of the 
study, the frequency of subject visits and the site enrolment rate. In order to verify that the study is 
conducted in accordance with ICH GCP, regulatory requirements, and the study protocol and that the 
data are authentic, accurate and complete, the study monitor will review eCRFs and other study 
documents and will conduct source data verification. 
Upon study completion, the sponsor representative (e.g. CRA or study monitor) will visit the site to 
conduct a Study termination visit. This will involve collection of any outstanding documentation 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). 


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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 IRB/IEC 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. 
14.8 PROTOCOL DEVIATIONS 
A protocol deviation is any noncompliance with the clinical trial protocol or International Conference 
on Harmonization Good Clinical Practice (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 IRB/IEC per their policies. The site 
investigator is responsible for knowing and adhering to the reviewing IRB/IEC 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 IRB/IEC.  


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Where required by local regulations, the sponsor (or delegate) will be responsible for informing the 
IRB/IEC 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, IRB/IEC approvals and all related correspondence including approved 
documents, drug accountability records, study correspondence and a list of the subjects’ names and 
addresses.  
The Investigator must retain copies of the essential documents for the period specified by ICH GCP and 
by applicable regulatory requirements. 
The Investigator will inform the sponsor of the storage location of the essential documents, and must 
contact the sponsor for approval before disposing of any. The Investigator should take measures to 
prevent accidental or premature destruction of these documents. 
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. 
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 – SCREENING AND TREATMENT PERIODS ............ 109 
APPENDIX B. SCHEDULE OF STUDY ASSESSMENTS – FOLLOW-UP PERIOD ......................................... 114 
APPENDIX C. MODIFIED BIBEROGLU & BEHRMAN SYMPTOM SEVERITY SCALE* ............................... 117 
APPENDIX D. ENDOMETRIOSIS HEALTH PROFILE QUESTIONNAIRE (EHP-30) ..................................... 119 
APPENDIX E. PROMIS FATIGUE – SHORT FORM 6A ........................................................................... 124 
APPENDIX F. HEALTH-RELATED PRODUCTIVITY QUESTIONNAIRE (HRPQ) ......................................... 125 
APPENDIX G. HEALTH RESOURCE UTILIZATION QUESTIONNAIRE (HRUQ) .......................................... 128 
APPENDIX H. PATIENT GLOBAL IMPRESSION OF CHANGE (PGIC) ....................................................... 133 
APPENDIX I. POST-TREATMENT PATIENT GLOBAL IMPRESSION OF CHANGE (PPGIC) ....................... 134 
APPENDIX J. PATIENT GLOBAL IMPRESSION OF SEVERITY (PGIS) ...................................................... 135 
APPENDIX K. SUBJECT SURGERY INTENTION QUESTIONNAIRE (SSIQ) ................................................ 136 
APPENDIX L. PHYSICIAN SURGERY INTENTION QUESTIONNAIRE (PSIQ) ............................................ 137 
APPENDIX M. EQ-5D-5L ...................................................................................................................... 138 
APPENDIX N. LABORATORY PARAMETERS ......................................................................................... 141 
APPENDIX O. ANALGESIC CHANGE DURING TREATMENT PERIOD ...................................................... 142 
APPENDIX P. STRONG CYP3A4 INDUCERS AND INHIBITORS .............................................................. 144 
APPENDIX Q. REFERENCE LIST ............................................................................................................ 146 
APPENDIX R. BASELINE C-SSRS .......................................................................................................... 148 
APPENDIX S. C-SSRS ALREADY ENROLLED SUBJECTS ......................................................................... 151 
APPENDIX T. C-SSRS SINCE LAST VISIT ............................................................................................... 154 
 


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Appendix A. Schedule of study assessments – Screening and Treatment Periods 
 
Schedule of study assessments – Screening and Treatment Periods 
Timing1 
Screening Period 
(up to 3 months2) 
Treatment Period 
Day 1 
M1 
M2 
M3 
M4 
M5 
M6 
Informed Consent 
x 
 
 
 
 
 
 
 
Inclusion-Exclusion criteria 
x 
x 
 
 
 
 
 
 
Demography, height, weight, medical history 
x 
 
 
 
 
 
 
 x3 
mB&B 
x 
 
 
 
 
 
 
 
Columbia-Suicide Severity Rating Scale 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
1 All post-baseline visits should take place at the end of the defined period (i.e. M1 visit should be scheduled at the end of Month 1, M2 visit should be scheduled at the end of Month 
2, etc.). Post-baseline visits dates are calculated from Day 1 visit date. A month is defined as 28 days/4 weeks. Visits should be scheduled ± 3 days from the calculated date. 
2 If required for washout of oral contraceptives, other sex hormones, or GnRH antagonists/agonists (provided that the reason for discontinuing the previous GnRH-antagonist is not 
lack of efficacy),  a period of up to 3 months is allowed between signing the informed consent and the screening visit. 
3 Only weight will be recorded. 


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Schedule of study assessments – Screening and Treatment Periods 
Timing1 
Screening Period 
(up to 3 months2) 
Treatment Period 
Day 1 
M1 
M2 
M3 
M4 
M5 
M6 
ECG 
x 
 x4 
x 
x 
x 
x 
x 
x 
Physical examination 
x 
 
 
 
x 
 
 
x 
Vital signs 
x 
x 
x 
x 
x 
x 
x 
x 
Urine pregnancy test 
x 
x 
x 
x 
x 
x 
x 
x 
TVUS of uterus 
x 
 
 
 
x 
 
 
x 
Gynecological examination 
x 
 
 
 
x 
 
 
x 
Endometrial biopsy 
x 
 
 
 
 
 
 
 x5 
Pap smear test 
x 
 
 
 
 
 
 
 
Breast examination (mammogram if required) 
x 
 
 
 
 
 
 
x 
 
 
 
4 ECG on Day 1 should be performed twice: once before treatment and once after treatment (just before PK sampling). 
5 If endometrium thickness in TVUS is ≤ 5 mm, no endometrial biopsy will be necessary. 


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Schedule of study assessments – Screening and Treatment Periods 
Timing1 
Screening Period 
(up to 3 months2) 
Treatment Period 
Day 1 
M1 
M2 
M3 
M4 
M5 
M6 
Clinical laboratory & urinary protein dipstick 
x 
x6 
x6 
x 
x6 
x 
x 
x6 
Blood sample for PK7 
 
x 
x 
x 
x 
x 
x 
x 
BMD by DXA 
x 
 
 
 
 
 
 
x 
Adverse events 
x 
x 
x 
x 
x 
x 
x 
x 
Previous/concomitant medication 
x 
x 
x 
x 
x 
x 
x 
x 
Contraceptive dispensing and counselling 
x 
x 
x 
x 
x 
x 
x 
x 
Permitted analgesic prescribing/dispensing 
x 
x 
x 
x 
x 
x 
x 
x 
Vitamin D and calcium dispensing 
 
x 
x 
x 
x 
x 
x 
x 
Subject eDiary completion training/check 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
6 Overnight fasting is required. 
7 PK samples should be taken after the ECG and before the daily dose of IMP, except on Day 1 when the PK sample should be taken at least 1.5 h after the IMP administration. 


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Schedule of study assessments – Screening and Treatment Periods 
Timing1 
Screening Period 
(up to 3 months2) 
Treatment Period 
Day 1 
M1 
M2 
M3 
M4 
M5 
M6 
IMP accountability 
 
 
x 
x 
x 
x 
x 
x 
Dispense study drug 
 
x 
x 
x 
x 
x 
x 
 
Dispense ABT 
 
x 
 
 
x 
 
 
 
EHP-30, EQ-5D-5L and PROMIS8 
 
x 
x 
 
x 
 
 
x 
mPGIS, PGIC, HRUQ and HRPQ 
 
 x9 
x 
x 
x 
x 
x 
x 
Specific monthly severity questions8 
 
x 
 
 
x 
 
 
x 
SSIQ and PSIQ8 
 
x 
 
 
 
 
 
x 
AMH 
 
x 
 
 
 
 
 
 
E2, LH, P4 
 
x 
x 
x 
x 
x 
x 
x 
SHBG 
 
x 
 
 
x 
 
 
x 
Bone biomarkers 
 
x 
 
 
x 
 
 
x 
 
 
 
8 ClinROs (Monthly dyspareunia question, 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, and specific monthly severity questions) will be filled in by the subject in the eDiary. 
9 PGIC not done at Day 1. 


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Schedule of study assessments – Screening and Treatment Periods 
Timing1 
Screening Period 
(up to 3 months2) 
Treatment Period 
Day 1 
M1 
M2 
M3 
M4 
M5 
M6 
Question regarding treatment received  
 
 
 
 
 
 
 
x 


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Appendix B. Schedule of study assessments – Follow-up Period 
 
Schedule of study assessments – Follow-up Period 
Timing1 
M1 FU 
M2 FU 
M3 FU 
M4 FU 
M5 FU 
M6 FU 
Previous/concomitant medication 
x 
x 
x 
x 
x 
x 
Adverse events 
x 
x 
x 
x 
x 
x 
Columbia-Suicide Severity Rating Scale 
x 
x 
x 
x 
x 
x 
ECG 
x 
 
x 
 
 
x 
Physical examination 
 
 
x 
 
 
x 
Weight 
 
 
 
 
 
x 
Vital signs 
x 
 
x 
 
 
 
Gynecological examination 
 
 
x 
 
 
 
 
 
 
1 All follow-up study visits should take place at the end of the defined period (i.e. M1 FU visit should be scheduled at the end of the first month of follow-up, M2 FU visit should be 
scheduled at the end of the second follow-up visit, etc.). A month is defined as 28 days/4 weeks. Visits should be scheduled ± 7 days from the calculated date. 


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Schedule of study assessments – Follow-up Period 
Timing1 
M1 FU 
M2 FU 
M3 FU 
M4 FU 
M5 FU 
M6 FU 
Breast manual examination 
 
 
x 
 
 
 
Endometrium TVUS 
 
 
x 
 
 
x 
Endometrial biopsy 
x2 
x2 
x2 
x2 
x2 
x3 
Clinical laboratory & urinary protein dipstick 
x 
 
x4 
 
 
 
Subject eDiary completion check 
x 
x 
x 
x 
x 
x 
Subject eDiary collection and deactivation 
 
 
 
 
 
x 
EHP-30, HRUQ, HRPQ, EQ-5D-5L and PROMIS 
 
 
x 
 
 
x 
mPGIS and PPGIC  
x 
x 
x 
x 
x 
x 
BMD by DXA 
x5 
E2, LH, P4 
x 
 
x 
 
 
 
 
 
 
2 Endometrial biopsy will be taken only if diagnosis at preceding month was different than “benign endometrium” or if no endometrial biopsy was done at Month 6 nor at any visit 
since Month 6. 
3 An end-of-study biopsy is mandatory if no endometrial biopsy was obtained at M6 nor at any of the subsequent monthly visits. 
4 Overnight fasting is required. 
5 Subjects with a BMD decrease from baseline of > 1.5% for lumbar spine and/or > 2.5% for total hip at Month 6 FU visit will have an additional DXA scan 6 months later. 


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Schedule of study assessments – Follow-up Period 
Timing1 
M1 FU 
M2 FU 
M3 FU 
M4 FU 
M5 FU 
M6 FU 
FSH at local laboratory for subjects that do not resume 
menses at M3 FU visit 
 
 
x 
 
 
 
Bone biomarkers 
x 
 
Permitted analgesic prescribing/dispensing 
x 
x 
x 
x 
x 
 
Vitamin D and calcium dispensing 
x 
x 
x 
x 
x 
 
Urine pregnancy test and contraceptive dispensing and 
counselling 
x 
x 
x 
 
 
x 
 


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OBSEVA CONFIDENTIAL 
Appendix C. Modified Biberoglu & Behrman symptom severity scale* 
 
A. Dysmenorrhea 
None 
0 = No symptoms 
Mild 
1 = Some loss of ability to work or carry out normal activities 
Moderate 
2 = Unable to work or carry out normal daily activities for part of 1 or more days 
and/or moderately decreased work efficiency 
Severe  
3 = Unable to work or carry out normal daily activities for 1 or more full days and/or 
significantly decreased work efficiency 
 
B. Deep Dyspareunia 
None 
0 = No symptoms 
Mild 
1 = Tolerated discomfort during intercourse 
Moderate 
2 = Interference of usual frequency of sexual intercourse due to pain 
Severe  
3 = Avoids, or wishes to avoid, intercourse because of pain 
 
C. Non Menstrual Pelvic Pain 
None 
0 = No symptoms 
Mild 
1 = Occasional pelvic discomfort 
Moderate 
2 = Noticeable discomfort for most of cycle 
Severe  
3 = Pain persistent during cycle other than during menstruation 
 
 
D. Pelvic Tenderness (assessed by the physician) 
None 
0 = No findings 
Mild 
1 = Minimal tenderness on palpation 
Moderate 
2 = Moderate tenderness on palpation 
Severe  
3 = Exam limited due to tenderness 
 
E. Induration (assessed by the physician) 
None 
0 = No findings 
Mild 
1 = Uterus freely mobile, minimal induration in the cul-de-sac 
Moderate 
2 = Significant induration in the cul-de-sac, restricted uterine mobility 
Severe  
3 = Nodular adnexa and cul-de-sac, uterus fixed 
 
Composite Pelvic Pain and Physical Sign Score (A + B + C + D + E) 
None 
 
0 
Total Pelvic Pain Score (A + B + C) 
None 
 
0 
Mild 
 
1 - 3 
Total Physical Sign Score (D + E) 
None 
 
0 
Mild 
 
1 - 2 


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OBSEVA CONFIDENTIAL 
Mild 
 
1 - 2 
Moderate 
 
3 - 5 
 
Severe 
 
6 - 10 
Very Severe 
11 – 15 
 
* based on Biberoglu KO, Behrman SJ. Dosage aspects of danazol therapy in endometriosis: 
short term and long term effectiveness. Am J Obstet Gynecol. 1981;139:645.  
 


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Appendix D. 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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OBSEVA CONFIDENTIAL 
 
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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OBSEVA CONFIDENTIAL 
 
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 E. 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 F. Health-Related Productivity Questionnaire (HRPQ) 


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Appendix G. Health Resource Utilization Questionnaire (HRUQ) 
 (To be completed by Site Staff) 
Subject number: ___________________________ 
Study Visit (please ensure to tick 1 visit only):  
Treatment period 
☐ Day 1 
☐ Month 1 
☐ Month 2 
☐ Month 3  
 
 
 
 
 
☐ Month 4  
☐ Month 5 
☐ Month 6 
Follow-up period 
☐ Month 3 FU  ☐ Month 6 FU  
Date of Assessment:  __________________________________________ 
 
Instructions to complete:  
At each scheduled on-site visit in the Treatment Period (Day 1 through Month 6) and at Month 3 FU 
and Month 6 FU 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 
☐ 
☐ 
 
 


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☐ 
INFECTIOUS 
DISEASE 
SPECIALIST 
☐ 
☐ 
 
 
☐ 
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 H. Patient Global Impression of Change (PGIC) 
 
 
 


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Appendix I. 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 J. 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 K. 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 L. 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 M. EQ-5D-5L 
 
EQ-5D-5L English US version 
© EuroQol Research Foundation. EQ-5D™ is a trade mark of the EuroQol Research Foundation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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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 N. 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, AMH 
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.  
 


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Appendix O. 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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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 
 
**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. 
 
 
 


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Appendix P. 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 


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nefazodone 
nelfinavir 
paritaprevir and ritonavir and (ombitasvir and/or dasabuvir) 
posaconazole 
ritonavir 
saquinavir and ritonavir 
telaprevir 
tipranavir and ritonavir 
troleandomycin 
voriconazole 
 
 


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Appendix Q. Reference List  
1. 
Eskenazi B, Warner ML. Epidemiology of endometriosis. Obstet Gynecol Clin North Am. 
1997;24(2):235-58. 
2. 
Fauconnier A, Chapron C. Endometriosis and pelvic pain: epidemiological evidence of the 
relationship and implications. Hum Reprod Update. 2005;11(6):595-606. 
3. 
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. 
4. 
Vercellini P, Somigliana E, Vigano P, Abbiati A, Daguati R, Crosignani PG. Endometriosis: 
current and future medical therapies. Best Pract Res Clin Obstet Gynaecol. 2008;22(2):275-
306. 
5. 
Vercellini P, Somigliana E, Vigano P, Abbiati A, Barbara G, Crosignani PG. Endometriosis: 
current therapies and new pharmacological developments. Drugs. 2009;69(6):649-75. 
6. 
Meresman GF, Auge L, Baranao RI, Lombardi E, Tesone M, Sueldo C. Oral contraceptives 
suppress cell proliferation and enhance apoptosis of eutopic endometrial tissue from patients 
with endometriosis. Fertil Steril. 2002;77(6):1141-7. 
7. 
Practice Committee of the American Society for Reproductive M. Treatment of pelvic pain 
associated with endometriosis: a committee opinion. Fertil Steril. 2014;101(4):927-35. 
8. 
Schweppe KW. Current place of progestins in the treatment of endometriosis-related 
complaints. Gynecol Endocrinol. 2001;15 Suppl 6:22-8. 
9. 
Vercellini P, Fedele L, Pietropaolo G, Frontino G, Somigliana E, Crosignani PG. Progestogens 
for endometriosis: forward to the past. Hum Reprod Update. 2003;9(4):387-96. 
10. Olive DL. Gonadotropin-releasing hormone agonists for endometriosis. N Engl J Med. 
2008;359(11):1136-42. 
11. Farmer JE, Prentice A, Breeze A. Gonadotrophin-releasing hormone analogues for 
endometriosis: bone mineral density. Cochrane Database Syst Rev. 2003(4):CD001297. 
12. 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. 
13. 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. 
14. Taylor HS, Giudice LC, Lessey BA, Abrao MS, Kotarski J, Archer DF, et al. Treatment of 
Endometriosis-Associated Pain with Elagolix, an Oral GnRH Antagonist. N Engl J Med. 2017. 


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OBSEVA CONFIDENTIAL 
15. Lewis JA, Jonsson B, Kreutz G, Sampaio C, van Zwieten-Boot B. Placebo-controlled trials 
and the Declaration of Helsinki. Lancet. 2002 Apr 13;359(9314):1337-40. 
16. AbbVie. Orilissa: Prescribing information. 2018. 
17. FDA. Guidance for Industry - Drug-Induced Liver Injury: Premarketing Clinical Evaluation. 
2009. 
18. 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. Baseline C-SSRS 
 
 
 
 


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Appendix S. C-SSRS Already Enrolled Subjects 
 
 


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Appendix T. C-SSRS Since Last Visit 
 
 


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SAP_003.pdf: 
     Statistical Analysis Plan  
Sponsor:  
ObsEva 
Protocol:  
18-OBE2109-003 
Document Version No.:  
V5.0 
Document Date: 
13-JUN-2022 
 
 
 CRS-BS-TP-000005 V 1.0  
 
Page 1 of 127 
Cytel Confidential: This is a controlled document and shall not be changed, saved, copied or reproduced by any unauthorized 
person.  
 
 
 
Protocol 18-OBE2109-003 
 
A Phase 3 multicenter, randomized, double-blind, placebo-controlled, clinical study to assess the 
efficacy and safety of linzagolix in subjects with moderate to severe endometriosis-associated pain. 
Protocol Number: 
(Version Date) 
18-OBE2109-003 
Version 4.0, 27 July 2020 
Name of Test Drug: 
Linzagolix (OBE2109) 
Phase: 
3 
Methodology: 
Randomized, double-blind, placebo-controlled 
Sponsor: 
ObsEva S.A. 
 
 
 
 
Sponsor Representative: 
 
 
Document Date: 
13 June 2022 
Document Version: 
Final V5.0  
 
 
 
 


     Statistical Analysis Plan  
Sponsor:  
ObsEva 
 
Protocol: 
18-OBE2109-003 
Document Version No.: 
V5.0 
Document Date: 
13-JUN-2022 
 
CRS-BS-TP-000005 V 1.0 
Page 2 of 127 
Cytel Confidential: This is a controlled document and shall not be changed, saved, copied or reproduced by any unauthorized 
person. 
 
SIGNATURE PAGE 
Protocol Title: 
A Phase 3 multicenter, randomized, double-blind, placebo-
controlled, clinical study to assess the efficacy and safety of 
linzagolix 
in 
subjects 
with 
moderate 
to 
severe 
endometriosis-associated pain. 
Sponsor: 
ObsEva S.A. 
 
 
 
 
Protocol Number: 
18-OBE2109-003 
Document Date/Version: 
13 June 2022/V5.0  
Cytel, Inc. Author: 
 
 
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). 


     Statistical Analysis Plan  
Sponsor:  
ObsEva 
 
Protocol: 
18-OBE2109-003 
Document Version No.: 
V5.0 
Document Date: 
13-JUN-2022 
 
CRS-BS-TP-000005 V 1.0 
Page 3 of 127 
Cytel Confidential: This is a controlled document and shall not be changed, saved, copied or reproduced by any unauthorized 
person. 
Sponsor Signatory: 
 
 
 
 
 
 
 
 
Sponsor Signatory: 
 
 
 
 
 
 
 
 
 


     Statistical Analysis Plan  
Sponsor:  
ObsEva 
 
Protocol: 
18-OBE2109-003 
Document Version No.: 
V5.0 
Document Date: 
13-JUN-2022 
 
CRS-BS-TP-000005 V 1.0 
Page 4 of 127 
Cytel Confidential: This is a controlled document and shall not be changed, saved, copied or reproduced by any unauthorized 
person. 
 
 TABLE OF CONTENTS 
 
1. 
INTRODUCTION AND OBJECTIVES OF ANALYSIS .................................................................. 12 
1.1. 
INTRODUCTION ............................................................................................................................. 12 
1.2. 
OBJECTIVES OF STATISTICAL ANALYSIS ......................................................................................... 12 
2. 
STUDY DESIGN ................................................................................................................... 14 
2.1. 
SYNOPSIS OF STUDY DESIGN......................................................................................................... 14 
2.2. 
RANDOMIZATION METHODOLOGY .............................................................................................. 16 
2.3. 
STOPPING RULES AND UNBLINDING ............................................................................................. 16 
2.4. 
STUDY PROCEDURES ..................................................................................................................... 18 
2.5. 
EFFICACY, PHARMACOKINETIC, AND SAFETY VARIABLES ............................................................. 29 
2.5.1. 
EFFICACY VARIABLES ................................................................................................... 29 
2.5.2. 
PHARMACOKINETIC VARIABLES .................................................................................. 31 
2.5.3. 
SAFETY VARIABLES ...................................................................................................... 32 
2.5.4. 
EXPLORATORY VARIABLES .......................................................................................... 32 
3. 
SUBJECT POPULATIONS ...................................................................................................... 33 
3.1. 
ANALYSES SETS DEFINITIONS ........................................................................................................ 33 
3.2. 
PROTOCOL VIOLATIONS ................................................................................................................ 34 
4. 
STATISTICAL METHODS ...................................................................................................... 36 
4.1. 
SAMPLE SIZE JUSTIFICATION ......................................................................................................... 36 
4.2. 
GENERAL STATISTICAL METHODS AND DATA HANDLING ............................................................ 36 
4.2.1. 
GENERAL METHODS .................................................................................................... 36 
4.2.2. 
COMPUTING ENVIRONMENT ...................................................................................... 37 
4.2.3. 
METHODS OF POOLING DATA .................................................................................... 37 
4.2.4. 
ADJUSTMENTS FOR COVARIATES ............................................................................... 37 
4.2.5. 
MULTIPLE COMPARISONS/MULTIPLICITY ................................................................... 37 
4.2.6. 
SUBPOPULATIONS....................................................................................................... 38 


     Statistical Analysis Plan  
Sponsor:  
ObsEva 
 
Protocol: 
18-OBE2109-003 
Document Version No.: 
V5.0 
Document Date: 
13-JUN-2022 
 
CRS-BS-TP-000005 V 1.0 
Page 5 of 127 
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person. 
4.2.7. 
WITHDRAWALS, DROPOUTS, LOSS TO FOLLOW-UP ................................................... 39 
4.2.8. 
MISSING, UNUSED, AND SPURIOUS DATA .................................................................. 40 
4.2.9. 
VISIT WINDOWS .......................................................................................................... 46 
4.2.10. 
BASELINE DEFINITION ................................................................................................. 49 
4.2.11. 
LAST TREATMENT ADMINISTRATION DATE, END OF STUDY DATE AND 
PERIOD DEFINITIONS .................................................................................................. 50 
4.3. 
INTERIM ANALYSES ....................................................................................................................... 50 
4.4. 
SUBJECT DISPOSITION ................................................................................................................... 51 
4.5. 
DEMOGRAPHIC AND BASELINE CHARACTERISTICS ....................................................................... 51 
4.5.1. 
DEMOGRAPHICS ......................................................................................................... 51 
4.5.2. 
BASELINE DISEASE CHARACTERISTICS ......................................................................... 52 
4.5.3. 
MEDICAL HISTORY....................................................................................................... 53 
4.5.4. 
ENDOMETRIOSIS HISTORY .......................................................................................... 53 
4.6. 
EFFICACY EVALUATION ................................................................................................................. 53 
4.6.1. 
MEANINGFUL CHANGE THRESHOLD ESTIMATION ..................................................... 53 
4.6.2. 
PRIMARY EFFICACY ENDPOINT ................................................................................... 60 
4.6.3. 
RANKED SECONDARY EFFICACY ENDPOINTS .............................................................. 65 
4.6.4. 
ADDITIONAL SECONDARY ENDPOINTS ....................................................................... 72 
4.6.5. 
ADDITIONAL EFFICACY ANALYSES ............................................................................... 84 
4.7. 
PHARMACOKINETIC EVALUATIONS .............................................................................................. 89 
4.8. 
SAFETY ANALYSES ......................................................................................................................... 89 
4.8.1. 
EXTENT OF TREATMENT EXPOSURE AND COMPLIANCE ............................................. 89 
4.8.2. 
ADVERSE EVENTS ........................................................................................................ 90 
4.8.3. 
BONE MINERAL DENSITY (BMD) BY DXA..................................................................... 93 
4.8.4. 
LABORATORY DATA..................................................................................................... 94 
4.8.5. 
VITAL SIGNS AND PHYSICAL EXAMINATIONS .............................................................. 96 
4.8.6. 
ELECTROCARDIOGRAM ............................................................................................... 97 
4.8.7. 
CONCOMITANT MEDICATIONS ................................................................................... 97 


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4.8.8. 
TRANSVAGINAL ULTRASOUND (TVUS) ........................................................................ 97 
4.8.9. 
OTHER EXAMINATIONS ............................................................................................... 98 
4.8.10. 
COLUMBIA-SUICIDE SEVERITY RATING SCALE (C-SSRS) .............................................. 99 
4.8.11. 
TIME TO THE FIRST POST-TREATMENT MENSES ....................................................... 101 
4.8.12. 
UNBLINDING OF SUBJECTS ....................................................................................... 102 
4.9. 
EXPLORATORY ANALYSES ............................................................................................................ 102 
5. 
CHANGES TO PLANNED ANALYSES .................................................................................... 103 
6. 
REFERENCES .................................................................................................................... 111 
7. 
APPENDICES .................................................................................................................... 112 
7.1. 
APPENDIX A: ANALGESIC CHANGE DURING TREATMENT PERIOD.............................................. 112 
7.2. 
APPENDIX B: EHP-30 SCORING ................................................................................................... 114 
7.3. 
APPENDIX C: HRPQ SCORING ...................................................................................................... 115 
7.4. 
APPENDIX D: EQ-5D TTO SCORING ............................................................................................. 118 
7.5. 
APPENDIX E: MAPPING RULES FOR EDIARY DATA ...................................................................... 121 
 
LIST OF IN-TEXT TABLES 


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Table 
Page 
Table 1 
Schedule of Assessments – Screening and Treatment Periods ........................................ 19 
Table 2 Schedule of study assessments - Follow-up Period ...................................................................... 25 
Table 3 Theoretical Visit Dates in Main Treatment Period ....................................................................... 47 
Table 4 Theoretical Visit Dates in Follow-up ........................................................................................... 47 
Table 5 Proposed anchors for MCT estimation for each endpoint ............................................................ 57 
Table 6 List of ATC codes for analgesics and opioids .............................................................................. 64 
Table 7 Morphine Milligram Equivalents for Narcotic Analgesics .......................................................... 70 
Table 8 Mapping Rules for 
 Device .......................................................................................... 121 
Table 9 Mapping Rules for Signant Health Device ................................................................................. 125 
 


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ABBREVIATIONS 
Abbreviation 
Definition 
ABT 
Add-back therapy 
AE 
Adverse events 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
AMH 
Anti-Mullerian hormone 
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 
BCP 
Best Cut Point 
BMD 
Bone Mineral Density 
BMI 
Body Mass Index 
CDF 
Cumulative Distribution Function 
CI 
Confidence Interval 
ClinRO 
Clinician Reported Outcome 
CM 
Concomitant Medication 
Cmax 
Maximum plasma concentration 
Cmin 
Trough plasma concentration, taken 24 hours after dose and prior to 
subsequent dose  
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 


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Abbreviation 
Definition 
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 
FAS 
Full Analysis Set 
FSH 
Follicle-Stimulating Hormone 
FU 
Follow-up 
GCP 
Good Clinical Practice 
GGT 
Gamma Glutamyl Transferase 
GnRH 
Gonadotropin releasing hormone 
HDL 
High-density lipoprotein 
HRPQ 
Health Related Productivity Questionnaire 
HRQoL 
Health Related Quality of Life 
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 
MAR 
Missing At Random 
mB&B 
Biberoglu & Behrman 
MCT 
Meaningful change threshold 
MedDRA 
Medical Dictionary for Regulatory Activities 
MME 
Morphine Milligram Equivalent 


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Abbreviation 
Definition 
mmHg 
Millimeters of mercury 
MNAR 
Missing Not At Random 
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 
PDF 
Probability Density Function 
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 
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 


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Abbreviation 
Definition 
Tmax 
Time to maximum plasma concentration 
TTO 
Time Trade Off 
TVUS  
TransVaginal UltraSound 
ULN 
Upper Limit of Normal 
VRS 
Verbal Rating Scale 


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1. 
INTRODUCTION AND OBJECTIVES OF ANALYSIS 
1.1. 
Introduction 
This is a prospective, randomized, double-blind, placebo-controlled study to demonstrate the efficacy 
and safety of linzagolix administered orally once daily at doses of 75 mg alone and 200 mg in combination 
with add-back therapy (ABT; E2 1 mg/NETA 0.5 mg) versus placebo in the management of moderate to 
severe endometriosis associated pain (EAP) in women with surgically confirmed endometriosis. 
1.2. 
Objectives of Statistical Analysis 
The primary objective of this study is to demonstrate the efficacy and safety of linzagolix administered 
orally once daily for up to 3 months at a dose of 75 mg alone or of 200 mg in combination with ABT (E2 
1 mg / NETA 0.5 mg) versus placebo, while under randomized treatment, in the management of moderate 
to severe EAP in women with surgically confirmed endometriosis. The two co-primary efficacy endpoints 
will be measured as clinically meaningful reduction in pain score over the last 28 days of randomized 
treatment up to the Month 3 visit, along with a stable or decreased use of rescue analgesics for EAP for 
1) dysmenorrhea (DYS) and for 2) non-menstrual pelvic pain (NMPP). 
Meaningful changes for the primary endpoints and for the additional supportive responder analyses for 
the ranked secondary endpoints will be estimated based on blinded Month 3 data for the primary 
endpoints and blinded Month 6 data for ranked secondary endpoints and will be applied on the 
responder threshold analyses. 
Secondary objectives include evaluation of persistence of efficacy over the last 28 days of randomized 
treatment up to the Month 6 visit, 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, Health Related Quality of Life (HRQoL) 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) data of linzagolix for a separate modelling exercise. 
This statistical analysis plan (SAP) is designed to outline the methods to be used in the analysis of study 
data to answer the study objective(s).  Populations for analysis, data handling rules, statistical methods, 
and formats for data presentation are provided.  The statistical analyses and summary tabulations 


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described in this SAP will provide the basis for the results sections of the clinical study report (CSR) for 
this trial. 
This SAP also will outline any differences in the currently planned analytical objectives relative to those 
planned in the study protocol. 


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2. 
STUDY DESIGN 
2.1. 
Synopsis of Study Design 
This is a prospective, randomized, double-blind, placebo-controlled study to demonstrate the efficacy 
and safety of linzagolix administered orally once daily at doses of 75 mg alone and 200 mg in combination 
with low dose ABT (E2 1 mg/NETA 0.5 mg) versus placebo in the management of moderate to severe EAP 
in women with surgically confirmed endometriosis.  
The study starts with an approximately 3-month screening period during which subjects will receive no 
study drug. Eligibility will be confirmed based on data collected during the screening period. After 
randomization, a 6-month Treatment Period will follow. Subjects will be randomized to one of the three 
treatment groups: 
1. Linzagolix 75 mg  
2. Linzagolix 200 mg combined with ABT  
3. Placebo  
Randomization will be conducted via an interactive web response system (IWRS) in a 1:1:1 ratio. There 
will be no stratification.  
At 6 months, BMD change will be assessed via DXA measurement. Eligible subjects who have completed 
the 6-month treatment period may enter a separate extension study for 6 additional months of active 
treatment (no placebo control). In this extension study, subjects who previously received placebo will be 
randomly switched to one of the two active treatments (75 mg alone or 200 mg + ABT). Subjects who 
received active treatment will continue with the same treatment.  
Subjects who decline to participate to or do not qualify for the extension study and who were exposed 
to at least 3 months of treatment will enter a 6-month drug-free follow-up. At the end of the 6-month 
follow-up period, subjects with a BMD decrease from baseline of >1.5% for lumbar spine and >2.5% for 
total hip will have an additional DXA scan 6 months later. Subjects who discontinue treatment prior to 
Month 3 will not enter the follow-up period.  
The main analysis will be performed after 6 months of treatment and will include all of the subjects’ data 
up to Month 6. The primary endpoint analysis will be based on subjects’ data up to Month 3. 
The study will last on average 15 months for each patient; 3-month Screening Period, 6-month Treatment 
Period and 6-month Follow-up (with 1 month being defined as 28 days/4 weeks). This estimated duration 
excludes any washout period.  


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A schematic of the study design is shown in Figure 1. 
 
All subjects will receive once daily either linzagolix 75 mg alone (with ABT placebo) or linzagolix 200 mg 
combined with ABT, or placebo (linzagolix placebo with ABT placebo) for 6 months. ABT is a combination 
of estradiol (E2) 1 mg and norethisterone acetate (NETA) 0.5 mg. Linzagolix or its corresponding placebo 
will be supplied as tablets for oral administration. ABT or its corresponding placebo will be supplied as 
capsules for oral administration.  
Linzagolix/placebo treatments 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. 
Blinded treatment kit numbers corresponding to each subject’s randomized treatment will be provided 
through an IWRS. 
Figure 1: Study design 


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2.2. 
Randomization Methodology 
Randomization will be performed via a centralized IWRS. Subjects will be randomized on Day 1 to one of 
three treatment groups in a 1:1:1 ratio for linzagolix 75 mg, linzagolix 200 mg with ABT and placebo.  
Subjects will be randomized into permutated blocks of a pre-determined length. 
Subjects participating in the extension phase and who are in the placebo treatment group will be 
randomized at the Month 6 visit to either linzagolix 75 mg or linzagolix 200 mg with ABT in a 1:1 ratio. 
Subjects participating in the extension phase and who are in the linzagolix treatment groups will remain 
on the same dose that they were taking at the end of Month 6 and will undergo a dummy randomization 
in order to maintain the blind. 
There will be no stratification. 
2.3. 
Stopping Rules and Unblinding 
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 a patient or 
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 addition, an Independent Data Monitoring Committee (IDMC) will regularly review safety data and 
make recommendations concerning the continuation, modification or termination of the study. 
After all subjects have completed the Treatment Period (Month 6 or Withdrawal visit), a complete 
analysis with unblinded treatments will be performed. A database lock will be performed prior to 
unblinding of treatment. 
Discontinuation criteria  
During the course of the study, a subject may be discontinued for the following reasons: 
-  Adverse Event 
- Subject’s request 
- Protocol Violation 
- Lost to Follow-up 


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- Pregnancy 
- Other 
Details are provided in the Protocol. 
Discontinuation Rules at Day 1: Subjects presenting with alanine aminotransferase (ALT), aspartate 
aminotransferase (AST), gamma glutamyl transferase (GGT) or total bilirubin (TBL) ≥ 2 upper limit of 
normal (ULN) should be discussed with the Sponsor and may have to discontinue study treatment if these 
results are indicative of liver involvement.  
Subjects presenting with a clinically significant finding in the biopsy sample collected at screening and 
who have completed Day 1, will have to discontinue study treatment. 
 
Discontinuation Rules during the Treatment Period:  
Endometrial biopsies: in case of endometrial biopsy diagnosis being an endometrial hyperplasia of any 
type or worse, the subject will have to discontinue the treatment (and will not be eligible to enter the 
extension study) and will be advised to consult for a 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 2.9 mmol/L, study 
treatment should definitively be discontinued and the subject should be advised to consult an 
endocrinologist for further evaluation. 
Bone mineral density 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 
(they will not be eligible to enter the extension study). 
Liver function tests: following the Food and Drug Administration (FDA) guidance on drug-induced liver 
injury, 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 international normalized ratio 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. 


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ECG : subjects who have a QTcF > 500 ms or increase > 60 ms from the highest value prior to first dose 
will 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. 
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 – Screening and Treatment Periods 
Schedule of study assessments – Screening and Treatment Periods 
Timing1 
Screening Period 
(up to 3 months2) 
Treatment Period 
Day 1 
M1 
M2 
M3 
M4 
M5 
M6 
Informed Consent 
x 
 
 
 
 
 
 
 
Inclusion-Exclusion criteria 
x 
x 
 
 
 
 
 
 
Demography, height, weight, medical history 
x 
 
 
 
 
 
 
 x3 
 
1 All post-baseline visits should take place at the end of the defined period (i.e., M1 visit should be scheduled at the end of Month 1, M2 visit should be scheduled at the end of 
Month 2, etc.). Post-baseline visits dates are calculated from Day 1 visit date. A month is defined as 28 days/4 weeks. Visits should be scheduled ± 3 days from the calculated 
date. 
2 If required for washout of oral contraceptives, other sex hormones, or GnRH antagonists/agonists (provided that the reason for discontinuing the previous GnRH-antagonist is 
not lack of efficacy), a period of up to 3 months is allowed between signing the informed consent and the screening visit. 
3 Only weight will be recorded. 


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Schedule of study assessments – Screening and Treatment Periods 
Timing1 
Screening Period 
(up to 3 months2) 
Treatment Period 
Day 1 
M1 
M2 
M3 
M4 
M5 
M6 
mB&B 
x 
 
 
 
 
 
 
 
Columbia-Suicide Severity Rating Scale 
x 
x 
x 
x 
x 
x 
x 
x 
ECG 
x 
 x4 
x 
x 
x 
x 
x 
x 
Physical examination 
x 
 
 
 
x 
 
 
x 
Vital signs 
x 
x 
x 
x 
x 
x 
x 
x 
Urine pregnancy test 
x 
x 
x 
x 
x 
x 
x 
x 
TVUS of uterus 
x 
 
 
 
x 
 
 
x 
Gynecological examination 
x 
 
 
 
x 
 
 
x 
 
4 ECG on Day 1 should be performed twice: once before treatment and once after treatment (just before PK sampling). 


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Schedule of study assessments – Screening and Treatment Periods 
Timing1 
Screening Period 
(up to 3 months2) 
Treatment Period 
Day 1 
M1 
M2 
M3 
M4 
M5 
M6 
Endometrial biopsy 
x 
 
 
 
 
 
 
 x5 
Pap test 
x 
 
 
 
 
 
 
 
Breast examination (mammogram if required) 
x 
 
 
 
 
 
 
x 
Clinical laboratory & urinary protein dipstick 
x 
x6 
x 
x 
x6 
x 
x 
x6 
Blood sample for PK7 
 
x 
x 
x 
x 
x 
x 
x 
BMD by DXA 
x 
 
 
 
 
 
 
x 
Adverse events 
x 
x 
x 
x 
x 
x 
x 
x 
 
5 If endometrium thickness in TVUS is ≤ 5 mm, no endometrial biopsy will be necessary. 
6 Overnight fasting is required. 
7 PK samples should be taken after the ECG and before the daily dose of IMP, except on Day 1 when the PK sample should be taken at least 1.5 h after the IMP administration. 


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Schedule of study assessments – Screening and Treatment Periods 
Timing1 
Screening Period 
(up to 3 months2) 
Treatment Period 
Day 1 
M1 
M2 
M3 
M4 
M5 
M6 
Previous/concomitant medication 
x 
x 
x 
x 
x 
x 
x 
x 
Contraceptive dispensing and counselling 
x 
x 
x 
x 
x 
x 
x 
x 
Permitted analgesic prescribing/dispensing 
x 
x 
x 
x 
x 
x 
x 
x 
Vitamin D and calcium dispensing 
 
x 
x 
x 
x 
x 
x 
x 
Subject eDiary completion training/check 
x 
x 
x 
x 
x 
x 
x 
x 
IMP accountability 
 
 
x 
x 
x 
x 
x 
x 
Dispense study drug 
 
x 
x 
x 
x 
x 
x 
 
Dispense ABT 
 
x 
 
 
x 
 
 
 


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Schedule of study assessments – Screening and Treatment Periods 
Timing1 
Screening Period 
(up to 3 months2) 
Treatment Period 
Day 1 
M1 
M2 
M3 
M4 
M5 
M6 
EHP-30, EQ-5D-5L and PROMIS8 
 
x 
x 
 
x 
 
 
x 
mPGIS, PGIC, HRUQ and HRPQ 
 
 x9 
x 
x 
x 
x 
x 
x 
Specific monthly severity questions8 
 
x 
 
 
x 
 
 
x 
SSIQ and PSIQ8 
 
x 
 
 
 
 
 
x 
AMH 
 
x 
 
 
 
 
 
 
E2, LH, P4 
 
x 
x 
x 
x 
x 
x 
x 
SHBG 
 
x 
 
 
x 
 
 
x 
 
8 ClinROs (Monthly dyspareunia question, 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, and specific monthly severity questions) will be filled in by the subject in the eDiary. 
9 PGIC not done at Day 1. 


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Schedule of study assessments – Screening and Treatment Periods 
Timing1 
Screening Period 
(up to 3 months2) 
Treatment Period 
Day 1 
M1 
M2 
M3 
M4 
M5 
M6 
Bone biomarkers 
 
x 
 
 
x 
 
 
x 
Question regarding treatment received  
 
 
 
 
 
 
 
x 


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Table 2 Schedule of study assessments - Follow-up Period 
Schedule of study assessments – Follow-up Period 
Timing1 
M1 FU 
M2 FU 
M3 FU 
M4 FU 
M5 FU 
M6 FU 
Previous/concomitant medication 
x 
x 
x 
x 
x 
x 
Adverse events 
x 
x 
x 
x 
x 
x 
Columbia-Suicide Severity Rating Scale 
x 
x 
x 
x 
x 
x 
ECG 
x 
 
x 
 
 
x 
Physical examination 
 
 
x 
 
 
x 
Weight 
 
 
 
 
 
x 
Vital signs 
x 
 
x 
 
 
 
 
1 All follow-up study visits should take place at the end of the defined period (i.e. M1 FU visit should be scheduled at the end of the first month of follow-up, M2 FU visit should 
be scheduled at the end of the second follow-up visit, etc.). A month is defined as 28 days/4 weeks. Visits should be scheduled ± 7 days from the calculated date. 


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Schedule of study assessments – Follow-up Period 
Timing1 
M1 FU 
M2 FU 
M3 FU 
M4 FU 
M5 FU 
M6 FU 
Gynecological examination 
 
 
x 
 
 
 
Breast manual examination 
 
 
x 
 
 
 
Endometrium TVUS 
 
 
x 
 
 
x 
Endometrial biopsy 
x2 
x2 
x2 
x2 
x2 
x3 
Clinical laboratory & urinary protein dipstick 
x 
 
x4 
 
 
 
Subject eDiary completion check 
x 
x 
x 
x 
x 
x 
Subject eDiary collection and deactivation 
 
 
 
 
 
x 
 
2 Endometrial biopsy will be taken only if diagnosis at preceding month was different than “benign endometrium” or if no endometrial biopsy was done at Month 6 nor at any 
visit since Month 6. 
3 An end-of-study biopsy is mandatory if no endometrial biopsy was obtained at M6 nor at any of the subsequent monthly visits. 
4 Overnight fasting is required. 


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Schedule of study assessments – Follow-up Period 
Timing1 
M1 FU 
M2 FU 
M3 FU 
M4 FU 
M5 FU 
M6 FU 
EHP-30, HRUQ, HRPQ, EQ-5D-5L and PROMIS 
 
 
x 
 
 
x 
mPGIS and PPGIC  
x 
x 
x 
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 FU visit 
 
 
x 
 
 
 
Bone biomarkers 
x 
 
Permitted analgesic prescribing/dispensing 
x 
x 
x 
x 
x 
 
Vitamin D and calcium dispensing 
x 
x 
x 
x 
x 
 
 
5 Subjects with a BMD decrease from baseline of > 1.5% for lumbar spine and/or > 2.5% for total hip at Month 6 FU visit will have an additional DXA scan 6 months later. 


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Schedule of study assessments – Follow-up Period 
Timing1 
M1 FU 
M2 FU 
M3 FU 
M4 FU 
M5 FU 
M6 FU 
Urine pregnancy test and contraceptive dispensing and 
counselling 
x 
x 
x 
 
 
x 


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2.5. 
Efficacy, Pharmacokinetic, and Safety Variables 
2.5.1. Efficacy Variables 
 
2.5.1.1. 
Primary efficacy endpoint 
The two co-primary, composite, efficacy endpoints are clinically meaningful reduction from baseline to 
the last 28 days preceding the Month 3 visit (the 4-week period preceding Month 3 visit) or, for subjects 
who discontinue randomized treatment prior to the Month 3 visit, to the last 28 days of randomized 
treatment, 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). 
Additional details on the primary endpoint definition and primary analysis are provided in Section 4.6.  
2.5.1.2. 
Ranked Secondary efficacy endpoints 
Ranked secondary efficacy endpoints (in the order of the endpoints to be tested) are:  
- 
Change from baseline to Month 6 in DYS (VRS) 
- 
Change from baseline to Month 6 in NMPP (VRS) 
- 
Change from baseline to Month 6 in dyschezia (Numeric Rating Scale - NRS) 
- 
Change from baseline to Month 6 in overall pelvic pain (NRS) 
- 
Change from baseline to Month 6 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 6 in dyspareunia (VRS) 
- 
No analgesics use for EAP during the preceding 4-week period at Month 6 
- 
No opiate use for EAP during the preceding 4-week period at Month 6  
Additional details on ranked secondary endpoints and analyses are provided in Section 4.6. 
2.5.1.3. 
Additional secondary efficacy endpoints 
Additional secondary efficacy endpoints include: 
- 
Clinically meaningful reduction at scheduled visits other than Month 3 for DYS and NMPP  
- 
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 


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- 
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 
- 
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 


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- 
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 
- 
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 
Additional details on secondary endpoints and analyses are provided in Section 4.6. 
 
2.5.2. Pharmacokinetic Variables 
 
PK blood samples will be collected from each subject for determining linzagolix and KP017 plasma levels.  
On Day 1, blood samples for PK assessment will be taken at least 1.5 h post-first dose.  
During the treatment period, on days of site visits (Months 1, 2, 3, 4, 5 and 6), the subject will be asked 
to take the dose of IMP at site, after a pre-dose PK sampling. The approximate time of dose 
administration on the four previous days and time of PK sampling will be recorded in the eCRF.  
Pharmacokinetic analyses will be considered exploratory. Analyses are described in Section 4.7. 
 


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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) 
- 
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 
Safety analyses are described in Section 4.8. 
2.5.4. Exploratory Variables 
Exploratory endpoints include: 
- 
Change from baseline in bone turnover markers at each scheduled assessment. 
Exploratory analyses are detailed in Section 4.9. 
 


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3. 
SUBJECT POPULATIONS 
3.1. 
Analyses Sets Definitions 
The following data sets will be used for the statistical analysis:  
Screened Set: All screened subjects. 
Randomized Set: All randomized subjects. 
Safety Set (SAF): All randomized subjects who received at least one dose of double-blind study drug 
irrespective of the treatment received. Subjects will be analyzed according to treatment received.  
Full Analysis Set (FAS): All randomized subjects who received at least one dose of double-blind study drug 
irrespective of the treatment received. This is the same as the Safety Set, but for the FAS, subjects will be 
analyzed according to randomized treatment. 
Threshold Analysis Set: All subjects from the FAS with any anchor data at both Baseline and Month 3 or 
early discontinuation visit, or available Month 3 or early discontinuation visit PGIC data only. 
Anchor data for the Threshold Analysis Set includes monthly Patient Global Impression of Severity 
(mPGIS), mPGIC, monthly DYS, monthly NMPP.  
M6 Threshold Analysis Set: All subjects from the FAS with any anchor data at both Baseline and Month 6 
or early discontinuation visit, or only available Month 6 or early discontinuation visit PGIC data. 
Anchor data for Month 6 include monthly Patient Global Impression of Severity (mPGIS), mPGIC, monthly 
DYS, monthly NMPP, monthly dyschezia, monthly overall pelvic pain, monthly difficulty in daily activities, 
and monthly dyspareunia. 
Per Protocol (PP) Set: All randomized subjects who completed the six months of treatment excluding 
those identified as having major protocol deviations that could potentially affect the efficacy assessments 
up to Month 6. Subjects will be analyzed according to randomized treatment. 
Follow-up (FU) Set: All randomized subjects who completed the six months of treatment or discontinued 
treatment between Month 3 and Month 6 and entered the drug free follow-up period. Subjects will be 
analyzed according to randomized treatment.  
Subjects who entered the drug free follow-up period are subjects eligible for the 6-month treatment free 
follow-up and with any data post month 6 or post treatment discontinuation. 
Follow-up Safety Set (FU SAF): All randomized subjects who completed the six months of treatment or 
discontinued treatment between Month 3 and Month 6, and entered the drug free follow-up period. 
Subjects will be analyzed according to treatment received.  


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Pharmacokinetic (PK) Set: all subjects who received active study medication, had no major protocol 
deviations impacting PK evaluation and with available PK data.  
In general, analyses of efficacy will be conducted using the FAS, PP and FU sets, analyses of safety will be 
conducted using the Safety Set and FU SAF, and analyses of PK will be conducted using the PK Set. 
The actual treatment will be derived as follows, based on daily e-diary IMP intake data: 
Subjects received a different kit of active linzagolix or placebo 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 intake 
of drug was taken on that day. 
Further rules are as follows: 
- 
Treatment administration errors: 
o If a subject received placebo with placebo ABT in more than 50% of days, then the actual 
treatment group will be placebo with placebo ABT. 
o Otherwise, the active treatment group (combined with add-back or placebo add-back) 
with the most days taken will be assigned. 
o If the number of days is equal for two treatments groups containing active treatment 
then LGX 200 mg with ABT will be assigned.  
- 
If a subject discontinued, only data received up to discontinuation will be used. 
- 
It is possible that the derived actual treatment group does not correspond to any of the planned 
treatment groups. In that case actual treatment group will be assigned to the planned treatment 
group with same dose of active treatment. Example: LGX 75mg with ABT will be assigned to LGX 
75mg with placebo ABT; LGX 200mg with placebo ABT will be assigned to LGX 200mg with ABT. 
A listing with such cases will be provided. 
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 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 IRB/IEC per their policies. The site 
investigator is responsible for knowing and adhering to the reviewing IRB/IEC requirements.  


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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. The final protocol deviation file (formatted as a Microsoft Excel file) will be provided to 
Cytel. 
Major protocol deviations will be summarized by category (if available) and by treatment group for the 
FAS population. 
Major deviations that could potentially affect the efficacy assessments up to Month 6 and thus may 
exclude subjects from the PP Set may include: 
- 
Non-compliance with inclusion criteria 3; 6; 8 
- 
Non-compliance with exclusion criteria 2 to 10 inclusive; 12; 13; 17; 19; 20; 21; 23; 24; 25 
- 
Non-compliance with study treatment: threshold to be defined during blinded data review 
meeting (e.g. IMP compliance in tablets <60% for Day1-Month 6 ) 
- 
IP Dispensing error; 
- 
Unauthorised prior or concomitant therapy; 
- 
M3 and/or M6 Visits performed outside the +/-14 days of the theoretical visit date; 
- 
Randomisation code broken; 
 
All protocol deviations will be presented in the data listings. 
 


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4. 
STATISTICAL METHODS 
4.1. 
Sample Size Justification 
The planned sample size for this study is 150 subjects per treatment group (450 subjects in total).  
An overall two-sided type I error of 0.05 will be used. As there are two linzagolix versus placebo 
comparisons, Bonferroni corrected p-values will be produced (raw p-values will be multiplied by two prior 
to comparing to 0.05). The planned sample size considers the hierarchical, fixed sequence testing of the 
ranked secondary endpoints as well as the co-primary endpoints. The assumptions used for the sample 
size calculations are based on analyses of clinically meaningful reduction in pain with a stable or 
decreased use of analgesics from the Phase 2b Edelweiss study. Calculations were performed using East® 
6.5 software. 
One hundred and fifty (150) subjects per treatment group will provide a power greater than 95% to reject 
the null hypothesis for both co-primary endpoints for either treatment group, assuming a placebo 
response rate of 14.6% and an active treatment response rate of 48.6% (75 mg, Edelweiss Phase II study 
results) or 64.7% (200 mg, Edelweiss Phase II study result) for DYS, and a placebo response rate of 18.8% 
and an active treatment response rate of 42.1% (75 mg, Edelweiss Phase II study result; the response 
rate for 200 mg in Edelweiss was lower but was inconsistent with the other doses and other timepoints 
for the same dose and so was not used) for NMPP. In addition, 150 subjects per treatment group provides 
85% power to reject the null hypotheses for all the ranked secondary endpoints based on the observed 
results from the placebo and 200 mg treatment group in the Edelweiss study.  
The values used for the sample size calculations assume that these responses rates  are what would be 
seen on average when under treatment including taking into account any subjects who might withdraw 
from treatment early; therefore the calculations do not need to be further adjusted for dropouts.  
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, efficacy, pharmacokinetic and 
safety parameters.   
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 


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for all subjects based on the FAS. For efficacy endpoints and BMD, 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. 
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.  
This study will be conducted at approximately 100 study sites, resulting in only a few subjects per site on 
average. Subjects from all sites will be pooled and no adjustment for sites will be carried out in the 
statistical analyses. 
Raw and derived data will be listed. 
All statistical hypothesis tests and confidence intervals will be two sided.  
 
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 using MedDRA available version.  
Concomitant medications will be coded using World Health Organization (WHO) Drug Dictionary 
available version.  
4.2.3. Methods of Pooling Data 
Not applicable to the present study. 
4.2.4. Adjustments for Covariates 
Adjustments for possible covariates will be described in the appropriate statistical analyses’ sections.  
4.2.5. Multiple Comparisons/Multiplicity 
All statistical hypothesis tests and confidence intervals will be two-sided. To maintain an overall type I 
error rate of 0.05, as there are two linzagolix versus placebo comparisons, Bonferroni corrected p-values 
will be produced (raw p-values will be multiplied by two prior to comparing to 0.05), along with 
corresponding 97.5% confidence intervals. 
The two co-primary efficacy endpoints will be clinically meaningful reduction from baseline over the last 
28 days of randomized treatment up to the Month 3 visit (i.e., the 4-week period preceding the Month 3 
visit) in the mean daily assessment of DYS and of NMPP measured on a VRS, along with a stable or 
decreased use of analgesics for EAP. 
The primary objective will be assessed by testing the following two-sided hypotheses for each co-primary 
endpoint, for each linzagolix group versus placebo separately: 
Null hypothesis (H0): There is no difference in the odds of subjects meeting the primary endpoint for the 
active treatment group compared to placebo, that is, the odds ratio (OR) equals 1. 


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H0: OR =1 
Alternative hypothesis (H1): There is a difference in the odds of subjects meeting the primary endpoint 
for the active treatment group compared to placebo, that is, the OR is not equal to 1. 
H1: OR ≠ 1 
Where odds are equal to the proportion of subjects meeting the endpoint divided by proportion of 
subjects not meeting the endpoint. 
Each linzagolix group will need to demonstrate a statistically significant difference for both co-primary 
endpoints for the group to be considered more efficacious than placebo, thus maintaining an overall type 
I error rate of 0.05.  
For each linzagolix group that is statistically significantly more efficacious than placebo for the co-primary 
endpoints, a fixed-sequence testing strategy shall be used within the group to test the ranked secondary 
endpoints as ordered in Section 2.5.1.2, to maintain the family-wise type I error rate. That is, the 
comparison for each linzagolix group versus placebo for each ranked endpoint will only be declared 
statistically significant different if the raw p-value multiplied by two is less than or equal to 0.05 for that 
endpoint and for all preceding endpoints for that dose versus placebo.  
Response rates for DYS and NMPP at each visit will be analyzed to evaluate the changes in pain over time, 
with nominal Bonferroni corrected p-values used in the comparisons of treatment groups at each visit. 
These are supportive analyses and will primarily be considered as descriptive. The analyses do not form 
part of the fixed-sequence strategy being used for the ranked secondary endpoints and will not be fully 
controlled for an overall type I error rate. However, to maintain consistency with the primary and 
secondary analyses, Bonferroni corrections will be used due to there being two linzagolix versus placebo 
comparisons for each endpoint / time point. 
4.2.6. Subpopulations 
Subgroup analyses will be performed for each co-primary endpoint and for BMD. 
Subgroups include: 
- 
Race: Black or African American, Other  
- 
Ethnicity: Hispanic or Latino, Not Hispanic or Latino 
- 
Age group 1 (<median value at baseline, ≥ median value at baseline) (based on FAS population) 
- 
Age group 2 (<25, ≥ 25 to < 35, ≥ 35 to < 45, ≥ 45) 
- 
Weight: < median value at baseline, ≥ median value at baseline (based on FAS population) 
- 
BMI group 1 (< median value at baseline, ≥ median value at baseline) (based on FAS population) 
- 
BMI group 2 (< 20, ≥ 20 to < 25, ≥ 25 to < 30, and ≥ 30) 


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- 
Baseline analgesic use: Subjects who took no rescue medication for endometriosis pain at 
baseline, subjects who took any NSAIDS and Narcotics at baseline 
- 
Baseline pain VRS scores for dysmenorrhea (DYS), non-menstrual pelvic pain (NMPP), and 
dyspareunia: < median value at baseline, ≥ median value at baseline (based on FAS population) 
- 
Time since endometriosis diagnosis (time in years): < 2 years, ≥ 2 – < 5 years, and ≥ 5 years 
- 
History of pregnancy at baseline – Yes, No 
A subgroup analysis will be performed for the secondary endpoint of dyspareunia on subjects who have 
a mean dyspareunia score >1 at baseline. Detailed analysis is described in Section 4.6.  
 
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 on the CRF will be included in data listings that will 
accompany the clinical study report.   
In case of early discontinuation, the subject will be instructed to complete the relevant eDiary 
questionnaires as soon as possible upon treatment discontinuation.  
Subjects who did not receive the study drug will be withdrawn from the study and no further study 
procedures will be performed.  
Withdrawal during treatment period:  
Subjects who discontinue between Day 1 and Month 3 should undergo the procedures required at Month 
6 (except the DXA scan and the endometrium biopsy if a biopsy was obtained at screening) and will not 
enter the 6-month follow-up period.  
Subjects discontinuing the study treatment between Month 3 and Month 6 should undergo the 
procedures required at Month 6. These subjects will enter a 6-month follow-up period and will continue 
daily eDiary recording for 6 months and up to Month 6 FU visit in order to continue to collect efficacy 
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: 
Subjects discontinuing participation in the study during the follow-up period should undergo the 
procedures required at Month 6 FU visit, which includes completion of all ClinRO and ePRO 
questionnaires, except the DXA in case of discontinuation before Month 3 FU visit. 
Subject Replacement: 
Discontinued subjects who did not receive the study drug may be replaced.  


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Additional subjects may be recruited due to subjects who were discontinued due to ALT, AST, GGT or 
total bilirubin ≥ 2 times the upper limit of normal at Day 1, or due to a clinically significant biopsy finding 
at Day 1 (treatment start), or due to high calcium level at Day 1. 
4.2.8. Missing, Unused, and Spurious Data 
4.2.8.1. 
Efficacy Endpoints Missing Data 
Summary statistics will be based primarily on non-missing values. The planned statistical analyses aim to 
estimate the efficacy of linzagolix versus placebo while under randomized treatment and therefore lack 
of data after treatment discontinuation will not be considered as missing for these analyses.  
Subjects who cannot be assessed as responders for the co-primary efficacy endpoints, e.g. due to lack of 
on treatment pain data (i.e. subjects who received less than 28 days of treatment), will be considered as 
non-responders. In addition, for endpoints assessing the numeric change from baseline, such subjects 
will be assigned a change from baseline of zero. It is expected that very few subjects will be affected by 
these rules. 
There may be missing data during the screening period and whilst under treatment, for example, missed 
days of completing the eDiary. The primary analyses will use observed data only in such cases provided 
that a minimum number of completed daily eDiary entries are available. This effectively assumes that the 
individual values such as daily eDiary assessments (observed or not) are independent of being missing.  
Further details on the handling of missing values and the methods and planned sensitivity analyses to 
check the robustness of the analysis results under alternative assumptions with regards to missing data 
are provided in the analyses sections. As additional analyses, in order to estimate the effect of treatment 
policy, a reference based multiple imputation approach will be used for the co-primary endpoints for 
subjects who discontinue the study early under the assumption that the efficacy of the linzagolix treated 
subjects gradually transitions to that observed in the placebo subjects.  
Missingness Assumptions: 
Missing At Random (MAR): Missingness is independent of unobserved outcomes given observed data. 
Subjects with missing data can be modeled based on similar subjects with available data if we account in 
the model for relevant observed factors. 
Missing Not At Random (MNAR): The probability of missingness depends on the unobserved outcome 
and cannot be predicted only based on observed data. 
Multiple Imputation Methodology: 
Multiple imputation inference involves three distinct steps:  


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1. The missing data are filled in m times to generate m complete data sets, using defined 
assumptions on missingness.  
2. The m complete data sets are analyzed using standard statistical analyses.  
3. The results from the m complete data sets are combined to produce inferential results.  
Reference-based multiple imputation: 
Imputation model for the missing observations in the active treatment groups that is constructed not 
from the observed data in the active treatment groups but rather from the observed data in the control 
group. Missing observations from the control group are also imputed using observed data from the 
control group. 
The fully conditional specification method will allow multivariate imputation of the different endpoints. 
Application of multiple imputation for binary endpoints: 
The two co-primary endpoints are binary endpoints derived from underlying continuous endpoints. The 
first step of multiple imputation will be performed on the continuous variables and transformation into 
a binary endpoint will be applied after imputation. 
As the second step, the statistical analysis for treatment effect on binary endpoints (logistic regression) 
will be performed on each m imputed datasets. 
Odds ratios of the contrast of interest will be presented. To obtain the combined estimates of odds ratios 
from each of the m models, the log of odds ratios estimates should be used in the MIANALYZE procedure, 
and the combined estimates should be back transformed afterwards. This is in order to fulfill the 
assumption that the statistics estimated from each imputed dataset are normally distributed (Ratitch, 
Lipkovich, & O’Kelly, 2013) 
 
4.2.8.2. 
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). 


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 
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 
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 onset dates for AEs  
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. 


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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 
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. 
 
4.2.8.3. 
eDiary Devices Data Cleaning 
To handle eDiary system issues, mapping rules are defined for data analysis, as described in Appendix E 
in Section 7.5.  
In addition, the following rules are defined. 
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 (same date, same name), the first non-empty record 
(with earliest date/time) should be used for analysis. 
Daily Records entered after 00:00 
For daily diaries, records entered with a time between 00:00 (midnight) and 02:00 AM should be 
considered for the previous day.  


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Additional rules to specific eDiary domains: 
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 
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 the 
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) presented to 
the subject will depend on the answer chosen by the subject to the current question. 
Due to device design issue, when an answer to a triggering question has been changed by the 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 if it had been her initial answer (in 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. 


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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. 
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” 
(i.e., 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 


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4.2.8.4. 
Transvaginal Ultrasound 
If the depth recorded for a TVUS of uterus is 0 mm, the depth and the volume should be considered as 
missing (i.e., this means that the assessment was done in 2 dimensions instead of 3 dimensions). 
 
4.2.8.5. 
Partial and Missing Dates of diagnosis 
For partial date of first medical diagnosis/treatment, first surgical diagnosis and most recent surgical 
diagnosis the following rules of imputation will be applied: 
- 
If only Day is missing, Day will be imputed to 01. 
- 
If Day and Month are missing:  
o if Year is the same as the screening date, Date will be imputed to Screening Date.  
o Otherwise, Day will be imputed to 01 and Month will be imputed to 07.  
- 
If Date is completely missing, no imputation will be done. 
 
4.2.9. Visit Windows 
For all analyses except for the DXA assessments and the diary questionnaires, the visits as collected in 
the eCRF will be used.  
E-diary questionnaires: 
For diary questionnaires (EHP-30, EQ-5D-5L, HRPQ, HRUQ, PGIC, PPGIC, PGIS, PROMIS, SSIQ) except for 
the PSIQ, the e-diary dates of assessment of each visit will be checked versus the dates of same visit in 
eCRF to handle for e-diary visit errors. Only assessments within the window of the date of eCRF+/-14 
days will be used in analyses. For Day 1 assessments, only data prior to the first dose will be used, 
regardless of the questionnaire visit name. In case of multiple assessments falling within the same 
window of an eCRF date, the non-empty record with completion date closest to the eCRF date will be 
used.  
For data from discontinued visits, the discontinuation visit date should be compared to theoretical visit 
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 main treatment period, date will be compared to the theoretical visit dates in main 
treatment period as described in Table 3. If a subject discontinued in the follow-up period, date will be 
compared to the theoretical visit dates in Follow-up period from Table 4. Note that assessments from 


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discontinued visits in 
 eDiary device are entered under Month 6 (Month 6 FU in follow-up). They 
will be recoded as discontinued visits before applying the windowing rules. 
Table 3 Theoretical Visit Dates in Main Treatment Period 
Visit 
Theoretical Date 
Month 1 
Day 29 
Month 2 
Day 57 
Month 3 
Day 85 
Month 4 
Day 113 
Month 5 
Day 141 
Month 6 
Day 169 
 
Table 4 Theoretical Visit Dates in Follow-up 
Visit 
Theoretical Date 
Month 1 FU 
Month 6 date or treatment discontinuation date + 28 
Month 2 FU 
Month 6 date or treatment discontinuation date + 56 
Month 3 FU 
Month 6 date or treatment discontinuation date + 84 
Month 4 FU 
Month 6 date or treatment discontinuation date + 112 
Month 5 FU 
Month 6 date or treatment discontinuation date + 140 
Month 6 FU 
Month 6 date or treatment discontinuation date + 168 
 
Pharmacokinetics data: 
Visit windows rules for PK data will be the following: 


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At day 1: PK assessment will be included in analysis if PK sampling is done >=1.5 hours after the 
dose and on the same day as Day 1.  
- 
At other visits: PK assessments will be included in analysis if:  
o Assessment is Pre-dose (or PK time = dose time), or IMP intake is not done on the day 
of PK sampling (i.e. considered as pre-dose), and, 
o PK assessment date is within +/-10 days of the theoretical visit and up to 2 days after 
last IMP intake for Month 6 visit. 
 
If the PK sampling time is missing, or the IMP intake on the same day is done and the IMP intake time is 
missing then assessments will not be included. 
IMP intake status (done/not done) and IMP intake time from the Pharmacokinetics eCRF page will be 
used. 
 
DXA data: 
Visit windows rules for DXA assessments will be the following: 
- 
The baseline DXA assessment will be derived as the latest non-missing DXA assessment with 
acceptable quality (accepted=”Yes”) prior to the baseline visit or the first non-missing assessment 
with acceptable quality (accepted=”Yes”) done up to 10 days after the baseline visit if there is no 
assessment prior to baseline.. 
- 
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 6 Follow-Up will be derived in the same way as the DXA 
assessment at Month 6. Theoretical date of Month 6 Follow-up is 168 days after Month 6 
theoretical date or after treatment discontinuation. 
Other Safety Data: 
Endometrial biopsy Screening window will include any assessment done prior to the first dose. 
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 main treatment period, date will be compared to the theoretical visit dates in main 
treatment period as described in Table 3. If a subject discontinued in the follow-up period, date will be 
compared to the theoretical visit dates in Follow-up period from Table 4. For unscheduled safety 
assessments, if the unscheduled assessment occurs in a window of +/- 14 days of a planned eCRF visit for 


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which it was planned per protocol to have such assessment, and no assessment was done for that visit, 
the unscheduled assessment will be assigned to that visit. If an unscheduled assessment is equally distant 
from two eCRF visits with no corresponding safety assessment, the unscheduled assessment will be 
assigned to the next visit. 
4.2.10. Baseline Definition 
The primary endpoint and other efficacy endpoints based on daily e-diary data (DYS, NMPP, dyschezia, 
overall pelvic pain, dyspareunia, analgesic use, difficulty in daily activities, uterine bleeding, missing 
school or work, having to sleep or laying down) will base the baseline calculation on diary data from 
menstrual cycles of the screening period. The screening period must cover at least two full menstrual 
cycles. The following rules apply to select the two baseline menstrual cycles for assessment of eligibility 
and baseline: 
- 
If only two full screening cycles are covered prior to Day 1: those two screening cycles should be 
used for both eligibility assessment and baseline calculation. 
- 
If 3 full screening cycles are covered during the screening period, for logistical reason, as allowed 
per protocol: "If for logistical reasons beyond her control, the subject is unable to come to the 
clinic for Day 1 within the acceptable time window (1st to 7th day inclusive of the cycle) then the 
subject will be allowed to start Day 1 in the following cycle (again on the 1st to 7th day of the 
cycle). In this case, the eligibility assessments should be assessed based on the first two cycles 
only"; the two first screening cycles should be used for both eligibility assessment and baseline 
calculation 
- 
If more than 3 full screening cycles are covered during the screening period: the last two 
menstrual cycles prior to the baseline visit will be considered for both eligibility assessment and 
baseline calculation. 
- 
Due to possible technical issues with the 
 e-diary device, some data during screening 
menstrual cycle may not have been collected properly. Consequently the menstrual cycles may 
not be considered as valid for assessment of eligibility and baseline and cycles other than the 
first and/or second ones might be used.  
ObsEva will provide an excel file listing all the menstrual cycles that were used for measurement of 
eligibility and baseline values.  
Further details on baseline calculations are specified in the analysis sections for each endpoint. 
The baseline DXA assessment will be derived as the latest non-missing DXA assessment with acceptable 
quality (accepted=”Yes”) prior to the baseline visit or the first non-missing assessment with acceptable 
quality (accepted=”Yes”) done up to 10 days after the baseline visit if there is no assessment prior to 
baseline. 


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For other data, unless otherwise specified, baseline will be defined as the data most recently collected 
prior to the first dose of IMP. 
4.2.11. Last treatment administration date, End of Study date and Period definitions 
The last treatment administration date will be defined as the date from the treatment termination of 
main period eCRF page. If this date is missing, the last date with a drug intake in eDiary strictly inferior to 
Month 6 date or the last date with a drug intake in eDiary available if the subject discontinued will be 
used. 
For each 28-day period prior to Month X (except Month 6), the end of the period will be defined as the 
Month X visit date. If subject discontinued prior to Month X, the end of the period will be the date from 
the treatment termination of main period eCRF page or the last date with a drug intake in the eDiary if 
missing. If the subject missed the Month X visit (but did not discontinued), the subject might still have 
filled the diary during that time: the theoretical Month X date will be used to define the end of the 28-
day period. The theoretical Month X is defined with respect to Day 1 as Month X= Day 1+ 28*X. 
Theoretical visits are presented in Table 3 of Section 4.2.9. 
For the 28-day period prior to Month 6, the end of the period will be defined as the last treatment 
administration date. 
The end of study date will be Month 6 date – 1 day for subjects entering the Extension, and the last 
assessment date defined as last eCRF (excluding AE and CM end dates) or eDiary date in main study or 
main Follow-up for subjects not entering the Extension. This will not necessarily be the same date as last 
assessment date as recorded in the eCRF. 
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 Month 
6 date will be part of the extension for subjects entering the extension study, and be part of the Follow-
up period for subjects entering the main study follow-up period. 
The main treatment period will be defined as Day 1 up to (Month 6 date -1) or treatment discontinuation 
date. 
The main follow-up period will be defined as the Month 6 date or (treatment discontinuation date+1) up 
to the end of study date (for subjects who entered the follow-up). 
 
4.3. 
Interim Analyses 
An interim analysis is not planned for this study. This SAP will however be updated twice prior to 
unblinding and analysis of the data up to Month 6, in order to incorporate the results of the blinded 
meaningful change estimation analyses at Month 3 and at Month 6. 


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At Month 6 Database Lock, the blinded meaningful change estimation for ranked secondary endpoints 
based on Month 6 data will be performed by a blinded team at Cytel and a blinded team at Clinical 
Outcome Solutions, while a Cytel restricted team will be unblinded to produce on the Month 6 CSR 
analysis. The blinded and unblinded teams will not be in contact, and any unblinded results will be 
provided to Sponsor only after the Month 6 meaningful change estimation has been completed and the 
SAP updated.  
Results will be presented twice: after Month 6 completion and after Month 6 Follow-up completion.  
4.4. 
Subject Disposition 
A tabulation of subject disposition will be presented, including the number of subjects screened, 
randomized, who received at least one dose of study drug, the number in each subject population for 
analysis, the number of subjects who withdrew prior to completing the study, and reasons for 
withdrawal, by treatment group and overall, for randomized subjects and for safety population.  
A subject will be considered to have completed study if the subject completed the treatment and follow-
up periods, or completed the treatment period and entered the extension study. 
The number of subjects who completed each visit will be summarized by treatment group and overall, 
for the FAS population. 
The following listings will be presented: 
- 
Study completion information, including the reason for premature study withdrawal, if applicable; 
- 
Inclusion/exclusion criteria not met for Screened Subjects; 
- 
Subject inclusion in each of the analysis sets (Randomized Set, Full Analysis Set, Per Protocol set, 
Threshold Analysis Set, M6 Threshold Analysis Set, PK Analysis Set, Safety Analysis Set, Follow-up 
Set, and Follow-up Safety Set). 
4.5. 
Demographic and Baseline Characteristics 
Baseline, demographic and medical history information will be analyzed for the (SAF), FAS and PP set. No 
formal statistical comparisons will be performed. 
4.5.1. Demographics 
Demographics and baseline characteristics will be summarized by treatment group and overall using 
descriptive statistics.   


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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*Height) (m2). 
Demographic and Baseline data will be provided in data listings. 
4.5.2. Baseline Disease Characteristics 
The definition of the two baseline menstrual cycles is described in section 4.2.10 
Baseline Dysmenorrhea (DYS) and Non-Menstrual Pelvic Pain (NMPP) will be calculated by averaging over 
the two baseline menstrual cycles, the e-diary daily answers of Endometriosis Related Pelvic Pain (PP VRS 
Questionnaire). Responses of "None," "Mild," "Moderate," and "Severe" will be assigned a score of 0, 1, 
2, and 3, respectively. Dysmenorrhea will be computed using days with uterine bleeding, defined as those 
days on which the subject records any uterine bleeding or spotting in the subject eDiary; Non-Menstrual 
Pelvic Pain will use days with no uterine bleeding. 
The baseline analgesic use will be calculated as the mean of daily pill count of analgesics over the two 
baseline menstrual cycles for each class of rescue analgesics (endometriosis-associated: Ibuprofen, 
Narcotic Analgesic) collected in the eDiary, separately for bleeding days, non-bleeding days and overall. 
Dysmenorrhea, Non-Menstrual Pelvic Pain and Analgesic use will be summarized as continuous variables 
The average duration of the two baseline menstrual cycles (days) will be summarized. The duration (days) 
of each of the two individual eligible baseline menstrual cycle will be calculated using the (menstrual start 
dates provided in the excel file. The duration is computed as (start date of Cyclex+1 – start date of cyclex). 
The average number of days with uterine bleeding over the two baseline menstrual cycles will be 
summarized as continuous variables. 
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 will be presented by treatment group 
and overall. Abnormality details will be provided in data listings. 
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) will be summarized.  
Dysmenorrhea, Deep Dyspareunia, Non Menstrual Pelvic Pain, Total Pelvic Pain (None: 0, Mild: 1-3, 
Moderate: 4-6, Severe: 7-9), Pelvic Tenderness, Induration, Total Physical Sign Score (None: 0, Mild: 1-2, 
Moderate: 3-4, Severe: 5-6) and Composite Pelvic pain and Physical Sign Score (None: 0, Mild: 1-2, 
Moderate: 3-5, Severe: 6-10, Very Severe 11-15) from the Modified Biberoglu & Behrman symptom 


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severity scale assessment as collected in eCRF will be summarized at baseline as categorical variables 
with the following categories: None, Mild, Moderate, Severe (Very Severe). 
Baseline Disease Characteristics will be reported in listings. 
4.5.3. Medical History 
Medical history 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 is 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 
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 of 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 
Efficacy analysis will be conducted using the Full Analysis Set. Primary and ranked secondary analyses will 
be repeated on the Per Protocol Set. 
4.6.1. Meaningful Change Threshold Estimation 
The analyses to estimate the meaningful change thresholds (MCTs) using the blinded interim data will be 
produced by an independent programming team and statistician to the Sponsor. Analysis datasets will 
be provided by Cytel. The external programming team will execute the analyses and the statistician will 
review and interpret the results and provide recommendations to the Sponsor for threshold estimation. 
Analyses to determine the MCTs will be described in a separate document. 
While the responder threshold analyses using these MCTs (see Section 4.6.2) will be conducted on all FAS 
subjects, the derivation of the MCTs for the co-primary endpoints was undertaken once patients had 
completed Month 3, using data up to Month 3 on the Threshold Analysis Set (FAS subjects with available 
anchor data). The derivation of the MCTs for the additional supportive responder analyses on the ranked 
secondary endpoints will be undertaken once patients have completed Month 6, using data up to Month 
6 on the M6 Threshold Analysis Set (FAS subjects with available anchor data at Month 6). For the specific 
mPGIS anchors, all subjects enrolled after Protocol Amendment V3.0 and collecting data using updated 


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e-Diary (expected to be approximately 50 subjects) with available anchor data at Baseline and Month 3 
(Month 6 for additional supportive responder analyses on the ranked secondary endpoints) are 
considered, as these specific mPGIS anchors were introduced as part of Amendment 3. For the generic 
mPGIS and PGIC anchors the analyses were (will be) performed on a random sample of 200 subjects with 
data for both anchors: mPGIS at Baseline and Month 3 (respectively Month 6 for ranked secondary 
endpoints) and mPGIC at Month 3 (respectively Month 6). The same random sample was (will be) used 
for PGIS and PGIC anchors. For the EHP-30 Pain Domain endpoint, the analyses will be repeated to 
confirm results using the remaining subjects (out of the selected sample of 200 subjects) from the study. 
As with the under treatment efficacy analysis, for subjects who discontinue treatment prior to Month 3 
(prior to Month 6 for ranked secondary endpoints), the 28 calendar days immediately prior to and 
including the last dose date will be used, along with the closest time-matched monthly anchor measures. 
SAS Code for Random Sample: 
proc surveyselect data=dataset out=sample method=srs sampsize=200 seed=12345; 
run; 
4.6.1.1. 
Responder Threshold Analysis  
Responder threshold analyses will be performed for the co-primary endpoints (See Section 4.6.2) and, as 
additional supportive analyses for the ranked secondary endpoints (see Sections  4.6.3.1 to 4.6.3.5) using 
the MCTs estimated from the blinded data.  
The final responder thresholds will be included in the final SAP prior to breaking the blind to the sponsor 
and main study team after Month 6. Based on the results from the Phase 2b Edelweiss study, it is 
expected that the responder threshold will be in the range of a 0.7 to 1.25 point reduction in pain in the 
4-point VRS for a 2-point improvement in anchor status and a 0.25 to 0.75 point reduction in pain in the 
4-point VRS for a 1-point improvement in anchor status. The numerical thresholds for DYS are expected 
to be larger than those for NMPP. No MCTs were estimated in Phase 2 for the other Phase 3 ranked 
secondary endpoints (overall pelvic pain, dyschezia, dyspareunia, EHP-30 pain domain). In Phase 3, 
additional anchor measures are included to estimate MCTs for these endpoints. 
 
Primary Efficacy Endpoints 
The two co-primary, composite, efficacy endpoints are reaching the responder threshold in 1) DYS and 
2) NMPP while having no accompanying increase in analgesics for EAP. These endpoints will be assessed 
at Month 3.  
For each of the co-primary endpoints, the criterion for defining a subject as a responder over the last 28 
days of randomized treatment up to the Month 3 visit will be a reduction of X (the MCT) or greater from 
baseline in pain. The threshold for response in the responder analysis (i.e., the value of X) will be chosen 
to represent a clinically meaningful reduction in pain and may not be the same for each endpoint (DYS 


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and NMPP). The obtained recommended values of X following meaningful change threshold estimation 
at Month 3 is reported in Section 4.6.1.3. 
 
Ranked Secondary Endpoints 
The six ranked secondary efficacy endpoints for which additional supportive responder analyses will be 
performed are reaching the MCT in 1) DYS, 2) NMPP, 3) dyschezia, 4) overall pelvic pain, 5) EHP-30 Pain 
domain, and 6) dyspareunia. These endpoints will be assessed at Month 6. 
For each of the additional supportive responder analyses for the ranked secondary efficacy endpoints, 
the criterion for defining a subject as a responder over the last 28 days of randomized treatment up to 
the Month 6 visit will be a reduction of X (the MCT) or greater from baseline. The threshold for 
response in the responder analysis (i.e., the value of X) will be chosen using data at Month 6, to 
represent a clinically meaningful reduction and may not be the same for each endpoint (DYS, NMPP, 
dyschezia, overall pelvic pain, EHP-30 Pain domain, dyspareunia). The MCT of DYS and NMPP may be 
different than those obtained at the Month 3 MCT analysis. The obtained recommended values of X 
following meaningful change threshold estimation at Month 6 is reported in Section 4.6.1.4. 
 
4.6.1.2. 
Estimation of Meaningful Change Threshold 
Anchor-based methods will be used to estimate the MCT for each co-primary and ranked secondary 
efficacy endpoint. Anchor-based methods are where an external criterion (anchor) is used to provide an 
indication of the minimal change in the PRO that is of (clinical) relevance. The anchor-based methods will 
include estimation of mean within-group change, with 95% confidence intervals (CIs), and receiver 
operating characteristic (ROC) curves to identify specific cut points. The MCT determination will also 
consider supportive information from cumulative distribution function (CDF) and probability distribution 
function (PDF) curves. Lastly, shift tables will be used, where appropriate, to examine the change in the 
endpoint by baseline and Month 3 (respectively Month 6 for ranked secondary endpoints) anchor score. 
Because linzagolix is expected to improve the symptoms of endometriosis, the MCT for each endpoint 
will indicate the amount of improvement in each endpoint which is perceived to indicate a meaningful 
change. The analyses will be conducted using blinded data from Edelweiss 3 that combine the data from 
all treatment arms including the Placebo arm and use change from Baseline to Month 3 for the co-primary 
endpoints and change from Baseline to Month 6 for the ranked secondary endpoints.  
Anchor-based methods are the preferred methods for estimating MCTs. An anchor is a reference 
measure that is used to determine change. The purpose of an anchor measure is to identify change on 
the target clinical outcome assessment (COA) measure that represents patient (or clinician) perceived 
improvement or deterioration. Any potential anchor should be less complex than the measure it is being 
used to assess. Anchors are expected to have a correlation coefficient of ⪆ 0.35 with the target COA 
measure to be used in the anchor-based analysis (Revicki et al. 2008). Correlation coefficients for Baseline 
scores and change from Baseline scores will be assessed to inform the suitability of the proposed anchor. 


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Potential anchor measures 
The following single-item measures were selected to be evaluated as possible anchors for the two co-
primary endpoints DYS and NMPP: monthly patient global impression of severity (mPGIS) items of DYS 
and NMPP, together with the non-specific mPGIS and patient global impression of change (PGIC) items 
of endometrial symptom severity (Table 5). The following single-item measures were selected to be 
evaluated as possible anchors for the ranked secondary efficacy endpoints (DYS, NMPP, dyschezia, overall 
pelvic pain, EHP-30 Pain domain, dyspareunia): mPGIS items of DYS, NMPP, dyschezia, overall pelvic pain, 
difficulty in daily activities, and dyspareunia, together with the non-specific mPGIS and patient global 
impression of change (PGIC) items of endometriosis symptom severity (Table 5). 
 
 


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Table 5 Proposed anchors for MCT estimation for each endpoint 
DYS 
NMPP 
Overall Pelvic 
Pain 
Dyschezia 
EHP-30 Pain 
domain 
Dyspareunia 
Endpoint (shaded = main study endpoints) 
Daily 0-3 VRS 
Daily 0-3 VRS 
Daily 0-10 NRS  
Daily 0-10 NRS 
Monthly 0-100 
Daily 0-3 VRS 
0 – No pain 
0 – No pain 
0 (No pelvic 
pain) to 10 
(Worst pain) 
NRS 
0 (No dyschezia 
pain) to 10 
(Worst pain) 
NRS 
EHP-30 Pain 
Domain score 
0 - No pain during sexual intercourse. 
1 – Mild 
1 – Mild 
1 - I was able to tolerate the pain during sexual intercourse. 
2 – Moderate 
2 – Moderate 
2 - Intercourse was interrupted due to pain.  
3 - Severe 
3 - Severe 
3 - I avoided sexual intercourse because of anticipation of pain 
Bleeding days 
Non-Bl days 
All days 
All days 
4-week recall 
All days 
Monthly anchors 
a) Specific anchors 
mPGIS 0-4 VRS 
menstrual PP 
mPGIS 0-4 VRS 
non-menstrual PP 
mPGIS 0-4 VRS 
Overall PP 
mPGIS 0-4 VRS 
Dyschezia 
mPGIS 0-4 VRS 
Difficulty activities 
mPGIS 0-4 VRS  
Dyspareunia 
0 – No pain 
0 – No pain 
0 – No pain 
0 – No pain 
0 – No difficulty 
0 – No symptoms 
1 - Very Mild 
1 - Very Mild 
1 - Very Mild 
1 - Very Mild 
1 – Slight 
1 - Tolerated discomfort during intercourse 
2 – Mild 
2 – Mild 
2 – Mild 
2 – Mild 
2 – Mild 
2 – Interference of usual frequency of sexual intercourse due 
to pain 
3 – Moderate 
3 – Moderate 
3 – Moderate 
3 – Moderate 
3 – Moderate 
3 – Avoids, or wishes to avoid, intercourse because of pain 
4 - Severe 
4 - Severe 
4 - Severe 
4 - Severe 
4 - Severe 
 
b) Generic anchors 
mPGIS 0-4 VRS  Endometriosis symptoms 
0 – No pain 


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1 - Very Mild 
2 – Mild 
3 – Moderate 
4 - Severe 
PGIC 7-pt VRS Endometriosis Symptoms 
-3 - Very much improved 
-2 - Much improved 
-1 - Minimally improved 
0 - No change 
1 - Minimally worse 
2 - Much worse 
3 - Very much worse 


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4.6.1.3. 
Results of Meaningful Change Threshold Analysis for the Co-Primary Endpoints 
Following the Meaningful Change Threshold analysis performed on soft locked data at Month 3, the 
recommendation for the final MCT estimates of the co-primary endpoints is the following: 
- 
Dysmenorrhea (VRS): X=-1.10 
- 
Non-Menstrual Pelvic Pain (VRS): X=-0.80 
The criterion for defining a subject as a responder over the last 28 days of randomized treatment up to 
Month 3 will be a reduction of 1.10 or greater from baseline pain for Dysmenorrhea; a reduction of 0.80 
or greater from baseline pain for Non-Menstrual Pelvic Pain. 
 
4.6.1.4. 
Results of Meaningful Change Threshold Analysis for the Ranked Secondary Endpoints 
Following the Meaningful Change Threshold analysis performed on Month 6 database lock, the 
recommendation for the final MCT estimates of the ranked secondary endpoints are the following: 
-  Dysmenorrhea (VRS): X=-1.25 
-  Non-Menstrual Pelvic Pain (VRS): X=-0.85 
-  Dyschezia (Numeric Rating Scale - NRS): X=-1.5 
- Overall pelvic pain (NRS): X=-2.7 
- EHP-30 pain domain: X=-28 
- Dyspareunia (VRS): X=-0.9 
 
The criterion for defining a subject as a responder over the last 28 days of randomized treatment up to 
Month 6 will be a reduction of 1.25 or greater from baseline pain for Dysmenorrhea; a reduction of 0.85 
or greater from baseline pain for Non-Menstrual Pelvic Pain; a reduction of 1.5 or greater from baseline 
pain for Dyschezia; a reduction of 2.7 or greater from baseline pain for Overall Pelvic Pain; a reduction of 
0.9 or greater from baseline pain for Dyspareunia. 
The criterion for defining a subject as a responder at Month 6 or discontinuation will be a reduction of 
28 or greater from baseline for EHP-30 pain. 
 
 


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4.6.2. Primary Efficacy Endpoint 
4.6.2.1. 
Primary Efficacy Analysis 
 
Primary Endpoint Specifications 
The primary efficacy analysis aims to estimate the effect of linzagolix versus placebo on DYS and NMPP 
over the last 28 days up to and including the Month 3 visit or, for subjects who discontinued randomized 
treatment prior to the Month 3 visit, over the last 28 days of randomized treatment. Use of analgesic 
medication for EAP will be included in the responder definitions. A responder for each of the co-primary 
endpoints needs to demonstrate both a reduction in pain (DYS or NMPP, depending on the endpoint) 
and a stable or decreased use of analgesics for EAP (assessed separately for DYS and NMPP). Any subject 
who does not meet both of these criteria will be defined as a non-responder. 
As detailed below, in line with ICH E9 (R1) addendum: four attributes (population, endpoint, treatment 
and population level summary) have been specified to translate the primary objective into treatment 
effect that is to be estimated (estimands): 
A. Population: Premenopausal women aged 18 to 49 years inclusive at screening, with surgically 
and, if available, histologically confirmed pelvic endometriosis and with moderate to severe EAP. 
B. Endpoint: The two co-primary, composite efficacy endpoints are clinically meaningful reduction 
from baseline to the last 28 days on randomized treatment, preceding the Month 3 visit or 
discontinuation, 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. 
C. Treatment: linzagolix administered orally once daily for up to 3 months at a dose of 75 mg alone 
or of 200 mg in combination with ABT, versus placebo 
D. Population-level summary: Odds-ratio of proportions of responders of linzagolix versus placebo 
from a logistic regression model for each co-primary endpoint, with treatment group as the main 
effect (three values) and including the baseline pain score as a covariate. 
Intercurrent events: Increased use of EAP analgesia is a non-response in the endpoint definition. 
Treatment discontinuations are assessed up to the time of discontinuation. Randomized treatment will 
be considered, regardless of lack of compliance to treatment or treatment assignment errors. The clinical 
question of interest is based on a while-on-treatment strategy for discontinuation and composite 
strategy for analgesic use. Lack of compliance to treatment and treatment assignment errors are handled 
using a treatment policy strategy. 
The “while-on-treatment strategy” was chosen for the intercurrent event of discontinuation of treatment 
for the co-primary endpoints based on the recommended strategies for addressing intercurrent events 
in the (then draft) ICH E9 (R1) guideline.   


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The response to treatment prior to the occurrence of the patient discontinuing treatment is of clinical 
interest for a symptomatic treatment of endometriosis-associated pain. Patients and prescribers are 
generally interested in what happens when a patient actually takes (and can take) the treatment. This 
corresponds most directly to the “while on treatment” strategy for treatment discontinuation. Of note, 
a comparison of patient disposition and discontinuation rates will also constitute an important aspect 
when interpreting the study results. In addition, a “while-on-treatment” strategy for efficacy aligns with 
the analysis of adverse events, which are also considered while on treatment. Moreover, as 
endometriosis-related pelvic pain is measured repeatedly each day, the variable can be readily calculated 
for the 28-day period up to the point of discontinuation and the value up to the time of discontinuation 
can be considered to account for the intercurrent event.  
For each of the co-primary endpoints, the criterion for defining a subject as a responder over the last 28 
days of randomized treatment up to the Month 3 visit will include a reduction of X or greater from 
baseline in pain, where X was determined by a meaningful change threshold estimation using appropriate 
anchors as described in Section 4.6.1, as well as stable or decreased use of analgesics for EAP. Results of 
the meaningful change threshold estimation for the primary endpoints are reported in Section 4.6.1.3.   
Mean pelvic pain scores for DYS and for NMPP will be calculated by averaging over the corresponding 28 
calendar days immediately prior to and including the day of the Month 3 visit. DYS will use days with 
uterine bleeding, defined as those days on which the subject records any uterine bleeding or spotting in 
the subject eDiary; NMPP will use days with no uterine bleeding. If a subject's mean score for DYS is 
undefined numerically because her daily eDiary reports indicate that she did not experience uterine 
bleeding on any days during the 28 calendar day period, then the mean score for DYS will be set equal to 
zero (which reflects the absence of any DYS during that reporting time period). Similarly, if a subject’s 
diary reports indicate that she only experienced days with uterine bleeding during the period, then the 
mean score for NMPP will be set equal to zero. For subjects who discontinue treatment prior to Month 
3, the last available observations prior to discontinuation will be used, in order to estimate the treatment 
effect while under treatment, that is the 28 calendar days immediately prior to and including the last 
dose date. The baseline mean overall pelvic pain scores for DYS and NMPP will be calculated by averaging 
over the two baseline menstrual cycles (as defined in section 4.2.10), which may not be exactly 28 days 
each. For both DYS and NMPP, responses of "None," "Mild," "Moderate," and "Severe" will be assigned 
a score of 0, 1, 2, and 3, respectively. 
For the assessment of stable or decreased use of analgesics for EAP (assessed separately for DYS and 
NMPP), the analgesic use for any defined period will be based on the mean of the total pill count for each 
class of rescue analgesics (endometriosis-associated). The total pill count for each class of rescue 
analgesic is the sum of the pill count of the corresponding class of rescue analgesic, as reported in the 
eDiary during the time period of interest.  Baseline analgesic use will be calculated as the mean of the 
daily pill count of analgesics over the two baseline menstrual cycles (as defined in section 4.5.2). For the 
purposes of determining a stable or decreased use of analgesics, the averaging will be done over the 
same calendar days as used for the pelvic pain scores (i.e. for DYS days with uterine bleeding, defined as 


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those days on which the subject records any uterine bleeding or spotting in the subject eDiary; for NMPP 
days with no uterine bleeding). The evaluation of stable or decreased use of analgesics will be done per 
the specification in 7.1 Appendix A.  
 
 
Primary Efficacy Analysis 
The primary efficacy analysis will be conducted using the FAS. 
The analysis of each co-primary endpoint will be conducted using a logistic regression model, with 
treatment group as the main effect (three values) and including the baseline pain score as a covariate. 
Individual linzagolix versus placebo treatment group comparisons will be made using the same logistic 
regression model. Estimated odds-ratios and 97.5% intervals of proportions of responders of linzagolix 
treatment groups versus placebo will be presented, along with Bonferroni corrected p-values. Estimates 
of proportions of responders with 95% confidence intervals will be presented as well, estimated at the 
overall mean baseline pain score. 
SAS Code (may be updated at analysis stage to fit the data): 
PROC LOGISTIC data=dataset order=internal; 
  Class treatment(ref=placebo) / param=glm ; 
  Model resp(event= “Yes”)= treatment base_pain /alpha=0.05; 
  Oddsratio treatment ; 
  Lsmeans treatment / ilink exp cl alpha=0.05 at means diffs=control(‘1’) 
adjust=bon; 
            Ods output OddsRatiosWald=or  ModelANOVA=ma ParameterEstimates=pe 
      lsmeans=lsm diffs=diffs; 
Run; 
In addition, the mean pelvic pain scores for DYS and NMPP and change from baseline for the last 28 days 
prior to Month 3 or the last 28 days of treatment (or less) for subjects who discontinued will be 
summarized as continuous variables by treatment group. Cumulative distribution functions (CDF) for 
change from baseline at Month 3 for DYS and NMPP will be provided, with separate lines for each 
treatment group. The x-axis will present the different values for the DYS or NMPP change from baseline, 
and the y-axis will present the proportion of subjects reaching each value of change. Vertical lines of the 
relevant MCT thresholds obtained at the Month 3 responder threshold analysis will be displayed on the 
plots.  
The number and percentage of subjects with: 
- 
Reduction of X for DYS, 
- 
Reduction of X for NMPP, 


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- 
Stable or decreased use of analgesics for EAP during bleeding days, during non-bleeding days, and 
overall,  
- 
Reduction of X for DYS and stable or decreased use of analgesics for EAP (during bleeding days), 
- 
Reduction of X for NMPP and stable or decreased use of analgesics for EAP (during non-bleeding 
days), 
will be presented. 
Subjects whose response cannot be assessed for the co-primary efficacy endpoints, e.g. due to lack of on 
treatment pain data (i.e. subjects who received less than 28 days of treatment), will be considered as 
non-responders. In addition, for outputs presenting the numeric change from baseline, such subject will 
be assigned a change from baseline of zero. It is expected that very few subjects will be affected by these 
rules. 
There may be missing data during the screening period and whilst under treatment, for example, missed 
days of completing the eDiary. The primary analyses will use observed data only in such cases, provided 
that a minimum number of completed daily eDiary entries are available. This effectively assumes that the 
individual values such as daily eDiary assessments (observed or not) are independent of being missing.  
Subjects who have less than the minimum number of days available will be excluded from the analysis. 
This is valid under the assumption that such data is MAR, conditional on the baseline value. 
The required minimum number of completed daily eDiary entries will be set to 12 days of each 28-day 
period (two Baseline menstrual cycles and the 28-day period prior to Month 3), i.e., 43% of non-missing 
assessments for the primary analysis,  consistent with the use of 3 days per week as the minimum number 
of completed diary entries as suggested in recent research ( (Griffiths & al, 2018), (Cappelleri & 
Bushmakin, Biopharmaceutical Report, 2020), (Cappelleri & Bushmakin, Biopharmaceutical Report, 
2021)). The analysis will be repeated using subjects with at least 75% (21 days) and 35% (10 days) of 
completed daily eDiaries for DYS, NMPP and analgesic use. 
  
4.6.2.2. 
Sensitivity Analyses 
• 
A Cochran-Mantel-Haenszel (CMH) test will be used to test the null hypothesis of no treatment 
effect at Month 3 for each linzagolix group vs. placebo with regards to the proportion of subjects 
with a response for DYS and NMPP. Odds ratios will be estimated from the CMH test together 
with the associated 97.5% confidence intervals (CIs) and corresponding Bonferroni corrected p-
values. The proportion per treatment arm will be displayed together with exact Clopper-Pearson 
95% CIs.  
PROC FREQ (SAS Institute) will be used for the statistical analysis.  
Sample SAS code (may be updated at analysis stage to fit the data): 


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Cochran-Mantel-Haenszel (CMH) test (to be performed pairwise). 
PROC FREQ data=dataset; 
  Tables Treatment*Response /CMH RELRISK RISKDIFF alpha=0.025; 
  Where treatment in (); 
  ods output riskdiffcol2=diff2 cmh=cmh commonrelrisks=cmrr;Run; 
 
data pvals_mult2 ; 
 
set cmh ; 
 
where ALTHYPOTHESIS="General Association" ; 
 
pval_vs_trt1=prob * 2 ; 
 
if pval_vs_trt1 > 1 then pval_vs_trt1 = 1; 
run; 
 
Note: Response is coded as 1 for responders and 0 for non-responders. 
• 
A sensitivity analysis will be performed, including in the definition of a responder any analgesic 
medication also taken for non-endometriosis associated pain. Information will be based on the 
concomitant medications collected in the eCRF during the two baseline menstrual cycles and the 
same calendar days as used for the assessment of pelvic pain (DYS and NMPP) for the 28 days 
prior to Month 3 visit.  
Concomitant medications in the study identified as analgesics and opioids will be reviewed and 
confirmed by the Sponsor and be provided in an excel file prior to Database Lock. These may 
include any medication with one of the following ATC codes from the WHO drug dictionary 
version March 2016: 
 
Table 6 List of ATC codes for analgesics and opioids 
ATC code 
Description 
 
A03D  
Antispasmodics 
in 
combination 
with 
analgesics 
A03EA  
Antispasmodics, psycholeptics and analgesics 
in combination 


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C03AH 
 Thiazides, combinations with psycholeptics 
and/or analgesics 
M01 
Anti-inflammatory and anti-rheumatic 
products 
M02 
Topical products for joint and muscular pain 
M03 
Muscle relaxants 
N02 
Analgesics 
N07BC 
 Drugs used in opioid dependence 
S02DA  
Analgesics and anesthetics 
Among those analgesic medications, all medications with Pharmacological Subgroup (3rd level of 
the ATC classification) equal to ‘OPIOIDS’ (ATC code = N02A) will be considered as opiate 
medications. Other analgesic medications will be considered as non-opiate medications. 
The increase/stable/decrease status of analgesic use will be defined in a blinded fashion case by 
case after review of the blinded data, and prior to Database Lock. 
Analyses described in Section 4.6.2.1.2 will be repeated using the new responder definition. 
4.6.2.3. 
Per Protocol Analysis 
The primary analysis as described in Section 4.6.2.1.2 will be repeated using the Per Protocol Set. 
 
4.6.2.4. 
Subgroup analysis 
The primary analysis model and descriptive statistics as described in Section 4.6.2.1.2 will be repeated 
for each co-primary endpoint by subgroups as specified in Section 4.2.6.  
 
4.6.3. Ranked Secondary Efficacy Endpoints 
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. As with the primary 
analysis, individual linzagolix versus placebo treatment groups comparisons will be made. 


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In general, between-group comparisons for continuous endpoints will be analyzed via analysis of (co)-
variance. Between-group comparisons for binary endpoints will be analyzed via logistic regression. 
Between-group comparisons for ordinal categorical data will be analyzed using a Mantel-Haenszel test 
or using Koch’s method when there is also a baseline covariate.  
As described in section 4.2.5, the ranked secondary endpoints will follow a fixed-sequence testing 
strategy within the group, so as to maintain the family-wise type I error rate. 
For endpoints based on daily ediary data, analyses will use observed data only in such cases, provided 
that a minimum number of 43% (at least 12 days of each 28-day period) completed daily eDiary entries 
are available. Subjects who have less than the minimum number of days available will be excluded from 
the analysis. This is valid under the assumption that such data is MAR, conditional on the baseline value. 
 
4.6.3.1. 
Change from baseline to Month 6 in DYS (VRS) and in NMPP (VRS) 
Mean pelvic pain scores for DYS and for NMPP for each subject will be calculated in the same way as for 
the primary endpoints. The change from baseline to Month 6 (the last 28 days of randomized treatment 
up to the Month 6 visit, defined as the last 28 days prior to and including the last treatment 
administration date as defined in Section 4.2.11, or the 28 calendar days immediately prior to and 
including the last dose date for subjects who discontinue treatment prior to Month 6) in DYS using the 
VRS, and the change from baseline to Month 6 (the last 28 days of randomized treatment up to the Month 
6 visit, defined as the last 28 days prior to and including last treatment administration date as defined in 
Section 4.2.11 or the 28 calendar days immediately prior to and including the last dose date for subjects 
who discontinue treatment prior to Month 6) in NMPP using the VRS, will be analyzed via analysis of 
covariance with treatment group as the main effect (three values) and including the baseline pain score 
as a covariate. The mean pelvic pain scores for DYS and NMPP and change from baseline will also be 
descriptively summarized. 
SAS Code (may be updated at analysis stage to fit the data): Analysis of covariance 
proc GLM data=dataset order=internal ; 
class treatment; 
model chg = base_pain treatment; 
lsmeans treatment / pdiff = control('1') cl alpha=0.05 at means 
adjust=bon; 
ods output lsmeans = lsm diff=pvals lsmeancl=lsmeancl 
lsmeandiffcl=lsmeandiffcl;  * contains the adjusted means; 
run; 


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The number and percentage of subjects with a reduction of X from baseline to Month 6 for DYS, with a 
reduction of X from baseline to Month 6 for NMPP will be presented. The reduction will be defined in a 
similar way as for the primary endpoint, but for the Month 6 timepoint. The value for the threshold X will 
be obtained from the MCT analysis based on blinded Month 6 data (X can be different for DYS and NMPP). 
4.6.3.2. 
Change from baseline to Month 6 in dyschezia (Numeric Rating Scale - NRS) 
Mean dyschezia scores for each subject will be calculated by averaging over the corresponding 28 
calendar days immediately prior to and including the day of the last treatment administration as defined 
in Section 4.2.11 (or the 28 calendar days immediately prior to and including the last dose date for 
subjects who discontinue treatment prior to Month 6). The baseline mean dyschezia score will be 
calculated by averaging scores over the two baseline menstrual cycles. The change from baseline to 
Month 6 in dyschezia using the NRS will be analyzed via analysis of covariance with treatment group as 
the main effect (three values) and including the baseline pain score as a covariate. The mean dyschezia 
score and change from baseline will be descriptively summarized as well. 
The number and percentage of subjects with a reduction of X from baseline to Month 6 for dyschezia will 
be presented. The reduction will be defined in a similar way as for the primary endpoint, but using 
dyschezia scores at the Month 6 timepoint. The value for the threshold X will be obtained from the MCT 
analysis based on blinded Month 6 data. 
4.6.3.3. 
Change from baseline to Month 6 in overall pelvic pain (NRS) 
The change from baseline to Month 6 (the last 28 days of randomized treatment up to the Month 6 visit, 
defined as the last 28 days prior to and including last treatment administration date as defined in Section 
4.2.11 or the 28 calendar days immediately prior to and including the last dose date for subjects who 
discontinue treatment prior to Month 6) in overall pelvic pain using the NRS will be analyzed the same 
way as for dyschezia as described in Section 4.6.3.2. The baseline will be computed as the mean of the 
overall pelvic pain score over the two baseline menstrual cycles. 
The number and percentage of subjects with a reduction of X from baseline to Month 6 for Overall Pelvic 
Pain will be presented. The reduction will be defined in a similar way as for the primary endpoint, but for 
Overall Pelvic Pain score at the Month 6 timepoint. The value for the threshold X will be obtained from 
the MCT analysis based on blinded Month 6 data. 
 
4.6.3.4. 
Change from baseline to Month 6 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)  
The EHP-30 pain dimension consists of 11 items each addressing the effect of pain on various activities 
and each assessed on a 5-point scale (0=Never through to 4=Always). The EHP-30 Pain Impact Domain 
comprises the following items: 


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During the last 4 weeks, because of your endometriosis, how often have you... 
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? 
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? 
This endpoint shall be scored as per the Appendix B in Section 7.2, resulting in a score on a scale from 0 
(best possible health status) to 100 (worst possible health status). The score will be computed as the sum 
of raw scores of each item (ranging from 0 to 4) divided by the maximum possible raw score (11*4), 
multiplied by 100.  The change from baseline to Month 6 (the last 28 days of randomized treatment up 
to the Month 6 visit) in ability to perform daily activities, measured using the pain dimension of the EHP-
30 will be analyzed via analysis of covariance with treatment group as the main effect (three values) and 
including the baseline value as a covariate. EHP-30 score at baseline and Month 6 and change from 
baseline will also be descriptively summarized. 
The number and percentage of subjects with a reduction of X from baseline to Month 6 for the EHP-30 
Pain Dimension score will be presented. The value for the threshold X will be obtained from the MCT 
analysis based on blinded Month 6 data. 
 
4.6.3.5. 
Change from baseline to Month 6 in dyspareunia (VRS) 
Responses to the daily dyspareunia questions will be scored as follows. Responses on days where the 
subject was not sexually active for reasons other than their endometriosis will not be included in the 
analysis. 
 
Response 
Score 
No pain during sexual intercourse. 
0 


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I was able to tolerate the pain during sexual intercourse. 
1 
Intercourse was interrupted due to pain.  
2 
I avoided sexual intercourse because of anticipation of pain.  3 
 
Mean dyspareunia scores for each subject will be calculated by averaging over the corresponding days 
during the 28 calendar days immediately prior to and including the last treatment administration date as 
defined in Section 4.2.11 (or the 28 calendar days immediately prior to and including the last dose date 
for subjects who discontinue treatment prior to Month 6). The baseline mean dyspareunia score will be 
calculated by averaging scores over the two baseline menstrual cycles.  
Dyspareunia scores will be summarized using the FAS and for the subgroup of subjects who have a mean 
dyspareunia score > 1 at baseline. The statistical analysis of dyspareunia will only use the sub-group of 
subjects in order to estimate the effect of treatment on such subjects. It is anticipated that this will be 
around 60% to 70% of the randomized subjects. This is a baseline assessment and does not influence the 
blinded, randomized treatment group. As per section 4.2.5, the type I error is maintained due to using 
fixed-sequence testing strategy. The change from baseline to Month 6 in dyspareunia will be analyzed 
via analysis of covariance with treatment group as the main effect (three values) and including the 
baseline value as a covariate. 
The number and percentage of subjects with a reduction of X from baseline to Month 6 for Dyspareunia 
will be presented. The reduction will be defined in a similar way as for the primary endpoint, but for 
Dyspareunia score and for the Month 6. The value for the threshold X will be obtained from the MCT 
analysis based on blinded Month 6 data. 
 
4.6.3.6. 
No analgesic use / no opiate use for EAP during the preceding 4-week period at Month 6 
The analysis of the proportion of subjects reporting no analgesic use for EAP, and the proportion of 
subjects reporting no opiate use for EAP during the preceding 4-week period at Month 6 (last 28 days 
prior to and including last treatment administration date) will be conducted using a logistic regression 
model, with treatment group as the main effect (three values). 
In addition to analgesic use for EAP as collected in the eDiary, concomitant medications in the study will 
be reviewed and medications to be considered as analgesic use for endometriosis associated pain will be 
confirmed by the Sponsor and be provided in an excel file prior to Database Lock. They may include any 


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medication with the ATC codes from WHO drug dictionary version March 2016 as listed in Table 6 in 
Section 4.6.2.2. 
In addition to analyzing the absence of analgesic use for EAP, the amount used for each 4-week period 
up to Month 6 will be summarized as a continuous variable, including the change from baseline. This 
analysis will be based on e-diary data only, as subjects did not record opioid intake in the concomitant 
medication page on a tablet-by-tablet basis.  
As it is likely that more than one opioid will be used (opioid analgesic may be different depending on 
countries), the amount of opioid used will be converted to morphine milligram equivalents (MME) in 
order to better quantify the actual amount of opioids used by subjects.  
For countries (Spain, Hungary, France, Czech Republic) where several opioids with different MME were 
allowed, the data collected in the e-diary is not sufficient to determine exactly which opioid was used 
and what the MME is. The MME will be derived as the average of possible MME of the allowed opioids 
in the country.  
No opioids are allowed in Ukraine. Subjects from Ukraine will therefore be excluded from the summary 
in MME. If some opioids are nevertheless recorded for subjects from Ukraine, they will not be considered 
for the summary in MME, as the conversion in MME would be unknown. Those opioids records will 
however be considered for other analgesic use analyses not requiring conversion in MME. 
The baseline amount of analgesic used will be computed by averaging the amount used during the two 
baseline menstrual cycles. 
Conversion to MME by country is described in Table 7. 
Table 7 Morphine Milligram Equivalents for Narcotic Analgesics 
Country 
Permitted rescue analgesic: Narcotic 
analgesic local equivalent 
Conversion in morphine milligram
equivalents 
Austria 
tramadol 37.5mg + paracetamol 
325mg  
3.75 MME 
Bulgaria 
tramadol 37.5mg + paracetamol 
325mg 
3.75 MME 
Czech Republic 
codeine 30mg 
4.125 MME 


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paracetamol 500 mg+ codeine 30 mg 
tramadol 37.5mg + paracetamol 
325mg 
France 
paracetamol 500 mg+ codeine 30 mg 
tramadol 37.5mg + paracetamol 
325mg 
4.125 MME 
Hungary 
paracetamol 500 mg+ codeine 30 mg 
codeine 30mg 
tramadol 37.5mg + paracetamol 
325mg 
4.125 MME 
Poland 
tramadol 37.5mg + paracetamol 
325mg 
3.75 MME 
Romania 
codeine 30mg 
paracetamol 500 mg+ codeine 30 mg 
4.5 MME 
Spain 
paracetamol 500 mg+ codeine 30 mg  
tramadol 37.5mg + paracetamol 
325mg 
4.125 MME 
Ukraine 
No Narcotic Analgesic allowed 
US 
5 mg hydrocodone + 300 mg 
acetaminophen 
5 MME 
 
 


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4.6.4. Additional Secondary Endpoints 
All additional efficacy endpoints will be summarized by descriptive statistics for each treatment group, 
for each time point, including summaries of change from baseline when applicable. Individual linzagolix 
versus placebo treatment group comparisons will be made. 
In general, between group comparisons for continuous endpoints will be analyzed via analysis of (co)-
variance. Between-group comparisons for binary endpoints will be analyzed via logistic regression. 
Between-group comparisons for ordinal categorical data will be analyzed using a Mantel-Haenszel test, 
or using Koch’s method when there is also a baseline covariate.  
As described in section 4.2.5 additional secondary endpoints will use Bonferroni correction for p-values 
of comparison of treatment groups at each visit. The analyses do not form part of the fixed-sequence 
strategy being used for the ranked secondary endpoints and will not be fully controlled for an overall 
type I error rate. 
Values for all endpoints that are collected daily using the eDiary (from Section 4.6.4.1 to Section 4.6.4.18) 
will be based on the 28 calendar days immediately prior to and including the day of the corresponding 
visit or prior to and including the last treatment administration date for Month 6, or the 28 calendar days 
immediately prior to and including the last dose date for subjects who discontinue treatment prior to the 
visit in question (or fewer if treatment is stopped less than 4 weeks after first dose date), in order to 
estimate the treatment effect while under treatment. The last 28 days on treatment will be used at all 
subsequent scheduled visits for those discontinued subjects. Descriptive summaries for each 28-day 
period will be performed in two ways however:  
- 
Once including only values of 28 days prior to Month X, i.e. using the last 28 days prior to Month X 
eCRF visit date for subjects who have not discontinued up to that month. If subjects discontinued 
prior to Month X the corresponding value will be missing from the summary at Month X; 
- 
Once applying the while on treatment strategy, i.e. using the last 28 days prior to Month X eCRF visit 
date for subjects who have not discontinued up to that month, and for subjects who discontinued 
prior to Month X, the last 28 days prior to treatment discontinuation will be used. For all subsequent 
timepoints (Month X+1, etc.) the same last 28 days prior to treatment discontinuation will be used.  
Corresponding baseline values will be calculated based on the two baseline menstrual cycles, which may 
not be exactly 28 days each. 
The values for other endpoints (monthly and 3-monthly questionnaires from Section 4.6.4.19 to Section 
4.6.4.26) are defined as the value at the corresponding visit or value falling into the corresponding visit 
window as described in section 4.2.9. For these other endpoints, descriptive summaries by visit will be 


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performed in two ways, once including values at the corresponding visit or value falling into the 
corresponding visit window as described in section 4.2.9, and once applying the while on treatment 
strategy, i.e., including values from the discontinued visits at each next scheduled visit. 
For endpoints based on daily diary data, analyses will use observed data only in such cases, provided that 
a minimum number of 43% (at least 12 days of each 28-day period) completed daily eDiary entries are 
available.  
4.6.4.1. 
Clinically meaningful reduction at scheduled visits other than Month 3 for DYS and NMPP  
The proportion of responders for DYS and NMPP based on daily e-diary data will be reported at each visit 
(each 28 days period) along with odds-ratio and 97.5% confidence intervals from logistic regression as 
described in Section 4.6.2.1.2.   
The same responder definition defined for primary endpoint in Section 4.6.2.1.1 will be used, but for 
other scheduled visits. 
Due to the war situation in Ukraine, data from subjects in Ukraine sites may be incomplete, missing or 
uncleaned. The descriptive analysis of proportion of responders for DYS and NMPP at each visit will be 
repeated, excluding data collected after 24FEB2022 for subjects from Ukraine sites, for the Follow-up 
period only (Follow-up set), as the main treatment period was completed before the start of the war. 
Listings will contain country information to identify those subjects. 
 
4.6.4.2. 
Change from baseline to each scheduled assessment in mean pelvic pain scores for DYS, 
NMPP and overall pelvic pain, during the previous 4-week period assessed on the NRS and 
VRS 
The change from baseline to each scheduled assessment in mean pelvic pain scores for DYS, NMPP and 
overall pelvic pain will be analyzed as described for the ranked secondary endpoint in Section 4.6.3.1 
(continuous summary and analysis of covariance at each visit).   
 
4.6.4.3. 
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 
The actual value and change from baseline of number of days with moderate or severe pelvic pain 
collected in the e-diary on the VRS will be summarized for each 28-day period. The baseline value will be 
computed by averaging the number of days with moderate or severe pelvic pain of the two baseline 
menstrual cycles. The number of days will be analyzed with a negative binomial model including baseline 


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as a covariate. The estimated least square means treatment differences along with 97.5% CI will be 
provided. 
SAS Code for negative binomial model with repeated measurements 
 
proc genmod data=dataset order=internal ; 
class treatment; 
model nbdays =  baseline treatment / dist=negbin type3 ; 
 
 
 
lsmeans treatment / diff = control('1') exp at means cl alpha=0.05  
adjust=bon; 
estimate 'TRT Placebo' intercept 1 base %sysevalf(&meanbase.) trt01pn 1 0 0 / 
exp E; 
estimate 'TRT LGX 75'  intercept 1 base %sysevalf(&meanbase.) trt01pn 0 1 0  / 
exp E; 
estimate 'TRT LGX 200'  intercept 1 base %sysevalf(&meanbase.) trt01pn 0 0 1  
/ exp E; 
 
ods output lsmeans=lsm diffs=lsmd Estimates=estimate   ; 
run; 
“meanbase” macro variable is the mean value of baseline over the same selection of subjects used in 
the model  
 
4.6.4.4. 
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 
The actual value and change from baseline of the mean worst pelvic pain score, defined as the mean of 
the 5 highest daily pain scores reported during each 28-day period will be summarized for each 28-day 
period. The baseline mean worst pelvic pain score will be the average of the mean pelvic pain score of 
each of the two baseline menstrual cycles. An analysis of covariance will be performed for each period. 
If less than 5 days of pain score data is available, the mean worst pelvic pain will be defined as the mean 
of the available daily pain scores.  
 
4.6.4.5. 
Change from baseline to each scheduled assessment in mean daily dyspareunia scores 


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reported during the previous 4-week period on the dyspareunia VRS  
The actual value and change from baseline in mean daily dyspareunia scores will be summarized as a 
continuous variable for each 28-day period. An analysis of covariance will be performed for each 
period. 
Subjects not sexually active for reasons other than endometriosis will have missing values for the 
corresponding 4-week periods. Subjects not sexually active for reasons other than endometriosis at 
baseline will be excluded from the analysis. 
 
4.6.4.6. 
Change from baseline to each scheduled assessment in mean daily dyschezia scores 
reported during the previous 4-week period assessed on the dyschezia NRS 
The actual value and change from baseline in mean daily dyschezia scores will be summarized as a 
continuous variable for each 28-day period. An analysis of covariance will be performed for each 
period. 
 
4.6.4.7. 
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 
Non-opioid, opioid and combined analgesic use for EAP will be measured using the mean of daily pill 
count collected in the eDiary over each 28-day period. For non-opioid and combined analgesic use, 
descriptive summary (actual values and changes from baseline) and analysis of covariance for each period 
will be performed. Due to a low number of subjects using any opioids, opioids use will not be analyzed 
as a continuous variable, only a listing with by subject opioid use mean daily pill count will be provided. 
The number and percentage of subjects reporting no analgesic use for EAP, and the proportion of subjects 
reporting no opiate use for EAP at baseline and during the preceding 4-week period at Month 3 (last 28 
days prior to and including last treatment administration date) will be presented. The proportion of 
subjects with no analgesic use for EAP, and with no opiate use for EAP will be conducted using a logistic 
regression model, with treatment group as the main effect. For these proportions, in addition to eDiary 
analgesic use, data from the concomitant medication page will be used, as described in Section 4.6.3.6. 
 
4.6.4.8. 
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 


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equivalent (MME) 
Opioid analgesic use for EAP will also be assessed based on morphine milligram equivalent (MME). The 
mean daily amount for each 28-day period reported in eDiary as pill count will be converted in MME. 
No opioids are allowed in Ukraine. Subjects from Ukraine will therefore be excluded from the analysis in 
MME. If some opioids are nevertheless recorded for subjects from Ukraine, they will not be considered, 
as the conversion in MME would be unknown. Those opioids records will however be considered for 
other analgesic use analyses not requiring conversion in MME. 
Due to a low number of subjects using any opioids, opioids use will not be analyzed, only a listing with by 
subject mean daily opioid use in MME will be provided. 
 
4.6.4.9. 
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 
The actual value and change from baseline in the number of days with analgesic use for EAP collected in 
the e-diary will be summarized for each 28-day period. The number of days will be analyzed using a 
negative binomial model, including baseline as a covariate The estimated least square means treatment 
differences along with 97.5% CI will be provided. The baseline value will be computed by averaging the 
number of days with analgesic use of the two baseline menstrual cycles. 
 
4.6.4.10. 
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 
The actual value and change from baseline in the number of days with opioid analgesic use for EAP 
collected in the e-diary will be calculated for each 28-day period. The baseline value will be computed by 
averaging the number of days with opioid analgesic use of the two baseline menstrual cycles. 
Due to a low number of subjects using any opioids, number of days with opioid analgesic use will not be 
analyzed, only a by subject listing will be provided. 
 
4.6.4.11. 
Change from baseline to each scheduled assessment in the number of pelvic pain-free days 


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(assessed on the VRS) during the previous 4-week period  
The actual value and change from baseline of number of pelvic pain-free days collected in the e-diary will 
be summarized for each 28-day period. The number of days will be analyzed with a negative binomial 
model, including baseline as a covariate. The estimated least square means treatment differences along 
with 97.5% CI will be provided. The baseline value will be computed by averaging the number of pelvic 
pain-free days of the two baseline menstrual cycles. 
 
4.6.4.12. 
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) 
Daily activities score for each subject will be calculated by averaging over the corresponding 28 calendar 
days immediately prior to and including the day each visit (or the 28 calendar days immediately prior to 
and including the last dose date for subjects who discontinue treatment prior to Month 6). The baseline 
mean of daily activities score will be calculated by averaging over the two baseline menstrual cycles. The 
actual value and change from baseline of daily activities score will be summarized as a continuous 
variable and change from baseline for each 28-day period will be evaluated using analysis of covariance. 
 
4.6.4.13. 
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) 
The actual value and change from baseline of number of days with no difficulty in doing daily activities 
due to EAP collected in the e-diary will be summarized for each 28-day period. The number of days will 
be analyzed with a negative binomial model, including baseline as a covariate. The estimated least square 
means treatment differences along with 97.5% CI will be provided. The baseline value will be computed 
by averaging the number of days of the two baseline menstrual cycles. 
 
4.6.4.14. 
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 
The actual value and change from baseline of number of days with answer to Sexual Intercourse in the 
last 24H questionnaire is “Intercourse was interrupted due to pain” or “No, I avoided sexual intercourse 
because of anticipation of pain” collected in the e-diary will be summarized for each 28-day period. The 
number of days will be analyzed with a negative binomial model, including baseline as a covariate. The 


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estimated least square means treatment differences along with 97.5% CI will be provided. The baseline 
value will be computed by averaging the number of days of the two baseline menstrual cycles. 
 
4.6.4.15. 
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 
The actual value and change from baseline in the number of days with answer to Sexual Intercourse in 
the last 24H questionnaire is “No, I avoided sexual intercourse because of anticipation of pain” collected 
in the e-diary will be summarized for each 28-day period. The number of days will be analyzed with a 
negative binomial model, including baseline as a covariate. The estimated least square means treatment 
differences along with 97.5% CI will be provided. The baseline value will be computed by averaging the 
number of days of the two baseline menstrual cycles. 
In addition, the proportion of days when sexual intercourse was avoided because of anticipation of pain 
will be also summarized for actual values and changes from baseline.  
The proportion is defined as:  
Number of days when sexual intercourse was avoided because of anticipation of pain/ (Number 
of days in period – Number of days with missing data – Number of days with no sexual intercourse 
for other reasons)  
The number of days in each period will be equal to 28, except at baseline, for which it will be the number 
of days in each baseline menstrual cycle. 
 
4.6.4.16. 
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 
The actual value and change from baseline in the number of days with uterine bleeding (“Bleeding”, 
“Spotting”, “Heavy Bleeding”) collected in the e-diary will be summarized for each 28-day period. The 
number of days will be analyzed with a negative binomial model, including baseline as a covariate. The 
estimated least square means treatment differences along with 97.5% CI will be provided. The baseline 
value will be computed by averaging the number of days with uterine bleeding during the two baseline 
menstrual cycles. 
 


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4.6.4.17. 
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 
The actual value and change from baseline in the number of days when school or work was missed due 
to EAP as collected in the e-diary will be summarized for each 28-day period. The number of days will be 
analyzed with a negative binomial model, including baseline as a covariate. The estimated least square 
means treatment differences along with 97.5% CI will be provided. The baseline value will be computed 
by averaging the number of days during the two baseline menstrual cycles when school or work was 
missed due to EAP. 
 
4.6.4.18. 
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 
The actual value and change from baseline in the number of days when the subject had to go to bed or 
lie down due to EAP as collected in the e-diary will be summarized for each 28-day period. The number 
of days will be analyzed using a negative binomial model, including baseline value as a covariate. The 
estimated least square means treatment differences along with 97.5% CI will be provided. The baseline 
value will be computed by averaging the number of days during the two baseline menstrual cycles when 
the subject had to go to bed or lie down due to EAP. 
 
4.6.4.19. 
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 
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 D of protocol. 
The questionnaire is composed of five scales and of the sexual relationship scale in the modular part: 
- 
Pain (Questions 1-11): See Section 4.6.3.4 for items included in Pain dimension 
- 
Control and powerlessness (Questions 12-17): 
o Generally felt unwell? 
o Felt frustrated because your symptoms are not getting better? 
o Felt frustrated because you are not able to control your symptoms? 


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o Felt unable to forget your symptoms? 
o Felt as though your symptoms are ruling your life? 
o Felt your symptoms are taking away your life? 
- 
Social support (Questions 24-27): 
o Felt unable to tell others how you feel? 
o Felt others do not understand what you are going through? 
o Felt as though others think you are whining? 
o Felt alone? 
- 
Emotional well-being (Questions 18-23): 
o Felt depressed? 
o Felt weepy/tearful? 
o Felt miserable? 
o Had mood swings? 
o Felt bad-tempered or short-tempered? 
o Felt violent or aggressive? 
- 
Self-image (Questions 28-30): 
o Felt frustrated that you cannot always wear the clothes you would choose? 
o Felt your appearance has been affected? 
o Lacked confidence? 
- 
Modular sexual relationship questionnaire 
Refer to Appendix B in Section 7.2 for scoring. Each scale is standardised on a scale of 0 – 100, where 0 
indicates the best health status and 100 the worst health status. Scale scores for each scale are calculated 
from the total of the raw scores of each item in the scale divided by the maximum possible raw score of 
all the items in the scale, multiplied by 100.   
Each item of each scale will be summarized by category at each visit (Day 1, Month 1, Month 3, Month 
6). The actual value and change from baseline of each scale score will be summarized as a continuous 
variable. 
Each scale score will be analyzed at each visit using an analysis of covariance. 
 
4.6.4.20. 
Change from baseline to each scheduled assessment in the Health-Related Productivity 


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Questionnaire (HRPQ) scores 
The Health-Related Productivity Questionnaire (HRPQ) is a validated, 9-item, self-reported questionnaire 
that has been used to evaluate health-related productivity. 
The HRPQ includes items on employment status; effect of health issues or treatment on working 
scheduled hours (absenteeism); effect of health issues or their treatment on work output (presenteeism); 
effect of health issues or their treatment on planned hours of household chores; effect of health issues 
or their treatment impact work output for household chores actually performed; how long since health 
issues developed; and effect of health issues on life. 
The questionnaire follows a skip pattern so that subjects can answer only the items applicable to them 
according to whether they work outside the home (eg, full- or part-time employment). Two subject 
groups are defined: employed and household (employed and not employed, combined). 
See Appendix C in Section 7.3 for HRPQ Scoring. 
 At Day 1, the following will be summarized: 
- 
Employment status,  
- 
Time since symptoms developed,  
- 
Number of subjects and time for which Endometriosis symptoms or its treatment(s) forced to work 
part-time when wanted to work full-time, 
- 
Number of subjects and time for which Endometriosis symptoms or its treatment(s) kept from having 
a job when wanted to work full-time, 
- 
Number of subjects and time for which Endometriosis symptoms or its treatment(s) kept from having 
a job when wanted to work part-time. 
The following scores (actual values and changes from baseline) will be summarized at each visit (Day 1, 
Month 1, Month 2, Month 3, Month 4, Month 5, Month 6): 
- 
For “Employed” group: 
o Number of hours of work lost due to absenteeism (“How many hours of work did you miss 
because of illnesses/treatments the last week?”)  
o Number of hours of work lost due to presenteeism (“For the hours that you did work during 
the past week, how did illnesses/treatments impact your work output?”) 
o Total number of hours of work lost 
o Percent of scheduled work lost due to absenteeism (Number of hours lost/Number of 
scheduled hours*100) 


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o Percent of scheduled work lost due to presenteeism (Number of hours lost/Number of 
scheduled hours*100) 
o Percent of scheduled work lost in total (Number of hours lost/Number of scheduled 
hours*100) 
- 
For “Household” group: 
o Number of hours household work lost due to absenteeism (“How many hours of work did 
you miss because of illnesses/treatments the last week?”) 
o Number of hours household work lost due to presenteeism (“For the hours of household 
chores that you did during the past week, how did illnesses/treatments impact your work 
output?”) 
o Total number of hours of household work lost 
o Percent of scheduled household work lost due to absenteeism (Number of hours 
lost/Number of scheduled hours*100) 
o Percent of scheduled household work lost due to presenteeism (Number of hours 
lost/Number of scheduled hours*100) 
o Percent of scheduled household work lost in total (Number of hours lost/Number of 
scheduled hours*100) 
The 
change 
from 
baseline 
in 
the 
percentage 
of 
scheduled 
work 
lost 
due 
to 
absenteeism/presenteeism/total for employed and household groups will be analyzed with an analysis 
of covariance.  
 
4.6.4.21. 
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 
The number of non-study endometriosis related health visits, number of subjects by type of 
clinician/clinic visit, number of subjects by type of therapeutic procedures, and number of nights spent 
in hospital will be summarized at each visit (Day 1, Month 1, Month 2, Month 3, Month 4, Month 5, 
Month 6). In case of many clinician/clinic types and therapeutic procedures, types may be regrouped for 
the descriptive summaries. 
The change from baseline of number of non-study endometriosis related health visits and number of 
nights in hospital will be analyzed with a negative binomial model, including baseline as a covariate. The 
estimated least square means treatment differences along with 97.5% CI will be provided. 
 


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4.6.4.22. 
Change from baseline to each scheduled assessment in the Physician/Subject Surgery 
Intention Question (PSIQ/SSIQ) 
The PSIQ/SSIQ answers will be summarized as continuous at Day 1 and Month 6. Comparison between 
treatment arms at Month 6 will be done using analysis of covariance.  
 
4.6.4.23. 
Change from baseline to each scheduled assessment in the PROMIS Fatigue – Short Form 
6a 
The PROMIS Fatigue Short Form 6a is composed of 6 items on 5-point scales (1-5). The total score is 
measured as the sum of answers of each item and will range from 6 to 30. The higher the total score, the 
more severe the symptom. Missing data will not be imputed. 
Each item will be summarized by category at each visit (Day 1, Month 1, Month 3, Month 6). The total 
score will be summarized as a continuous variable. 
An analysis of covariance will be performed on the total score. 
 
4.6.4.24. 
Change from baseline to each scheduled assessment in the EuroQoL 5-Dimension 5-Level 
(EQ-5D-5L) questionnaire 
The EuroQoL 5-dimension questionnaire (EQ-5D) is a self-administered, generic utility instrument 
developed by the EuroQoL Group in 1990. The EQ-5D consists of 2 parts, a descriptive system of 5 
dimensions and a 20-cm vertical visual analogue scale (VAS) with endpoints 0 and 100. It is collected by 
the subject in the eDiary at Day 1, Month 1, Month 3, Month 6. 
The descriptive system includes five single-item dimensions: mobility, self-care, usual activities, 
pain/discomfort, and anxiety/depression. Subjects must choose between five levels of difficulty (from 1 
to 5) in accomplishing tasks in each dimension. The health states will be described in terms of five-digit 
numbers based on the answers to each of the five questions. The states will then be converted to a single 
index score using the TTO (Time Trade-Off) method. The TTO method has been chosen since this is the 
only one available for the United States (US) and also because for economic studies where cost utility 
analysis is anticipated, most health economists are recommending a value set that has been derived using 
a choice-based method. An index score based on the individual dimensions will be calculated using a 
scoring algorithm (see Reference document EQ-5D-5L_UserGuide_2015.pdf) and the US Index from 
Crosswalk value set downloaded from the EuroQol website.  


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In the present study, the available US-specific scoring will be used (see Appendix D in Section 7.4. how to 
compute EQ-5D-5L crosswalk index values with SAS using the United States value set as an example).  
Answers to each dimension will be summarized by category at each visit. The index value and VAS Score 
will be summarized as continuous variables (actual values and changes from baseline). Index value and 
VAS Score will be analyzed via an analysis of covariance  
 
4.6.4.25. 
Response at each scheduled assessment according to Patient Global Impression of Change 
(PGIC) (and Post-treatment Patient Global Impression of Change, PPGIC) 
Responses to the Patient Global Impression of Change questionnaire range from 0- Very much worse to 
6-Very much improved. Responses will be summarized by category at each visit (Month 1, Month 2, 
Month 3, Month 4, Month 5, Month 6). A generalized linear model analysis for ordinal data will be 
performed. Odds-ratio and 97.5% confidence intervals estimates of having higher ordered responses 
categories, of each treatment group versus Placebo will be presented. 
SAS Code (may be updated at analysis stage to fit the data): Generalized Linear Model for Ordinal Data 
Proc genmod data=dataset order=internal descending ; 
Freq count; 
Class treatment ; 
Model pgic=treatment / dist=multinomial link=clogit; 
Estimate ‘logor 75 vs pbo’ -1 1 0 / exp alpha=0.025 ; 
Estimate ‘logor 200 vs pbo’ -1 0 1 / exp alpha=0.025 ; 
Ods output estimates=estimates ; 
Run; 
 
4.6.4.26. 
Change from baseline to each scheduled assessment in the monthly PGIS (mPGIS) score 
Responses to the Patient Global Impression of Severity range from 0- No symptoms to 4-Severe. 
Responses will be summarized by category at each visit (Day 1, Month 1, Month 2, Month 3, Month 4, 
Month 5, Month 6). A generalized linear model analysis for ordinal data will be performed. Odds-ratio 
and 97.5% confidence intervals estimates of having higher ordered responses categories, of each 
treatment group versus Placebo will be presented. 
 
4.6.5. Additional Efficacy Analyses 
 
4.6.5.1. 
Clinically meaningful reduction at Month 3 for the two co-primary endpoints with 


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discontinued subjects considered as non-responders 
A supportive analysis of the co-primary endpoint analysis will be conducted that considers all subjects 
who prematurely discontinue the study treatment before the Month 3 visit as non-responders. These are 
composite endpoints that estimate the proportion of subjects with clinically meaningful reduction in 
pain, a stable or decreased use of rescue medication, and who complete 3 months of treatment. The 
same analyses as described in Section 4.6.2.1.2 will be performed, i.e., using a composite strategy for 
discontinuation as opposed to a while on treatment strategy used for the primary estimand.  
The analysis will be performed on the Full Analysis Set and the Per Protocol Set.  
 
4.6.5.2. 
Clinically meaningful reduction at Month 3 for the two co-primary endpoints with multiple 
imputation approach for subjects who discontinued the study early 
As supportive analysis of the co-primary endpoint analysis, in order to estimate the effect of treatment 
policy, a reference based multiple imputation approach will be used for the co-primary endpoints for 
subjects who discontinue the study early, under the assumption that the efficacy of the linzagolix treated 
subjects gradually transitions to that observed in the placebo subjects, i.e., using a treatment policy 
strategy for discontinuation as opposed to a while on treatment strategy used for the primary estimand.  
Details on multiple imputation methodology are described in section 4.2.8. 
DYS and NMPP mean scores changes, and ibuprofen and analgesic use (pill counts) will be simultaneously 
imputed using multivariate imputation by a fully conditional specification method, with 20 burn-in 
iterations before each imputation. The predictive mean matching method for continuous variables will 
be used where the imputed values will be randomly taken from the 5 closest observed values whose 
predicted values are closest to the predicted value for the missing value from the simulated imputation 
model. The imputation model will include baseline value as a covariate. Following imputation, the 
corresponding binary endpoints of response for DYS, NMPP including use of analgesics, will be computed.  
For each imputed dataset, the logistic regression analyses for DYS and NMPP as described in section 
4.6.2.1.2 will be performed. The combined estimate of odds ratios will be obtained from each of the m 
models estimates. 
SAS Code for multiple imputation: 
  Step 1: Multiple imputation 
proc mi data=dataset seed=1910 nimpute=500 out=outmi; 
           class treatment ; 
 
    fcs regpmm ( DYS_chg = DYS_base / k=5 ) nbiter=20; 
 
    fcs regpmm ( ibu = ibu_base / k=5 ) nbiter=20; 
 
    fcs regpmm ( narco = narco_base / k=5 ) nbiter=20; 
           mnar model( DYS_chg / modelobs=(treatment='placebo') ); 
    mnar model( ibu / modelobs=(treatment='placebo') ); 
    mnar model( narco / modelobs=(treatment='placebo') ); 


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           var DYS_base ibu_base nar_base DYS_chg ibu narco; 
        run; 
 
 
data outmi2 ; 
 
    set outmi ; 
 
    /* Derive binary endpoints as described in primary endpoint section*/ 
 
Run; 
 
  Step 2: Statistical analysis for treatment effect: Logistic Regression 
PROC LOGISTIC data=outmi2 order=internal; 
 
By _imputation_ ; 
       
Class treatment(ref=placebo); 
       
Model DYS_resp(event= “Yes”)= treatment DYS_base  /alpha=0.05; 
       
Oddsratio treatment ; 
Lsmeans treatment / ilink exp cl alpha=0.05 at means diffs=control("1") 
adjust=bon; 
             Ods output OddsRatiosWald=or  
             lsmeans=lsm diffs=diffs ParameterEstimates=es; 
       
 
run; 
 
  Step 3: Combine estimates from each imputation dataset 
  Data or2 ; 
 
Set diffs ; 
 
Logodds=estimate; 
 
 
Logoddsse=(AdjUpper-AdjLower)/(2*2.24); 
  Run;  
  proc mianalyze data=or2; 
    ods output parameterestimates=mian_logodds; 
    modeleffects logodds; 
    stderr logoddsse; 
  run; 
 
* Back-transform to get odds ratio ; 
  data mian_odds; set mian_logodds; 
    estimate_back = exp(estimate); *pooled odds ratio; 
    lcl_back=estimate_back*exp(-2.24*stderr); *pooled lower limit; 
    ucl_back=estimate_back*exp(+2.24*stderr); *pooled upper limit; 
  run; 
* pooled p-value ; 
 
%macro trtby(n=); 
 
data es_; 
 
  set es; 
 
  where variable in ('treatment') and CLASSVAL0="&n"; 
 
run; 
 
proc sort data=es_ out=lgs_anova1_es; 
 
  by variable _imputation_ ; 
 
run; 
 
** calculate Rx; 
 
data lgs_anova2_es; 


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13-JUN-2022 
 
CRS-BS-TP-000005 V 1.0 
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  set lgs_anova1_es; 
 
  by variable _imputation_ ; 
 
  StChi=SQRT(WaldChiSq); 
 
run; 
 
proc means data=lgs_anova2_es noprint; 
 
  by variable ; 
 
  var StChi; 
 
  output out=lgs_anova3_es(drop=_:) mean=mnStChi;  
 
run; 
 
data lgs_anova4_es; 
 
  merge lgs_anova2_es lgs_anova3_es; 
 
  by variable ; 
 
  StDif2=(StChi-mnStChi)**2; 
 
run; 
 
proc means data=lgs_anova4_es noprint; 
 
  by variable ; 
 
  var df WaldChiSq StDif2; 
 
  output out=lgs_anova5_es(drop=_t: rename=(_freq_=M)) mean=DF mnChi2 mnStDif2 
sum=smDf smChi2 smStDif2;  
 
run; 
 
data lgs_anova6_es_&n; 
 
  set lgs_anova5_es; 
 
  by variable ; 
 
  Rx=(1+1/M)/(M-1)*smStDif2; 
 
  Dx=(mnChi2/DF-(M+1)/(M-1)*Rx)/(1+Rx); 
 
  DF_d=DF**(-3/M)*(M-1)*(1+1/Rx)**2; 
 
  Pval=1-CDF("F",Dx,DF,DF_d); 
 
  trtn=&n; 
 
   
 
run; 
%mend; 
%trtby(n=2); 
%trtby(n=3); 
/* Bonferroni adjustment */ 
 
data bonf_2 ; 
 
 
set LGS_ANOVA6_ES_2 ; 
 
 
pvalbon=pval * 2 ; 
 
 
if pvalbon > 1 then pvalbon = 1; 
 
run; 
SAS Code may be updated to fit the data.  
The analysis will be performed on the Full Analysis Set.  
4.6.5.3. 
Clinically meaningful reduction at Month 3 for the two co-primary endpoints with stable 
or decreased use of analgesics for EAP assessed across all days 
An additional analysis of DYS and of NMPP will be conducted where the assessment of stable or 
decreased use of analgesics for EAP will be assessed over all days rather than separately for bleeding days 


     Statistical Analysis Plan  
Sponsor:  
ObsEva 
 
Protocol: 
18-OBE2109-003 
Document Version No.: 
V5.0 
Document Date: 
13-JUN-2022 
 
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and non-bleeding days. This same assessment will then be incorporated into the DYS and NMPP 
endpoints. The same logistic regression analysis as described at the start of Section 4.6.2.1.2 will be 
performed.  
The analysis will be performed on the Full Analysis Set. 
 
4.6.5.4. 
COVID-19 Considerations 
 
ObsEva in consultation with its Independent Data safety Monitoring Committee (IDMC) evaluated the 
overall benefit/risk of continuing to conduct this study during the COVID-19 pandemic and concluded 
that the integrity of the trial, the safety and wellbeing of trial participants and the safety of clinical trial 
staff were adequately assured by the measures put in place, as described below. 
To ensure continuity in patient’s safety monitoring, treatment, and study data collection, remote study 
visits, use of local laboratory and shipment of materials and study drugs from site to subject were put in 
place, whenever feasible, for subjects who cannot attend their visits due to quarantine, travel 
restrictions, site closure or other unforeseen reasons. Sites were to schedule telephone calls to subjects 
as replacement for on-site visits to identify adverse events and ensure continuous medical care and 
oversight. Phone scripts and detailed instructions for the study conduct during COVID-19 pandemic were 
distributed to all sites. 
Any COVID-19 related study protocol deviations were being documented and regularly reviewed and 
analyzed by ObsEva in order to take appropriate corrective and/or preventive actions as needed. 
In addition, remote monitoring visits were being approved by ObsEva when the monitors were not able 
to conduct in-person visits to the study sites to perform their oversight activities. The clinical monitoring 
plan was updated accordingly to define the content of remote monitoring visits. 
ObsEva believes that COVID-19 related protocol changes do not impact the clinical data interpretability 
considering that: 
- 
co-primary efficacy endpoints and most of the study secondary efficacy endpoints are patient-driven 
data collected by the patient on her e-diary and not during an on-site visit, 
- 
very few protocol deviations related to COVID-19 have been reported, 
- 
although COVID-19 could potentially affect pain values, very few participating subjects were affected 
with the condition, thus the impact on pain values is expected to be negligible 
 
4.6.5.5. 
Daily Patient Global Impression of Severity (dPGIS), Daily Event Cancelled, Daily Difficulty 


     Statistical Analysis Plan  
Sponsor:  
ObsEva 
 
Protocol: 
18-OBE2109-003 
Document Version No.: 
V5.0 
Document Date: 
13-JUN-2022 
 
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Sleeping 
The dPGIS, Event Cancelled and Difficulty Sleeping daily diaries were collected for subjects enrolled 
prior to amended Protocol V4.0 only.  
The dPGIS mean scores and changes from baseline, the number of days with difficulty sleeping, the 
number of days for which events were cancelled and the number of days with no event planned will be 
computed for each 4-week period and reported in listings only. 
The dPGIS scores will be calculated by averaging over the corresponding 28 calendar days immediately 
prior to and including the day of each scheduled assessment (or prior to and including the last dose 
date for subjects who discontinue treatment). 
 
4.7. 
Pharmacokinetic Evaluations 
Pharmacokinetic analyses will be conducted using the Pharmacokinetic Set. 
PK samples are collected at each monthly visit. 
For descriptive statistics of plasma concentrations mean (arithmetic and geometric), standard deviation, 
median, 1st and 3rd quartiles, minimum, maximum, coefficient of variation (CV%) and number of 
observations will be provided. Concentrations below the limit of quantification (LOQ) will be assigned a 
value of zero. Missing values will not be imputed, and if sufficient data are missing for a given subject, 
that subject may be considered non-evaluable for pharmacokinetic analysis and would not be included 
in the PK Set. 
All plasma concentration data will be displayed in listings. PK assessment day and time, IMP intake status 
and IMP intake time on the day of PK assessment and on the previous days will be included in the listings. 
Explorative analyses of correlations between plasma concentrations and intrinsic PK factors such as  body 
weight/BMI, race, age will be performed, as appropriate, and will be reported separately.  
4.8. 
Safety Analyses 
Safety analyses will be conducted using the Safety Population.   
4.8.1. Extent of treatment exposure and compliance 
 


     Statistical Analysis Plan  
Sponsor:  
ObsEva 
 
Protocol: 
18-OBE2109-003 
Document Version No.: 
V5.0 
Document Date: 
13-JUN-2022 
 
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4.8.1.1. 
Extent of treatment exposure 
Duration of treatment (in weeks and in days) will be summarized for each treatment group. Duration is 
defined as: [(date of last treatment administration as described in section 4.2.11) - (date of first 
administration as collected in eCRF) +1] / 7 (weeks), [(date of last treatment administration as described 
in section 4.2.11) - (date of first administration as collected in eCRF) +1] (days). 
Time on study (in weeks and in days) will be summarized for each treatment group, defined as: [(end of 
study date as described in section 4.2.11) – (first dose date) +1.]/7 (weeks), [(end of study date as 
described in section 4.2.11) – (first dose date) +1.] (days). 
Exposure data will be reported in listings. 
4.8.1.2. 
Compliance 
 
Lingazolix/Placebo Grey blister (200 mg or matching placebo), Lingazolix/Placebo Pink blister (75 mg or 
matching placebo) and Add-back therapy compliance from the study treatment accountability page will 
be averaged among the Day 1-Month 3 and Month 3-End of study periods and summarized by treatment 
group. 
If Lingazolix/Placebo and Add-back therapy compliance from accountability data are missing, compliance 
will be computed from daily e-diary data for the corresponding 3-month period. Compliance will be 
computed as the number of days with pink tablet/grey tablet/red capsule taken divided by the number 
of days in the period (Month 3 visit date/early discontinuation visit date-Day 1 or Month 6 visit date/early 
discontinuation visit date-Month 3 visit date). Data from “Today” will be used primarily. If data from 
today is missing, data 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 intake of drug was taken on that day. 
Study treatment overdose and misuse will be reported in a listing. 
Compliance will be reported in a listing. 
 
4.8.1.3. 
Question Regarding Treatment Received 
Subjects were asked at treatment termination which treatment they believed they received during the 
blinded treatment period. The number of subjects who believed they received active treatment, placebo 
or unknown will be summarized by treatment group on the Safety Population. 
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. 


     Statistical Analysis Plan  
Sponsor:  
ObsEva 
 
Protocol: 
18-OBE2109-003 
Document Version No.: 
V5.0 
Document Date: 
13-JUN-2022 
 
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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 study 
drug through 30 days after discontinuation of study drug or the Month 6 date, or any event that was 
present at baseline but worsened in intensity or was subsequently considered drug-related by the 
investigator through 30 days after discontinuation of study drug or the Month 6 date.  
Adverse Event tables will be presented for the following periods, as defined in Section 4.2.11: 
- 
Day 1 to Month 6 date -1 or treatment discontinuation date (treatment period) 
- 
Month 6 date or (treatment discontinuation date+1) to Month 6 FU (follow-up period): 
o TEAE: AEs starting within 30 days after discontinuation of study drug or Month 6 visit date 
o Post-treatment AE: Adverse events starting more than 30 days after end of treatment 
- 
Day 1 to Month 6 FU 
If, for a subject not entering the follow-up period or the extension, an AE occurs within the 30 days 
following Month 6 date-1 or treatment discontinuation, then the AE will be counted in the treatment 
period. 
For each of the treatment and follow-up periods, an overall summary table will be prepared presenting, 
by treatment group and overall, the number and percentage of subjects with  
• 
any TEAE,   
• 
Severe TEAE 
• 
any TEAE assessed by the Investigator as related to Linzagolix,  
• 
any TEAE assessed by the Investigator as related to add-back therapy,  
• 
any TEAE leading to permanent discontinuation of IMP,  
• 
any serious adverse event, 
• 
any serious Treatment Emergent Adverse Event, 
• 
any serious Treatment Emergent adverse event related to Linzagolix, 
• 
any serious Treatment Emergent adverse event related to add-back therapy,  
• 
Any TEAE leading to permanent discontinuation of IMP 
• 
any fatal TEAE (where outcome is “Fatal”) 
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. 


     Statistical Analysis Plan  
Sponsor:  
ObsEva 
 
Protocol: 
18-OBE2109-003 
Document Version No.: 
V5.0 
Document Date: 
13-JUN-2022 
 
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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, with any 
treatment-emergent adverse events assessed by the Investigator as related to treatment (definite, 
probable, or possible relationship), and with any treatment-emergent serious adverse event and with 
any treatment-emergent non-serious adverse event will be summarized by treatment group and overall.  
Tabulation by severity will also be made. In these tabulations, each subject will contribute only once (i.e., 
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. 
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.   
All adverse events occurring on study will be listed in subject data listings. 
By-subject listings also will be provided for the following: subject deaths; serious adverse events; and 
adverse events leading to withdrawal.  
 


     Statistical Analysis Plan  
Sponsor:  
ObsEva 
 
Protocol: 
18-OBE2109-003 
Document Version No.: 
V5.0 
Document Date: 
13-JUN-2022 
 
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4.8.3. Bone Mineral Density (BMD) by DXA 
BMD of the femoral neck, total hip and lumbar spine will be assessed by DXA at Baseline, Month 6 and 
Month 6 follow-up. Unacceptable DXA assessments (accepted=”No”) will not be summarized (hip, and 
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 should be provided once all cross-calibration data are made available to the vendor in 
charge of the scan assessment. These calibrated values will be used in the summary tables if available, 
otherwise initial values will be considered. 
BMD values and corresponding Z-scores will be summarized for each treatment group. The within-group 
percent changes from baseline for BMD values will also be summarized, including 2-sided 95% confidence 
intervals.  
Percent change from baseline to Month 6 and Month 6 follow-up will be described and will also be 
summarized in categories of percent change with the following classes: 
• 
No change or increase, 
• 
Decrease ≤ 3%, 
• 
Decrease > 3% and ≤ 5%, 
• 
Decrease > 5% and ≤ 7%, 
• 
Decrease > 7% and ≤ 8%, 
• 
Decrease > 8%. 
The percent changes from baseline to Month 6 will be compared between each of the linzagolix groups 
and the placebo group via analysis of covariance with treatment group as the main effect (three values) 
and including the baseline as a covariate. 
Sample SAS code (SAS code will be fully validated at the analysis stage) for analysis of covariance: 
Proc GLM data=dataset order=internal; 
 
Class Treat; 
 
Model BMD_pchg = BaselineBMD Treat; 
 
LSMEANS Treat / at means pdiff= control('1') alpha=0.05  cl adjust=bon; 
 
ODS 
OUTPUT 
lsmeans=lsm 
diff=pvals 
lsmeancl=lsmeancl 
lsmeandiffcl=lsmeandiffcl; 
Run; 
All data will be listed.  
A listing of BMD for subjects who discontinued treatment will be provided. 


     Statistical Analysis Plan  
Sponsor:  
ObsEva 
 
Protocol: 
18-OBE2109-003 
Document Version No.: 
V5.0 
Document Date: 
13-JUN-2022 
 
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Subgroup analyses by race, age groups 1 and 2, weight and BMI groups 1 and 2 will be performed for 
BMD, including descriptive summaries, percent changes categories summaries and analysis of 
covariance. 
Due to the war situation in Ukraine, data from subjects in Ukraine sites may be incomplete, missing or 
uncleaned.  A sensitivity analysis of the BMD will be performed, excluding data collected after 24FEB2022 
for subjects from Ukraine sites, for the Follow-up period only (Follow-up Safety set), as the main 
treatment period was completed before the start of the war. Listings will contain country information to 
identify those subjects. 
 
4.8.4. Laboratory Data 
Clinical laboratory values will be expressed using conventional SI units. 
Hematology, coagulation parameters, chemistry and lipids are assessed at screening and at each visit 
during the treatment period, as well as at M1 FU and M3 FU visits. E2, progesterone (P4) and LH will be 
assessed at each visit during the treatment period (not at the screening visit), as well as at M1 FU and 
M3 FU visits. Serum levels of anti-müllerian hormone (AMH) and fasting glucose will be assessed on Day 
1 only. Serum levels of sex hormone-binding globulin (SHBG) will be assessed on Day 1 and Month 3 and 
Month 6 visits. Follicle-Stimulating Hormone (FSH) will be assessed at Month 3 FU at local laboratories 
for subjects who did not resume menses.  
Blood samples will be analyzed by the central laboratory. Due to the COVID-19 situation, some samples 
may be collected by local laboratories.  
Laboratory parameters values will be summarized for each visit for each treatment group and overall 
including within-group changes from baseline. In the event of repeated values, the last non-missing value 
per study day/time will be used.  
Semi-quantitative laboratory results will be imputed as follows: “<X.X” will be imputed as “X.X/2” and 
“>X.X” will be imputed as “X.X”. 
Evaluation of shifts for changes from baseline to all visits, according to the normal ranges with categories 
“Low”, “Normal”, “High” where available (for ALT, AST, ALP, Bilirubin, Albumin, Calcium, Creatine Kinase) 
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, albumin), evaluation of shifts for 
changes from baseline to the worst (highest) on-treatment value (including unscheduled assessments) 
according to the normal ranges with categories “Low”, “Normal”, “High” will be provided. 
Assessments from local laboratories will not be included in summaries and shift tables, as normal ranges 
may not be comparable. 


     Statistical Analysis Plan  
Sponsor:  
ObsEva 
 
Protocol: 
18-OBE2109-003 
Document Version No.: 
V5.0 
Document Date: 
13-JUN-2022 
 
CRS-BS-TP-000005 V 1.0 
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All laboratory data will be provided in data listings. 
A subset listing will be presented for all abnormal clinically significant laboratory values. 
 
For the lipid panel (Triglycerides, HDL, LDL, Total Cholesterol, LDL/HDL ratio), the percent change from 
baseline to each on-study visit will also be summarized. 
For serum levels of E2, 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. 
In addition, for E2, the proportion of subjects with the following categories: 
• 
E2 <20 pg/mL,  
• 
E2 between ≥20 and <60 pg/mL, 
• 
E2 ≥60 pg/mL 
at each visit and for each treatment group will be provided in tables and graphically (bar charts).  
The relationship between E2 serum levels and bone mineral density loss will be explored graphically in 
different ways: 
• 
First, the E2 serum level measured at Month 6 will be plotted on the x-axis against the percent 
BMD change measured at Month 6 on the left side y-axis and the percentage of subjects with 
clinically meaningful reduction of DYS (resp. NMPP) with stable or decreased use of analgesics 
for EAP on the right side y-axis.  
• 
Second, bar charts will be produced at each visit up to Month 6 and presented with the percent 
BMD change from baseline to Month 6 on the y-axis and the proportion of subjects with the E2 
categories described above on the x-axis. Similar graphs will be produced for each of the BMD 
sites (femoral neck, hip, and spine).  
• 
Lastly, bar charts of the proportion of subjects with the E2 categories described above on the x-
axis will be plotted against the percentage of responders according to the primary endpoint. 
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 Study Day 1 to Month 3, from Month 3 to Month 6, and 
from Study Day 1 to Month 6 will also be provided in tables and graphically (bar charts). 
The number and percentage of subjects at the following categories 
• 
LDL ≥ 160 mg/dL  
• 
LDL ≥ 190 mg/dL  
• 
HDL < 40 mg/dL  


     Statistical Analysis Plan  
Sponsor:  
ObsEva 
 
Protocol: 
18-OBE2109-003 
Document Version No.: 
V5.0 
Document Date: 
13-JUN-2022 
 
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will be reported at each visit. 
Shift tables from baseline 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 
 
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; weight is assessed at Screening, Month 6 and Month 6 of the follow-up 
period. Other Vital Signs are assessed at Screening, Day 1, every month during the treatment period and 
at Months 1 and 3 from the follow-up period. 
Physical Examination is assessed at Screening, Months 3 and 6 of treatment and follow-up periods. 
The actual value and change from baseline to each on study evaluation will be summarized by treatment 
group and overall 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 and overall; shifts 
from baseline in physical examination findings to each on study visit will also be presented.  All physical 
examination findings will be presented in a data listing. 
 


     Statistical Analysis Plan  
Sponsor:  
ObsEva 
 
Protocol: 
18-OBE2109-003 
Document Version No.: 
V5.0 
Document Date: 
13-JUN-2022 
 
CRS-BS-TP-000005 V 1.0 
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4.8.6. Electrocardiogram 
 
Local 12-lead ECG readings of QTcF are performed at Screening, Day 1 (pre and post-dose) and every 
month from the treatment period, as well as Months 1,3,6 from the follow-up period. 
Baseline will be defined as the highest value prior to first dose. 
Actual values and changes from baseline 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 
baseline and each study visit by treatment group and overall. 
All ECG data for each subject will be provided in data listings. 
 
4.8.7. Concomitant Medications 
Prior and Concomitant medications will be coded using the WHO Drug dictionary. Frequencies and 
percentages will be presented for each treatment group and overall by Anatomic Therapeutic Class (ATC) 
and preferred name. Vitamin D and Calcium supplementation as collected in the eCRF at each visit will 
be summarized as well. 
The use of concomitant medications will be included in a by-subject data listing. 
Prior medications are those the subject used prior to the first day of treatment. 
All medications administered between the date of the first dose of study drug and the date of the last 
dose of study drug, inclusive, (i.e., all medications starting or ongoing during the time interval) are 
concomitant. A medication taken prior to Study Day 1 and continuing post Study Day 1 will be considered 
both prior and concomitant.  
Prior interventional surgeries/procedures for endometriosis/endometriosis symptoms will also be 
summarized. 
4.8.8. Transvaginal Ultrasound (TVUS) 
TVUS will be performed at Screening, Month 3, Month 6, Month 3 and Month 6 of the Follow-up period. 
Actual values and changes from baseline will be summarized by treatment group and overall for uterus 
length, width, and depth in mm and corresponding uterine volume in cm3, as well as endometrium 
thickness in mm. 
The number and percentage of subjects with any ovarian endometrioma with a diameter of 7 cm or 
greater, and presence of any uterus, left ovary or right ovary abnormality over time will be presented by 
treatment group and overall. 


     Statistical Analysis Plan  
Sponsor:  
ObsEva 
 
Protocol: 
18-OBE2109-003 
Document Version No.: 
V5.0 
Document Date: 
13-JUN-2022 
 
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4.8.9. Other Examinations 
At least two endometrial biopsies for histological assessment were obtained for each subject:  
- 
One at screening, unless an endometrium biopsy was performed within the past 6 months of the 
screening visit, which shows no atypical hyperplasia or adenocarcinoma and for which slides are 
available for current study assessment through retrospective central laboratory reading.  
- 
One at Month 6 if the endometrium thickness via TVUS is > 5 mm  
- 
One at Month 1 FU, 2 FU, 3 FU, 4 FU, 5 FU or 6 FU if not obtained at Month 6 or if the preceding 
biopsy diagnosis is different than “benign endometrium”  
A summary at each time point will be performed (number and percentage of subjects with normal, 
abnormal, not assessable).  
Biopsy diagnosis will be summarized by classification and primary diagnosis at each visit. Subjects will be 
counted only once per classification and diagnosis. A subject can be counted in several diagnoses. 
Possible classifications and diagnoses 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, Not applicable. 
 If any diagnosis does not correspond to any on the list, the diagnosis will be coded as: Other Malignant 
if classification is Malignant Endometrial Neoplasm, and Other for any other classification. 
For biopsies with reported primary diagnosis “Hyperplasia” or “Malignant Endometrial Neoplasm” at 
other visits than screening, a second read of the biopsy was to be performed. If the diagnosis of the two 
reads was different, then the sample was to be re-read a 3rd time. In case of multiple readings, the 
following rules will be applied for the statistical analysis: 
- 
If 2 readings out of 3 lead to the same diagnosis, one of these 2 records will be selected. 
- 
 Otherwise, the record corresponding to the most severe diagnosis should be selected considering 
the following order, from less severe to more severe: simple without Atypia hyperplasia < complex 
without Atypia hyperplasia < simple with atypia hyperplasia < complex with Atypia hyperplasia < 
endometrial malignant neoplasm < other malignant neoplasm. 
In addition, in order to perform a quality check of the readings, 15% of biopsies were sent blinded for a 
second read when the primary diagnosis was “Benign Endometrium”. In case of multiple readings when 
the primary diagnosis from the first read is “Benign Endometrium”, this first read will be used for the 
analysis. 


     Statistical Analysis Plan  
Sponsor:  
ObsEva 
 
Protocol: 
18-OBE2109-003 
Document Version No.: 
V5.0 
Document Date: 
13-JUN-2022 
 
CRS-BS-TP-000005 V 1.0 
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Endometrial biopsy results will be reported in listings. 
Due to the war situation in Ukraine, some biopsy samples may have been collected and analyzed by local 
laboratories. Those assessments will be flagged in the listings, for the Follow-up period only, as the main 
treatment period was completed before the start of the war. Information about local biopsy assessment 
is reported in Data Management Close queries file. This file will be provided by data management 
department and reviewed by Sponsor. Biopsy assessments performed locally can be identified in the 
queries list from Endometrial Biopsy page, by subject and visit and by word search, with answer to query 
containing the word “local”. 
Gynecological Examination is assessed at Screening, Month 3, Month 6 and Month 3 of Follow-Up period.  
Breast examination (by palpation) will be performed at the Screening, Month 6 and Month 3 FU visits. 
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. 
PAP Smear is collected at Screening. A listing of abnormality information and a listing of diagnosis results 
will be provided, including possible unscheduled assessments. 
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 will complete: 
- either the “Baseline” C-SSRS version, capturing lifetime history of suicidal ideation and behavior, for 
subjects under screening at the time of/after protocol amendment 3 implementation,  
- or the “already enrolled subjects” C-SSRS version, for subjects already randomized at the time of 
protocol amendment 3 implementation, and who are 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 is to be completed during Screening, or at Day 1 if not done during 
Screening. 
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): 
- 
Incidence of the following suicidal ideation: 
o Wish to be dead. 


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o Non-specific active suicidal thoughts. 
o Active suicidal ideation with any methods (not plan) without intent to act. 
o Active suicidal ideation with some intent to act, without specific plan. 
o Active suicidal ideation with specific plan and intent. 
- 
Incidence of the following suicidal behavior: 
o Actual attempt. 
o Interrupted attempt. 
o Aborted attempt. 
o Preparatory acts or behavior. 
o Completed suicide (Actual attempt leading to death). 
The number of subjects with any suicidal ideation, any suicidal behavior, and any suicidal ideation or 
behavior will be summarized at each time point.  
  
The number of subjects experiencing the following, at any time post-baseline, will also be summarized  
- 
Suicidal ideation or behavior 
- 
Emergence of suicidal ideation. 
- 
Worsening of suicidal ideation. 
- 
Emergence of 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.  The 
Suicidal ideation rating is defined as the following, as recommended in the C-SSRS scoring and analysis 
guide 
in 
https://cssrs.columbia.edu/wp-content/uploads/ScoringandDataAnalysisGuide-for-Clinical-
Trials-1.pdf: 
Maximal suicidal ideation category during the period (baseline, post-baseline up to Month 6, FU period) 
where categories range from 0 to 5: 
0. No ideation 
1. Wish to be dead 
2. Non-specific active suicidal thoughts. 


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3. Active suicidal ideation with any methods (not plan) without intent to act. 
4. Active suicidal ideation with some intent to act, without specific plan. 
5. Active suicidal ideation with specific plan and intent. 
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 implementation of Amendment 3. If a subject completed this “prior to Entry Study” questionnaire 
at several visits, the worst severity answers will be considered as baseline in the analysis. 
The same analysis will be repeated at any time post-baseline from Month 1 FU to Month 6 FU, on the 
follow-up Safety analysis set. 
 
4.8.11. Time to the first post-treatment menses 
The first post-treatment menses will be defined from the Vaginal Bleeding daily ediary, as the first day 
for which the subject recorded bleeding after the last treatment administration date of the main study, 
i.e., the first day with “BLEEDING” or “HEAVY BLEEDING” after the last treatment administration date of 
the main study. 
Time to first post-treatment menses is defined as: 
Time to first post-treatment menses (days) = (day of first post-treatment menses – last treatment 
administration date) + 1 
Only data from the follow-up treatment period will be included, and the analysis will be provided on the 
Follow-up Safety Analysis Set, by treatment group. 
Subjects who have not recorded any bleeding up to the end of the follow-up period will be considered as 
right-censored data at the last ediary vaginal bleeding record date before the end of the main follow-up 
period (as defined in section 4.2.11) with time of censoring = last non-missing ediary vaginal bleeding 
record date – last treatment administration date +1.  
The probability of subjects having bleeding will be displayed by treatment group in the form of cumulative 
probability curves estimated using the non-parametric Kaplan-Meier method. Point estimates and 
corresponding 2-sided 95% CIs using the Greenwood’s variance estimate will be provided at 28 days, 56 
days, 84 days, 112 days, 140 days, 168 days, 196 days after the last treatment administration date.  
Percentiles (25th, 50th, and 75th) and corresponding 2-sided 95% CIs will also be provided; “N/A” will be 
presented for any of the percentiles not reached. 
Subjects with or without first post-treatment menses, time to first post-treatment menses, end of study 
status and end of study date will be presented in a by-subject listing. 


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4.8.12. Unblinding of subjects 
Subjects that were unblinded during the course of the study will be summarized and listed. The 
cumulative unblinding history report from IWRS will be provided by the Sponsor in an excel format. This 
file will only contain unblinding status but no treatment information.  
4.9. 
Exploratory Analyses 
Bone turnover markers will be analyzed on the Safety Population.  
Blood samples for exploratory bone biomarkers include, but may not be limited to, collagen type 1 β-
carboxy-telopeptide (CTx), procollagen 1 Intact N-Terminal (P1NP), bone-specific alkaline phosphatase 
(B-ALP) and osteocalcin as part of clinical chemistry, and are collected at Day 1, Month 3, Month 6 and 
Month 3 Follow-up. These exploratory data will be kept blinded up to the unblinding of the database. 
Actual values and changes from baseline will be summarized overtime by treatment group. Bone marker 
data will be reported in listings as well. 


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5. 
CHANGES TO PLANNED ANALYSES 
 
The following change to the protocol-defined statistical analyses is presented in this statistical analysis 
plan:  
For secondary endpoints of change from baseline to Month 6 that are collected daily using the eDiary, 
the protocol states  (Sections 13.5.3.1, 13.5.3.2, 13.5.3.3, 13.5.3.5, 13.5.3.6, 13.5.4) that the endpoints 
will be based on the 28 calendar days immediately prior to and including the day of the Month 6 visit (or 
the 28 calendar days immediately prior to and including the last dose date for subjects who discontinue 
treatment prior to Month 6). 
In this SAP this definition has been modified to not include the Month 6 day, as for subjects entering the 
Extension Study, the Extension Treatment is received at Month 6 (i.e., on the Month 6 day), and for 
subjects entering the Main Study Follow-up, no treatment is received at Month 6 (i.e., on the Month 6 
day).  
The end of the 28-day period prior to Month 6 is defined in Section 4.2.11 as the last treatment 
administration date in the Main Study. 
The following endpoints are impacted: 
- 
Ranked Secondary Endpoints: 
o Change from baseline to Month 6 in DYS (VRS) and in NMPP (VRS) (Section 4.6.3.1) 
o Change from baseline to Month 6 in dyschezia (NRS) (Section 4.6.3.2) 
o Change from baseline to Month 6 in overall pelvic pain (NRS) (Section 4.6.3.3) 
o Change from baseline to Month 6 in dyspareunia (VRS) (Section 4.6.3.5) 
o No analgesics use/ no opiate use for EAP during the preceding 4-week period at Month 
6 (Section 4.6.3.6) 
- 
Additional Secondary Endpoints (Section 4.6.4): endpoints based on daily e-Diary entries 
 
Updates from SAP Amendments since SAP V1.0 are summarized in the table below: 
 
 
 


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SAP Version 
Update description 
SAP Section 
Reason 
V2.0 
Addition of MCT analysis using 
Month 6 data for ranked 
secondary endpoints  
- 
Addition of 
corresponding M6 
threshold analysis 
population  
- 
Addition of random 
sample for Month 6 
MCT (N=200) 
- 
Clarification of 
blinding/unblinding 
process for M6 
- 
For threshold analysis 
population at Month 3, 
available anchor data 
needed among PGIC or 
PGIS or DYSME or 
NMPP only (since only 
the primary endpoint 
MCT are assessed at 
Month 3) 
Section 3.1 
Section 4.6.1 
Section 4.3 
FDA Advice/Information 
request  
Dated 16Aug2021 
(Comment 14a) 
V2.0 
Correction of definition for 
threshold analysis population 
and random sample to clarify 
that PGIC is needed at Month 3 
(or Month 6) only (not at 
baseline)  
Section 3.1 
Section 4.6.1 
FDA Advice/Information 
request 
Dated 16Aug2021 
(Comment 14b) 
V2.0 
For MCT analysis of EHP-30 Pain 
Domain, increase of the size of 
the random sample to n=200 
instead of n=100  
Section 4.6.1 
FDA Advice/Information 
request 
Dated 16Aug2021 
(Comment 15) 
V2.0 
Clarification of rationale for the 
while on treatment strategy 
Section 4.6.2.1.1 
FDA Advice/Information 
request 


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Dated 16Aug2021 
(Comment 19a) 
V2.0 
Added subgroups of Age and 
BMI  
 
 
Section 4.2.6 
FDA Advice/Information 
request 
Dated 16Aug2021 
(Comment 20) 
V2.0 
Clarification of how the 
theoretical Month X date will be 
used if the subject missed the 
Month X visit: The theoretical 
Month X date will be the 
reference end date of the 
Month X 28-day period in which 
the subject may have available 
daily diary data. 
Section 4.2.11 
FDA Advice/Information 
request 
Dated 16Aug2021 
(Comment 22) 
V2.0 
Clarification of “the last 28 days 
on treatment will be used at all 
subsequent scheduled visits for 
those discontinued subjects” 
applicability and of the twos 
ways to perform descriptive 
summaries on efficacy endpoints 
Section 4.6.4 
FDA Advice/Information 
request 
Dated 16Aug2021 
(Comment 24) 
V2.0 
Data cleaning rule for 
considering daily ediary records 
entered after 00:00 on the 
correct day. 
Section 4.2.8.3 
Blinded data review finding  
V2.0 
Deletion of potential major 
deviations non-applicable on 
eDiary completion compliance 
Section 3.2 
Efficacy analyses on daily 
eDiary endpoints are 
already considering subjects 
with a minimum of daily 
diary data completed 
V2.0 
Update of visit window rule for 
baseline questionnaires: the 
Section 4.2.9 
Blinded data review finding:  
update to consider baseline 


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most recent data entered before 
first dose regardless of 
questionnaire name 
questionnaires entered in 
the wrong visit page (Month 
1) but correct date (before 
first dose) 
V2.0 
Addition of definition of study 
completion status (different 
from eCRF completion guideline 
definition): Subjects who 
completed the treatment and 
follow-up periods, or completed 
the treatment period and 
entered the extension study. 
Section 4.4 
Per eCRF completion 
guideline, subjects who 
discontinued treatment 
before 3 months are 
considered as completed 
study. Addition of new 
relevant definition for 
analysis. 
V2.0 
Addition of C-SSRS worsening 
score derivation clarification and 
source document  
Section 4.8.10 
Details were missing in the 
SAP 
V2.0 
Minor updates (Typographical 
errors, wording update, SAS 
code details) 
 
N/A 
V3.0 
Addition of results from Month 
3 Meaningful Change Threshold 
analysis for Primary Endpoints 
Section 4.6.1.3 
Planned update with 
obtained relevant 
meaningful change 
thresholds for the primary 
endpoints 
V3.0 
Clarification of some major 
deviations definitions 
Section 3.2 
Outcome of blinded data 
review 
V3.0 
Addition of Screened set and 
Randomized set definitions 
Section 3.1 
Definitions were missing 
from the SAP 
V3.0 
Addition of visit windows rules 
for PK analysis 
Section 4.2.9 
Outcome of blinded data 
review 
V3.0 
Efficacy analyses repeated on 
Per Protocol Set only for Primary 
Section 4.6 
Repetition of efficacy 
analyses of all secondary 


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and Ranked Secondary 
endpoints.  
endpoints deemed 
unnecessary 
V3.0 
Analysis of analgesic use in 
Morphine Milligram Equivalents 
(MME) 
- 
In countries where 
several opioids were 
allowed, take the 
average of possible 
MME 
- 
Subjects from Ukraine 
excluded from MME 
analysis 
Section 4.6.3.9 
Section 4.6.4.8 
- 
In order to not lose 
a lot of subjects 
from countries with 
several opioids are 
allowed and MME 
unknown, the 
average of possible 
MME will be taken 
- 
Some subjects from 
Ukraine recorded 
some opioids even 
if not allowed 
(confirmed eDiary 
data entry issue). 
MME is not 
assessable 
V3.0 
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) 
The mean daily pill count will be 
presented instead of total pill 
count 
Section 4.6.4.7 
Section 4.6.4.8 
Mean daily pill count and 
mean daily MME amount 
are more appropriate than 
total pill count/MME in the 
28-day period, as the mean 
adjusts with missing days. 


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V3.0 
Update of opioid analgesic use 
(pill count and MME) and 
endpoints analyses: 
Summary and analysis of 
covariance removed. A listing 
will be presented.  
Addition of analysis of 
proportion of subjects with no 
analgesic use/no opiate use for 
EAP at Baseline and Month 3. 
  
Update of number of days with 
any opioid analgesic use 
endpoint analysis:  
Summary and negative binomial 
analysis removed. Only a listing 
will be presented. 
 
Section 4.6.4.7 
Section 4.6.4.8 
Section 4.6.4.10 
Due to a low number of 
subjects using any opioid, 
the planned analyses were 
not appropriate.  
V3.0 
Clarification of analgesic status 
derivation  
- 
The “**” criteria applies 
in all cases 
- 
Increase of exactly= 
15% of the baseline 
dose is considered as 
stable 
Section 7.1: Appendix 
A 
Derivation rules of analgesic 
status needed minor 
clarification 
V3.0 
Addition of summary of time on 
treatment and time on study in 
days. 
 
Section 4.8.1.1 
Time on treatment/study in 
days is as relevant as time in 
weeks. 
V3.0 
Addition of Weight Group, Age 
Group 2, BMI Group 2 and 
deletion of Ethnicity group 
subgroup analyses for BMD.  
 
Section 4.8.3 
Subgroups analyses added 
per FDA Advice/Information 
request 
Dated 16Aug2021 
(Comment 20) 
Ethnicity subgroup analysis 
is not relevant  


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V3.0 
C-SSRS Already enrolled “Prior to 
Entry Study” questionnaire:  
 
If a subject completed this “prior 
to Entry Study” questionnaire at 
several visits, the worst severity 
answers will be considered as 
baseline in the analysis. 
 
Section 4.8.10 
Blinded Data Review finding: 
Some subjects completed at 
several visits the “Prior to 
Entry Study” questionnaire, 
while it should have been 
completed only once. 
 
V3.0 
EQ-5D-5l questionnaire : 
Addition of detail on source 
documentation 
 
 
Section 4.6.4.24 
Detail on source 
documentation was missing 
in the SAP 
V3.0 
Minor updates (Typographical 
errors, wording update, SAS 
code details) 
 
 
N/A 
V4.0 
Clarification that the assessment 
of stable or decreased use of 
analgesics for EAP is assessed 
separately for DYS and NMPP, 
using days with uterine bleeding 
and days with no uterine 
bleeding respectively. 
 
Section 4.6.2.1.1 
Section 4.6.2.1.2 
Derivation rules of analgesic 
status for each co-primary 
endpoint needed 
clarification. 
V4.0 
Added an additional analysis of 
DYS and NMPP where the 
assessment of stable or 
decreased use of analgesics for 
EAP will be assessed over all 
days rather than separately for 
bleeding days and non-bleeding 
days 
Section 4.6.5.3 
Add additional analysis. 
V4.0 
Addition of results from Month 
6 Meaningful Change Threshold 
analysis for Ranked Secondary 
Endpoints 
Section 4.6.1.4 
Section 4.6.1.1.2 
Planned update with 
obtained relevant 
meaningful change 
thresholds for the Ranked 
Secondary Endpoints 
V5.0 
Addition of sensitivity analysis 
excluding data from Ukraine site 
Section 4.6.4.1 
Section 4.8.3 
Due to the war situation in 
Ukraine, data from subjects 


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after the start of war on 
24FEB2022, for proportion of 
responders for DYS and NMPP 
and BMD analysis, for Follow-up 
period only. 
in Ukraine sites may be 
incomplete, missing or 
uncleaned. Sensitivity 
analysis is added to assess 
the impact. 
V5.0 
Assessments from Local 
Laboratories (due to Covid-19 
situation) will be excluded from 
summary tables of laboratory 
data 
Section 4.8.4 
Local laboratories may not 
have comparable normal 
ranges, thus it does not 
make sense to pool them 
with central laboratory data 
in numeric summaries.  
V5.0 
Biopsy assessments from Local 
Laboratories (due to war 
situation in Ukraine) should be 
flagged in listings for the follow-
up period. Information is 
available in Data Management 
Closed Queries File. 
Section 4.8.9 
Due to war situation in 
Ukraine, there were some 
Biopsies assessed locally. 
This information should be 
incorporated in listings. 
V5.0 
Addition of listings for PAP 
Smear for both abnormality and 
diagnosis information. 
Section 4.8.9 
PAP Smear listings were 
missing from original SAP 
Version. 
V5.0 
Addition of table and listing of 
subjects who were unblinding 
during the course of the study 
Section 4.8.12 
At least one patient was 
subject to unblinding during 
the course of the study, 
table and listing is added for 
complete reporting. 
 


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6. 
REFERENCES 
Cappelleri, & Bushmakin. (2020). Biopharmaceutical Report.  
Cappelleri, & Bushmakin. (2021). Biopharmaceutical Report.  
Griffiths, & al, e. (2018). Psychometric Properties in the Face of Missing Data- A Simulation 
Study Assessing the Effect of Missing Data on Test-Retest Reliability in Diary Studies. 
Quality of Life Research 25th Annual Conference.  
Ratitch, B., Lipkovich, I., & O’Kelly, M. (2013). Combining Analysis Results from Multiply 
Imputed Categorical Data. PharmaSUG, Paper SP03. 
 


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7. 
APPENDICES 
7.1. 
Appendix A: 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 


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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 
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 
 


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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 
**Stable =Dose is the same as the screening dose or increases by less than or equal to 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. 
7.2. 
Appendix B: EHP-30 Scoring 
The mapping of the response categories for the EHP-30 core questionnaire and the 
modular questionnaire is as follows: 
0 = Never, 1 = Rarely, 2 = Sometimes, 3 = Often, 4 = Always 
For the modular questionnaire, records indicating "Not Applicable" will be excluded from 
summary/analysis. 
 
Missing data will not be imputed. 
 
The EHP-30 core questionnaire is structured into the following five dimensions. 
1. Pain (Questions 1 – 11) 
2. Control and Powerlessness (Questions 12 – 17) 
3. Emotional Well-Being (Questions 18 – 23) 
4. Social Support (Questions 24 – 27) 
5. Self-Image (Questions 28 – 30) 
Each dimension for the core and modular questionnaire is calculated on a scale from 0 to 


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100. 
0 = best possible health status as measured by the questionnaire; 100 = worst possible 
health status as measured by the questionnaire. Within each dimension, assessment will 
be based on the following equation:  
 
Sum of scores for each dimension / 4 (maximum score per item) * number of items in the dimension 
 
 
Sum of the scores for each item in the dimension 
Core questionnaire: Pain 
((Ql + Q2 + Q3 + Q4 + Q5 + Q6 + Q7 + Q8 + Q9 + Q10 + Q11)/44) × 100 
2. Core questionnaire: Control and Powerlessness 
((Q12 + Q13 + Q14 + Q15 + Q16 + Q17)/24) × 100 
3. Core questionnaire: Emotional well-being 
((Q18 + Q19 + Q20 + Q21 + Q22 + Q23)/24) × 100 
4. Core questionnaire: Social Support 
((Q24 + Q25 + Q26 + Q27)/16) × 100 
5. Core questionnaire: Self-Image 
((Q28 + Q29 + Q30)/12) × 100 
Modular questionnaire: Sexual intercourse 
((C1 + C2 + C3 + C4 + C5)/(total or 20)) × 100 
For Modular questionnaire: Sexual intercourse, if a "not applicable" box is 
checked for one or more of the five items (Questions C1 – C5), the score is 
calculated by omitting those "not applicable" items from the numerator and the 
denominator. 
If any of the components of a dimension on the core or modular questionnaire is 
missing, no score will be calculated for that dimension. For example, if answer for 
Q1 is missing, no score for Core questionnaire: Pain is calculated. If answer for 
C1 is missing, no score for Modular questionnaire: Sexual intercourse will be calculated. 
7.3. 
Appendix C: HRPQ Scoring 
 
Data Cleaning 
1. No imputation of data should be conducted. Missing data fields should be treated 
as missing. 


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2. For respondents indicating they are not currently employed (checking box 1c), 
Responses 2 – 4 should be coded as missing. 
3. Code Response 3b to zero if Response 3c is checked. Code Response 6b to zero if 
Response 6c is checked. 
4. The hours of work missed at work or in the home cannot be greater than the hours 
of work for which they were scheduled. 
a. If Response 3b is > Response 2, Response 3b = Response 2 
b. If Response 6b is > Response 5, Response 6b = Response 5 
Note: Respondents with no reported scheduled hours (zero hours or missing 
values) of paid work (Response 2) or planned hours of work in the household 
(Response 5), should be excluded from the analyses regarding productivity in those 
respective venues. 
- 
 
Calculation of hours of lost work due to absenteeism by class of work 
5. Calculate the number of hours absent by class of work: 
a. Workplace: Response 3b 
b. Household: Response 6b 
 
Calculation of hours of lost work due to presenteeism by class of work 
6. Calculate the number of hours worked by class of work: 
a. Workplace: Response 2 – Response 3b 
b. Household: Response 5 – Response 6b 
7. Calculate the hours of work lost due to presenteeism by class of work: 
a. Workplace: Calc 6a × (Response 4/100) 
b. Household: Calc 6b × (Response 7/100) 
 
Calculation of total [absenteeism + presenteeism] hours of lost work by class of work 
8. Calculate the sum by class of work: 
a. Workplace: Calc 5a + Calc 7a 
b. Household: Calc 5b + Calc 7b 
 
Calculation of the % of scheduled work lost due to absenteeism, presenteeism, and 
total productivity loss by class of work 
9. Calculate the % of work lost due to absenteeism 
a. Workplace: (Calc 5a/Response 2) × 100 
b. Household: (Calc 5b/Response 5) × 100 
10. Calculate the % of work lost due to presenteeism 
a. Workplace: (Calc 7a/Response 2) × 100 


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b. Household: (Calc 7b/Response 5) × 100 
11. Calculate the total % of work lost 
a. Workplace: Calc 9a + Calc 10a 
b. Household: Calc 9b + Calc 10b 
 
Calculation of the workplace productivity impacts by current employment status 
12. Subset subjects by their current employment status to report productivity impacts 
among those employed full-time and those employed part-time 
 
Calculation of hours of lifetime productivity lost until the time of measurement due 
to illness impacts on workforce participation 
Note: Calculations 13 and 14 should be made for only those respondents who have 
non-zero non-missing responses to Question 2 
13. Mean weekly hours of scheduled work in previous week for subjects full-time 
employed 
a. Mean of Response 2 among subjects selecting Response 1a at baseline 
14. Mean weekly hours of scheduled work in previous week for subjects part-time 
employed at baseline 
a. Mean of Response 2 among subjects selecting Response 1b at baseline 
Note: Calculations 15 through 17 should be made for only those respondents 
indicating they have experienced that workforce participation impact 
15. Hours of lifetime productivity lost due to illness induced part-time employment 
when subject would have continued full-time employment 
a. ((Response 9a × 4.33 wks/mo) + (Response 9b × 52 wks/yr)) × (Calc 13 – 
Calc 14) 
16. Hours of lifetime productivity lost due to illness induced premature retirement 
when subject would have continued full-time employment 
a. ((Response 9c × 4.33 wks/mo) + (Response 9d × 52 wks/yr)) × Calc 13 
17. Hours of lifetime productivity lost due to illness induced premature retirement 
when subject would have continued part-time employment 
a. ((Response 9e × 4.33 wks/mo) + (Response 9f × 52 wks/yr)) × Calc 14 
18. Total hours of lifetime productivity lost due to illness impact on workforce 
participation 
a. Calc 15 + Calc 16 + Calc 17 
 


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7.4. 
Appendix D: EQ-5D TTO Scoring 
Computing EQ-5D-5L crosswalk index values with SAS using the United States (US) value set: 
The variables for the 5 dimensions of the EQ-5D-5L descriptive system should be named 
'mobility', 'selfcare', 'activity', 'pain', and 'anxiety'. If they are given different names the syntax 
code below will not work properly. The 5 variables should contain the values for the different 
dimensions in the EQ-5D health profile (i.e. 1, 2, 3, 4, or 5). The variable 'EQindex' contains the 
values of the EQ-5D-5L crosswalk index values on the basis of the US set of weights.  
You can copy and paste the syntax below directly into a SAS syntax window. 
****************************************************************** 
*SAS syntax code for the computation of index* 
*values with the US TTO value set* 
******************************************************************; 
 
data Euroqol.US_tto; 
set Euroqol.EQ5D_states; 
EQindex = .; 
 
if (mobility=1 and selfcare=1 and activity=1 and pain=1 and anxiety=1) then EQindex = 1.000; 
if (mobility=1 and selfcare=1 and activity=1 and pain=1 and anxiety=2) then EQindex = 0.876; 
if (mobility=1 and selfcare=1 and activity=1 and pain=1 and anxiety=3) then EQindex = 0.844; 
if (mobility=1 and selfcare=1 and activity=1 and pain=1 and anxiety=4) then EQindex = 0.700; 
if (mobility=1 and selfcare=1 and activity=1 and pain=1 and anxiety=5) then EQindex = 0.550; 
if (mobility=1 and selfcare=1 and activity=1 and pain=2 and anxiety=1) then EQindex = 0.861; 
if (mobility=1 and selfcare=1 and activity=1 and pain=2 and anxiety=2) then EQindex = 0.820; 
if (mobility=1 and selfcare=1 and activity=1 and pain=2 and anxiety=3) then EQindex = 0.809; 
if (mobility=1 and selfcare=1 and activity=1 and pain=2 and anxiety=4) then EQindex = 0.669; 
if (mobility=1 and selfcare=1 and activity=1 and pain=2 and anxiety=5) then EQindex = 0.524; 
if (mobility=1 and selfcare=1 and activity=1 and pain=3 and anxiety=1) then EQindex = 0.827; 
if (mobility=1 and selfcare=1 and activity=1 and pain=3 and anxiety=2) then EQindex = 0.806; 
if (mobility=1 and selfcare=1 and activity=1 and pain=3 and anxiety=3) then EQindex = 0.800; 
if (mobility=1 and selfcare=1 and activity=1 and pain=3 and anxiety=4) then EQindex = 0.661; 
if (mobility=1 and selfcare=1 and activity=1 and pain=3 and anxiety=5) then EQindex = 0.517; 
if (mobility=1 and selfcare=1 and activity=1 and pain=4 and anxiety=1) then EQindex = 0.682; 
if (mobility=1 and selfcare=1 and activity=1 and pain=4 and anxiety=2) then EQindex = 0.663; 


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if (mobility=1 and selfcare=1 and activity=1 and pain=4 and anxiety=3) then EQindex = 0.659; 
if (mobility=1 and selfcare=1 and activity=1 and pain=4 and anxiety=4) then EQindex = 0.544; 
if (mobility=1 and selfcare=1 and activity=1 and pain=4 and anxiety=5) then EQindex = 0.426; 
if (mobility=1 and selfcare=1 and activity=1 and pain=5 and anxiety=1) then EQindex = 0.463; 
if (mobility=1 and selfcare=1 and activity=1 and pain=5 and anxiety=2) then EQindex = 0.450; 
if (mobility=1 and selfcare=1 and activity=1 and pain=5 and anxiety=3) then EQindex = 0.446; 
if (mobility=1 and selfcare=1 and activity=1 and pain=5 and anxiety=4) then EQindex = 0.369; 
if (mobility=1 and selfcare=1 and activity=1 and pain=5 and anxiety=5) then EQindex = 0.289; 
---------------------------------------------------------------------------------------------------------------  = -------: 
---------------------------------------------------------------------------------------------------------------  = -------: 
---------------------------------------------------------------------------------------------------------------  = -------: 
---------------------------------------------------------------------------------------------------------------  = -------: 
---------------------------------------------------------------------------------------------------------------  = -------: 
---------------------------------------------------------------------------------------------------------------  = -------: 
if (mobility=5 and selfcare=5 and activity=5 and pain=1 and anxiety=1) then EQindex = 0.178; 
if (mobility=5 and selfcare=5 and activity=5 and pain=1 and anxiety=2) then EQindex = 0.165; 
if (mobility=5 and selfcare=5 and activity=5 and pain=1 and anxiety=3) then EQindex = 0.162; 
if (mobility=5 and selfcare=5 and activity=5 and pain=1 and anxiety=4) then EQindex = 0.113; 
if (mobility=5 and selfcare=5 and activity=5 and pain=1 and anxiety=5) then EQindex = 0.063; 
if (mobility=5 and selfcare=5 and activity=5 and pain=2 and anxiety=1) then EQindex = 0.152; 
if (mobility=5 and selfcare=5 and activity=5 and pain=2 and anxiety=2) then EQindex = 0.132; 
if (mobility=5 and selfcare=5 and activity=5 and pain=2 and anxiety=3) then EQindex = 0.127; 
if (mobility=5 and selfcare=5 and activity=5 and pain=2 and anxiety=4) then EQindex = 0.083; 
if (mobility=5 and selfcare=5 and activity=5 and pain=2 and anxiety=5) then EQindex = 0.037; 
if (mobility=5 and selfcare=5 and activity=5 and pain=3 and anxiety=1) then EQindex = 0.145; 
if (mobility=5 and selfcare=5 and activity=5 and pain=3 and anxiety=2) then EQindex = 0.124; 
if (mobility=5 and selfcare=5 and activity=5 and pain=3 and anxiety=3) then EQindex = 0.118; 
if (mobility=5 and selfcare=5 and activity=5 and pain=3 and anxiety=4) then EQindex = 0.075; 
if (mobility=5 and selfcare=5 and activity=5 and pain=3 and anxiety=5) then EQindex = 0.030; 
if (mobility=5 and selfcare=5 and activity=5 and pain=4 and anxiety=1) then EQindex = 0.078; 
if (mobility=5 and selfcare=5 and activity=5 and pain=4 and anxiety=2) then EQindex = 0.060; 
if (mobility=5 and selfcare=5 and activity=5 and pain=4 and anxiety=3) then EQindex = 0.055; 
if (mobility=5 and selfcare=5 and activity=5 and pain=4 and anxiety=4) then EQindex = 0.015; 
if (mobility=5 and selfcare=5 and activity=5 and pain=4 and anxiety=5) then EQindex = -0.026; 
if (mobility=5 and selfcare=5 and activity=5 and pain=5 and anxiety=1) then EQindex = -0.024; 
if (mobility=5 and selfcare=5 and activity=5 and pain=5 and anxiety=2) then EQindex = -0.037; 
if (mobility=5 and selfcare=5 and activity=5 and pain=5 and anxiety=3) then EQindex = -0.040; 
if (mobility=5 and selfcare=5 and activity=5 and pain=5 and anxiety=4) then EQindex = -0.074; 
if (mobility=5 and selfcare=5 and activity=5 and pain=5 and anxiety=5) then EQindex = -0.109; 
 


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if (mobility = .) or (selfcare = .) or (activity = .) or (pain = .) or (anxiety = .) then EQindex = . ; 
 
output; 
run; 
 
 
 


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7.5. 
Appendix E: Mapping rules for ediary data 
Table 8 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 


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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 


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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 


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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 
 
 
 


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Table 9 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 
mapping 
n/a 
from MAIN 
FU to EXT 
TREAT 
First IMP 
intake in EXT 


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3 
Month 6 
patient 
entered 
MAIN FU 
rescheduled to 
EXT 
TREATMENT 
(site error in 
diary 
completion)  
data present 
in the 
Extension 
datasets 
should be 
considered for 
the analysis of 
the Main 
study 
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 
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  
mapping 
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 


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6 
Any 
Monthly 
visit of 
the Main 
Treatmen
t period 
patient in 
MAIN 
TREATMENT 
Set-up in 
screening 
period (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  
mapping 
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 
 
 


Obseva-18-OBE2109-003_SAP_5.0_13JUN202
2
Final Audit Report
2022-06-14
Created:
2022-06-13
By:
Status:
Signed
Transaction ID:
CBJCHBCAABAAh0b_RMbUzkIW4ODMVG9CthKNFw6JonnJ
"Obseva-18-OBE2109-003_SAP_5.0_13JUN2022" History